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      Diabetes in Older Adults

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          Abstract

          More than 25% of the U.S. population aged ≥65 years has diabetes (1), and the aging of the overall population is a significant driver of the diabetes epidemic. Although the burden of diabetes is often described in terms of its impact on working-age adults, diabetes in older adults is linked to higher mortality, reduced functional status, and increased risk of institutionalization (2). Older adults with diabetes are at substantial risk for both acute and chronic microvascular and cardiovascular complications of the disease. Despite having the highest prevalence of diabetes of any age-group, older persons and/or those with multiple comorbidities have often been excluded from randomized controlled trials of treatments—and treatment targets—for diabetes and its associated conditions. Heterogeneity of health status of older adults (even within an age range) and the dearth of evidence from clinical trials present challenges to determining standard intervention strategies that fit all older adults. To address these issues, the American Diabetes Association (ADA) convened a Consensus Development Conference on Diabetes and Older Adults (defined as those aged ≥65 years) in February 2012. Following a series of scientific presentations by experts in the field, the writing group independently developed this consensus report to address the following questions: What is the epidemiology and pathogenesis of diabetes in older adults? What is the evidence for preventing and treating diabetes and its common comorbidities in older adults? What current guidelines exist for treating diabetes in older adults? What issues need to be considered in individualizing treatment recommendations for older adults? What are consensus recommendations for treating older adults with or at risk for diabetes? How can gaps in the evidence best be filled? What is the epidemiology and pathogenesis of diabetes in older adults? According to the most recent surveillance data, the prevalence of diabetes among U.S. adults aged ≥65 years varies from 22 to 33%, depending on the diagnostic criteria used. Postprandial hyperglycemia is a prominent characteristic of type 2 diabetes in older adults (3,4), contributing to observed differences in prevalence depending on which diagnostic test is used (5). Using the A1C or fasting plasma glucose (FPG) diagnostic criteria, as is currently done for national surveillance, one-third of older adults with diabetes are undiagnosed (1). The epidemic of type 2 diabetes is clearly linked to increasing rates of overweight and obesity in the U.S. population, but projections by the Centers for Disease Control and Prevention (CDC) suggest that even if diabetes incidence rates level off, the prevalence of diabetes will double in the next 20 years, in part due to the aging of the population (6). Other projections suggest that the number of cases of diagnosed diabetes in those aged ≥65 years will increase by 4.5-fold (compared to 3-fold in the total population) between 2005 and 2050 (7). The incidence of diabetes increases with age until about age 65 years, after which both incidence and prevalence seem to level off (www.cdc.gov/diabetes/statistics). As a result, older adults with diabetes may either have incident disease (diagnosed after age 65 years) or long-standing diabetes with onset in middle age or earlier. Demographic and clinical characteristics of these two groups differ in a number of ways, adding to the complexity of making generalized treatment recommendations for older patients with diabetes. Older-age–onset diabetes is more common in non-Hispanic whites and is characterized by lower mean A1C and lower likelihood of insulin use than is middle-age–onset diabetes. Although a history of retinopathy is significantly more common in older adults with middle-age–onset diabetes than those with older-age onset, there is, interestingly, no difference in prevalence of cardiovascular disease (CVD) or peripheral neuropathy by age of onset (8). Older adults with diabetes have the highest rates of major lower-extremity amputation (9), myocardial infarction (MI), visual impairment, and end-stage renal disease of any age-group. Those aged ≥75 years have higher rates than those aged 65–74 years for most complications. Deaths from hyperglycemic crises also are significantly higher in older adults (although rates have declined markedly in the past 2 decades). Those aged ≥75 years also have double the rate of emergency department visits for hypoglycemia than the general population with diabetes (10). Although increasing numbers of individuals with type 1 diabetes are living into old age (11), this discussion of pathophysiology concerns type 2 diabetes—overwhelmingly the most common incident and prevalent type in older age-groups. Older adults are at high risk for the development of type 2 diabetes due to the combined effects of increasing insulin resistance and impaired pancreatic islet function with aging. Age-related insulin resistance appears to be primarily associated with adiposity, sarcopenia, and physical inactivity (12), which may partially explain the disproportionate success of the intensive lifestyle intervention in older participants in the Diabetes Prevention Program (DPP) (13). However, age-related declines of pancreatic islet function (4,14) and islet proliferative capacity (15,16) have previously been described. What is the evidence for preventing and treating diabetes and its common comorbidities in older adults? Screening for diabetes and prediabetes Older adults are at high risk for both diabetes and prediabetes, with surveillance data suggesting that half of older adults have the latter (1). The ADA recommends that overweight adults with risk factors—and all adults aged ≥45 years—be screened in the clinical setting every 1–3 years using either an FPG test, A1C, or oral glucose tolerance test. The recommendations are based on substantial indirect evidence for the benefits of early treatment of type 2 diabetes, the fact that type 2 diabetes is typically present for years before clinical diagnosis, and the evidence that signs of complications are prevalent in “newly diagnosed” patients (17). The benefits of identification of prediabetes and asymptomatic type 2 diabetes in older adults depend on whether primary or secondary preventive interventions would likely be effective and on the anticipated timeframe of the benefit of interventions versus the patient’s life expectancy. Most would agree that a functional and generally healthy 66-year-old individual should be offered diabetes screening since interventions to prevent type 2 diabetes or the complications of type 2 diabetes would likely be beneficial given the presumption of decades of remaining life. Most would also agree that finding prediabetes or early type 2 diabetes in a 95-year-old individual with advanced dementia would be unlikely to provide benefit. Prevention or delay of type 2 diabetes Numerous clinical trials have shown that in high-risk subjects (particularly those with impaired glucose tolerance), type 2 diabetes can be prevented or delayed by lifestyle interventions or by various classes of medications. These trials primarily enrolled middle-aged participants. In the DPP, which is the largest trial to date, ∼20% of participants were aged ≥60 years at enrollment. These participants seemed to have more efficacy from the lifestyle intervention than younger participants, but did not appear to benefit from metformin (13,18). Follow-up of the DPP cohort for 10 years after randomization showed ongoing greater impact of the original lifestyle intervention in older participants (49% risk reduction in those aged ≥60 years at randomization vs. 34% for the total cohort) (19) and additional benefits of the lifestyle intervention that might impact older adults, such as reduction in urinary incontinence (20), improvement in several quality-of-life domains (21), and improvements in cardiovascular risk factors (22). Although these results suggest that diabetes prevention through lifestyle intervention be pursued in relatively healthy older adults, the DPP did not enroll significant numbers over the age of 70 years or those with functional or cognitive impairments. Preventive strategies that can be efficiently implemented in clinical settings and in the community have been developed and evaluated (23), but as yet there has been little focus on older adults in these translational studies. Interventions to treat diabetes Glycemic control. A limited number of randomized clinical trials in type 2 diabetes form the basis of our current understanding of the effects of glucose lowering on microvascular complications, cardiovascular complications, and mortality. While these trials have provided invaluable data and insights, they were not designed to evaluate the health effects of glucose control in patients aged ≥75 years or in older adults with poor health status. There are essentially no directly applicable clinical trial data on glucose control for large segments of the older diabetic patient population. The UK Prospective Diabetes Study (UKPDS), which provided valuable evidence of the benefits of glycemic control on microvascular complications, enrolled middle-aged patients with newly diagnosed type 2 diabetes, excluding those aged ≥65 years at the time of enrollment (24,25). Microvascular benefits persisted during the post-trial follow-up period, and statistically significant reductions in both mortality and MIs emerged, referred to as the “legacy effect” of early glycemic control (26). After the publication of the main UKPDS results, three major randomized controlled trials (the Action to Control Cardiovascular Risk in Diabetes [ACCORD] trial, the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation [ADVANCE] trial, and the Veterans Affairs Diabetes Trial [VADT]) were designed to specifically examine the role of glycemic control in preventing CVD events in middle-aged and older patients with type 2 diabetes. The trials enrolled patients at significantly higher cardiovascular risk than did the UKPDS, with each having a substantial proportion of participants with a prior cardiovascular event, mean age at enrollment in the 60s, and established diabetes (8–11 years). Each of these trials aimed, in the intensive glycemic control arm, to reduce glucose levels to near-normal levels (A1C <6.0 or <6.5%). The glucose control portion of the ACCORD trial was terminated after approximately 3 years because of excessive deaths in the intensive glucose control arm (27). The primary combined outcome of MI, stroke, and cardiovascular death was not significantly reduced. Prespecified subgroup analyses suggested that the disproportionate cardiovascular mortality risk in the intensive glycemic control group was in participants under the age of 65 years as opposed to older participants. However, hypoglycemia and other adverse effects of treatment were more common in older participants (28). The ADVANCE trial did not demonstrate excessive deaths attributable to intensive glucose control during a median follow-up of 5 years. While there were no statistically significant cardiovascular benefits, there was a significant reduction in the incidence of nephropathy. In prespecified subgroup analysis of age < or ≥65 years, there was no difference between age-groups for the primary outcome (29). Over 5 years of follow-up, the VADT found no statistically significant effect of intensive glucose control on major cardiovascular events or death, but it did find significant reductions in onset and progression of albuminuria (30). The trial did not have prespecified subgroup analyses by age. Post hoc analyses suggested that mortality in the intensive versus standard glycemic control arm was related to duration of diabetes at the time of study enrollment. Those with diabetes duration less than 15 years had a mortality benefit in the intensive arm, while those with duration of 20 years or more had higher mortality in the intensive arm (31). These three trials add to the uncertainty regarding the benefits and risks of more intensive treatment of hyperglycemia in older adults. An ADA position statement surmised that the combination of the UKPDS follow-up study and subset analyses of the later trials ‘‘… suggest the hypothesis that patients with shorter duration of type 2 diabetes and without established atherosclerosis might reap cardiovascular benefit from intensive glycemic control, [while] … potential risks of intensive glycemic control may outweigh its benefits in other patients, such as those with a very long duration of diabetes, known history of severe hypoglycemia, advanced atherosclerosis, and advanced age/frailty” (32). Recently, a Japanese trial reported results of a multifactorial intervention versus standard care in about 1,000 patients aged ≥65 years (mean age 72 years). After 6 years, no differences in mortality or cardiovascular events were found, but the intervention’s effect on glycemia was minimal and the number of events was low (33). Since randomized controlled trials have not included many older patients typical of those in general practice, it is instructive to observe the relationship between glycemic control and complications in general populations of older diabetic patients. A study from the U.K. General Practice Research Database showed that for type 2 diabetic patients aged ≥50 years (mean age 64 years) whose treatment was intensified from oral monotherapy to addition of other oral agents or insulin, there was a U-shaped association between A1C and mortality, with the lowest hazard ratio for death at an A1C of about 7.5%. Low and high mean A1C values were associated with increased all-cause mortality and cardiac events (34). A retrospective cohort study of 71,092 patients with type 2 diabetes aged ≥60 years evaluated the relationships between baseline A1C and subsequent outcomes (acute nonfatal metabolic, microvascular, and cardiovascular events and mortality). As in the prior study, mortality had a U-shaped relationship with A1C. Compared to risk with A1C <6.0%, mortality risk was lower for A1C between 6.0 and 9.0% and higher at A1C ≥11.0%. Risk of any end point (complication or death) became significantly higher at A1C ≥8.0%. Patterns were generally consistent across age-groups (60–69, 70–79, and ≥80 years) (35). Diabetes is associated with increased risk of multiple coexisting medical conditions in older adults ranging from CVD to cancer and potentially impacting treatment decisions, such as whether stringent glycemic control would be of net benefit (36,37). A 5-year longitudinal, observational study of Italian patients with type 2 diabetes categorized patients into subgroups of high (mean age 64.3 years [SD 9.5]) and low-to-moderate comorbidity (mean age 61.7 years [SD 10.5]) using a validated patient-reported measure of comorbidity. Having an A1C of ≤6.5 or <7% at baseline was associated with lower 5-year incidence of cardiovascular events in the low-to-moderate comorbidity subgroup, but not in the high comorbidity subgroup, suggesting that patients with high levels of comorbidity may not receive cardiovascular benefit from intensive blood glucose control (38). Lipid lowering. There are no large trials of lipid-lowering interventions specifically in older adults with diabetes. Benefits have been extrapolated from trials of older adults that include but are not limited to those with diabetes and trials of people with diabetes including but not limited to older adults. A statin study in older adults (participants aged 70–82 years) found a 15% reduction in coronary artery disease events with pravastatin (39,40). A meta-analysis of 18,686 people with diabetes in 14 trials of statin therapy for primary prevention showed similar 20% relative reductions in major adverse vascular outcomes in those under compared with those over age 65 years (41). Statin trials for secondary prevention of CVD in adults with diabetes have also demonstrated comparable relative reductions in recurrent cardiovascular events and mortality by age-group (42). Since older patients are at higher risk, absolute risk reductions with statin therapy would be greater in older patients. Cardiovascular prevention with statins, especially secondary benefit, emerges fairly quickly (within 1–2 years), suggesting that statins may be indicated in nearly all older adults with diabetes except those with very limited life expectancy. The evidence for reduction in major cardiovascular end points with drugs other than statins is limited in any age-group. The ACCORD lipid trial found no benefit of adding fenofibrate to statin therapy (43), and post hoc analyses suggested that the negative results applied to both those under and those over age 65 years (M. Miller, personal communication). Subgroup analyses of the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study, which suggested some benefit of fenofibrate in people with type 2 diabetes, suggested no benefit in those aged ≥65 years (44). Blood pressure control. Multiple trials have investigated the role of treatment of hypertension to reduce the risk of cardiovascular events (17). Benefit for older adults with diabetes has been inferred from the trials of older adults including but not limited to those with diabetes and from the trials of middle- and older-aged adults with diabetes (42). There is consistent evidence that lowering blood pressure from very high levels (e.g., systolic blood pressure [SBP] 170 mmHg) to moderate targets (e.g., SBP 150 mmHg) reduces cardiovascular risk in older adults with diabetes. Selected trials have shown benefit with targets progressively lower, down to SBP <140 mmHg and diastolic blood pressure (DBP) <80 mmHg (45). The ACCORD-BP trial showed no benefit on the primary outcome (major adverse cardiovascular events) of SBP targets <120 mmHg compared with <140 mmHg, but found a significant reduction in stroke, a secondary outcome (46). Subgroup analyses of those aged < versus ≥65 years suggested that the stroke benefit may have been limited to the older cohort (M. Miller, personal communication). Observational analyses of other trial cohorts suggest no benefit to SBP targets more aggressive than <140 mmHg and that low DBP may be a risk factor for mortality in older adults. A post hoc analysis of the cohort of participants with diabetes in the International Verapamil SR-Trandolapril Study (INVEST), whose mean age was ∼65 years, showed that achieved SBP under 130 mmHg was not associated with improved cardiovascular outcomes compared with SBP under 140 mmHg (47). This report validated SBP control under 140 mmHg, as death and cardiovascular events were more likely in subjects whose SBP was over 140 mmHg. A post hoc analysis of the VADT (in which the goal blood pressure was <130/80 mmHg) similarly showed that those whose SBP was ≥140 mmHg had increased mortality, while those at <105 mmHg, 105–129 mmHg, and 130–139 mmHg had equally low mortality rates. For DBP, achieved values <70 mmHg were associated with higher mortality, while those of 70–79 mmHg or >80 mmHg were equally low (48). Aspirin. In populations without diabetes, the greatest absolute benefit of aspirin therapy (75–162 mg) is for individuals with a 10-year risk of coronary heart disease of 10% or greater (49). The increased cardiovascular risk posed by diabetes and aging and the known benefits of aspirin for secondary prevention suggest that, in the absence of contraindications, this therapy should be offered to virtually all older adults with diabetes and known CVD. However, the benefits of aspirin for primary prevention of CVD events have not been thoroughly elucidated in older adults with diabetes and must be balanced against risk of adverse events such as bleeding. A randomized study of Japanese individuals with diabetes but no CVD history demonstrated no significant benefit of aspirin on the composite primary outcome, but a subgroup analysis of subjects aged ≥65 years demonstrated a significantly lower risk of the primary end point with aspirin (50). The incidence of gastrointestinal bleeding with the use of aspirin has not been directly compared in older- versus middle-aged adults, but in separate studies the rates were higher (1–10 per 1,000 annually) for older adults (51) than those for middle-aged adults (3 per 10,000 annually) (49). More recently, the greater risk of major gastrointestinal or intracerebral bleeding in older adults who use aspirin was suggested by an observational analysis, but diabetes per se was not associated with increased bleeding with aspirin (52). In light of the probable higher risk of bleeding with age, the benefit of aspirin therapy in older adults with diabetes is likely strongest for those with high cardiovascular risk and low risk of bleeding. Unfortunately, the risk factors for these outcomes tend to overlap. When aspirin is initiated, the use of agents such as proton pump inhibitors to protect against gastrointestinal bleeding may be warranted (53). Further evidence is needed to confirm a clear role of aspirin for primary prevention of cardiovascular events in older adults with diabetes. Screening for chronic diabetes complications The screening and interventions for chronic diabetes complications recommended by the ADA have a strong evidence base and are cost-effective (54). However, as is the case for many diabetes interventions, the underlying evidence generally comes from studies of younger adults. When considering chronic complications, the issues of incident versus prevalent diabetes and diabetes heterogeneity again need to be raised. Some older adults have long-standing diabetes with associated microvascular and macrovascular complications. Others have newly diagnosed diabetes with evidence of complications (on screening tests) at initial presentation, while still others have newly diagnosed diabetes without evidence of complications. For relatively healthy older adults with long life expectancy, following the screening recommendations for all adults with diabetes is reasonable. For very old patients and/or those with multiple comorbidities and short life expectancy, it is prudent to weigh the expected benefit time frame of identifying early signs of complications and intervening to prevent worsening to end-stage disease. For the latter group, particular attention should be paid to screening for risk factors of complications that might further impair functional status or quality of life over a relatively short period of time, such as foot ulcers/amputations and visual impairment. Considerations in clinical decision making should also include prior test results. For example, there is evidence, including in the older adult population, that dilated eye examinations that are initially normal can safely be repeated every 2–3 years instead of yearly (55). What current guidelines exist for treating diabetes in older adults? Several organizations have developed diabetes guidelines specific to, or including, older adults. The ADA includes a section on older adults in its annual Standards of Medical Care in Diabetes (17). The section discusses the heterogeneity of persons aged ≥65 years and the lack of high-level evidence. The overall recommendations, all based on expert opinion, include the following: Older adults who are functional, are cognitively intact, and have significant life expectancy should receive diabetes care using goals developed for younger adults. Glycemic goals for older adults not meeting the above criteria may be relaxed using individualized criteria, but hyperglycemia leading to symptoms or risk of acute hyperglycemic complications should be avoided in all patients. Other cardiovascular risk factors should be treated in older adults with consideration of the timeframe of benefit and the individual patient. Treatment of hypertension is indicated in virtually all older adults, and lipid and aspirin therapy may benefit those with life expectancy at least equal to the timeframe of primary or secondary prevention trials. Screening for diabetes complications should be individualized in older adults, but particular attention should be paid to complications that would lead to functional impairment. The ADA goals for glycemic control do not specifically mention age. The recommendation for many adults is an A1C <7%, but less stringent goals are recommended for those with limited life expectancy, advanced diabetes complications, or extensive comorbid conditions (17). In collaboration with the ADA and other medical organizations, the California HealthCare Foundation/American Geriatrics Society panel published guidelines for improving the care of older adults with diabetes in 2003. A significant proportion of the recommendations concerns geriatric syndromes. Highlights of diabetes-specific recommendations include A1C targets of ≤7.0% in “relatively healthy adults,” while for those who are frail or with life expectancy less than 5 years, a less stringent target, such as 8%, was considered appropriate. The guidelines also suggested that the timeline of benefits was estimated to be at least 8 years for glycemic control and 2–3 years for blood pressure and lipid control (2). The U.S. Department of Veterans Affairs and the U.S. Department of Defense (VA/DOD) diabetes guidelines were updated in 2010. As with other guidelines, the VA/DOD guidelines do not distinguish by age-group. They highlight the frequency of comorbid conditions in patients with diabetes and stratify glycemic goals based on comorbidity and life expectancy. For glycemic goals, for example, the guidelines have three categories: The patient with either none or very mild microvascular complications of diabetes, who is free of major concurrent illnesses and who has a life expectancy of at least 10–15 years, should have an A1C target of <7%, if it can be achieved without risk. The patient with longer-duration diabetes (more than 10 years) or with comorbid conditions and who requires a combination medication regimen including insulin should have an A1C target of <8%. The patient with advanced microvascular complications and/or major comorbid illness and/or a life expectancy of less than 5 years is unlikely to benefit from aggressive glucose-lowering management and should have an A1C target of 8–9%. Lower targets (<8%) can be established on an individual basis (56). The European Diabetes Working Party for Older People recently published guidelines for treating people with diabetes aged ≥70 years. These extensive guidelines recommend that “the decision to offer treatment should be based on the likely benefit/risk ratio of the intervention for the individual concerned, but factors such as vulnerability to hypoglycemia, ability to self-manage, the presence or absence of other pathologies, the cognitive status, and life expectancy must be considered” (57). There are recommendations to carry out annual evaluations of functional status (global/physical, cognitive, affective) using validated instruments to avoid the use of glyburide due to its high risk of hypoglycemia in this population and to calculate cardiovascular risk in all patients less than 85 years of age. Suggested A1C targets are based on age and comorbidity. A range of 7–7.5% is suggested for older patients with type 2 diabetes without major comorbidities and 7.6–8.5% for frail patients (dependent, multisystem disease, home care residency including those with dementia) where the hypoglycemia risk may be high and the likelihood of benefit relatively low. Extensive review of the guidelines is beyond the scope of this report, but there are similar themes, which suggest pursuing an individualized approach with a focus on clinical and functional heterogeneity and comorbidities, and weighing the expected time frame of benefit of interventions against life expectancy. What issues need to be considered in individualizing treatment recommendations for older adults? Comorbidities and geriatric syndromes Diabetes is associated with increased risk of multiple coexisting medical conditions in older adults. In addition to the classic cardiovascular and microvascular diseases, a group of conditions termed geriatric syndromes, described below, also occur at higher frequency in older adults with diabetes and may affect self-care abilities and health outcomes including quality of life (58). Cognitive dysfunction. Alzheimer’s-type and multi-infarct dementia are approximately twice as likely to occur in those with diabetes compared with age-matched nondiabetic control subjects (59). The presentation of cognitive dysfunction can vary from subtle executive dysfunction to overt dementia and memory loss. In the ACCORD trial, for which referred participants were felt to be capable of adhering to a very complex protocol, 20% of those in the ancillary trial of cognition were found to have undiagnosed cognitive dysfunction at baseline (J. Williamson, personal communication) (60). In this trial, neither intensive glycemic control nor blood pressure control to a target SBP <120 mmHg was shown to prevent a decline in brain function (61). Cross-sectional studies have shown an association between hyperglycemia and cognitive dysfunction (62). Hypoglycemia is linked to cognitive dysfunction in a bidirectional fashion: cognitive impairment increases the subsequent risk of hypoglycemia (60), and a history of severe hypoglycemia is linked to the incidence of dementia (63). High rates of unidentified cognitive deficits in older adults suggest that it is important to periodically screen for cognitive dysfunction. Simple assessment tools can be accessed at www.hospitalmedicine.org/geriresource/toolbox/howto.htm. Such dysfunction makes it difficult for patients to perform complex self-care tasks such as glucose monitoring, changing insulin doses, or appropriately maintaining timing and content of diet. In older patients with cognitive dysfunction, regimens should be simplified, caregivers involved, and the occurrence of hypoglycemia carefully assessed. Functional impairment. Aging and diabetes are both risk factors for functional impairment. After controlling for age, people with diabetes are less physically active and have more functional impairment than those without diabetes (64,65). The etiology of functional impairment in diabetes may include interaction between coexisting medical conditions, peripheral neuropathy, vision and hearing difficulty, and gait and balance problems. Peripheral neuropathy, present in 50–70% of older patients with diabetes, increases the risk of postural instability, balance problems, and muscle atrophy (66–68), limiting physical activity and increasing the risk of falls. Other medical conditions that commonly accompany diabetes such as coronary artery disease, obesity, degenerative joint disease, stroke, depression, and visual impairment also negatively impact physical activity and functionality (69). Falls and fractures. Normal aging and diabetes, and the conditions described above that impair functionality, are associated with the higher risk of falls and fractures (70,71). Women with diabetes have a higher risk of hip and proximal humeral fractures after adjustment for age, BMI, and bone density (71). It is important to assess fall risks and perform functional assessment periodically in older adults (72). Avoidance of severe hyperglycemia and hypoglycemia can decrease the risk of falls. Physical therapy should be encouraged in patients who are at high risk or who have experienced a recent fall. Medicare may cover physical therapy for a limited time in some of these situations. Polypharmacy. Older adults with diabetes are at high risk of polypharmacy, increasing the risk of drug side effects and drug-to-drug interactions. A challenge in treating type 2 diabetes is that polypharmacy may be intentional and necessary to control related comorbidities and reduce the risk of diabetes complications (73,74). In one study, polypharmacy (defined as the use of six or more prescription medications) was associated with an increased risk of falling in older people (75). The costs of multiple medications can be substantial, especially when older patients fall into the “doughnut hole” of Medicare Part D coverage. Medication reconciliation, ongoing assessment of the indications for each medication, and the assessment of medication adherence and barriers are needed at each visit. Depression. Diabetes is associated with a high prevalence of depression (76). Untreated depression can lead to difficulty with self-care and with implementing healthier lifestyle choices (77) and is associated with a higher risk of mortality and dementia in patients with diabetes (78,79). In older adults, depression may remain undiagnosed if screening is not performed. Clinical tools such as the Geriatric Depression Scale (80) can be used to periodically screen older patients with diabetes. Vision and hearing impairment. Sensory impairments should be considered when educating older adults and supporting their self-care. Nearly one in five older U.S. adults with diabetes report visual impairment (81). Hearing impairment involving both high- and low/mid-frequency sound is about twice as prevalent in people with diabetes, even after controlling for age (82) and may be linked to both vascular disease and neuropathy (83). Other commonly occurring medical conditions. Persistent pain from neuropathy or other causes or its inadequate treatment is associated with adverse outcomes in older adults including functional impairment, falls, slow rehabilitation, depression and anxiety, decreased socialization, sleep and appetite disturbances, and higher health care costs and utilization (2). Pain should be assessed at every visit in older patients with the implementation of strategies for amelioration of pain. Urinary incontinence is common in older patients, especially women, with diabetes. In addition to standard assessments and treatments for incontinence, clinicians should remember that uncontrolled hyperglycemia can increase the amount and frequency of urination. Unique nutrition issues Nutrition is an integral part of diabetes care for all ages, but there are additional considerations for older adults with diabetes. Though energy needs decline with age, macronutrient needs are similar throughout adulthood. Meeting micronutrient needs with lower caloric intake is challenging; therefore older adults with diabetes are at higher risk for deficiencies. Older adults may be at risk for undernutrition due to anorexia, altered taste and smell, swallowing difficulties, oral/dental issues, and functional impairments leading to difficulties in preparing or consuming food. Overly restrictive eating patterns, either self-imposed or provider-directed, may contribute additional risk for older adults with diabetes. The Mini-Nutritional Assessment, specifically designed for older adults, is simple to perform and may help determine whether referral to a registered dietitian for medical nutrition therapy (MNT) is needed (http://www.mna-elderly.com/). MNT has proven to be beneficial in older adults with diabetes (84). Recommendations should take into account the patient’s culture, preferences, and personal goals and abilities. When nutrition needs are not being met with usual intake, additional interventions may include encouraging smaller more frequent meals, fortifying usual foods, changing food texture, or adding liquid nutrition supplements (either regular or diabetes-specific formulas) between meals. For nutritionally vulnerable older adults, identifying community resources such as Meals on Wheels, senior centers, and the U.S. Department of Agriculture’s Older Americans Nutrition Program may help maintain independent living status. Overweight and obesity are prevalent among older adults. BMI may not be an accurate predictor of the degree of adiposity in some older adults due to changes in body composition with aging (85). Sarcopenia may occur in both over- and underweight older adults. Obesity exacerbates decline in physical function due to aging and increases the risk of frailty (86). While unintentional weight loss is a known nutrition concern, intentional weight loss in overweight and obese older adults could potentially worsen sarcopenia, bone mineral density, and nutrition deficits (87,88). Strategies that combine physical activity with nutrition therapy to promote weight loss may result in improved physical performance and function and reduced cardiometabolic risk in older adults (86,87). Unique needs in diabetes self-management education/training and support As with all persons with diabetes, diabetes self-management education/training (DSME/T) for older adults should be individualized and tailored to the individual’s unique medical, cultural, and social situation. Additionally, for older adults, DSME/T may need to account for possible impairments in sensation (vision, hearing), cognition, and functional/physical status. Care partners—family, friends, or other caregivers—should be involved in DSME/T to increase the likelihood of successful self-care behaviors (89). When communicating with cognitively impaired patients, educators should address the patient by name (even when a caregiver will provide most care), speak in simple terms, use signals (cues) that aid memory (verbal analogies, hands-on experience, demonstrations and models), and utilize strategies such as sequenced visits to build on information. Other tactics include summarizing important points frequently, focusing on one skill at a time, teaching tasks from simple to complex, and providing easy-to-read handouts. Even in the absence of cognitive impairment, educators should consider that many patients may have low health literacy and numeracy skills or may be overwhelmed by the presence of multiple comorbidities. Physical activity and fitness Muscle mass and strength decline with age, and these decrements may be exacerbated by diabetes complications, comorbidities, and periods of hospitalization in older adults with diabetes. People with diabetes of longer duration and those with higher A1C have lower muscle strength per unit of muscle mass than BMI- and age-matched people without diabetes and than those whose disease is of shorter duration or under better glycemic control (90). Although age and diabetes conspire to reduce fitness and strength, physical activity interventions improve functional status in older adults (91) with and without diabetes. In the Look AHEAD (Action for Health in Diabetes) study, participants aged 65–76 years had lower gains in fitness with the intensive lifestyle intervention than younger patients, but still improved their measures of fitness by a mean of over 15% (92). In older adults, even light-intensity physical activity is associated with higher self-rated physical health and psychosocial well-being (93). Older adults with diabetes who are otherwise healthy and functional should be encouraged to exercise to targets recommended for all adults with diabetes (17). Even patients with poorer health status benefit from modest increases in physical activity. Tactics to facilitate activity for older adults may include referring to supervised group exercise and community resources such as senior centers, YMCAs, the EnhanceFitness program, and the resources of the Arthritis Foundation. Age-specific aspects of pharmacotherapy Older patients are at increased risk for adverse drug events from most medications due to age-related changes in pharmacokinetics (in particular reduced renal elimination) and pharmacodynamics (increased sensitivity to certain medications) affecting drug disposition. These changes may translate into increased risk for hypoglycemia, the potential need for reduced doses of certain medications, and attention to renal function to minimize side effects (94,95). The risk for medication-related problems is compounded by the use of complex regimens, high-cost therapies, and polypharmacy or medication burden. Collectively, these factors should be considered and weighed against the expected benefits of a therapy before incorporating it into any therapeutic plan. Attention to the selection of medications with a strong benefit-to-risk ratio is essential to promote efficacy, persistence on therapy, and safety. Antihyperglycemic medication use in older adults. Comparative effectiveness studies of medications to treat diabetes in older adult populations are lacking. Type 2 diabetes with onset later in life is characterized by prominent defects in β-cell function, suggesting therapeutic attention to β-cell function and sufficiency of insulin release, as well as the traditional focus on hepatic glucose overproduction and insulin resistance. Understanding the advantages and disadvantages of each antihyperglycemic drug class helps clinicians individualize therapy for patients with type 2 diabetes (96). Issues particularly relevant to older patients are described for each drug class. Metformin is often considered the first-line therapy in type 2 diabetes. Its low risk for hypoglycemia may be beneficial in older adults, but gastrointestinal intolerance and weight loss from the drug may be detrimental in frail patients. Despite early concerns, the evidence for an increase in the risk of lactic acidosis with metformin is minimal. The dose should be reduced if estimated glomerular filtration rate (eGFR) is 30–60 mL/min, and the drug should not be used if eGFR is <30 mL/min (94,97). Metformin’s low cost may be a benefit in those on multiple medications or who are subject to the Medicare Part D “doughnut hole.” Sulfonylureas are also a low-cost class of medications, but the risk of hypoglycemia with these agents may be problematic for older patients. Glyburide has the highest hypoglycemia risk and should not be prescribed for older adults (98). Glinides are dosed prior to meals, and their short half-life may be useful for postprandial hyperglycemia. They impart a lower risk for hypoglycemia than sulfonylureas, especially in patients who eat irregularly, but their dosing frequency and high cost may be barriers. α-Glucosidase inhibitors specifically target postprandial hyperglycemia and have low hypoglycemia risk, making them theoretically attractive for older patients. However, gastrointestinal intolerance may be limiting, frequent dosing adds to regimen complexity, and this class of medications is costly. Thiazolidinediones have associated risks of weight gain, edema, heart failure, bone fractures, and possibly bladder cancer, which may argue against their use in older adults. The use of rosiglitazone is now highly restricted. The class has traditionally been expensive, although the approval of generic pioglitazone may reduce its cost. Dipeptidyl peptidase-4 inhibitors are useful for postprandial hyperglycemia, impart little risk for hypoglycemia, and are well tolerated, suggesting potential benefits for older patients. However, their high cost may be limiting. Glucagon-like peptide-1 agonists also target postprandial hyperglycemia and impart low risk of hypoglycemia, but their associated nausea and weight loss may be problematic in frail older patients. Injection therapy may add to regimen complexity, and its very high cost may be problematic. For some agents, dose reduction is required for renal dysfunction. Insulin therapy can be used to achieve glycemic goals in selected older adults with type 2 diabetes with similar efficacy and hypoglycemia risk as in younger patients. However, given the heterogeneity of the older adult population, the risk of hypoglycemia must be carefully considered before using an insulin regimen to achieve an aggressive target for hyperglycemia control. A mean A1C of 7% was achieved and maintained for 12 months with either an insulin pump regimen or multiple daily insulin injections in otherwise healthy and functional older adults (mean age 66 years), with low rates of hypoglycemia (99). The addition of long-acting insulin was similarly effective in achieving A1C goals for older patients with type 2 diabetes (mean age 69 years) in a series of trials with no greater rates of hypoglycemia than in younger patients (mean age 53 years) (100). However, there are few data on such regimens in people over age 75 years or in older adults with multiple comorbidities and/or limited functional status who were excluded from these trials. Problems with vision or manual dexterity may be barriers to insulin therapy for some older adults. Pen devices improve ease of use but are more costly than the use of vials and syringes. Hypoglycemia risk (especially nocturnal) is somewhat lower with analog compared with human insulins, but the former are more expensive. Insulin-induced weight gain is a concern for some patients, and the need for more blood glucose monitoring may increase treatment burden. Other approved therapies for which there is little evidence in older patients include colesevelam, bromocriptine, and pramlintide. An emerging drug class, sodium-glucose cotransporter-2 inhibitors, may require additional study in older adults to assess whether drug-associated genital infections or urinary incontinence is problematic in this population. Vulnerability to hypoglycemia. Age appears to affect counter-regulatory responses to hypoglycemia in nondiabetic individuals. During hypoglycemic clamp studies, symptoms begin at higher glucose levels and have greater intensity in younger men (aged 22–26 years), while measures of psychomotor coordination deteriorate earlier and to a greater degree in the older subjects (aged 60–70 years), erasing the usual 10–20 mg/dL plasma glucose difference between subjective awareness of hypoglycemia and onset of cognitive dysfunction (101). Studies in older individuals with diabetes are limited. One small study compared responses to hypoglycemic clamps in older (mean age 70 years) versus middle-aged (mean age 51 years) people with type 2 diabetes. Hormonal counter-regulatory responses to hypoglycemia did not differ between age-groups, but middle-aged participants had a significant increase in autonomic and neuroglycopenic symptoms at the end of the hypoglycemic period, while older participants did not. Half of the middle-aged participants, but only 1 out of 13 older participants, correctly reported that their blood glucose was low during hypoglycemia (102). The prevalence of any hypoglycemia (measured blood glucose below 70 mg/dL) or severe hypoglycemia (requiring third-party assistance) in older populations is not known. In the ACCORD trial, older participants in both glycemic intervention arms had ∼50% higher rates of severe hypoglycemia (hypoglycemia requiring third-party assistance) than participants under age 65 years (M. Miller, personal communication). In a population analysis of Medicaid enrollees treated with insulin or sulfonylureas, the incidence of serious hypoglycemia (defined as that leading to emergency department visit, hospitalization, or death) was approximately 2 per 100 person-years (103), but clearly studies based on administrative databases miss less catastrophic hypoglycemia. The risk factors for hypoglycemia in diabetes in general (use of insulin or insulin secretagogues, duration of diabetes, antecedent hypoglycemia, erratic meals, exercise, renal insufficiency) (104) presumably apply to older patients as well. In the Medicaid study cited above, independent risk factors included hospital discharge within the prior 30 days, advanced age, black race, and use of five or more concomitant medications (103). Assessment of risk factors for hypoglycemia is an important part of the clinical care of older adults with hypoglycemia. Education of both patient and caregiver on the prevention, detection, and treatment of hypoglycemia is paramount. Risks of undertreatment of hyperglycemia. Although attention has rightly been paid to the risks of overtreatment of hyperglycemia in older adults (hypoglycemia, treatment burden, possibly increased mortality), untreated or undertreated hyperglycemia also has risks, even in patients with life expectancy too short to be impacted by the development of chronic complications. Blood glucose levels consistently over the renal threshold for glycosuria (∼180–200 mg/dL, but can vary) increase the risks for dehydration, electrolyte abnormalities, urinary incontinence, dizziness, and falls. Hyperglycemic hyperosmolar syndrome is a particularly severe complication of unrecognized or undertreated hyperglycemia in older adults. Although it is appropriate to relax glycemic targets for older patients with a history of hypoglycemia, a high burden of comorbidities, and limited life expectancy, goals that minimize severe hyperglycemia are indicated for almost all patients. Life expectancy A central concept in geriatric diabetes care guidelines is that providers should base decisions regarding treatment targets or interventions on life expectancy (2,17,56,57). Patients whose life expectancy is limited (e.g., <5 years, <10 years) are considered unlikely to benefit from intensive glucose control, for example, whereas those with longer life expectancy may be appropriate candidates for this intervention. An observation supporting this concept is that cumulative event curves for the intensive and conventional glycemic control arms of the UKPDS separated after the 9-year mark. National Vital Statistics life table estimates of average life expectancy for adults of specific ages, sexes, and races (105) may not apply to older adults with diabetes, who have shorter life expectancies than the average older adult. Mortality prediction models that account for variables such as comorbidities and functional status can serve as the basis for making more refined life expectancy estimates (106–108). Mortality prediction models specific to diabetes exist but were not designed to inform treatment decisions (109,110). A limitation of existing mortality models is that they can help to rank patients by probability of death, but these probabilities must still be transformed into a life expectancy for a particular older diabetic patient. Simulation models can help transform mortality prediction into a usable life expectancy. One such model estimated the benefits of lowering A1C from 8.0 to 7.0% for hypothetical older diabetic patients with varying levels of age, comorbidity, and functional status (111). A combination of multiple comorbid illnesses and functional impairments was a better predictor of limited life expectancy and diminished benefits of intensive glucose control than age alone. This model suggests that life expectancy averages less than 5 years for patients aged 60–64 years with seven additional index points (points due to comorbid conditions and functional impairments), aged 65–69 years with six additional points, aged 70–74 years with five additional points, and aged 75–79 years with four additional points. An example of comorbid illnesses is the diagnosis of cancer, which confers two points, whereas an example of a functional impairment is the inability to bathe oneself, conferring two points. Shared decision making In light of the paucity of data for diabetes care in older adults, treatment decisions are frequently made with considerable uncertainty. Shared decision making has been advocated as an approach to improving the quality of these so-called preference-sensitive medical decisions (112,113). Key components of the shared decision-making approach are 1) establishing an ongoing partnership between patient and provider, 2) information exchange, 3) deliberation on choices, and 4) deciding and acting on decisions (114). When asked about their health care goals, older diabetic patients focus most on their functional status and independence (115). A key component of improving communication in the clinical setting may be finding congruence between patient goals and the biomedical goals on which clinicians tend to focus. Discussions eliciting and incorporating patients’ preferences regarding treatments and treatment targets may be difficult when patients do not understand the significance of risk factors or the value of risk reduction. Thus, providers must first educate patients and their caregivers about what is known about the role of risk factors in the development of complications and then discuss the possible harms and benefits of interventions to reduce these risk factors. Equally important is discussing the actual medications that may be needed to achieve treatment goals because patients may have strong preferences about the treatment regimen. In a study of patient preferences regarding diabetes complications and treatments, end-stage complications had the greatest perceived burden on quality of life; however, comprehensive diabetes treatments had significant negative perceived quality-of-life effects, similar to those of intermediate complications (116). Preferences for each health state varied widely among patients, and this variation was not related to health status (117), implying that the preferences of an individual patient cannot be assumed to be known based on health status. Many older adults rely on family members or friends to help them with their treatment decisions or to implement day-to-day treatments. In the case of the older person with cognitive deficits, the family member or friend may in fact be serving as a surrogate decision maker. Prior studies of older cognitively intact patients have shown that surrogate decision makers often report treatment preferences for the patient that have little correlation with the patient’s views (118), highlighting the importance of eliciting patient preferences whenever possible. Racial and ethnic disparities Among older adults, African Americans and Hispanics have higher incidence and prevalence of type 2 diabetes than non-Hispanic whites, and those with diagnosed diabetes have worse glycemic control and higher rates of comorbid conditions and complications (119). The Institute of Medicine found that although health care access and demographic variables account for some racial and ethnic disparities, there are persistent, residual gaps in outcomes attributed to differences in the quality of care received (120). There is clearly a need for more research into the disparities in diabetes, particularly to understand the full impact of quality improvement programs and culturally tailored interventions among vulnerable older adults with diabetes. Settings outside the home Long-term care facilities. Long-term care (LTC) facilities include nursing homes, which provide 24-h nursing care for patients in either residential care or rehabilitative care, and adult family homes where the level of care is not as acute. Diabetes is common in LTC facilities, with an overall diabetes prevalence of 25% (22% in Caucasian and 36% in non-Caucasian residents) (121). LTC residents with diabetes have more falls (122), higher rates of CVD and depression, more functional impairment, and more cognitive decline and dependency than residents without diabetes (123). The LTC facility resident may have irregular and unpredictable meal consumption, undernutrition, anorexia, and impaired swallowing. Therapeutic diets may inadvertently lead to decreased food intake and contribute to unintentional weight loss and undernutrition. Serving meals that take into account the patient’s culture, preferences, personal goals, and abilities may increase quality of life, satisfaction with meals, and nutrition status (124). Vulnerable older adults, particularly those with cognitive dysfunction, may have impaired thirst sensation, contributing to the risk of volume depletion and hyperglycemic crises. Precipitating situations include illness, institutional settings (LTC or hospital), aversion to drinking water, dysphasia requiring thickened liquids, and some medications (125). Fluid intake should be encouraged and monitored in an institutional setting. A major issue in LTC facilities is frequent staff turnover with resultant unfamiliarity with vulnerable residents (126). There is often inadequate oversight of glycemic control related to infrequent review of glycemic trends, complex and difficult-to-read glucose logs, and lack of specific diabetes treatment algorithms including glycemic parameters for provider notification (127). Excessive reliance on sliding-scale insulin (SSI) has been documented. One study showed that 83% of residents started on SSI were still treated by SSI alone 6 months later (128). Evidence-based policies for glycemic control, use of insulin, and treatment of hypoglycemia have the potential to improve the care of residents with diabetes, alleviate some of the burden caused by frequent staff turnover, and even lead to more staff satisfaction. Hospitals. Older adults are more apt to require hospitalization than younger adults, and those with diabetes are at very high risk of requiring hospitalization. There is a dearth of studies addressing older adults with diabetes, particularly more frail older adults, in the hospital. Many guidelines that apply to hospitalized adults with hyperglycemia can probably be extrapolated to older adults (129,130). Current guidelines recommend preprandial glycemic targets of 100–140 mg/dL with maximal random values of 180 mg/dL in the majority of noncritically ill hospitalized patients, provided these targets can be safely achieved with low risk for hypoglycemia. Less stringent glycemic targets may be appropriate for patients with multiple comorbidities and reduced life expectancy—criteria that could be applicable to many hospitalized older adults. However, in general, glucose levels should be maintained at values below 200 mg/dL to minimize symptomatic hyperglycemia with associated fluid and electrolyte abnormalities, renal complications, and risk for infection (129,130). Studies of glycemic control targets in critically ill patients did include older adults, and therefore the recommendations for insulin infusions and glycemic goals of the ADA (17) are reasonable for older adults in intensive care units. Other recommendations for all adults, such as avoiding the use of sliding scale–only regimens and noninsulin antihyperglycemic drugs, are also reasonable for hospitalized older adults. Transitions from hospital to home or to short- or long-term care facilities are times of risk for patients with diabetes, and probably more so for older patients. Older patients on insulin may need to increase or decrease their dose as they recuperate from their acute illness and their diet improves. Delirium (acute decline in cognitive function) is a common complication seen in older adults during and after hospitalization and may require more supervision to avoid errors in dosing. Medication reconciliation, patient and caregiver education, and close communication between inpatient and outpatient care teams, are critically important to ensure patient safety and reduce readmission rates. What are consensus recommendations for clinicians treating older adults with or at risk for diabetes? Although several organizations have developed guidelines that pertain to older adults and/or those with significant comorbidity, lack of evidence makes it somewhat difficult to provide concrete guidance for clinicians. After review of the available evidence and consideration of issues that might influence treatment decisions in older adults with diabetes, the authors have developed recommendations in a number of areas. Table 1 provides a framework for considering treatment goals for glycemia, blood pressure, and dyslipidemia. This framework is based on the work of Blaum et al. (131), in which health status, defined by the presence and number of comorbidities or impairments of functional status, leads to the identification of three major classes of older patients: 1) those who are relatively healthy, 2) those with complex medical histories where self-care may be difficult, and 3) those with a very significant comorbid illness and functional impairment. The three classes correspond with increasing levels of mortality risk (131). The observation that there are three major classes of older diabetic patients is supported by other research (132). The framework is an attempt to balance the expected time frame of benefit of interventions with anticipated life expectancy. Table 2 provides additional consensus recommendations beyond goals of treatment of glycemia, blood pressure, and dyslipidemia. Table 1 A framework for considering treatment goals for glycemia, blood pressure, and dyslipidemia in older adults with diabetes Table 2 Additional consensus recommendations for care of older adults with diabetes How can gaps in the evidence best be filled? The exclusion of older, and especially frail older, participants from most traditional randomized controlled trials of diabetes interventions has left us with large gaps in our knowledge of how best to address diabetes in the age-group with the highest prevalence rates. Future research should allow and account for the complexity and heterogeneity of older adults. Studies will need to include patients with multiple comorbidities, dependent living situations, and geriatric syndromes in order to advance our knowledge about these populations. Beyond broadening the inclusion criteria for randomized controlled trials, we will increasingly need sophisticated observational or comparative effectiveness evidence from “real world” settings and populations. Suggested research questions and topics are listed in Table 3. Table 3 Consensus recommendations for research questions about diabetes in older adults Supplementary Material News Release

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          Standards of Medical Care in Diabetes—2012

          Diabetes mellitus is a chronic illness that requires continuing medical care and ongoing patient self-management education and support to prevent acute complications and to reduce the risk of long-term complications. Diabetes care is complex and requires that many issues, beyond glycemic control, be addressed. A large body of evidence exists that supports a range of interventions to improve diabetes outcomes. These standards of care are intended to provide clinicians, patients, researchers, payers, and other interested individuals with the components of diabetes care, general treatment goals, and tools to evaluate the quality of care. While individual preferences, comorbidities, and other patient factors may require modification of goals, targets that are desirable for most patients with diabetes are provided. Specifically titled sections of the standards address children with diabetes, pregnant women, and people with prediabetes. These standards are not intended to preclude clinical judgment or more extensive evaluation and management of the patient by other specialists as needed. For more detailed information about management of diabetes, refer to references 1–3. The recommendations included are screening, diagnostic, and therapeutic actions that are known or believed to favorably affect health outcomes of patients with diabetes. A large number of these interventions have been shown to be cost-effective (4). A grading system (Table 1), developed by the American Diabetes Association (ADA) and modeled after existing methods, was utilized to clarify and codify the evidence that forms the basis for the recommendations. The level of evidence that supports each recommendation is listed after each recommendation using the letters A, B, C, or E. Table 1 ADA evidence grading system for clinical practice recommendations Level of evidence Description A Clear evidence from well-conducted, generalizable, RCTs that are adequately powered, including: Evidence from a well-conducted multicenter trial Evidence from a meta-analysis that incorporated quality ratings in the analysis Compelling nonexperimental evidence, i.e., “all or none” rule developed by Center for Evidence Based Medicine at Oxford Supportive evidence from well-conducted randomized controlled trials that are adequately powered, including: Evidence from a well-conducted trial at one or more institutions Evidence from a meta-analysis that incorporated quality ratings in the analysis B Supportive evidence from well-conducted cohort studies Evidence from a well-conducted prospective cohort study or registry Evidence from a well-conducted meta-analysis of cohort studies Supportive evidence from a well-conducted case-control study C Supportive evidence from poorly controlled or uncontrolled studies Evidence from RCTs with one or more major or three or more minor methodological flaws that could invalidate the results Evidence from observational studies with high potential for bias (such as case series with comparison with historical controls) Evidence from case series or case reports Conflicting evidence with the weight of evidence supporting the recommendation E Expert consensus or clinical experience These standards of care are revised annually by the ADA's multidisciplinary Professional Practice Committee, incorporating new evidence. For the current revision, committee members systematically searched Medline for human studies related to each subsection and published since 1 January 2010. Recommendations (bulleted at the beginning of each subsection and also listed in the “Executive Summary: Standards of Medical Care in Diabetes—2012”) were revised based on new evidence or, in some cases, to clarify the prior recommendation or match the strength of the wording to the strength of the evidence. A table linking the changes in recommendations to new evidence can be reviewed at http://professional.diabetes.org/CPR_Search.aspx. Subsequently, as is the case for all Position Statements, the standards of care were reviewed and approved by the Executive Committee of ADA's Board of Directors, which includes health care professionals, scientists, and lay people. Feedback from the larger clinical community was valuable for the 2012 revision of the standards. Readers who wish to comment on the “Standards of Medical Care in Diabetes—2012” are invited to do so at http://professional.diabetes.org/CPR_Search.aspx. Members of the Professional Practice Committee disclose all potential financial conflicts of interest with industry. These disclosures were discussed at the onset of the standards revision meeting. Members of the committee, their employer, and their disclosed conflicts of interest are listed in the “Professional Practice Committee Members” table (see pg. S109). The American Diabetes Association funds development of the standards and all its position statements out of its general revenues and does not utilize industry support for these purposes. I. CLASSIFICATION AND DIAGNOSIS A. Classification The classification of diabetes includes four clinical classes: Type 1 diabetes (results from β-cell destruction, usually leading to absolute insulin deficiency) Type 2 diabetes (results from a progressive insulin secretory defect on the background of insulin resistance) Other specific types of diabetes due to other causes, e.g., genetic defects in β-cell function, genetic defects in insulin action, diseases of the exocrine pancreas (such as cystic fibrosis), and drug- or chemical-induced (such as in the treatment of HIV/AIDS or after organ transplantation) Gestational diabetes mellitus (GDM) (diabetes diagnosed during pregnancy that is not clearly overt diabetes) Some patients cannot be clearly classified as having type 1 or type 2 diabetes. Clinical presentation and disease progression vary considerably in both types of diabetes. Occasionally, patients who otherwise have type 2 diabetes may present with ketoacidosis. Similarly, patients with type 1 may have a late onset and slow (but relentless) progression of disease despite having features of autoimmune disease. Such difficulties in diagnosis may occur in children, adolescents, and adults. The true diagnosis may become more obvious over time. B. Diagnosis of diabetes Recommendations. For decades, the diagnosis of diabetes was based on plasma glucose criteria, either the fasting plasma glucose (FPG) or the 2-h value in the 75-g oral glucose tolerance test (OGTT) (5). In 2009, an International Expert Committee that included representatives of the American Diabetes Association (ADA), the International Diabetes Federation (IDF), and the European Association for the Study of Diabetes (EASD) recommended the use of the A1C test to diagnose diabetes, with a threshold of ≥6.5% (6), and ADA adopted this criterion in 2010 (5). The diagnostic test should be performed using a method that is certified by the National Glycohemoglobin Standardization Program (NGSP) and standardized or traceable to the Diabetes Control and Complications Trial (DCCT) reference assay. Point-of-care A1C assays, for which proficiency testing is not mandated, are not sufficiently accurate at this time to use for diagnostic purposes. Epidemiologic datasets show a similar relationship between A1C and risk of retinopathy as has been shown for the corresponding FPG and 2-h PG thresholds. The A1C has several advantages to the FPG and OGTT, including greater convenience (since fasting is not required), evidence to suggest greater preanalytical stability, and less day-to-day perturbations during periods of stress and illness. These advantages must be balanced by greater cost, the limited availability of A1C testing in certain regions of the developing world, and the incomplete correlation between A1C and average glucose in certain individuals. In addition, HbA1c levels may vary with patients’ race/ethnicity (7,8). Some have posited that glycation rates differ by race (with, for example, African Americans having higher rates of glycation), but this is controversial. A recent epidemiologic study found that, when matched for FPG, African Americans (with and without diabetes) indeed had higher A1C than whites, but also had higher levels of fructosamine and glycated albumin and lower levels of 1,5-anhydroglucitol, suggesting that their glycemic burden (particularly postprandially) may be higher (9). Epidemiologic studies forming the framework for recommending use of the A1C to diagnose diabetes have all been in adult populations. Whether the cut point would be the same to diagnose children with type 2 diabetes is an area of uncertainty (10). A1C inaccurately reflects glycemia with certain anemias and hemoglobinopathies. For patients with an abnormal hemoglobin but normal red cell turnover, such as sickle cell trait, an A1C assay without interference from abnormal hemoglobins should be used (an updated list is available at www.ngsp.org/npsp.org/interf.asp). For conditions with abnormal red cell turnover, such as pregnancy, recent blood loss or transfusion, or some anemias, the diagnosis of diabetes must employ glucose criteria exclusively. The established glucose criteria for the diagnosis of diabetes (FPG and 2-h PG) remain valid as well (Table 2). Just as there is less than 100% concordance between the FPG and 2-h PG tests, there is not perfect concordance between A1C and either glucose-based test. Analyses of National Health and Nutrition Examination Survey (NHANES) data indicate that, assuming universal screening of the undiagnosed, the A1C cut point of ≥6.5% identifies one-third fewer cases of undiagnosed diabetes than a fasting glucose cut point of ≥126 mg/dL (7.0 mmol/L) (11). However, in practice, a large portion of the diabetic population remains unaware of their condition. Thus, the lower sensitivity of A1C at the designated cut point may well be offset by the test's greater practicality, and wider application of a more convenient test (A1C) may actually increase the number of diagnoses made. Table 2 Criteria for the diagnosis of diabetes As with most diagnostic tests, a test result diagnostic of diabetes should be repeated to rule out laboratory error, unless the diagnosis is clear on clinical grounds, such as a patient with a hyperglycemic crisis or classic symptoms of hyperglycemia and a random plasma glucose ≥200 mg/dL. It is preferable that the same test be repeated for confirmation, since there will be a greater likelihood of concurrence in this case. For example, if the A1C is 7.0% and a repeat result is 6.8%, the diagnosis of diabetes is confirmed. However, if two different tests (such as A1C and FPG) are both above the diagnostic thresholds, the diagnosis of diabetes is also confirmed. On the other hand, if two different tests are available in an individual and the results are discordant, the test whose result is above the diagnostic cut point should be repeated, and the diagnosis is made on the basis of the confirmed test. That is, if a patient meets the diabetes criterion of the A1C (two results ≥6.5%) but not the FPG ( 6.0%, who should be considered to be at very high risk. Table 3 summarizes the categories of increased risk for diabetes. Table 3 Categories of increased risk for diabetes (prediabetes)* II. TESTING FOR DIABETES IN ASYMPTOMATIC PATIENTS Recommendations. Testing to detect type 2 diabetes and assess risk for future diabetes in asymptomatic people should be considered in adults of any age who are overweight or obese (BMI ≥25 kg/m2) and who have one or more additional risk factors for diabetes (Table 4). In those without these risk factors, testing should begin at age 45 years. (B) If tests are normal, repeat testing at least at 3-year intervals is reasonable. (E) To test for diabetes or to assess risk of future diabetes, the A1C, FPG, or 2-h 75-g OGTT are appropriate. (B) In those identified with increased risk for future diabetes, identify and, if appropriate, treat other CVD risk factors. (B) Table 4 Criteria for testing for diabetes in asymptomatic adult individuals 1. Testing should be considered in all adults who are overweight (BMI ≥25 kg/m2 *) and who have one or more additional risk factors: physical inactivity first-degree relative with diabetes high-risk race/ethnicity (e.g., African American, Latino, Native American, Asian American, Pacific Islander) women who delivered a baby weighing >9 lb or who were diagnosed with GDM hypertension (blood pressure ≥140/90 mmHg or on therapy for hypertension) HDL cholesterol level 250 mg/dL (2.82 mmol/L) women with PCOS A1C ≥5.7%, IGT, or IFG on previous testing other clinical conditions associated with insulin resistance (e.g., severe obesity, acanthosis nigricans) history of CVD 2. In the absence of the above criteria, testing for diabetes should begin at age 45 years 3. If results are normal, testing should be repeated at least at 3-year intervals, with consideration of more-frequent testing depending on initial results (e.g., those with prediabetes should be tested yearly) and risk status. * At-risk BMI may be lower in some ethnic groups. PCOS, polycystic ovary syndrome. For many illnesses, there is a major distinction between screening and diagnostic testing. However, for diabetes, the same tests would be used for “screening” as for diagnosis. Diabetes may be identified anywhere along a spectrum of clinical scenarios ranging from a seemingly low-risk individual who happens to have glucose testing, to a higher-risk individual whom the provider tests because of high suspicion of diabetes, to the symptomatic patient. The discussion herein is primarily framed as testing for diabetes in those without symptoms. The same assays used for testing for diabetes will also detect individuals with prediabetes. A. Testing for type 2 diabetes and risk of future diabetes in adults Prediabetes and diabetes meet established criteria for conditions in which early detection is appropriate. Both conditions are common, increasing in prevalence, and impose significant public health burdens. There is a long presymptomatic phase before the diagnosis of type 2 diabetes is usually made. Relatively simple tests are available to detect preclinical disease. Additionally, the duration of glycemic burden is a strong predictor of adverse outcomes, and effective interventions exist to prevent progression of prediabetes to diabetes (see section IV. PREVENTION/DELAY OF TYPE 2 DIABETES) and to reduce risk of complications of diabetes (see section V.I. PREVENTION AND MANAGEMENT OF DIABETES COMPLICATIONS). Type 2 diabetes is frequently not diagnosed until complications appear, and approximately one-fourth of all people with diabetes in the U.S. may be undiagnosed. The effectiveness of early identification of prediabetes and diabetes through mass testing of asymptomatic individuals has not been proven definitively, and rigorous trials to provide such proof are unlikely to occur. In a large randomized controlled trial (RCT) in Europe, general practice patients between the ages of 40 and 69 years were screened for diabetes and then randomized by practice to routine care of diabetes or intensive treatment of multiple risk factors. After 5.3 years of follow-up, CVD risk factors were modestly but significantly more improved with intensive treatment. Incidence of first CVD event and mortality rates were not significantly different between groups (16). This study would seem to add support for early treatment of screen-detected diabetes, as risk factor control was excellent even in the routine treatment arm and both groups had lower event rates than predicted. The absence of a control unscreened arm limits the ability to definitely prove that screening impacts outcomes. Mathematical modeling studies suggest that screening independent of risk factors beginning at age 30 or age 45 years is highly cost-effective ( 85th percentile for age and sex, weight for height >85th percentile, or weight >120% of ideal for height  Plus any two of the following risk factors: Family history of type 2 diabetes in first- or second-degree relative Race/ethnicity (Native American, African American, Latino, Asian American, Pacific Islander) Signs of insulin resistance or conditions associated with insulin resistance (acanthosis nigricans, hypertension, dyslipidemia, PCOS, or birth weight small for gestational age birthweight) Maternal history of diabetes or GDM during the child's gestation  Age of initiation: 10 years or at onset of puberty, if puberty occurs at a younger age  Frequency: every 3 years PCOS, polycystic ovary syndrome C. Screening for type 1 diabetes Generally, people with type 1 diabetes present with acute symptoms of diabetes and markedly elevated blood glucose levels, and most cases are diagnosed soon after the onset of hyperglycemia. However, evidence from type 1 prevention studies suggests that measurement of islet autoantibodies identifies individuals who are at risk for developing type 1 diabetes. Such testing may be appropriate in high-risk individuals, such as those with prior transient hyperglycemia or those who have relatives with type 1 diabetes, in the context of clinical research studies (see, e.g., http://www2.diabetestrialnet.org). Widespread clinical testing of asymptomatic low-risk individuals cannot currently be recommended, as it would identify very few individuals in the general population who are at risk. Individuals who screen positive should be counseled about their risk of developing diabetes. Clinical studies are being conducted to test various methods of preventing type 1 diabetes, or reversing early type 1 diabetes, in those with evidence of autoimmunity. III. DETECTION AND DIAGNOSIS OF GESTATIONAL DIABETES MELLITUS (GDM) Recommendations. Screen for undiagnosed type 2 diabetes at the first prenatal visit in those with risk factors, using standard diagnostic criteria. (B) In pregnant women not previously known to have diabetes, screen for GDM at 24–28 weeks’ gestation, using a 75-g 2-h OGTT and the diagnostic cut points in Table 6. (B) Screen women with GDM for persistent diabetes at 6–12 weeks’ postpartum, using a test other than A1C. (E) Women with a history of GDM should have lifelong screening for the development of diabetes or prediabetes at least every 3 years. (B) Women with a history of GDM found to have prediabetes should receive lifestyle interventions or metformin to prevent diabetes. (A) Table 6 Screening for and diagnosis of GDM Perform a 75-g OGTT, with plasma glucose measurement fasting and at 1 and 2 h, at 24–28 weeks’ gestation in women not previously diagnosed with overt diabetes. The OGTT should be performed in the morning after an overnight fast of at least 8 h. The diagnosis of GDM is made when any of the following plasma glucose values are exceeded: Fasting ≥92 mg/dL (5.1 mmol/L) 1 h ≥180 mg/dL (10.0 mmol/L) 2 h ≥153 mg/dL (8.5 mmol/L) For many years, GDM was defined as any degree of glucose intolerance with onset or first recognition during pregnancy (12), whether or not the condition persisted after pregnancy, and not excluding the possibility that unrecognized glucose intolerance may have antedated or begun concomitantly with the pregnancy. This definition facilitated a uniform strategy for detection and classification of GDM, but its limitations were recognized for many years. As the ongoing epidemic of obesity and diabetes has led to more type 2 diabetes in women of childbearing age, the number of pregnant women with undiagnosed type 2 diabetes has increased (31). Because of this, it is reasonable to screen women with risk factors for type 2 diabetes (Table 4) for diabetes at their initial prenatal visit, using standard diagnostic criteria (Table 2). Women found to have diabetes at this visit should receive a diagnosis of overt, not gestational, diabetes. GDM carries risks for the mother and neonate. The Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study (32), a large-scale (∼25,000 pregnant women) multinational epidemiologic study, demonstrated that risk of adverse maternal, fetal, and neonatal outcomes continuously increased as a function of maternal glycemia at 24–28 weeks, even within ranges previously considered normal for pregnancy. For most complications, there was no threshold for risk. These results have led to careful reconsideration of the diagnostic criteria for GDM. After deliberations in 2008–2009, the International Association of Diabetes and Pregnancy Study Groups (IADPSG), an international consensus group with representatives from multiple obstetrical and diabetes organizations, including ADA, developed revised recommendations for diagnosing GDM. The group recommended that all women not known to have prior diabetes undergo a 75-g OGTT at 24–28 weeks of gestation. Additionally, the group developed diagnostic cut points for the fasting, 1-h, and 2-h plasma glucose measurements that conveyed an odds ratio for adverse outcomes of at least 1.75 compared with women with the mean glucose levels in the HAPO study. Current screening and diagnostic strategies, based on the IADPSG statement (33), are outlined in Table 6. These new criteria will significantly increase the prevalence of GDM, primarily because only one abnormal value, not two, is sufficient to make the diagnosis. ADA recognizes the anticipated significant increase in the incidence of GDM diagnosed by these criteria and is sensitive to concerns about the “medicalization” of pregnancies previously categorized as normal. These diagnostic criteria changes are being made in the context of worrisome worldwide increases in obesity and diabetes rates, with the intent of optimizing gestational outcomes for women and their babies. Admittedly, there are few data from randomized clinical trials regarding therapeutic interventions in women who will now be diagnosed with GDM based on only one blood glucose value above the specified cut points (in contrast to the older criteria that stipulated at least two abnormal values). However, there is emerging observational and retrospective evidence that women diagnosed with the new criteria (even if they would not have been diagnosed with older criteria) have increased rates of poor pregnancy outcomes similar to those of women with GDM by prior criteria (34,35). Expected benefits to these pregnancies and offspring is inferred from intervention trials that focused on women with more mild hyperglycemia than identified using older GDM diagnostic criteria and that found modest benefits (36,37). The frequency of follow-up and blood glucose monitoring for these women is not yet clear but likely to be less intensive than for women diagnosed by the older criteria. It is important to note that 80–90% of women in both of the mild GDM studies (whose glucose values overlapped with the thresholds recommended herein) could be managed with lifestyle therapy alone. The American College of Obstetrics and Gynecology announced in 2011 that they continue to recommend use of prior diagnostic criteria for GDM (38). Several other countries have adopted the new criteria, and a report from the WHO on this topic is pending at the time of the publication of these standards. Because some cases of GDM may represent preexisting undiagnosed type 2 diabetes, women with a history of GDM should be screened for diabetes 6–12 weeks’ postpartum, using nonpregnant OGTT criteria. Because of their prepartum treatment for hyperglycemia, use of the A1C for diagnosis of persistent diabetes at the postpartum visit is not recommended (39). Women with a history of GDM have a greatly increased subsequent risk for diabetes (40) and should be followed up with subsequent screening for the development of diabetes or prediabetes, as outlined in section II. TESTING FOR DIABETES IN ASYMPTOMATIC PATIENTS. Lifestyle interventions or metformin should be offered to women with a history of GDM who develop prediabetes, as discussed in section IV. PREVENTION/DELAY OF TYPE 2 DIABETES. IV. PREVENTION/DELAY OF TYPE 2 DIABETES Recommendations. Patients with IGT (A), IFG (E), or an A1C of 5.7–6.4% (E) should be referred to an effective ongoing support program targeting weight loss of 7% of body weight and increasing physical activity to at least 150 min per week of moderate activity such as walking. Follow-up counseling appears to be important for success. (B) Based on the cost-effectiveness of diabetes prevention, such programs should be covered by third-party payers. (B) Metformin therapy for prevention of type 2 diabetes may be considered in those with IGT (A), IFG (E), or an A1C of 5.7–6.4% (E), especially for those with BMI >35 kg/m2, age 35 kg/m2 and type 2 diabetes, especially if the diabetes or associated comorbidities are difficult to control with lifestyle and pharmacologic therapy. (B) Patients with type 2 diabetes who have undergone bariatric surgery need life-long lifestyle support and medical monitoring. (B) Although small trials have shown glycemic benefit of bariatric surgery in patients with type 2 diabetes and BMI of 30–35 kg/m2, there is currently insufficient evidence to generally recommend surgery in patients with BMI 35 kg/m2. Bariatric surgery has been shown to lead to near- or complete normalization of glycemia in ∼55–95% of patients with type 2 diabetes, depending on the surgical procedure. A meta-analysis of studies of bariatric surgery involving 3,188 patients with diabetes reported that 78% had remission of diabetes (normalization of blood glucose levels in the absence of medications), and that the remission rates were sustained in studies that had follow-up exceeding 2 years (203). Remission rates tend to be lower with procedures that only constrict the stomach and higher with those that bypass portions of the small intestine. Additionally, there is a suggestion that intestinal bypass procedures may have glycemic effects that are independent of their effects on weight, perhaps involving the incretin axis. One RCT compared adjustable gastric banding to “best available” medical and lifestyle therapy in subjects with type 2 diabetes diagnosed less than 2 years before randomization and with BMI 30–40 kg/m2 (204). In this trial, 73% of surgically treated patients achieved “remission” of their diabetes, compared with 13% of those treated medically. The latter group lost only 1.7% of body weight, suggesting that their therapy was not optimal. Overall the trial had 60 subjects, and only 13 had a BMI 64 years of age previously immunized when they were 5 years ago. Other indications for repeat vaccination include nephrotic syndrome, chronic renal disease, and other immunocompromised states, such as after transplantation. (C) Administer hepatitis B vaccination to adults with diabetes as per Centers for Disease Control and Prevention (CDC) recommendations. (C) Influenza and pneumonia are common, preventable infectious diseases associated with high mortality and morbidity in the elderly and in people with chronic diseases. Though there are limited studies reporting the morbidity and mortality of influenza and pneumococcal pneumonia specifically in people with diabetes, observational studies of patients with a variety of chronic illnesses, including diabetes, show that these conditions are associated with an increase in hospitalizations for influenza and its complications. People with diabetes may be at increased risk of the bacteremic form of pneumococcal infection and have been reported to have a high risk of nosocomial bacteremia, which has a mortality rate as high as 50% (213). Safe and effective vaccines are available that can greatly reduce the risk of serious complications from these diseases (214,215). In a case-control series, influenza vaccine was shown to reduce diabetes-related hospital admission by as much as 79% during flu epidemics (214). There is sufficient evidence to support that people with diabetes have appropriate serologic and clinical responses to these vaccinations. The Centers for Disease Control and Prevention (CDC) Advisory Committee on Immunization Practices recommends influenza and pneumococcal vaccines for all individuals with diabetes (http://www.cdc.gov/vaccines/recs/). At the time these standards went to press, the CDC was considering recommendations to immunize all or some adults with diabetes for hepatitis B. ADA awaits the final recommendations and will support them when they are released in 2012. VI. PREVENTION AND MANAGEMENT OF DIABETES COMPLICATIONS A. CVD CVD is the major cause of morbidity and mortality for individuals with diabetes and the largest contributor to the direct and indirect costs of diabetes. The common conditions coexisting with type 2 diabetes (e.g., hypertension and dyslipidemia) are clear risk factors for CVD, and diabetes itself confers independent risk. Numerous studies have shown the efficacy of controlling individual cardiovascular risk factors in preventing or slowing CVD in people with diabetes. Large benefits are seen when multiple risk factors are addressed globally (216,217). There is evidence that measures of 10-year coronary heart disease (CHD) risk among U.S. adults with diabetes have improved significantly over the past decade (218). 1. Hypertension/blood pressure control. Recommendations. Screening and diagnosis Blood pressure should be measured at every routine diabetes visit. Patients found to have systolic blood pressure (SBP) ≥ 130mmHg or diastolic blood pressure (DBP) ≥80 mmHg should have blood pressure confirmed on a separate day. Repeat SBP ≥130 mmHg or DBP ≥80 mmHg confirms a diagnosis of hypertension. (C) Goals A goal SBP 115/75 mmHg is associated with increased cardiovascular event rates and mortality in individuals with diabetes (219,222,223). Randomized clinical trials have demonstrated the benefit (reduction of CHD events, stroke, and nephropathy) of lowering blood pressure to 140 mmHg. Treatment strategies. Although there are no well-controlled studies of diet and exercise in the treatment of hypertension in individuals with diabetes, the Dietary Approaches to Stop Hypertension (DASH) study in nondiabetic individuals has shown antihypertensive effects similar to pharmacologic monotherapy. Lifestyle therapy consists of reducing sodium intake (to 50 mg/dL, and triglycerides 100 mg/dL or in those with multiple CVD risk factors. (E) In individuals without overt CVD, the primary goal is an LDL cholesterol 40 mg/dL (1.0 mmol/L) in men and >50 mg/dL (1.3 mmol/L) in women, are desirable. However, LDL cholesterol–targeted statin therapy remains the preferred strategy. (C) If targets are not reached on maximally tolerated doses of statins, combination therapy using statins and other lipid-lowering agents may be considered to achieve lipid targets but has not been evaluated in outcome studies for either CVD outcomes or safety. (E) Statin therapy is contraindicated in pregnancy. (B) Evidence for benefits of lipid-lowering therapy. Patients with type 2 diabetes have an increased prevalence of lipid abnormalities, contributing to their high risk of CVD. For the past decade or more, multiple clinical trials demonstrated significant effects of pharmacologic (primarily statin) therapy on CVD outcomes in subjects with CHD and for primary CVD prevention (245). Subanalyses of diabetic subgroups of larger trials (246–250) and trials specifically in subjects with diabetes (251,252) showed significant primary and secondary prevention of CVD events +/− CHD deaths in diabetic populations. Similar to findings in nondiabetic subjects, reduction in “hard” CVD outcomes (CHD death and nonfatal MI) can be more clearly seen in diabetic subjects with high baseline CVD risk (known CVD and/or very high LDL cholesterol levels), but overall the benefits of statin therapy in people with diabetes at moderate or high risk for CVD are convincing. Low levels of HDL cholesterol, often associated with elevated triglyceride levels, are the most prevalent pattern of dyslipidemia in persons with type 2 diabetes. However, the evidence base for drugs that target these lipid fractions is significantly less robust than that for statin therapy (253). Nicotinic acid has been shown to reduce CVD outcomes (254), although the study was done in a nondiabetic cohort. Gemfibrozil has been shown to decrease rates of CVD events in subjects without diabetes (255,256) and in the diabetic subgroup of one of the larger trials (255). However, in a large trial specific to diabetic patients, fenofibrate failed to reduce overall cardiovascular outcomes (257). Dyslipidemia treatment and target lipid levels. For most patients with diabetes, the first priority of dyslipidemia therapy (unless severe hypertriglyceridemia is the immediate issue) is to lower LDL cholesterol to a target goal of 100 mg/dL, prescribing statin therapy to lower LDL cholesterol ∼30–40% from baseline is probably more effective than prescribing just enough to get LDL cholesterol slightly 10%). This includes most men >50 years of age or women >60 years of age who have at least one additional major risk factor (family history of CVD, hypertension, smoking, dyslipidemia, or albuminuria). (C) Aspirin should not be recommended for CVD prevention for adults with diabetes at low CVD risk (10-year CVD risk 1% per year, the number of CVD events prevented will be similar to or greater than the number of episodes of bleeding induced, although these complications do not have equal effects on long-term health (274). In 2010, a position statement of the ADA, AHA, and the American College of Cardiology Foundation (ACCF) updated prior joint recommendations for primary prevention (275). Low-dose (75–162 mg/day) aspirin use for primary prevention is reasonable for adults with diabetes and no previous history of vascular disease who are at increased CVD risk (10-year risk of CVD events >10%) and who are not at increased risk for bleeding. This generally includes most men over age 50 years and women over age 60 years who also have one or more of the following major risk factors: smoking, hypertension, dyslipidemia,) family history of premature CVD, or albuminuria. However, aspirin is no longer recommended for those at low CVD risk (women under age 60 years and men under age 50 years with no major CVD risk factors; 10-year CVD risk 30 mg/g) to the normal or near-normal range may improve renal and cardiovascular prognosis, but this approach has not been formally evaluated in prospective trials. Complications of kidney disease correlate with level of kidney function. When the eGFR is 87% sensitivity in detecting DPN. Loss of 10-g monofilament perception and reduced vibration perception predict foot ulcers (335). Importantly, in patients with neuropathy, particularly when severe, causes other than diabetes should always be considered, such as neurotoxic mediations, heavy metal poisoning, alcohol abuse, vitamin B12 deficiency (especially in those taking metformin for prolonged periods (336), renal disease, chronic inflammatory demyelinating neuropathy, inherited neuropathies, and vasculitis (337). Diabetic autonomic neuropathy (338) The symptoms and signs of autonomic dysfunction should be elicited carefully during the history and physical examination. Major clinical manifestations of diabetic autonomic neuropathy include resting tachycardia, exercise intolerance, orthostatic hypotension, constipation, gastroparesis, erectile dysfunction, sudomotor dysfunction, impaired neurovascular function, and potentially autonomic failure in response to hypoglycemia. Cardiovascular autonomic neuropathy (CAN), a CVD risk factor (93), is the most studied and clinically important form of diabetic autonomic neuropathy. CAN may be indicated by resting tachycardia (>100 bpm) or orthostasis (a fall in SBP >20 mmHg upon standing without an appropriate heart rate response); it is also associated with increased cardiac event rates. Although some societies have developed guidelines for screening for CAN, the benefits of sophisticated testing beyond risk stratification are not clear (339). Gastrointestinal neuropathies (e.g., esophageal enteropathy, gastroparesis, constipation, diarrhea, fecal incontinence) are common, and any section of the gastrointestinal tract may be affected. Gastroparesis should be suspected in individuals with erratic glucose control or with upper gastrointestinal symptoms without other identified cause. Evaluation of solid-phase gastric emptying using double-isotope scintigraphy may be done if symptoms are suggestive, but test results often correlate poorly with symptoms. Constipation is the most common lower-gastrointestinal symptom but can alternate with episodes of diarrhea. Diabetic autonomic neuropathy is also associated with genitourinary tract disturbances. In men, diabetic autonomic neuropathy may cause erectile dysfunction and/or retrograde ejaculation. Evaluation of bladder dysfunction should be performed for individuals with diabetes who have recurrent urinary tract infections, pyelonephritis, incontinence, or a palpable bladder. Symptomatic treatments. DPN The first step in management of patients with DPN should be to aim for stable and optimal glycemic control. Although controlled trial evidence is lacking, several observational studies suggest that neuropathic symptoms improve not only with optimization of control, but also with the avoidance of extreme blood glucose fluctuations. Patients with painful DPN may benefit from pharmacological treatment of their symptoms; many agents have confirmed or probable efficacy confirmed in systematic reviews of RCTs (334), with several U.S. Food and Drug Administration (FDA)-approved for the management of painful DPN. Autonomic neuropathy Gastroparesis symptoms may improve with dietary changes and prokinetic agents such as metoclopramide or erythromycin. Treatments for erectile dysfunction may include phosphodiesterase type 5 inhibitors, intracorporeal or intraurethral prostaglandins, vacuum devices, or penile prostheses. Interventions for other manifestations of autonomic neuropathy are described in an ADA statement on neuropathy (335). As with DPN treatments, these interventions do not change the underlying pathology and natural history of the disease process, but may have a positive impact on the quality of life of the patient. E. Foot care Recommendations For all patients with diabetes, perform an annual comprehensive foot examination to identify risk factors predictive of ulcers and amputations. The foot examination should include inspection, assessment of foot pulses, and testing for loss of protective sensation (10-g monofilament plus testing any one of the following: vibration using 128-Hz tuning fork, pinprick sensation, ankle reflexes, or vibration perception threshold). (B) Provide general foot self-care education to all patients with diabetes. (B) A multidisciplinary approach is recommended for individuals with foot ulcers and high-risk feet, especially those with a history of prior ulcer or amputation. (B) Refer patients who smoke, have loss of protective sensation and structural abnormalities, or have history of prior lower-extremity complications to foot care specialists for ongoing preventive care and life-long surveillance. (C) Initial screening for peripheral arterial disease (PAD) should include a history for claudication and an assessment of the pedal pulses. Consider obtaining an ankle-brachial index (ABI), as many patients with PAD are asymptomatic. (C) Refer patients with significant claudication or a positive ABI for further vascular assessment and consider exercise, medications, and surgical options. (C) Amputation and foot ulceration, consequences of diabetic neuropathy and/or PAD, are common and major causes of morbidity and disability in people with diabetes. Early recognition and management of risk factors can prevent or delay adverse outcomes. The risk of ulcers or amputations is increased in people who have the following risk factors: Previous amputation Past foot ulcer history Peripheral neuropathy Foot deformity Peripheral vascular disease Visual impairment Diabetic nephropathy (especially patients on dialysis) Poor glycemic control Cigarette smoking Many studies have been published proposing a range of tests that might usefully identify patients at risk for foot ulceration, creating confusion among practitioners as to which screening tests should be adopted in clinical practice. An ADA task force was therefore assembled in 2008 to concisely summarize recent literature in this area and then recommend what should be included in the comprehensive foot exam for adult patients with diabetes. Their recommendations are summarized below, but clinicians should refer to the task force report (340) for further details and practical descriptions of how to perform components of the comprehensive foot examination. At least annually, all adults with diabetes should undergo a comprehensive foot examination to identify high risk conditions. Clinicians should ask about history of previous foot ulceration or amputation, neuropathic or peripheral vascular symptoms, impaired vision, tobacco use, and foot care practices. A general inspection of skin integrity and musculoskeletal deformities should be done in a well-lit room. Vascular assessment would include inspection and assessment of pedal pulses. The neurologic exam recommended is designed to identify loss of protective sensation (LOPS) rather than early neuropathy. The clinical examination to identify LOPS is simple and requires no expensive equipment. Five simple clinical tests (use of a 10-g monofilament, vibration testing using a 128-Hz tuning fork, tests of pinprick sensation, ankle reflex assessment, and testing vibration perception threshold with a biothesiometer), each with evidence from well-conducted prospective clinical cohort studies, are considered useful in the diagnosis of LOPS in the diabetic foot. The task force agrees that any of the five tests listed could be used by clinicians to identify LOPS, although ideally two of these should be regularly performed during the screening exam—normally the 10-g monofilament and one other test. One or more abnormal tests would suggest LOPS, while at least two normal tests (and no abnormal test) would rule out LOPS. The last test listed, vibration assessment using a biothesiometer or similar instrument, is widely used in the U.S.; however, identification of the patient with LOPS can easily be carried out without this or other expensive equipment. Initial screening for PAD should include a history for claudication and an assessment of the pedal pulses. A diagnostic ABI should be performed in any patient with symptoms of PAD. Due to the high estimated prevalence of PAD in patients with diabetes and the fact that many patients with PAD are asymptomatic, an ADA consensus statement on PAD (341) suggested that a screening ABI be performed in patients over 50 years of age and be considered in patients under 50 years of age who have other PAD risk factors (e.g., smoking, hypertension, hyperlipidemia, or duration of diabetes >10 years). Refer patients with significant symptoms or a positive ABI for further vascular assessment and consider exercise, medications, and surgical options (341). Patients with diabetes and high-risk foot conditions should be educated regarding their risk factors and appropriate management. Patients at risk should understand the implications of the loss of protective sensation, the importance of foot monitoring on a daily basis, the proper care of the foot, including nail and skin care, and the selection of appropriate footwear. Patients with loss of protective sensation should be educated on ways to substitute other sensory modalities (hand palpation, visual inspection) for surveillance of early foot problems. The patients’ understanding of these issues and their physical ability to conduct proper foot surveillance and care should be assessed. Patients with visual difficulties, physical constraints preventing movement, or cognitive problems that impair their ability to assess the condition of the foot and to institute appropriate responses will need other people, such as family members, to assist in their care. People with neuropathy or evidence of increased plantar pressure (e.g., erythema, warmth, callus, or measured pressure) may be adequately managed with well-fitted walking shoes or athletic shoes that cushion the feet and redistribute pressure. Callus can be debrided with a scalpel by a foot care specialist or other health professional with experience and training in foot care. People with bony deformities (e.g., hammertoes, prominent metatarsal heads, bunions) may need extra-wide or -depth shoes. People with extreme bony deformities (e.g., Charcot foot) who cannot be accommodated with commercial therapeutic footwear may need custom-molded shoes. Foot ulcers and wound care may require care by a podiatrist, orthopedic or vascular surgeon, or rehabilitation specialist experienced in the management of individuals with diabetes. VII. ASSESSMENT OF COMMON COMORBID CONDITIONS Recommendations For patients with risk factors, signs or symptoms, consider assessment and treatment for common diabetes-associated conditions (see Table 15). (B) Table 15 Common comorbidities for which increased risk is associated with diabetes Hearing impairment Obstructive sleep apnea Fatty liver disease Low testosterone in men Periodontal disease Certain cancers Fractures Cognitive impairment In addition to the commonly appreciated comorbidities of obesity, hypertension, and dyslipidemia, diabetes is also associated with other diseases or conditions at rates higher than those of age-matched people without diabetes. A few of the more common comorbidities are described herein, and listed in Table 15. Hearing impairment Hearing impairment, both high frequency and low/mid frequency, is more common in people with diabetes, perhaps due to neuropathy and/or vascular disease. In an NHANES analysis, hearing impairment was about twice as great in people with diabetes than in those without diabetes, after adjusting for age and other risk factors for hearing impairment (342). Controlling for age, race, and other demographic factors, high-frequency loss in those with diabetes was significantly associated with history of CHD and with peripheral neuropathy, while low/mid frequency loss was associated with low HDL cholesterol and with poor reported health status (343). Obstructive sleep apnea Age-adjusted rates of obstructive sleep apnea, a risk factor for CVD, are significantly higher (4- to 10-fold) with obesity, especially with central obesity, in men and women (344). The prevalence in general populations with type 2 diabetes may be up to 23% (345) and in obese participants enrolled in the Look AHEAD trial exceeded 80% (346). Treatment of sleep apnea significantly improves quality of life and blood pressure control. The evidence for a treatment effect on glycemic control is mixed (347). Fatty liver disease Unexplained elevation of hepatic transaminase concentrations are significantly associated with higher BMI, waist circumference, triglycerides, and fasting insulin and with lower HDL cholesterol. Type 2 diabetes and hypertension are independently associated with transaminase elevations in women (348). In a prospective analysis, diabetes was significantly associated with incident nonalcoholic chronic liver disease and with hepatocellular carcinoma (349). Interventions that improve metabolic abnormalities in patients with diabetes (weight loss, glycemic control, treatment with specific drugs for hyperglycemia or dyslipidemia) are also beneficial for fatty liver disease (350). Low testosterone in men Mean levels of testosterone are lower in men with diabetes compared with age-matched men without diabetes, but obesity is a major confounder (351). The issue of treatment in asymptomatic men is controversial. The evidence for effects of testosterone replacement on outcomes is mixed, and recent guidelines suggest that screening and treatment of men without symptoms is not recommended (352). Periodontal disease Periodontal disease is more severe, but not necessarily more prevalent, in patients with diabetes than those without (353). Numerous studies have suggested associations with poor glycemic control, nephropathy, and CVD, but most studies are highly confounded. A comprehensive assessment, and treatment of identified disease, is indicated in patients with diabetes, but the evidence that periodontal disease treatment improves glycemic control is mixed. A meta-analysis reported a significant 0.47% improvement in A1C, but noted multiple problems with the quality of the published studies included in the analysis (354). Several high-quality RCTs have not shown a significant effect (355). Cancer Diabetes (possibly only type 2 diabetes) is associated with increased risk of cancers of the liver, pancreas, endometrium, colon/ rectum, breast, and bladder (356). The association may result from shared risk factors between type 2 diabetes and cancer (obesity, age, physical inactivity) but may also be due to hyperinsulinemia or hyperglycemia (356a). Patients with diabetes should be encouraged to undergo recommended age- and sex-appropriate cancer screenings and to reduce their modifiable cancer risk factors (obesity, smoking, physical inactivity). Fractures Age-matched hip fracture risk is significantly increased in both type 1 (summary RR 6.3) and type 2 diabetes (summary RR 1.7) in both sexes (357). Type 1 diabetes is associated with osteoporosis, but in type 2 diabetes an increased risk of hip fracture is seen despite higher bone mineral density (BMD) (358). One study showed that prevalent vertebral fractures were significantly more common in men and women with type 2 diabetes, but were not associated with BMD (359). In three large observational studies of older adults, femoral neck BMD T-score and the World Health Organization Fracture Risk Algorithm (FRAX) score were associated with hip and nonspine fracture, although fracture risk was higher in diabetic participants compared with participants without diabetes for a given T-score and age or for a given FRAX score risk (360). It is appropriate to assess fracture history and risk factors in older patients with diabetes and to recommend BMD testing if appropriate for the patient's age and sex. For at-risk patients, it is reasonable to consider standard primary or secondary prevention strategies (reduce risk factors for falls, ensure adequate calcium and vitamin D intake, and avoid use of medications that lower BMD, such as glucocorticoids) and to consider pharmacotherapy for high-risk patients. For patients with type 2 diabetes with fracture risk factors, avoidance of TZDs is warranted. Cognitive impairment Diabetes is associated with significantly increased risk of cognitive decline, a greater rate of cognitive decline, and increased risk of dementia (361,362). In a 15-year prospective study of a community-dwelling people over the age of 60 years, the presence of diabetes at baseline significantly increased the age- and sex-adjusted incidence of all-cause dementia, Alzheimer disease, and vascular dementia compared with rates in those with normal glucose tolerance (363). In a substudy of the ACCORD study, there were no differences in cognitive outcomes between intensive and standard glycemic control, although there was significantly less of a decrement in total brain volume by MRI in participants in the intensive arm (364). The effects of hyperglycemia and insulin on the brain are areas of intense research interest. VIII. DIABETES CARE IN SPECIFIC POPULATIONS A. Children and adolescents 1. Type 1 diabetes. Three-quarters of all cases of type 1 diabetes are diagnosed in individuals 130/80 mmHg, if 95% exceeds that value) should be considered as soon as the diagnosis is confirmed. (E) ACE inhibitors should be considered for the initial treatment of hypertension, following appropriate reproductive counseling due to its potential teratogenic effects. (E) The goal of treatment is a blood pressure consistently 2 years of age soon after diagnosis (after glucose control has been established). If family history is not of concern, then consider the first lipid screening at puberty (≥10 years of age). For children diagnosed with diabetes at or after puberty, consider obtaining a fasting lipid profile soon after diagnosis (after glucose control has been established). (E) For both age-groups, if lipids are abnormal, annual monitoring is reasonable. If LDL cholesterol values are within the accepted risk levels ( 160 mg/dL (4.1 mmol/L), or LDL cholesterol >130 mg/dL (3.4 mmol/L) and one or more CVD risk factors, is reasonable. (E) The goal of therapy is an LDL cholesterol value 1% above the normal range for a nondiabetic pregnant woman. Preconception care of diabetes appears to reduce the risk of congenital malformations. Five nonrandomized studies compared rates of major malformations in infants between women who participated in preconception diabetes care programs and women who initiated intensive diabetes management after they were already pregnant. The preconception care programs were multidisciplinary and designed to train patients in diabetes self-management with diet, intensified insulin therapy, and SMBG. Goals were set to achieve normal blood glucose concentrations, and >80% of subjects achieved normal A1C concentrations before they became pregnant. In all five studies, the incidence of major congenital malformations in women who participated in preconception care (range 1.0–1.7% of infants) was much lower than the incidence in women who did not participate (range 1.4–10.9% of infants) (94). One limitation of these studies is that participation in preconception care was self-selected rather than randomized. Thus, it is impossible to be certain that the lower malformation rates resulted fully from improved diabetes care. Nonetheless, the evidence supports the concept that malformations can be reduced or prevented by careful management of diabetes before pregnancy. Planned pregnancies greatly facilitate preconception diabetes care. Unfortunately, nearly two-thirds of pregnancies in women with diabetes are unplanned, leading to a persistent excess of malformations in infants of diabetic mothers. To minimize the occurrence of these devastating malformations, standard care for all women with diabetes who have child-bearing potential, beginning at the onset of puberty or at diagnosis, should include 1) education about the risk of malformations associated with unplanned pregnancies and poor metabolic control; and 2) use of effective contraception at all times, unless the patient has good metabolic control and is actively trying to conceive. Women contemplating pregnancy need to be seen frequently by a multidisciplinary team experienced in the management of diabetes before and during pregnancy. The goals of preconception care are to 1) involve and empower the patient in the management of her diabetes, 2) achieve the lowest A1C test results possible without excessive hypoglycemia, 3) assure effective contraception until stable and acceptable glycemia is achieved, and 4) identify, evaluate, and treat long-term diabetes complications such as retinopathy, nephropathy, neuropathy, hypertension, and CHD (94). Among the drugs commonly used in the treatment of patients with diabetes, a number may be relatively or absolutely contraindicated during pregnancy. Statins are category X (contraindicated for use in pregnancy) and should be discontinued before conception, as should ACE inhibitors (402). ARBs are category C (risk cannot be ruled out) in the first trimester, but category D (positive evidence of risk) in later pregnancy, and should generally be discontinued before pregnancy. Since many pregnancies are unplanned, health care professionals caring for any woman of childbearing potential should consider the potential risks and benefits of medications that are contraindicated in pregnancy. Women using medications such as statins or ACE inhibitors need ongoing family planning counseling. Among the oral antidiabetic agents, metformin and acarbose are classified as category B (no evidence of risk in humans) and all others as category C. Potential risks and benefits of oral antidiabetic agents in the preconception period must be carefully weighed, recognizing that data are insufficient to establish the safety of these agents in pregnancy. For further discussion of preconception care, see the ADA consensus statement on preexisting diabetes and pregnancy (94) and also the position statement (403) on this subject. C. Older adults Recommendations Older adults who are functional, cognitively intact, and have significant life expectancy should receive diabetes care using goals developed for younger adults. (E) Glycemic goals for older adults not meeting the above criteria may be relaxed using individual criteria, but hyperglycemia leading to symptoms or risk of acute hyperglycemic complications should be avoided in all patients. (E) Other cardiovascular risk factors should be treated in older adults with consideration of the time frame of benefit and the individual patient. Treatment of hypertension is indicated in virtually all older adults, and lipid and aspirin therapy may benefit those with life expectancy at least equal to the time frame of primary or secondary prevention trials. (E) Screening for diabetes complications should be individualized in older adults, but particular attention should be paid to complications that would lead to functional impairment. (E) Diabetes is an important health condition for the aging population; at least 20% of patients over the age of 65 years have diabetes, and this number can be expected to grow rapidly in the coming decades. Older individuals with diabetes have higher rates of premature death, functional disability, and coexisting illnesses such as hypertension, CHD, and stroke than those without diabetes. Older adults with diabetes are also at greater risk than other older adults for several common geriatric syndromes, such as polypharmacy, depression, cognitive impairment, urinary incontinence, injurious falls, and persistent pain. The American Geriatric Society's guidelines for improving the care of the older person with diabetes (404) have influenced the following discussion and recommendations. The care of older adults with diabetes is complicated by their clinical and functional heterogeneity. Some older individuals developed diabetes years earlier and may have significant complications; others who are newly diagnosed may have had years of undiagnosed diabetes with resultant complications or may have few complications from the disease. Some older adults with diabetes are frail and have other underlying chronic conditions, substantial diabetes-related comorbidity, or limited physical or cognitive functioning. Other older individuals with diabetes have little comorbidity and are active. Life expectancies are highly variable for this population, but often longer than clinicians realize. Providers caring for older adults with diabetes must take this heterogeneity into consideration when setting and prioritizing treatment goals. There are few long-term studies in older adults demonstrating the benefits of intensive glycemic, blood pressure, and lipid control. Patients who can be expected to live long enough to reap the benefits of long-term intensive diabetes management and who are active, have good cognitive function, and are willing should be provided with the needed education and skills to do so and be treated using the goals for younger adults with diabetes. For patients with advanced diabetes complications, life-limiting comorbid illness, or substantial cognitive or functional impairment, it is reasonable to set less intensive glycemic target goals. These patients are less likely to benefit from reducing the risk of microvascular complications and more likely to suffer serious adverse effects from hypoglycemia. However, patients with poorly controlled diabetes may be subject to acute complications of diabetes, including dehydration, poor wound healing, and hyperglycemic hyperosmolar coma. Glycemic goals at a minimum should avoid these consequences. Although control of hyperglycemia may be important in older individuals with diabetes, greater reductions in morbidity and mortality may result from control of other cardiovascular risk factors rather than from tight glycemic control alone. There is strong evidence from clinical trials of the value of treating hypertension in the elderly (405,406). There is less evidence for lipid-lowering and aspirin therapy, although the benefits of these interventions for primary and secondary prevention are likely to apply to older adults whose life expectancies equal or exceed the time frames seen in clinical trials. Special care is required in prescribing and monitoring pharmacologic therapy in older adults. Metformin is often contraindicated because of renal insufficiency or significant heart failure. TZDs can cause fluid retention, which may exacerbate or lead to heart failure. They are contraindicated in patients with CHF (New York Heart Association Class III and IV), and if used at all should be used very cautiously in those with, or at risk for, milder degrees of CHF. Sulfonylureas, other insulin secretagogues, and insulin can cause hypoglycemia. Insulin use requires that patients or caregivers have good visual and motor skills and cognitive ability. Drugs should be started at the lowest dose and titrated up gradually until targets are reached or side effects develop. Screening for diabetes complications in older adults also should be individualized. Particular attention should be paid to complications that can develop over short periods of time and/or that would significantly impair functional status, such as visual and lower extremity complications. D. Cystic fibrosis–related diabetes (CFRD) Recommendations Annual screening for CFRD with OGTT should begin by age 10 years in all patients with cystic fibrosis who do not have CFRD (B). Use of A1C as a screening test for CFRD is not recommended. (B) During a period of stable health the diagnosis of CFRD can be made in cystic fibrosis patients according to usual diagnostic criteria. (E) Patients with CFRD should be treated with insulin to attain individualized glycemic goals. (A) Annual monitoring for complications of diabetes is recommended, beginning 5 years after the diagnosis of CFRD. (E) CFRD is the most common comorbidity in persons with cystic fibrosis, occurring in about 20% of adolescents and 40–50% of adults. The additional diagnosis of diabetes in this population is associated with worse nutritional status, more severe inflammatory lung disease, and greater mortality from respiratory failure. Insulin insufficiency related to partial fibrotic destruction of the islet mass is the primary defect in CFRD. Genetically determined function of the remaining β-cells and insulin resistance associated with infection and inflammation may also play a role. Encouraging new data suggest that early detection and aggressive insulin therapy have narrowed the gap in mortality between cystic fibrosis patients with and without diabetes, and have eliminated the difference in mortality between the sexes (407). Recommendations for the clinical management of CFRD can be found in a recent ADA position statement on this topic (408). IX. DIABETES CARE IN SPECIFIC SETTINGS A. Diabetes care in the hospital Recommendations All patients with diabetes admitted to the hospital should have their diabetes clearly identified in the medical record. (E) All patients with diabetes should have an order for blood glucose monitoring, with results available to all members of the health care team. (E) Goals for blood glucose levels: ○ Critically ill patients: Insulin therapy should be initiated for treatment of persistent hyperglycemia starting at a threshold of no greater than 180 mg/dL (10 mmol/L). Once insulin therapy is started, a glucose range of 140–180 mg/dL (7.8 to 10 mmol/L) is recommended for the majority of critically ill patients. (A) ○ More stringent goals, such as 110–140 mg/dL (6.1–7.8 mmol/L) may be appropriate for selected patients, as long as this can be achieved without significant hypoglycemia. (C) ○ Critically ill patients require an intravenous insulin protocol that has demonstrated efficacy and safety in achieving the desired glucose range without increasing risk for severe hypoglycemia. (E) ○ Non–critically ill patients: There is no clear evidence for specific blood glucose goals. If treated with insulin, premeal blood glucose targets generally 140 mg/dL (7.8 mmol/L). Levels that are significantly and persistently above this may require treatment in hospitalized patients. A1C values >6.5% suggest, in undiagnosed patients, that diabetes preceded hospitalization (419). Hypoglycemia has been defined as any blood glucose <70 mg/dL (3.9 mmol/L). This is the standard definition in outpatients and correlates with the initial threshold for the release of counterregulatory hormones. Severe hypoglycemia in hospitalized patients has been defined by many as <40 mg/dL (2.2 mmol/L), although this is lower than the ∼50 mg/dL (2.8 mmol/L) level at which cognitive impairment begins in normal individuals (420). As with hyperglycemia, hypoglycemia among inpatients is also associated with adverse short- and long-term outcomes. Early recognition and treatment of mild-to-moderate hypoglycemia (40–69 mg/dL (2.2–3.8 mmol/L) can prevent deterioration to a more severe episode with potential adverse sequelae (410). Critically ill patients. Based on the weight of the available evidence, for the majority of critically ill patients in the ICU setting, insulin infusion should be used to control hyperglycemia, with a starting threshold of no higher than 180 mg/dL (10.0 mmol/L). Once intravenous insulin is started, the glucose level should be maintained between 140 and 180 mg/dL (7.8–10.0 mmol/L). Greater benefit maybe realized at the lower end of this range. Although strong evidence is lacking, somewhat lower glucose targets may be appropriate in selected patients. However, targets <110 mg/dL (6.1 mmol/L) are not recommended. Use of insulin infusion protocols with demonstrated safety and efficacy, resulting in low rates of hypoglycemia, are highly recommended (410). Noncritically ill patients. With no prospective RCT data to inform specific glycemic targets in noncritically ill patients, recommendations are based on clinical experience and judgment. For the majority of noncritically ill patients treated with insulin, premeal glucose targets should generally be <140 mg/dL (7.8 mmol/L) with random blood glucose <180 mg/dL (10.0 mmol/L), as long as these targets can be safely achieved. To avoid hypoglycemia, consideration should be given to reassessing the insulin regimen if blood glucose levels fall <100 mg/dL (5.6 mmol/L). Modification of the regimen is required when blood glucose values are <70 mg/dL (3.9 mmol/L), unless the event is easily explained by other factors (such as a missed meal). There is some evidence that systematic attention to hyperglycemia in the emergency room leads to better glycemic control in the hospital for those subsequently admitted (421). Occasional patients with a prior history of successful tight glycemic control in the outpatient setting who are clinically stable may be maintained with a glucose range below the above cut points. Conversely, higher glucose ranges may be acceptable in terminally ill patients or in patients with severe comorbidities, as well as in those in patient-care settings where frequent glucose monitoring or close nursing supervision is not feasible. Clinical judgment, combined with ongoing assessment of the patient's clinical status, including changes in the trajectory of glucose measures, the severity of illness, nutritional status, or concurrent use of medications that might affect glucose levels (e.g., steroids, octreotide), must be incorporated into the day-to-day decisions regarding insulin dosing (410). 2. Antihyperglycemic agents in hospitalized patients. In the hospital setting, insulin therapy is the preferred method of glycemic control in majority of clinical situations (410). In the ICU, intravenous infusion is the preferred route of insulin administration. When the patient is transitioned off intravenous insulin to subcutaneous therapy, precautions should be taken to prevent hyperglycemia escape (422,423). Outside of critical care units, scheduled subcutaneous insulin that delivers basal, nutritional, and correction (supplemental) components is preferred. Prolonged therapy with sliding scale insulin (SSI) as the sole regimen is ineffective in the majority of patients, increases risk of both hypoglycemia and hyperglycemia, and has recently been shown in a randomized trial to be associated with adverse outcomes in general surgery patients with type 2 diabetes (424). SSI is potentially dangerous in type 1 diabetes (410). The reader is referred to several recent publications and reviews that describe currently available insulin preparations and protocols and provide guidance in use of insulin therapy in specific clinical settings including parenteral nutrition (425) and enteral tube feedings and with high-dose glucocorticoid therapy (410). There are no data on the safety and efficacy of oral agents and injectable noninsulin therapies such as GLP1 analogs and pramlintide in the hospital. They are generally considered to have a limited role in the management of hyperglycemia in conjunction with acute illness. Continuation of these agents may be appropriate in selected stable patients who are expected to consume meals at regular intervals, and they may be initiated or resumed in anticipation of discharge once the patient is clinically stable. Specific caution is required with metformin due to the possibility that a contraindication may develop during the hospitalization, such as renal insufficiency, unstable hemodynamic status, or need for an imaging study that requires a radio-contrast dye. 3. Preventing hypoglycemia. In the hospital, multiple risk factors for hypoglycemia are present. Patients with or without diabetes may experience hypoglycemia in the hospital in association with altered nutritional state, heart failure, renal or liver disease, malignancy, infection, or sepsis. Additional triggering events leading to iatrogenic hypoglycemia include sudden reduction of corticosteroid dose, altered ability of the patient to report symptoms, reduction of oral intake, emesis, new n.p.o. status, inappropriate timing of short- or rapid-acting insulin in relation to meals, reduction of rate of administration of intravenous dextrose, and unexpected interruption of enteral feedings or parenteral nutrition. Despite the preventable nature of many inpatient episodes of hypoglycemia, institutions are more likely to have nursing protocols for the treatment of hypoglycemia than for its prevention. Tracking such episodes and analyzing their causes are important quality improvement activities (410). 4. Diabetes care providers in the hospital. Inpatient diabetes management may be effectively championed and/or provided by primary care physicians, endocrinologists, intensivists or hospitalists. Involvement of appropriately trained specialists or specialty teams may reduce length of stay, improve glycemic control, and improve outcomes (410). In the care of diabetes, implementation of standardized order sets for scheduled and correction-dose insulin may reduce reliance on sliding-scale management. As hospitals move to comply with “meaningful use” regulations for electronic health records, as mandated by the Health Information Technology Act, efforts should be made to assure that all components of structured insulin order sets are incorporated into electronic insulin order sets (426,427). A team approach is needed to establish hospital pathways. To achieve glycemic targets associated with improved hospital outcomes, hospitals will need multidisciplinary support to develop insulin management protocols that effectively and safely enable achievement of glycemic targets (428). 5. Self-management in the hospital. Self-management of diabetes in the hospital may be appropriate for competent adult patients who have a stable level of consciousness, have reasonably stable daily insulin requirements, successfully conduct self-management of diabetes at home, have physical skills needed to successfully self-administer insulin and perform SMBG, have adequate oral intake, are proficient in carbohydrate counting, use multiple daily insulin injections or insulin pump therapy, and employ sick-day management. The patient and physician, in consultation with nursing staff, must agree that patient self-management is appropriate under the conditions of hospitalization. Patients who use CSII pump therapy in the outpatient setting can be candidates for diabetes self-management in the hospital, provided that they have the mental and physical capacity to do so (410). A hospital policy and procedures delineating inpatient guidelines for CSII therapy are advisable, and availability of hospital personnel with expertise in CSII therapy is essential. It is important that nursing personnel document basal rates and bolus doses taken on a regular basis (at least daily). 6. MNT in the hospital. The goals of MNT are to optimize glycemic control, provide adequate calories to meet metabolic demands, and create a discharge plan for follow-up care (409,429). ADA does not endorse any single meal plan or specified percentages of macronutrients, and the term “ADA diet” should no longer be used. Current nutrition recommendations advise individualization based on treatment goals, physiologic parameters, and medication usage. Consistent carbohydrate meal plans are preferred by many hospitals because they facilitate matching the prandial insulin dose to the amount of carbohydrate consumed (430). Because of the complexity of nutrition issues in the hospital, a registered dietitian, knowledgeable and skilled in MNT, should serve as an inpatient team member. The dietitian is responsible for integrating information about the patient's clinical condition, eating, and lifestyle habits and for establishing treatment goals in order to determine a realistic plan for nutrition therapy (431,432). 7. Bedside blood glucose monitoring. Point-of-care (POC) blood glucose monitoring performed at the bedside is used to guide insulin dosing. In the patient who is receiving nutrition, the timing of glucose monitoring should match carbohydrate exposure. In the patient who is not receiving nutrition, glucose monitoring is performed every 4 to 6 h (433,434). More-frequent blood glucose testing ranging from every 30 min to every 2 h is required for patients on intravenous insulin infusions. Safety standards should be established for blood glucose monitoring prohibiting sharing of fingerstick lancing devices, lancets, needles, and meters to reduce the risk of transmission of blood borne diseases. Shared lancing devices carry essentially the same risk as is conferred from sharing of syringes and needles (435). Accuracy of blood glucose measurements using POC meters has limitations that must be considered. Although the FDA allows a +/− 20% error for blood glucose meters, questions about the appropriateness of these criteria have been raised (388). Glucose measures differ significantly between plasma and whole blood, terms that are often used interchangeably and can lead to misinterpretation. Most commercially available capillary blood glucose meters introduce a correction factor of ∼1.12 to report a “plasma adjusted” value (436). Significant discrepancies between capillary, venous, and arterial plasma samples have been observed in patients with low or high hemoglobin concentrations, hypoperfusion, and the presence of interfering substances, particularly maltose, as contained in immunoglobulins (437). Analytical variability has been described with several POC meters (438). Increasingly newer generation POC blood glucose meters correct for variation in hematocrit and for interfering substances. Any glucose result that does not correlate with the patient's status should be confirmed through conventional laboratory sampling of plasma glucose. The FDA has become increasingly concerned about the use of POC blood glucose meters in the hospital and is presently reviewing matters related to their use. 8. Discharge planning and DSME. Transition from the acute care setting is a high risk time for all patients, not just those with diabetes or new hyperglycemia. Although there is an extensive literature concerning safe transition within and from the hospital, little of it is specific to diabetes (439). It is important to remember that diabetes discharge planning is not a separate entity, but is part of an overall discharge plan. As such, discharge planning begins at admission to the hospital and is updated as projected patient needs change. Inpatients may be discharged to varied settings, including home (with or without visiting nurse services), assisted living, rehabilitation, or skilled nursing facilities. The latter two sites are generally staffed by health professionals, so diabetes discharge planning will be limited to communication of medication and diet orders. For the patient who is discharged to assisted living or to home, the optimal program will need to consider the type and severity of diabetes, the effects of the patient's illness on blood glucose levels, and the capacities and desires of the patient. Smooth transition to outpatient care should be ensured. The Agency for Healthcare Research and Quality recommends that at a minimum, discharge plans include: Medication reconciliation: The patient's medications must be cross-checked to ensure that no chronic medications were stopped and to ensure the safety of new prescriptions. Whenever possible, prescriptions for new or changed medication should be filled and reviewed with the patient and family at or before discharge. Structured discharge communication: Information on medication changes, pending tests and studies, and follow-up needs must be accurately and promptly communicated to outpatient physicians. Discharge summaries should be transmitted to the primary physician as soon as possible after discharge. Appointment-keeping behavior is enhanced when the inpatient team schedules outpatient medical follow up prior to discharge. Ideally the inpatient care providers or case managers/discharge planners will schedule follow-up visit(s) with the appropriate professionals, including the primary care provider, endocrinologist, and diabetes educator (99). Teaching diabetes self-management to patients in hospitals is a challenging task. Patients are ill, under increased stress related to their hospitalization and diagnosis, and in an environment not conducive to learning. Ideally, people with diabetes should be taught at a time and place conducive to learning—as an outpatient in a recognized program of diabetes education. For the hospitalized patient, diabetes “survival skills” education is generally a feasible approach to provide sufficient information and training to enable safe care at home. Patients hospitalized because of a crisis related to diabetes management or poor care at home need education to prevent subsequent episodes of hospitalization. An assessment of the need for a home health referral or referral to an outpatient diabetes education program should be part of discharge planning for all patients. DSME cannot wait until discharge, especially in those new to insulin therapy or in whom the diabetes regimen has been substantially altered during the hospitalization. It is recommended that the following areas of knowledge be reviewed and addressed prior to hospital discharge: Identification of health care provider who will provide diabetes care after discharge Level of understanding related to the diagnosis of diabetes, SMBG, and explanation of home blood glucose goals Definition, recognition, treatment, and prevention of hyperglycemia and hypoglycemia Information on consistent eating patterns When and how to take blood glucose–lowering medications including insulin administration (if going home on insulin) Sick-day management Proper use and disposal of needles and syringes It is important that patients be provided with appropriate durable medical equipment, medication, supplies, and prescriptions at the time of discharge in order to avoid a potentially dangerous hiatus in care. These supplies/prescriptions should include: Insulin (vials or pens) if needed Syringes or pen needles (if needed) Oral medications (if needed) Blood glucose meter and strips Lancets and lancing device Urine ketone strips (type 1) Glucagon emergency kit (insulin-treated) Medical alert application/charm More expanded diabetes education can be arranged in the community. An outpatient follow-up visit with the primary care provider, endocrinologist, or diabetes educator within 1 month of discharge is advised for all patients having hyperglycemia in the hospital. Clear communication with outpatient providers either directly or via hospital discharge summaries facilitates safe transitions to outpatient care. Providing information regarding the cause or the plan for determining the cause of hyperglycemia, related complications and comorbidities, and recommended treatments can assist outpatient providers as they assume ongoing care. B. Diabetes and employment Any person with diabetes, whether insulin-treated or noninsulin treated, should be eligible for any employment for which he/she is otherwise qualified. Employment decisions should never be based on generalizations or stereotypes regarding the effects of diabetes. When questions arise about the medical fitness of a person with diabetes for a particular job, a health care professional with expertise in treating diabetes should perform an individualized assessment. See the ADA position statement on diabetes and employment (440). C. Diabetes and driving A large percentage of people with diabetes in the U.S. and elsewhere seek a license to drive, either for personal or employment purposes. There has been considerable debate whether, and the extent to which, diabetes may be a relevant factor in determining the driver ability and eligibility for a license. People with diabetes are subject to a great variety of licensing requirements applied by both state and federal jurisdictions, which may lead to loss of employment or significant restrictions on a person's license. Presence of a medical condition that can lead to significantly impaired consciousness or cognition may lead to drivers being evaluated for fitness to drive. For diabetes, this typically arises when the person has had a hypoglycemic episode behind the wheel, even if this did not lead to a motor vehicle accident. Epidemiologic and simulator data suggest that people with insulin-treated diabetes have a small increase in risk of motor vehicle accidents, primarily due to hypoglycemia and decreased awareness of hypoglycemia. This increase (RR 1.12–1.19) is much smaller than the risks associated with teenage male drivers (RR 42), driving at night (RR 142), driving on rural roads compared with urban roads (RR 9.2), and obstructive sleep apnea (RR 2.4), all of which are accepted for unrestricted licensure. The ADA position statement on diabetes and driving (441) recommends against blanket restrictions based on the diagnosis of diabetes and urges individual assessment by a health care professional knowledgeable in diabetes if restrictions on licensure are being considered. Patients should be evaluated for decreased awareness of hypoglycemia, hypoglycemia episodes while driving, or severe hypoglycemia. Patients with retinopathy or peripheral neuropathy require assessment to determine if those complications interfere with operation of a motor vehicle. Health care professionals should be cognizant of the potential risk of driving with diabetes and counsel their patients about detecting and avoiding hypoglycemia while driving. D. Diabetes management in correctional institutions People with diabetes in correctional facilities should receive care that meets national standards. Because it is estimated that nearly 80,000 inmates have diabetes, correctional institutions should have written policies and procedures for the management of diabetes and for training of medical and correctional staff in diabetes care practices. See the ADA position statement on diabetes management in correctional institutions (442) for further discussion. X. STRATEGIES FOR IMPROVING DIABETES CARE Recommendations Care should be aligned with components of the Chronic Care Model to ensure productive interactions between a prepared proactive practice team and an informed activated patient. (A) When feasible, care systems should support team-based care, community involvement, patient registries, and embedded decision support tools to meet patient needs (B). Treatment decisions should be timely and based on evidence-based guidelines that are tailored to individual patient preferences, prognoses, and comorbidities. (B) A patient-centered communication style should be employed that incorporates patient preferences, assesses literacy and numeracy, and addresses cultural barriers to care. (B) There has been steady improvement in the proportion of diabetes patients achieving recommended levels of A1C, blood pressure, and LDL cholesterol in the last 10 years, both in primary care settings and in endocrinology practices. Mean A1C nationally has declined from 7.82% in 1999–2000 to 7.18% in 2004 based on NHANES data (443). This has been accompanied by improvements in lipids and blood pressure control and has led to substantial reductions in end-stage microvascular complications in those with diabetes. Nevertheless in some studies only 57.1% of adults with diagnosed diabetes achieved an A1C <7%, only 45.5% had a blood pressure <130/80 mmHg, and only 46.5% had a total cholesterol <200 mg/dL, with only 12.2% of people with diabetes achieving all three treatment goals (444). Evidence also suggests that progress in risk factor control may be slowing (445). Certain patient groups, such as those with complex comorbidities, financial or other social hardships, and/or limited English proficiency (LEP), may present particular challenges to goal-based care (446,447). Persistent variation in quality of diabetes care across providers and across practice settings even after adjusting for patient factors indicates that there remains potential for substantial further improvements in diabetes care. While numerous interventions to improve adherence to the recommended standards have been implemented, a major barrier to optimal care is a delivery system that too often is fragmented, lacks clinical information capabilities, often duplicates services, and is poorly designed for the coordinated delivery of chronic care. The Chronic Care Model (CCM) has been shown in numerous studies to be an effective framework for improving the quality of diabetes care (448). The CCM includes six core elements for the provision of optimal care of patients with chronic disease: 1) delivery system design (moving from a reactive to a proactive care delivery system where planned visits are coordinated through a team based approach), 2) self-management support, 3) decision support (basing care on evidence-based, effective care guidelines), 4) clinical information systems (using registries that can provide patient-specific and population-based support to the care team), 5) community resources and policies (identifying or developing resources to support healthy lifestyles), and 6) health systems (to create a quality-oriented culture). Redefinition of the roles of the clinic staff and promoting self-management on the part of the patient are fundamental to the successful implementation of the CCM (449). Collaborative, multidisciplinary teams are best suited to provide such care for people with chronic conditions like diabetes and to facilitate patients’ performance of appropriate self-management (148,150,450,451). NDEP maintains an online resource (www.betterdiabetescare.nih.gov) to help health care professionals design and implement more effective health care delivery systems for those with diabetes. Three specific objectives, with references to literature that outline practical strategies to achieve each, are below. Objective 1: Optimize provider and team behavior The care team should prioritize timely and appropriate intensification of lifestyle and/or pharmaceutical therapy of patients who have not achieved beneficial levels of blood pressure, lipid, or glucose control (452). Strategies such as explicit goal setting with patients (453); identifying and addressing language, numeracy, or cultural barriers to care (454–456); integrating evidence-based guidelines and clinical information tools into the process of care (457–459); and incorporating care management teams including nurses, pharmacists, and other providers (460–463) have each been shown to optimize provider and team behavior and thereby catalyze reduction in A1C, blood pressure, and LDL cholesterol. Objective 2: Support patient behavior change Successful diabetes care requires a systematic approach to supporting patients’ behavior change efforts, including (a) healthy lifestyle changes (physical activity, healthy eating, nonuse of tobacco, weight management, effective coping), (b) disease self-management (medication taking and management, self-monitoring of glucose and blood pressure when clinically appropriate); and (c) prevention of diabetes complications (self-monitoring of foot health, active participation in screening for eye, foot, and renal complications, and immunizations). High-quality DSME has been shown to improve patient self-management, satisfaction, and glucose control (166,464), as has delivery of on-going diabetes self-management support (DSMS) so that gains achieved during DSME are sustained (120,121,137). National DSME standards call for an integrated approach that includes clinical content and skills and behavioral strategies (goal-setting, problem solving) and addresses emotional concerns in each needed curriculum content area. Objective 3: Change the system of care The most successful practices have an institutional priority for providing high quality of care (465). Changes that have been shown to increase quality of diabetes care include basing care on evidence-based guidelines (466), expanding the role of teams and staff (449,467), redesigning the processes of care (468,469), implementing electronic health record tools (470,471), activating and educating patients (472,473), and identifying and/or developing and engaging community resources and public policy that support healthy lifestyles (474). Recent initiatives such as the Patient Centered Medical Home show promise to improve outcomes through coordinated primary care and offer new opportunities for team-based chronic disease care (475). Alterations in reimbursement that reward the provision of appropriate and high quality care rather than visit-based billing (476), and that can accommodate the need to personalize care goals, may provide additional incentives to improve diabetes care (477). It is clear that optimal diabetes management requires an organized, systematic approach and involvement of a coordinated team of dedicated health care professionals working in an environment where patient-centered high quality care is a priority.
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            Projection of the year 2050 burden of diabetes in the US adult population: dynamic modeling of incidence, mortality, and prediabetes prevalence

            Background People with diabetes can suffer from diverse complications that seriously erode quality of life. Diabetes, costing the United States more than $174 billion per year in 2007, is expected to take an increasingly large financial toll in subsequent years. Accurate projections of diabetes burden are essential to policymakers planning for future health care needs and costs. Methods Using data on prediabetes and diabetes prevalence in the United States, forecasted incidence, and current US Census projections of mortality and migration, the authors constructed a series of dynamic models employing systems of difference equations to project the future burden of diabetes among US adults. A three-state model partitions the US population into no diabetes, undiagnosed diabetes, and diagnosed diabetes. A four-state model divides the state of "no diabetes" into high-risk (prediabetes) and low-risk (normal glucose) states. A five-state model incorporates an intervention designed to prevent or delay diabetes in adults at high risk. Results The authors project that annual diagnosed diabetes incidence (new cases) will increase from about 8 cases per 1,000 in 2008 to about 15 in 2050. Assuming low incidence and relatively high diabetes mortality, total diabetes prevalence (diagnosed and undiagnosed cases) is projected to increase from 14% in 2010 to 21% of the US adult population by 2050. However, if recent increases in diabetes incidence continue and diabetes mortality is relatively low, prevalence will increase to 33% by 2050. A middle-ground scenario projects a prevalence of 25% to 28% by 2050. Intervention can reduce, but not eliminate, increases in diabetes prevalence. Conclusions These projected increases are largely attributable to the aging of the US population, increasing numbers of members of higher-risk minority groups in the population, and people with diabetes living longer. Effective strategies will need to be undertaken to moderate the impact of these factors on national diabetes burden. Our analysis suggests that widespread implementation of reasonably effective preventive interventions focused on high-risk subgroups of the population can considerably reduce, but not eliminate, future increases in diabetes prevalence.
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              American Association of Clinical Endocrinologists and American Diabetes Association Consensus Statement on Inpatient Glycemic Control

              People with diabetes are more likely to be hospitalized and to have longer durations of hospital stay than those without diabetes. A recent survey estimated that 22% of all hospital inpatient days were incurred by people with diabetes and that hospital inpatient care accounted for half of the 174 billion USD total U.S. medical expenditures for this disease (1). These findings are due, in part, to the continued expansion of the worldwide epidemic of type 2 diabetes. In the U.S. alone, there are ∼1.6 million new cases of diabetes each year, with an over all prevalence of 23.6 million people (7.8% of the population, with one-fourth of the cases remaining undiagnosed). An additional 57 million American adults are at high risk for type 2 diabetes (2). Although the costs of illness-related stress hyperglycemia are not known, they are likely to be considerable in light of the poor prognosis of such patients (3 –6). There is substantial observational evidence linking hyperglycemia in hospitalized patients (with or without diabetes) to poor outcomes. Cohort studies as well as a few early randomized controlled trials (RCTs) have suggested that intensive treatment of hyperglycemia improved hospital outcomes (5 –8). In 2004, this evidence led the American College of Endocrinology (ACE) and the American Association of Clinical Endocrinologists (AACE), in collaboration with the American Diabetes Association (ADA) and other medical organizations, to develop recommendations for treatment of inpatient hyperglycemia (9). In 2005, the ADA added recommendations for treatment of hyperglycemia in the hospitalto itsannual Standards of Medical Care (10). Recommendations from the ACE and the ADA generally endorsed tight glycemic control in critical care units. For patients in general medical and surgical units, where RCT evidence regarding treatment targets was lacking, glycemic goals similar to those advised for outpatients were advocated (9,10). In 2006, the ACE and the ADA partnered on a joint “call to action” for inpatient glycemic control, addressing a number of systematic implementation barriers in hospitals (11). These efforts contributed to a growing national movement viewing the management of inpatient hyperglycemia as a quality-of-care measure. Although hyperglycemia is associated with adverse patient outcomes, intervention to normalize glycemia has yielded inconsistent results. Indeed, recent trials in critically ill patients have failed to showa significant improvement in mortality with intensive glycemic control (12,13) or have even shown increased mortality risk (14). Moreover, these recent RCTs have highlighted the risk of severe hypoglycemia resulting from such efforts (12 –17). These outcomes have contributed to confusion regarding specific glycemic targets and the means for achieving them in both critically ill and noncritically ill patients. Recognizing the importance of glycemic control across the continuum of care, the AACE and the ADA joined forces to develop this updated consensus statement on inpatient glycemic management. The central goals were to identify reasonable, achievable, and safe glycemic targets and to describe the protocols, procedures, and system improvements needed to facilitate their implementation. This document is addressed to health care professionals, supporting staff, hospital administrators, and other stakeholders focused on improved management of hyperglycemia in inpatient settings. Consensus panel members extensively reviewed the most current literature and considered the following questions: Does improving glycemic control improve clinical outcomes for inpatients with hyperglycemia? What glycemic targets can be recommended in different patient populations? What treatment options are available for achieving optimal glycemic targets safely and effectively in specific clinical situations? Does inpatient management of hyperglycemia represent a safety concern? What systems need to be in place to achieve these recommendations? Is treatment of inpatient hyperglycemia cost-effective? What are the optimal strategies for transition to outpatient care? What are areas for future research? QUESTION 1: DOES IMPROVING GLYCEMIC CONTROL IMPROVE CLINICAL OUTCOMES FOR INPATIENTS WITH HYPERGLYCEMIA? Hyperglycemia in hospitalized patients, irrespective of its cause, is unequivocally associated with adverse outcomes (5,6,18 –25). Hyperglycemia occurs in patients with known or undiagnosed diabetes, or it occurs during acute illness in those with previously normal glucose tolerance (termed “stress hyperglycemia”) (8,26). Intervention directed at reducing blood glucose (BG) levels has resulted in improved outcomes in some, but not all, studies (5,18 –25). Several recent clinical trials in critically ill patients have reported no reduction in mortality from intensive treatment targeting near-euglycemia versus conventional management targeting BG 200 randomized patients) a Trial N Setting Blood glucose target [mg/dl (mmol/l)] Blood glucose achieved [mg/dl (mmol/l)] b Primary outcome End point rate (%) ARR (%) c RRR (%) c Odds ratio (95% CI) Intensive Conventional Intensive Conventional Intensive Conventional DIGAMI (ref. 33), 1995 620 CCU (AMI) 126–196 (7–10.9) Usual care 173 (9.6) 211 (11.7) 1-year mortality 18.6 26.1 7.5 29 d NR Van den Berghe et al. (ref. 5), 2001 1,548 SICU 80–110 (4.4–6.1) 180–200 (10–11) 103 (5.7) 153 (8.5) ICU mortality 4.6 8.0 3.4 42 0.58(0.38–0.78) d DIGAMI 2 (ref. 34), 2005 1,253 CCU (AMI) 126–180 (7–10) (groups 1 and 2) Usual care (group 3) 164 (9.1) 180 (10) 2-year mortality Group 1, 23.4; group 2, 21.2 Group 3, 17.9 — e — e NR Van den Berghe et al. (ref. 16), 2006 1,200 MICU 80–110 (4.4–6.1) 180–200 (10–11) 111 (6.2) 153 (8.5) Hospital mortality 37.3 40.0 2.7 7.0 0.94(0.84–1.06) e HI-5 (ref. 35), 2006 240 CCU (Ami) (GIK) 72–180 (4–10) Usual care 0.05). fPresented as abstract only. gComposite of death, sternal infection, prolonged ventilation, cardiac arrhythmias, stroke, and renal failure at 30 days. hOnly patients with sepsis. iPersonal communication, Dr. Frank Brunkhorst. The Efficacy of Volume Substitution and Insulin Therapy in Severe Sepsis (VISEP) study reported no decrease in mortality and higher rates of severe hypoglycemia with intensive insulin therapy in patients with severe sepsis (17 vs. 4.1%; P 95%) required mechanical ventilation (14). The 90-day mortality was significantly higher in the intensively treated versus the conventionally treated group (78 more deaths; 27.5 vs. 24.9%; P = 0.02) in both surgical and medical patients. Mortality from cardiovascular causes was more common in the intensively treated group (76 more deaths; 41.6 vs. 35.8%; P = 0.02). Severe hypoglycemia was also more common in the intensively treated group (6.8 vs. 0.5%; P 200 mg/dl [11.1 mmol/l]) were found to have a 2.2-fold higher rate of mortality than those with admission glucose of 140 mg/dl (>7.8 mmol/l). Levels that are significantly and persistently above this level may necessitate treatment in hospitalized patients. In patients without a previous diagnosis of diabetes, elevated BG concentrations may be due to stress hyperglycemia, a condition that can be established by a review of prior medical records or measurement of A1C. A1C values of >6.5–7.0% suggest that diabetes preceded hospitalization (87). Hypoglycemia is defined as any BG level <70 mg/dl (<3.9 mmol/l) (88). This is the standard definition in outpatients and correlates with the initial threshold for the release of counterregulatory hormones (89). Severe hypoglycemia in hospitalized patients has been defined by many clinicians as <40 mg/dl (<2.2 mmol/l), although this value is lower than the approximate 50 mg/dl (2.8 mmol/l) level at which cognitive impairment begins in normal individuals (89 –91). As with hyperglycemia, hypoglycemia among inpatients is also associated with adverse short-term and long-term outcomes. Early recognition and treatment of mild to moderate hypoglycemia (40 and 69 mg/dl [2.2 and 3.8 mmol/l], respectively) can prevent deterioration to a more severe episode with potential adverse sequelae (91,92). Treatment of hyperglycemia in critically ill patients On the basis of the available evidence, insulin infusion should be used to control hyperglycemia in the majority of critically ill patients in the ICU setting, with a starting threshold of no higher than 180 mg/dl (10.0 mmol/l). Once IV insulin therapy has been initiated, the glucose level should be maintained between 140 and 180 mg/dl (7.8 and 10.0 mmol/l). Greater benefit may be realized at the lower end of this range. Although strong evidence is lacking, somewhat lower glucose targets may be appropriate in selected patients. Targets <110 mg/dl (6.1 mmol/l), however, are not recommended. Use of insulin infusion protocols with demonstrated safety and efficacy, resulting in low rates of occurrence of hypoglycemia, is highly recommended. Treatment of hyperglycemia in noncritically ill patients With no prospective, RCT data for establishing specific guidelines in noncritically ill patients, our recommendations are based on clinical experience and judgment. For the majority of noncritically ill patients treated with insulin, premeal glucose targets should generally be <140 mg/dl (<7.8 mmol/l) in conjunctionwith random BG values <180 mg/dl (<10.0 mmol/l), as long as these targets can be safely achieved. For avoidance of hypoglycemia, consideration should be given to reassessing the insulin regimen if BG levels decline below 100 mg/dl (5.6 mmol/l). Modification of the regimen is necessary when BG values are <70 mg/dl (<3.9 mmol/l), unless the event is easily explained by other factors (such as a missed meal). Occasional clinically stable patients with a prior history of successful tight glycemic control in the outpatient setting may be maintained with a glucose range below the aforementioned cut points. In contrast, higher glucose ranges may be acceptable in terminally ill patients or in patients with severe comorbidities, as well as in those in patient-care settings where frequent glucose monitoring or close nursing supervision is not feasible. We emphasize that clinical judgment in combination with ongoing assessment of the patient's clinical status, including changes in the trajectory of glucose measures, the severity of illness, the nutritional status, or the concurrent use of medications that might affect glucose levels (for example, corticosteroids or octreotide), must be incorporated into the day-to-day decisions regarding insulin dosing (93,94). Inpatient glucose metrics Hospitals attempting to improve the quality of their glycemic control and clinical investigators who analyze glycemic management require standardized glucose measures for assessment of baseline performance and the effect of any intervention (11). Several methods have been proposed for determining the adequacyof glycemic control across a hospital or unit. A recent study indicated that a simple measure of mean BG (39) provides information similar to that from more complex metrics (hyperglycemic index, time-averaged glucose) (14,48). The “patient-day” unit of measure is anotherproposedmetric of hospital glucose data, especially when there is substantial variability in the duration of hospital stay (95). The patient-day metric may yield a more accurate assessment of the frequency of hypoglycemia and severe hyperglycemic events, providing an approach for obtaining measures of performance for clinical investigation (95). The absolute definition of high-quality BG control has not been determined. Of course, one should aim for the highest percentage of patients within a prespecified BG target range. The opposite holds true for hypoglycemia. What is reasonable for a hospital to achieve and with what consistency have not been studied, and information regarding best practices in this area is needed. QUESTION 3: WHAT TREATMENT OPTIONS ARE AVAILABLE FOR ACHIEVING OPTIMAL GLYCEMIC TARGETS SAFELY AND EFFECTIVELY IN SPECIFIC CLINICAL SITUATIONS? In the hospital setting, insulin therapy is the preferred method for achieving glycemic control in most clinical situations (8). In the ICU, IV infusion is the preferred route of insulin administration. Outside of critical care units, subcutaneous administration of insulinis usedmuch more frequently. Orally administered agents have a limited role in the inpatient setting. IV insulin infusions In the critical care setting, continuous IV insulin infusion has been shown to be the most effective method for achieving specific glycemic targets (8). Because of the very short half-life of circulating insulin, IV delivery allows rapid dosing adjustments to address alterations in the status of patients. IV insulin therapy is ideally administered by means of validated written or computerized protocols that allow for predefined adjustments in the insulin infusion rate based on glycemic fluctuations and insulin dose. An extensive review of the merits and deficiencies of published protocols is beyond the intent of this statement, and readers are referred to several available reports and reviews (96 –101). Continued education of staff in conjunction with periodic ongoing review of patient data is critical for successful implementation of any insulin protocol (97 –101). Patients who receive IV insulin infusions will usually require transition to subcutaneously administered insulin when they begin eating regular meals or are transferred to lower-intensity care. Typically, a percentage (usually 75–80%) of the total daily IV infusion dose isproportionately divided into basal and prandial components (see subsequent material). Importantly, subcutaneously administered insulin must be given 1–4 h before discontinuation of IV insulin therapy in order to prevent hyperglycemia (102). Despite these recommendations, a safe and effective transition regimen has not been substantiated. Subcutaneously administered insulin Scheduled subcutaneous administration of insulin is the preferred method for achieving and maintaining glucose control in non-ICU patients with diabetes or stress hyperglycemia. The recommended components of inpatient subcutaneous insulin regimens are a basal, a nutritional, and a supplemental (correction) element (8,103). Each component can be met by one of several available insulin products, depending on the particular hospital situation. Readers are referred to severalrecentpublications and reviews that describe currently available insulin preparations and protocols (101 –106). A topic that deserves particular attention is the persistent overuse of what has been branded as sliding scale insulin (SSI) for management of hyperglycemia. The term “correction insulin,” which refers to the use of additional short- or rapid-acting insulin in conjunction with scheduled insulin doses to treat BG levels above desired targets, is preferred (8). Prolonged therapy with SSI as the sole regimen is ineffective in the majority of patients (and potentially dangerous in those with type 1 diabetes) (106 –112). Noninsulin agents Noninsulin agents are inappropriate in most hospitalized patients. Continued use of such agents may be appropriate in selected stable patients who are expected to consume meals at regular intervals. Caution must be exercised with use of metformin because of the potential development of a contraindication during the hospitalization, such as renal insufficiency, unstable hemodynamic status, or need for imaging studies with radiocontrast dye (8,113). Injectable noninsulin therapies such as exenatide and pramlintide have limitations similar to those with orally administered agents in the hospital setting. Specific clinical situations Patients using an insulin pump. Patients who use continuous subcutaneous insulin infusion (pump) therapy in the outpatient setting can be candidates for diabetes self-management in the hospital, provided they have the mental and physical capacity to do so (8,103,114,115). Of importance, nursing personnel must document basal rates and bolus doses on a regular basis (at least daily). The availability of hospital personnel with expertise in continuous subcutaneous insulin infusion therapy is essential (115). Patients receiving enteral nutrition. Hyperglycemia is a common side effect of inpatient enteral nutrition therapy (116,117). A recent study, in which a combination of basal insulin and correction insulin was used, achieved a mean glucose value of 160 mg/dl (8.9 mmol/l). Similar results were achieved in the group randomized to receive SSI only; however, 48% of patients required the addition of intermediate-acting insulin to achieve glycemic targets (109). Patients receiving parenteral nutrition. The high glucose load in standard parenteral nutrition frequently results in hyperglycemia, which is associated with a higher incidence of complications and mortality in critically ill patients in the ICU (118). Insulin therapy is highly recommended, with glucose targets as defined previously on the basis of the severity of illness. Patients receiving glucocorticoid therapy. Hyperglycemia is a common complication of corticosteroid therapy (93). Several approaches have been proposed for treatment of this condition, but no published protocols or studies have investigated the efficacy of these approaches. A reasonable approach is to institute glucose monitoring for at least 48 h in all patients receiving high-dose glucocorticoid therapy and to initiate insulin therapy as appropriate (94). In patients who are already being treated for hyperglycemia, early adjustment of insulin doses is recommended (119). Importantly, during corticosteroid tapers, insulin dosing should be proactively adjusted to avoid hypoglycemia. QUESTION 4: DOES INPATIENT MANAGEMENT OF HYPERGLYCEMIA REPRESENT A SAFETY CONCERN? Overtreatment and undertreatment of hyperglycemia represent major safety issues in hospitalized patients with and without diabetes (90,120,121). Fear of hypoglycemia, clinical inertia, and medical errors are major barriers to achieving optimal blood glucose control (90,122 –131). In most clinical situations, safe and reasonable glycemic control can be achieved with appropriate use of insulin, adjusted according to results of bedside glucose monitoring (102,106,109). Clinical situations that increase the risk for hypoglycemia and hyperglycemia in the hospital include the following: Changes in caloric or carbohydrate intake (“nothing by mouth” status, enteral nutrition, or parenteral nutrition) (94,128) Change in clinical status or medications (for example, corticosteroids or vasopressors) (93,98) Failure of the clinician to make adjustments to glycemic therapy based on daily BG patterns (102,128) Prolonged use of SSI as monotherapy (107,108) Poor coordination of BG testing and administration of insulin with meals (121,129) Poor communication during times of patient transfer to different care teams (120,121) Use of long-acting sulfonylureas in elderly patients and those with kidney or liver insufficiency Errors in order writing and transcription (102,120) Hypoglycemia is a major safety concern with use of insulin and insulin secretagogues. Hypoglycemia can occur spontaneously in patients with sepsis (130) orin patients who receive certain medications, including quinolone antibiotics and β-adrenergic agonists. Although not all hypoglycemic episodes are avoidable, the use of nurse-driven hypoglycemia treatment protocols that prompt early therapy for any BG levels <70 mg/dl (<3.9 mmol/l) can prevent deterioration of potentially mild events—for example, BG values of 60–69 mg/dl (3.3–3.8 mmol/l)—to more severe events—for example, BG concentrations <40 mg/dl (<2.2 mmol/l) (88,90 –92,98,131). Particular attention is required in high-risk patients, including those with malnutrition; advanced age; a history of severehypoglycemia (88,132); or autonomic, kidney, liver, or cardiac failure. Clinical inertia can be defined as not adjusting glycemic therapy in response to persistently abnormal results on BG determination (123). Often, there is a lack of ownership for diabetes management, particularly in hospitalized patients admitted with a primary diagnosis other than diabetes (128). This inaction may be due in part to insufficient knowledge or confidence in diabetes management (123,133). Improvements in care can be achieved by ongoing education and training (134,135). Insulin errors Insulin has consistently been designated as a high-alert medication because of the risk of harm that can accompany errorsin prescribing, transcribing, or dosing (136). The true frequency of such errors is unknown because the available data sources depend on voluntary reporting of errors (102,137) and mechanisms forreal-time root-cause analysis are not available in most hospitals. BG monitoring Bedside BG monitoring with use of point-of-care (POC) glucose meters is performed before meals and at bedtime in most inpatients who are eating usual meals. It is important to avoid routineuse ofcorrection insulin at bedtime. In patients who are receiving continuousenteralor parenteral nutrition, glucose monitoring is optimally performed every 4–6 h. In patients who are receiving cycled enteral nutrition or parenteral nutrition, the schedule for glucose monitoring can be individualized but should be frequent enough to detect hyperglycemia during feedings and the risk of hypoglycemia when feedings are interrupted (109,112). More frequent BG testing, ranging from every 30 min to every 2 h, is required for patients receiving IV insulin infusions. Glucose meters Safe and rational glycemic management relies on the accuracy of BG measurements performed with use of POC glucose meters, which have several important limitations. Although the U.S. Food and Drug Administration allows a 20% error for glucose meters, questions have been raised about the appropriateness of this criterion (138). Glucose measurements differ significantly between plasma and whole blood, terms that are often used interchangeably and can lead tomisinterpretation. Most commercially available capillary glucose meters introduce a correction factor of ∼1.12 to report a “plasma adjusted” value (139). Significant discrepancies among capillary, venous, and arterial plasma samples have been observed in patients with low or high hemoglobin concentrations, hypoperfusion, or the presence of interfering substances (139,140). Analytical variability has been described with several POC glucose meters (141). Any glucose result that does not correlate withthe patient's clinical status should be confirmed through conventional laboratory sampling of plasma glucose. Although laboratory measurement of plasma glucose has less variability and interference, multiple daily phlebotomies are not practical. Moreover, the use of indwelling lines as the sampling source poses risks for infection. Studies performed with use of continuous interstitial glucose-monitoring systems in the critical care setting (142,143) currently are limited by the lack of reliability of BG measurements in the hypoglycemic range as well as by cost. QUESTION 5: WHAT SYSTEMS NEED TO BE IN PLACE TO ACHIEVE THESE RECOMMENDATIONS? The complexity of inpatient glycemic management necessitates a systems approach that facilitates safe practices and reduces the risk for errors (120,121). Systems that facilitate the appropriate use of scheduled insulin therapy, with institutional support for inpatient personnel who are knowledgeable in glycemic management, are essential for achieving safe and reasonable levels of glycemic control in hospitalized patients. Readers are referred to the 2006 ACE/ADA consensus statement, which outlines the systems that must be in place to promote effective glycemic management in the hospital (11). Some of these recommendations are reviewed briefly in the following paragraphs. The success of any glycemic management program depends on the ability to obtain financial support from hospital administrators, who should be made aware of the potential for cost savings with reductions in morbidity, durations of hospital stay, and need for readmission. This support is necessary for covering the costs of staff education, equipment, and personnel to oversee an inpatient diabetes management program (144). The creation of a multidisciplinary steering committee guided by local diabetes experts can establish reasonable and achievable glycemic management goals with use of protocols and order sets (90). Preprinted order sets or computerized ordering systems with adequate technical support are useful tools for facilitating appropriate glycemic therapy (8,11,145). These tools can advance orders that contain contingencies that promote patient safety, such as withholding prandial insulin if a patient will not eat (102). Protocols need to be reviewed periodically and revised in accordance with available evidence. Inpatient providers often have insufficient knowledge about the many aspects of inpatient diabetes care (133). Thus, education of personnel is essential, especially early during the implementation phase (101,127). Formal communication among various disciplines and services helps to garner support from hospital personnel for new practices and protocols, as well as providing a venue for identifying concerns. Many hospitals are challenged by poor coordination of meal delivery and prandial insulin administration (130), as well as variability in the carbohydrate content of meals (94). Ensuring appropriate administration of insulin with respect to meals despite variations in food delivery necessitates coordination between dietary and nursing services (122). A systems approach can also promote the coordination of glucose monitoring, insulin administration, and meal delivery, particularly during change of shifts and times of patient transfer (121,122). Electronic health records and computerized physician order entry systems have the potential to improve the sharing of information, including POC glucose results and associated medication administration—which can contribute to the reduction of medical errors. These systems can also provide access to algorithms, protocols, and decision support tools that can help guide therapy (146,147). QUESTION 6: IS TREATMENT OF INPATIENT HYPERGLYCEMIA COST-EFFECTIVE? A program of inpatient glycemic control with prespecified glycemic targets will have associated costs attributable to an increase in time needed from physicians, nurses, pharmacists, and other services. These costs are best viewed as short-term investments that ultimately provide long-term cost savings because of improved clinical outcomes, with observed decreases in LOS, inpatient complications, and need for rehospitalization (148 –155). Pharmacoeconomic analyses haveexaminedthe cost-effectiveness of improved glycemic control in the hospital setting (148,149). In the Portland Diabetic Project, a 17-year prospective nonrandomized study of 4,864 patients with diabetes who underwent open-heart surgical procedures, institution of continuous IV insulin therapy to achieve predetermined target BG levels reduced the incidence of deep sternal wound infections by 66%, resulting in a total net savings to the hospital of 4,638 USD per patient (148). In another study, intensive glycemic control in 1,600 patients treated in a medical ICU was associated with a total cost savings of 1,580 USD per patient (149). Van den Berghe et al. (150) reported cost savings of 3,476 USD per patient by strict normalization of BG levels with use of a post hoc health careresourceutilization analysis of their randomized mechanically ventilated surgical ICU patients. In a retrospective analysis of patients undergoing coronary artery bypass grafting, each 50 mg/dl (2.8 mmol/l) increase in BG values on the day of and after the surgical procedure was associated with an increase in hospital cost of 1,769 USD and an increase in duration of hospital stay of 0.76 days (151). In a tertiary care trauma center, implementation of a diabetes management program to reduce the monthly mean BG level by 26 mg/dl (1.4 mmol/l) (177–151 mg/dl [9.8–8.4 mmol/l]) resulted in significant reductions in LOS (0.26 days) in association with estimated hospital savings of more than two million USD per year (152). In another study, implementation of a subcutaneous insulin protocol for treatment of patients with hyperglycemia in the emergency department resulted in a subsequent reduction of hospital stay by 1.5 days (153). The use of an intensified inpatient protocol by a diabetes management team resulted in correct coding and treatment of patients with previously unrecognized hyperglycemia. The LOS was reduced for both primary and secondary diagnoses of diabetes, and readmission rates declined (154). In a different study, the use of diabetes team consultation resulted in a 56% reduction in LOS and a cost reduction of 2,353 USD per patient (155). Thus, intensive glycemic control programs have reported substantial cost savings, primarily attributable to decreases in laboratory, pharmacy, and radiology costs; fewer inpatient complications; decreased ventilator days; and reductionsin ICUand hospital LOS. These reports demonstrate that optimization of inpatient glycemic management not only iseffective in reducing morbidity and mortality but also is cost-effective. The business case for hospital support of glycemic management programs is based on opportunities for improving the accuracy of documentation and coding for diabetes-related diagnoses. The case for revenue generation through billing for clinical services is based on opportunities to increase the provision of glycemic management services in the hospital. It is imperative to involve hospital administration in providing the necessary financial support for inpatient glycemic management programs that will ultimately result in cost savings in conjunction with improved patient outcomes. QUESTION 7: WHAT ARE THE OPTIMAL STRATEGIES FOR TRANSITION TO OUTPATIENT CARE? Preparation for transition to the outpatient setting is an important goal of inpatient diabetes management and begins with the hospital admission. This entails a fundamental shift in responsibility from a situation in which hospital personnel provide the diabetes care to one in which the patient is capable of self-management. Successful coordination of this transition requires a team approach that may involve physicians, nurses, medical assistants, dietitians, case managers, and social workers (8). Hospitals with certified diabetes educators benefit from their expertise during the discharge process. Admission assessment obtains information regarding any prior history of diabetes or hyperglycemia, its management, and the level of glycemic control. Early assessment of a patient's cognitive abilities, literacy level, visual acuity, dexterity, cultural context, and financial resources for acquiring outpatient diabetic supplies allows sufficient time to prepare the patient and address problem areas. Hospitalization provides a unique opportunity for addressing a patient's education in diabetes self-management (3). Because the mean hospital LOS is usually <5 days (2) and the capacity to learn new material may be limited during acute illness, diabetes-related education is frequently limited to an inventory of basic “survival skills.” It is recommended that the following areas be reviewed and addressed before the patient is discharged from the hospital (8): Level of understanding related to the diagnosis of diabetes Self-monitoring of BG and explanation of home BG goals Definition, recognition, treatment, and prevention of hyperglycemia and hypoglycemia Identification of health care provider who will be responsible for diabetes care after discharge Information on consistent eating patterns When and how to take BG-lowering medications, including administration of insulin (if the patient is receiving insulin for ongoing management at home) Sick day management Proper use and disposal of needles and syringes Medication errors and adverse drug events have been linked to poor communication of instructions to the patient at the time of discharge (156,157). This is particularly true for insulin regimens, which are inherently more complex. Because the day of discharge is not always conducive to retention of verbal instructions (158), clearly written instructions provide a reference for patients and their outpatient providers, and they provide a format for medication reconciliation between inpatient and outpatient settings. In one recent study, an insulin-specific discharge instruction form provided greater clarity and more consistent directions for insulin dosing and self-testing of BG in comparison with a generic hospital discharge form (159). An outpatient follow-up visit with the primary care provider, endocrinologist, or diabetes educator within 1 month after discharge from the hospital is advised for all patients having hyperglycemia in the hospital (8). Clear communication with outpatient providers either directly or by means of hospital discharge summaries facilitates safe transitions to outpatient care. Providing information regarding the cause or the plan for determining the cause of hyperglycemia, related complications and comorbidities, and recommended treatments can assist outpatient providers as they assume ongoing care. QUESTION 8: WHAT ARE AREAS FOR FUTURE RESEARCH? The following are selected research topics and questions proposed for guiding the management of patients with hyperglycemia in various hospital settings. Stress hyperglycemia What are the underlying mechanisms? What abnormalities lead to variability in insulin resistance observed in some critically ill patients? What therapeutic modalities, in addition to glycemic control, would improve outcomes in critically ill patients with hyperglycemia? Are there optimal and safe glycemic targets specific to certain populations of critically ill patients? Severe hypoglycemia What is the profile of inpatients at greatest risk for severe hypoglycemia? What are the short-term and long-term outcomes of patients experiencing severe hypoglycemia? What are the true costs of inpatient hypoglycemia? Glycemic targets on general medical and surgical wards What are optimal and safe glycemic targets in noncritically ill patients on medical and surgical wards? Recommended end points for an RCT include rates of hypoglycemia, hospital-acquired infections, other in-hospital complications, LOS, and readmission. Glycemic variability What is the effect of glycemic variability and the rate of change in glycemia on short-term and long-term outcomes, both in ICU and non-ICU settings? Hospital systems and safety What hospital systems and safety measures are important for improving glycemic control and patient outcomes? What teams and support systems are required for safe and effective transition of patients to the outpatient setting? Insulin treatment and monitoring instruments What are safe and effective strategies for inpatient use of insulin and insulin analogues? What is the role of continuous glucose- monitoring systems in inpatient settings? Pediatric inpatient populations What are the optimal and safe glycemic targets in noncritically ill hospitalized children? SUMMARY OF RECOMMENDATIONS I. Critically ill patients Insulin therapy should be initiated for treatment of persistent hyperglycemia, starting at a threshold of no greater than 180 mg/dl (10.0 mmol/l). Once insulin therapy has been started, a glucose range of 140–180 mg/dl (7.8–10.0 mmol/l) is recommended for the majority of critically ill patients. Intravenous insulin infusions are the preferred method for achieving and maintaining glycemic control in critically ill patients. Validated insulin infusion protocols with demonstrated safety and efficacy, and with low rates of occurrence of hypoglycemia, are recommended. With IV insulin therapy, frequent glucose monitoring is essential to minimize the occurrence of hypoglycemia and to achieve optimal glucose control. II. Noncritically ill patients For the majority of noncritically ill patients treated with insulin, the premeal BG target should generally be <140 mg/dl (<7.8 mmol/l) in conjunction with random BG values <180 mg/dl (<10.0 mmol/l), provided these targets can be safely achieved. More stringent targets may be appropriate in stable patients with previous tight glycemic control. Less stringent targets may be appropriate in terminally ill patients or in patients with severe comorbidities. Scheduled subcutaneous administration of insulin, with basal, nutritional, and correction components, is the preferred method for achieving and maintaining glucose control. Prolonged therapy with SSI as the sole regimen is discouraged. Noninsulin antihyperglycemic agents are not appropriate in most hospitalized patients who require therapy for hyperglycemia. Clinical judgment and ongoing assessment of clinical status must be incorporated into day-to-day decisions regarding treatment of hyperglycemia. III. Safety issues Overtreatment and undertreatment of hyperglycemia represent major safety concerns. Education of hospital personnel is essential in engaging the support of those involved in the care of inpatients with hyperglycemia. Caution is required in interpreting results of POC glucose meters in patients with anemia, polycythemia, hypoperfusion, or use of some medications. Buy-in and financial support from hospital administration are required for promoting a rational systems approach to inpatient glycemic management. IV. Cost Appropriate inpatient management of hyperglycemia is cost-effective. V. Discharge planning Preparation for transition to the outpatient setting should begin at the time of hospital admission. Discharge planning, patient education, and clear communication with outpatient providers are critical for ensuring a safe and successful transition to outpatient glycemic management. VI. Needed research A selected number of research questions and topics for guiding the management of inpatient hyperglycemia in various hospital settings are proposed.
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                Author and article information

                Journal
                Diabetes Care
                Diabetes Care
                diacare
                dcare
                Diabetes Care
                Diabetes Care
                American Diabetes Association
                0149-5992
                1935-5548
                December 2012
                14 November 2012
                : 35
                : 12
                : 2650-2664
                Affiliations
                [1]From 1Medical Affairs and Community Information, American Diabetes Association, Alexandria, Virginia; the
                [2] 2Department of Medicine, Vanderbilt University, Nashville, Tennessee; the
                [3] 3Diabetes Center of Cape Cod, Emerald Physicians, Hyannis, Massachusetts; the
                [4] 4Miami Veterans Affairs Healthcare System, Geriatric Research, Education and Clinical Center, and the University of Miami, Miami, Florida; the
                [5] 5Veterans Affairs Puget Sound Health Care System, Seattle, Washington; the
                [6] 6Division of Geriatric Medicine, University of Michigan, Ann Arbor, Michigan; the
                [7] 7Section of General Internal Medicine, The University of Chicago, Chicago, Illinois; the
                [8] 8Division of Endocrinology, University of Pittsburgh, Pittsburgh, Pennsylvania;
                [9] 9Beth Israel Deaconess Medical Center and the Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts; the
                [10] 10Department of Pharmacy, University of Washington, Seattle, Washington; the
                [11] 11Florida Hospital Diabetes Institute, Orlando, Florida; and
                [12] 12Kadlec Medical Center, Richland, Washington.
                Author notes
                Corresponding author: M. Sue Kirkman, skirkman@ 123456diabetes.org .

                The clinical recommendations and recommendations for a research agenda in this article are solely the opinion of the authors and do not represent the official position of the American Diabetes Association.

                This article has been copublished in the Journal of the American Geriatrics Society.

                Article
                1801
                10.2337/dc12-1801
                3507610
                23100048
                c35336c9-7dc8-4f96-9866-9ebaece2aaaf
                © 2012 by the American Diabetes Association and the American Geriatrics Society.

                Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

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                Consensus Report

                Endocrinology & Diabetes
                Endocrinology & Diabetes

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