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      Non-alcoholic fatty liver disease

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          Abstract

          Summary points Non-alcoholic fatty liver disease (NAFLD) represents a spectrum of liver disease with key stages consisting of hepatic steatosis (NAFL), steatohepatitis (NASH), fibrosis, and eventual cirrhosis NAFLD affects more than 20% of populations worldwide and most patients with type 2 diabetes mellitus The risk of progressive liver disease in the earliest stage of NAFLD, hepatic steatosis, is low but patients with NASH are at far higher risk, and hepatic steatosis due to NAFLD is also a major risk factor for the development of type 2 diabetes Most patients with NAFLD are asymptomatic and the disease is typically suspected based on raised alanine aminotransferase (ALT) levels together with other clinical and biochemical features, or an incidental finding during abdominal ultrasonography Owing to the slow progression of NAFLD, randomised clinical trials have been unable to identify drugs that conclusively reduce progression to cirrhosis, but sustained weight loss has been shown to improve liver function test results and liver histology and thus lifestyle improvement remains the key intervention There is no convincing evidence that NAFLD independently increases a patient’s cardiovascular risk but there is also no reason to withhold statins in patients with NAFLD who are at high cardiovascular risk unless transaminase levels are more than three times the upper limit of normal Non-alcoholic fatty liver disease (NAFLD) is now more common than alcoholic liver disease owing to the rapid rise in the prevalence of obesity,1 and NAFLD is the most common cause of abnormal liver function tests.2 Its prevalence worldwide is thought to be approximately 20% in the general population and up to 70% in patients with type 2 diabetes mellitus.3 The first recognisable stage of NAFLD is hepatic steatosis, when fat content exceeds 5% of liver volume. Simple steatosis is usually benign in terms of risk of progression to more advanced liver disease, but given its high prevalence it none the less represents an important cause of cirrhosis.4 Notably, NAFLD is strongly associated with insulin resistance and hyperglycaemia and it is therefore closely linked to type 2 diabetes. Non-alcoholic steatohepatitis (NASH), the next stage of NAFLD, develops when hepatic inflammation ensues, and its prevalence in the general population is estimated at 3-5%3; people with NASH are at much higher risk of clinically significant and progressive liver fibrosis, cirrhosis, and hepatocellular carcinoma.4 5 Relevant clinical questions include how to evaluate abnormal liver function test results, whether it is important to identify NAFLD, how to pragmatically identify patients who may have NASH, and who to refer for specialist evaluation. In this article we outline how NAFLD may be recognised in primary care, we suggest when further investigations are needed, and we show why NAFLD should be a strong driver for sustainable weight loss to reduce metabolic and, potentially, hepatic risks. Sources and selection criteria We sought relevant studies from the Cochrane Database of Systematic Reviews, Medline, and Embase, with particular emphasis on systematic reviews, randomised controlled trials, and meta-analyses of trials. Search terms included “non-alcoholic fatty liver disease” and “non-alcoholic steatohepatitis”. Studies were limited to those in adults and written in English. Who gets NAFLD? Obesity is a major risk factor for the development of NAFLD. The increase in obesity is therefore the main driver for the greater prevalence of NAFLD in the community. There is a strong link between NAFLD and type 2 diabetes, even beyond adiposity.6 Male sex and a family history of type 2 diabetes are also associated with a greater risk of NAFLD and NASH at any given body mass index,7 and preliminary evidence suggests greater liver fat content in certain ethnicities that are also known to be at increased risk of type 2 diabetes.8 Preliminary evidence suggests a genetic predisposition to hepatic accumulation of fat in some people through the PNP3A gene.9 Such people may not necessarily display the usual metabolic associations with NAFLD, but genetic screening for PNP3A is not currently recommended.3 Strictly speaking, NAFLD should only be diagnosed in people who consume no or only modest amounts of alcohol (daily intake <20 g (2.5 units) in women and <30 g (3.75 units) in men), although the clinical reality is that in many people both obesity and alcohol will contribute to their level of liver fat and risk of progressive liver disease.10 Uncommon causes of fatty liver also should be considered (drugs including amiodarone, diltiazem, steroids, synthetic oestrogens, tamoxifen, and highly active antiretroviral therapy; refeeding syndrome and total parenteral nutrition; severe weight loss after jejunoileal or gastric bypass; lipodystrophy and other rare disorders) by taking an appropriate medical history. When should NAFLD be suspected and how is it diagnosed? It is important to stress that many patients with NAFLD will be overweight or obese, asymptomatic, and have normal liver function test results. As NAFLD may have a benign asymptomatic course and because there is a lack of definitive evidence about effective interventions, there is currently no compelling reason to screen for the condition in an untargeted fashion. NAFLD is typically first suspected when the results of liver function tests, measured as part of routine testing (for example, health checks), are moderately abnormal. The usual observed biochemical pattern in hepatic steatosis due to NAFLD is of increased levels of transaminases, with alanine aminotransferase (ALT) levels exceeding those of aspartate aminotransferase (AST). This classical pattern is particularly useful in differentiating between hepatic steatosis from NAFLD and alcoholic liver injury, with the latter normally associated with a high AST:ALT ratio. With the progression of hepatic steatosis to NASH and associated hepatic fibrosis, however, AST levels increase with a resultant rise in the AST:ALT ratio.1 11 γ glutamyltransferase (GGT) may also be modestly increased along with the NAFLD pattern for transaminases. Both ALT and GGT have been shown in cross sectional studies to be modestly associated with the presence of fatty liver on ultrasonography and with liver fat content as measured by magnetic resonance imaging spectroscopy,12 whereas AST is not related. Another common way in which NAFLD is identified is by incidental finding of increased hepatic echogenicity on abdominal ultrasonography, when carried out for other reasons such as right upper quadrant abdominal pain. However, ultrasonography has poor sensitivity for diagnosing NAFLD, and many patients with important steatosis on biopsy are not recognised by such imaging,13 underlining the imperfect nature of both biochemistry and imaging for identifying NAFLD. Common forms of presentation of NAFLD Case 1 (box 1) shows one of the common presentations of NAFLD in which liver function tests have been checked. Although some uncertainty about alcohol intake is often present, this patient’s pattern of an increased ALT level with AST levels less than those for ALT along with other characteristics linked to insulin resistance or higher risk of type 2 diabetes—namely, high body mass index, high triglyceride level, low high density lipoprotein cholesterol level, and high or high normal HbA1c level—strongly suggests the presence of NAFLD, specifically hepatic steatosis. The question of whether ultrasonography of the liver is required to confirm the suspicion is discussed below. Box 1 Typical scenario for identified NAFLD Case 1 Mr A is seen for cardiovascular risk screening: Age 43, body mass index 31 kg/m2, 14 units of alcohol per week Cholesterol 6.2 mmol/L, triglyceride 3.5 mmol/L, high density lipoprotein cholesterol 0.9 mmol/L ALT 62 U/L, AST 38 U/L (normal <50 U/L) Blood pressure: systolic 145 mm Hg, diastolic 88 mm Hg HbA1c 44 mmol/mol ALT=alanine aminotransferase; AST=aspartate aminotransferase. In case 2 (box 2), fatty liver has been identified on abdominal ultrasonography and the clinician must distinguish between NAFLD and alcoholic liver disease. In this case, the patient is adamant about abstinence from alcohol. The clinician had recently checked the patient’s liver function test results and both transaminases were within the normal reference interval, with the ALT level higher than that of AST. Notably, higher ALT and GGT levels within the normal range are associated with a greater risk of type 2 diabetes.14 Further supportive evidence for the presence of NAFLD in this patient includes the related finding of hypertriglyceridaemia together with a family history of type 2 diabetes, although no formal glycaemia testing had been performed for this patient. Although overweight, the patient was not obese. Box 2 Typical scenario for suspected NAFLD Case 2 Mrs B is referred for abdominal ultrasonography because of abdominal discomfort: Age 56, body mass index 28 kg/m2, no alcohol Ultrasound findings: increased hepatic echogenicity in keeping with fatty liver Family history of type 2 diabetes ALT 38 U/L, AST 25 U/L Cholesterol 5.2 mmol/L, triglyceride 4.1 mmol/L, high density lipoprotein cholesterol 1.2 mmol/L No glycaemia testing ever performed ALT=alanine aminotransferase; AST=aspartate aminotransferase. How is NAFLD distinguished from alcoholic liver disease? Hepatic steatosis due to alcohol excess is often associated with an AST:ALT ratio >1.5, unlike non-alcoholic fatty liver disease. Alcohol excess also commonly results in an increased high density lipoprotein cholesterol together with triglyceride levels, which can vary between being normal and vastly increased, even in the same patient, depending on the timing of blood sampling in relation to alcohol intake. This pattern of biochemistry is less consistent with insulin resistance and NAFLD. Some other features can help to distinguish one from the other (table). People may have mixed patterns of biochemistry and both obesity and alcohol related risk factors. Typical features of non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease Characteristics NAFLD Alcoholic liver disease Body weight Increased Variable Fasting plasma glucose or HbA1c Increased Normal Reported daily alcohol intake <20 g for women, <30 g for men >20 g for women, >30 g for men ALT Increased or normal Increased or normal AST Normal Increased AST:ALT ratio <0.8 (>0.8 with more advanced disease) >1.5 GGT Increased or normal Considerably increased Triglycerides Increased Variable, may be considerably increased HDL cholesterol Low Increased Mean corpuscular volume Normal Increased ALT=alanine aminotransferase; AST=aspartate aminotransferasse; GGT=γ glutamyltransferase; HDL=high density lipoprotein. How should suspected or confirmed NAFLD be managed? Several points require consideration in deciding how to treat patients with NAFLD (figure ): Proposed algorithm for diagnosis and initial management of suspected or confirmed non-alcoholic fatty liver disease (NAFLD) in primary care. ALT=alanine aminotransferase; LFTs=liver function tests; AST=aspartate aminotransferase. *Some biochemistry laboratories only measure one of the transaminases and in such cases it will be necessary to request both ALT and AST tests in relevant patients Depending on how NAFLD is first suspected, whether based on abnormal transaminase levels (with AST levels less than those of ALT) or an incidental finding on ultrasonography, additional evidence is often helpful. Details of previous lipid profiles, type 2 diabetes in patients and their families, past results for fasting glucose or HbA1c, alcohol intake, and current weight provide incremental information to help in the diagnosis of NAFLD. Where such information is not available or where lipid profiles or screening tests for type 2 diabetes have not been done in recent years, this medical history should be obtained and the necessary blood tests performed. The patient should be provided with lifestyle advice to aid sustained weight loss and reduce alcohol intake. Repeating liver function tests in 3-6 months in those with NAFLD on ultrasonography gives patients time to implement lifestyle changes, at which point they can be reassessed by the clinician. Similar or improved results (a reduction in ALT or other metabolic parameters such as body weight, triglyceride, HbA1c) should drive ongoing improvements to lifestyle, whereas deterioration in results can be approached as described below. Screening for type 2 diabetes is particularly important given the close relation between NAFLD and dysglycaemia, as it provides the opportunity to not only potentially identify undiagnosed type 2 diabetes15 but to also identify those at increased risk, as defined in recent guidelines from the National Institute for Health and Care Excellence.16 Hepatic steatosis due to NAFLD is a risk factor for both type 2 diabetes and NASH, and its occurrence should form a major incentive for improvements to lifestyle. Where the liver function test results are mildly or moderately raised (transaminases 50-150 U/L (1 to 3 times the upper limit of normal) with AST levels less than those of ALT) and the available information (based on body weight, lipids, HbA1c or glucose, family history of type 2 diabetes, alcohol intake) suggests NAFLD, patients should also be asked to return for repeat liver function tests in 2-3 months, having been advised to reduce any alcohol intake or preferably discontinue it and to pursue lifestyle improvements to sustainably reduce weight. Noticeable increases in transaminases (>150 U/L (>3 times the upper limit of normal) with AST levels less than those of ALT) or the additional increase of alkaline phosphatase (ALP) should heighten awareness of the possibility of other causes and of the potential for progressive liver disease, whether due to NAFLD or another cause. These patients should be seen again within a few weeks for repeat testing and consideration of specialist referral. Published recommendations for the management of abnormal transaminase levels exist, and this review is not intended to be a comprehensive guide to investigating all abnormal liver function test results. On the basis of the available clinical information, it is important to consider other liver conditions that are treatable or that may have important consequences for family screening such as chronic viral hepatitis, autoimmune liver disease, haemochromatosis, or drug induced liver injury. With the increasing prevalence of obesity it is inevitable that other liver diseases will be present among those with risk factors for NAFLD. This clinical overlap is sometimes compounded by the presence of mild to moderately raised ferritin and immunoglobulin (predominantly IgA) levels in NAFLD, both of which may reflect on the stage of liver damage in NAFLD without evidence of primary iron overload or autoimmune disease.17 18 Coexisting hepatic steatosis is itself a cofactor for the progression of other primary liver diseases. Although only a few patients with abnormal liver function test results will have serious liver disease requiring immediate treatment, studies have shown that most abnormal results remain so on repeat testing. Therefore appropriate investigation and treatment can be planned when these are first identified.19 Is ultrasonography needed if NAFLD is strongly suspected? In most patients with mildly abnormal transaminase levels plus a suggestive biochemical and risk factor profile in keeping with hepatic steatosis due to NAFLD, many clinicians pursue the diagnosis by means of liver ultrasonography. Proponents suggest a low threshold for ultrasonography scans for screening patients with suspected NAFLD.20 However, ultrasonography has several notable limitations: the variability between sonographers; the technical difficulties of scanning obese patients in a robust and reproducible way; the inability to distinguish NASH, which is far more likely to progress to advanced liver disease, from simple steatosis; the lack of an agreed grading system; the huge number of patients potentially requiring ultrasonography, which would overwhelm local services; and the lack of additional treatment options based on the scan result.21 22 In our opinion the additional benefit of routinely requesting liver ultrasonography to diagnose NAFLD in patients with suggestive phenotypic and biochemical features and no features of other liver disease or more advanced liver disease is therefore unproved and highly questionable. Weight loss and lifestyle improvements are the key goal in NAFLD Because of the low incidence of progressive liver disease in early NAFLD and the duration required for advanced liver disease to occur, randomised trials of lifestyle improvements and various drugs have necessarily been limited to changes in surrogate markers as their primary outcomes. Therefore, as yet there is no conclusive evidence for any particular treatment approach, and cost effective and non-invasive surrogates that robustly track with later development of cirrhosis are much sought after. For most patients with presumed or confirmed NAFLD, the key is to offer lifestyle advice that can lead to sustained weight loss. A recent systematic review of 23 studies evaluating the effect of diet or physical activity in adult populations with NAFLD showed that these lifestyle modifications consistently reduced liver fat and improved glucose control and insulin sensitivity.23 Limited data suggest that lifestyle interventions may also yield benefits for liver histology. Should glycaemia testing confirm type 2 diabetes or show that a patient is at high risk of its development, then lifestyle advice is recognised to be critical to the management of these patients as per universal guidance for the disease,24 and here it may have a dual benefit. General advice on healthy eating and increasing levels of physical activity can be delivered in primary care, or specialist settings where required. Patients can also be encouraged to attend a commercial weight loss programme of their choice. Recent evidence from a randomised trial shows that commercial weight loss programmes perform potentially better than advice given by the National Health Service in achieving weight loss.25 Should ALT and GGT levels decline along with weight reduction, these encouraging results should be shared with patients as further incentive to sustain their lifestyle improvements. Numerous trials of drug treatments, such as metformin, pioglitazone, vitamin E, and statins have failed to deliver conclusive evidence of reductions in clinically significant progression of liver disease, although some studies have yielded improvements in surrogate markers.26 Does NAFLD indicate that patients are at increased cardiovascular risk? Undoubtedly NAFLD is often accompanied by classical cardiovascular risk factors including, but not limited to, type 2 diabetes and low levels of high density lipoprotein cholesterol. This has driven a plethora of observational studies linking markers of NAFLD (including ALT and GGT, fatty liver on ultrasonography, steatosis on liver histology) to cardiovascular surrogate markers and cardiovascular outcomes.27 While some studies have found associations between these NAFLD surrogates and cardiovascular risk, many have been limited by inadequate adjustment for established cardiovascular risk factors.28 Crucially, for NAFLD to be considered as a truly important and independent risk factor, it will need to show clinically meaningful improvements in cardiovascular risk prediction when added to calculators that already include these established risk factors.29 No such evidence yet exists. Importantly, our suggested approach for evaluating the likelihood of NAFLD provides much of the information needed to calculate cardiovascular risk using established risk calculators. Therefore, current evidence suggests that cardiovascular risk should be calculated using the usual available tools without consideration of the presence or absence of NAFLD. What if patients are already using a statin or require a statin based on cardiovascular risk? Given that many patients with NAFLD will have risk factors for cardiovascular disease, many will already be taking a statin or may require statin treatment because of their increased cardiovascular risk. Statin treatment, including high potency statin treatment, is safe in the presence of NAFLD and should not be avoided because of mild to moderately raised transaminase levels (up to three times the upper limit of normal).30 Indeed, preliminary evidence from the Greek Atorvastatin and Coronary Heart Disease Evaluation study suggests that those with increased transaminase levels (up to three times the upper limit of normal) may derive an even greater cardiovascular benefit from statins.31 Robust evidence for the safety of statins in those with NAFLD and transaminases over three times the upper limit of normal is lacking and statin treatment is probably best avoided in such people unless recommended after specialist hepatology review. In those with moderately abnormal liver function test results (<150 U/L (<3 times the upper limit of normal)) at the time of starting statins, it is prudent to redo the tests one or two months after the start of statin treatment. When should patients with confirmed or suspected NAFLD be referred to a gastroenterologist? Given the high prevalence of NAFLD coupled with the low risk of progressive liver disease in most people with simple steatosis, only those considered to be at high risk of progressive liver disease should be referred to secondary care for further evaluation. Several risk scores have been developed for the assessment of NAFLD severity.32 33 The NAFLD fibrosis score seems to be the most accurate in comparative studies, but it is not readily calculable and a large proportion of patients have indeterminate results. A simpler score, FIB-4, seems to be of similar accuracy but it still requires clinicians to carry out some form of electronic calculation. The simplest instrument is the BARD score, which places a heavy weighting on the AST:ALT ratio, with a value >0.8 considered to be associated with advanced fibrosis. Indeed an AST:ALT ratio >0.8 on its own has been found to perform well as an indicator of more severe liver disease.33 In this study, the AST:ALT ratio provided the best negative predictive value for advanced fibrosis and also demonstrated good diagnostic accuracy with a C statistic of 0.83 which was comparable to or better than results for more complex scores, where C statistics ranged from 0.67 to 0.86. In practical terms, patients with features of NAFLD in whom other major liver disease has been excluded and whose AST:ALT ratio is increasing to >0.8 as a result of a rising AST level should be considered at risk of progressive liver disease and referred for further evaluation. In addition, we would suggest that patients with ALT or AST levels more than three times the upper limit of normal or with abnormal ALP levels should be considered for specialist referral. Development of other clinical or laboratory features of advanced liver disease or portal hypertension, such as the appearance of spider naevi or unexplained thrombocytopenia, would warrant specialist referral. Liver ultrasonography and assessment of the severity of NAFLD using more specific severity scoring, serological assessment of fibrosis, or measurement of liver stiffness (transient elastography or acoustic radiation force imaging), can be performed in a secondary care setting. Liver biopsy may be required to clarify the severity of the underlying liver disease but even this “definitive” investigation is subject to considerable variability.34 Recognition of those patients with more advanced liver disease or at risk of progressive liver damage allows appropriate monitoring; in particular patients with cirrhosis can be entered into surveillance programmes for hepatocellular carcinoma and the presence of oesophagogastric varices. Tips for non-specialists In patients with raised alanine aminotransferase (ALT) or γ glutamyltransferase (GGT) levels or with hepatic steatosis noted on ultrasonography, non-alcoholic fatty liver disease (NAFLD) should be suspected in those with risk factors (increased body weight, raised fasting glucose or HbA1c, modestly raised triglycerides, low high density lipoprotein cholesterol, and AST:ALT ratio <0.8) and with daily alcohol intake <20 g in women and <30 g in men Patients with or suspected of having NAFLD should be screened for type 2 diabetes and, in the absence of type 2 diabetes, patients with NAFLD should be given preventive advice whether or not they fall into the high diabetes risk category Cardiovascular risk in NAFLD should be calculated using the usual risk scores There should be no hesitation in recommending statins for patients with NAFLD who are at increased cardiovascular risk unless their transaminase levels are more than three times the upper limit of normal Routine liver ultrasonography is not required in most patients with suspected NAFLD Patients with suspected or confirmed NAFLD should be given lifestyle advice on sustainable weight reduction and, because obesity and alcohol may act synergistically to promote liver disease, a reduction in alcohol intake should also be strongly advised Referral to a gastroenterologist should be considered in patients with features of NAFLD, in whom other significant liver disease has been excluded and whose AST:ALT ratio reaches >0.8 owing to increasing AST levels Additional educational resources Resources for healthcare professionals British Society of Gastroenterology (www.bsg.org.uk/clinical/commissioning-report/nash-and-non-alcoholic-fatty-liver-disease.html)—a source of information for clinicians on background, current practice, and recommended practice for NAFLD in the United Kingdom American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association (http://gi.org/clinical-guidelines/clinical-guidelines-sortable-list/)—a comprehensive American guideline on all aspects of NAFLD Resources for patients National Health Service (www.nhs.uk/conditions/fatty-liver-disease/pages/introduction.aspx)—comprehensive source of information for patients on NAFLD, its stages, and sensible lifestyle modifications American College of Gastroenterology (http://patients.gi.org/topics/fatty-liver-disease-nafld/)—a source of patient information on the causes, risk factors, investigation, and treatment of NAFLD All the websites are free to access and do not require registration Questions for future research Are there non-invasive surrogates for progression to advanced liver disease (fibrosis, cirrhosis) that can be robustly applied in future trials in non-alcoholic fatty liver disease (NAFLD)? What simple algorithms can be developed that effectively predict the presence of or progression to progressive liver disease? Is NAFLD an independent predictor of cardiovascular disease after established risk factors have been fully accounted for?

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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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            Derivation, validation, and evaluation of a new QRISK model to estimate lifetime risk of cardiovascular disease: cohort study using QResearch database

            Objective To develop, validate, and evaluate a new QRISK model to estimate lifetime risk of cardiovascular disease. Design Prospective cohort study with routinely collected data from general practice. Cox proportional hazards models in the derivation cohort to derive risk equations accounting for competing risks. Measures of calibration and discrimination in the validation cohort. Setting 563 general practices in England and Wales contributing to the QResearch database. Subjects Patients aged 30–84 years who were free of cardiovascular disease and not taking statins between 1 January 1994 and 30 April 2010: 2 343 759 in the derivation dataset, and 1 267 159 in the validation dataset. Main outcomes measures Individualised estimate of lifetime risk of cardiovascular disease accounting for smoking status, ethnic group, systolic blood pressure, ratio of total cholesterol:high density lipoprotein cholesterol, body mass index, family history of coronary heart disease in first degree relative aged <60 years, Townsend deprivation score, treated hypertension, rheumatoid arthritis, chronic renal disease, type 2 diabetes, and atrial fibrillation. Age-sex centile values for lifetime cardiovascular risk compared with 10 year risk estimated using QRISK2 (2010). Results Across all the 1 267 159 patients in the validation dataset, the 50th, 75th, 90th, and 95th centile values for lifetime risk were 31%, 39%, 50%, and 57% respectively. Of the 10% of patients in the validation cohort classified at highest risk with either the lifetime risk model or the 10 year risk model, only 18 385(14.5%) were at high risk on both measures. Patients identified as high risk with the lifetime risk approach were more likely to be younger, male, from ethnic minority groups, and have a positive family history of premature coronary heart disease than those identified with the 10 year QRISK2 score. The lifetime risk calculator is available at www.qrisk.org/lifetime/. Conclusions Compared with using a 10 year QRISK2 score, a lifetime risk score will tend to identify patients for intervention at a younger age. Although lifestyle interventions at an earlier age could be advantageous, there would be small gains under the age of 65, and medical interventions carry risks as soon as they are initiated. Research is needed to examine closely the cost effectiveness and acceptability of such an approach.
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              Alanine Aminotransferase, γ-Glutamyltransferase, and Incident Diabetes

              OBJECTIVE To estimate and compare associations of alanine aminotransferase (ALT) and γ-glutamyltransferase (GGT) with incident diabetes. RESEARCH DESIGN AND METHODS ALT and GGT were studied as determinants of diabetes in the British Women's Heart and Health Study, a cohort of 4,286 women 60–79 years old (median follow-up 7.3 years). A systematic review and a meta-analysis of 21 prospective, population-based studies of ultrasonography, which diagnosed nonalcoholic fatty liver disease (NAFLD), ALT, and GGT as determinants of diabetes, were conducted, and associations of ALT and GGT with diabetes were compared. RESULTS Ultrasonography-diagnosed NAFLD was associated with more than a doubling in the risk of incident diabetes (three studies). ALT and GGT both predicted diabetes. The fully adjusted hazard ratio (HR) for diabetes per increase in one unit of logged ALT was 1.83 (95% CI 1.57–2.14, I 2 = 8%) and for GGT was 1.92 (1.66–2.21, I 2 = 55%). To directly compare ALT and GGT as determinants of diabetes, the fully adjusted risk of diabetes in the top versus bottom fourth of the ALT and GGT distributions was estimated using data from studies that included results for both markers. For ALT, the HR was 2.02 (1.59–2.58, I 2 = 27%), and for GGT the HR was 2.94 (1.98–3.88, I 2 = 20%), suggesting that GGT may be a better predictor (P = 0.05). CONCLUSIONS Findings are consistent with the role of liver fat in diabetes pathogenesis. GGT may be a better diabetes predictor than ALT, but additional studies with directly determined liver fat content, ALT, and GGT are needed to confirm this finding.
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                Author and article information

                Contributors
                Role: professor
                Role: consultant
                Role: clinical senior lecturer
                Journal
                BMJ
                BMJ
                bmj
                BMJ : British Medical Journal
                BMJ Publishing Group Ltd.
                0959-8138
                1756-1833
                2014
                29 July 2014
                : 349
                : g4596
                Affiliations
                [1 ]BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow G12 8TA, UK
                [2 ]Department of Gastroenterology, Glasgow Royal Infirmary, Glasgow, UK
                Author notes
                Correspondence to: N Sattar naveed.sattar@ 123456glasgow.ac.uk
                Article
                satn020712
                10.1136/bmj.g4596
                4168663
                25239614
                2c3fdebd-b36e-477d-8cb7-f160c3e5c412
                © BMJ Publishing Group Ltd 2014
                History
                Categories
                Clinical Review
                1600

                Medicine
                Medicine

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