Blog
About

  • Record: found
  • Abstract: found
  • Article: found
Is Open Access

Real-world outcomes of US employees with type 2 diabetes mellitus treated with insulin glargine or neutral protamine Hagedorn insulin: a comparative retrospective database study

Read this article at

Bookmark
      There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

      Abstract

      Objectives

      To compare real-world outcomes of initiating insulin glargine (GLA) versus neutral protamine Hagedorn (NPH) insulin among employees with type 2 diabetes mellitus (T2DM) who had both employer-sponsored health insurance and short-tem-disability coverages.

      Design

      Retrospective cohort study.

      Setting

      MarketScan Commercial Claims and Encounters/Health and Productivity Management Databases 2003–2009.

      Participants

      Adult employees with T2DM who were previously treated with oral antidiabetic drugs and/or glucagon-like-peptide 1 receptor agonists and initiated GLA or NPH were included if they were continuously enrolled in healthcare and short-term-disability coverages for 3 months before (baseline) and 1 year after (follow-up) initiation. Treatment selection bias was addressed by 2:1 propensity score matching. Sensitivity analyses were conducted using different matching ratios.

      Primary and secondary outcome measures

      Outcomes during 1-year follow-up were measured and compared: insulin treatment persistence and adherence; hypoglycaemia rates and daily average consumption of insulin; total and diabetes-specific healthcare resource utilisation and costs and loss in productivity, as measured by short-term disability, and the associated costs.

      Results

      A total of 534 patients were matched and analysed (GLA: 356; NPH 178) with no significant differences in baseline characteristics. GLA patients were more persistent and adherent (both p<0.05), had lower rates of hospitalisation (23% vs 31.4%; p=0.036) and endocrinologist visits (19.1% vs 26.9%; p=0.038), similar hypoglycaemia rates (both 4.4%; p=1.0), higher diabetes drug costs ($2031 vs $1522; p<0.001), but similar total healthcare costs ($14 550 vs $16 093; p=0.448) and total diabetes-related healthcare costs ($4686 vs $5604; p=0.416). Short-term disability days and costs were numerically lower in the GLA cohort (16.0 vs 24.5 days; p=0.086 and $2824 vs $4363; p=0.081, respectively). Sensitivity analyses yielded similar findings.

      Conclusions

      Insulin GLA results in better persistence and adherence, compared with NPH insulin, with no overall cost disadvantages. Better persistence and adherence may lead to long-term health benefits for employees with T2DM.

      Related collections

      Most cited references 43

      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Management of Hyperglycemia in Type 2 Diabetes: A Patient-Centered Approach

      Glycemic management in type 2 diabetes mellitus has become increasingly complex and, to some extent, controversial, with a widening array of pharmacological agents now available (1–5), mounting concerns about their potential adverse effects and new uncertainties regarding the benefits of intensive glycemic control on macrovascular complications (6–9). Many clinicians are therefore perplexed as to the optimal strategies for their patients. As a consequence, the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) convened a joint task force to examine the evidence and develop recommendations for antihyperglycemic therapy in nonpregnant adults with type 2 diabetes. Several guideline documents have been developed by members of these two organizations (10) and by other societies and federations (2,11–15). However, an update was deemed necessary because of contemporary information on the benefits/risks of glycemic control, recent evidence concerning efficacy and safety of several new drug classes (16,17), the withdrawal/restriction of others, and increasing calls for a move toward more patient-centered care (18,19). This statement has been written incorporating the best available evidence and, where solid support does not exist, using the experience and insight of the writing group, incorporating an extensive review by additional experts (acknowledged below). The document refers to glycemic control; yet this clearly needs to be pursued within a multifactorial risk reduction framework. This stems from the fact that patients with type 2 diabetes are at increased risk of cardiovascular morbidity and mortality; the aggressive management of cardiovascular risk factors (blood pressure and lipid therapy, antiplatelet treatment, and smoking cessation) is likely to have even greater benefits. These recommendations should be considered within the context of the needs, preferences, and tolerances of each patient; individualization of treatment is the cornerstone of success. Our recommendations are less prescriptive than and not as algorithmic as prior guidelines. This follows from the general lack of comparative-effectiveness research in this area. Our intent is therefore to encourage an appreciation of the variable and progressive nature of type 2 diabetes, the specific role of each drug, the patient and disease factors that drive clinical decision making (20–23), and the constraints imposed by age and comorbidity (4,6). The implementation of these guidelines will require thoughtful clinicians to integrate current evidence with other constraints and imperatives in the context of patient-specific factors. PATIENT-CENTERED APPROACH Evidence-based advice depends on the existence of primary source evidence. This emerges only from clinical trial results in highly selected patients, using limited strategies. It does not address the range of choices available, or the order of use of additional therapies. Even if such evidence were available, the data would show median responses and not address the vital question of who responded to which therapy and why (24). Patient-centered care is defined as an approach to “providing care that is respectful of and responsive to individual patient preferences, needs, and values and ensuring that patient values guide all clinical decisions” (25). This should be the organizing principle underlying health care for individuals with any chronic disease, but given our uncertainties in terms of choice or sequence of therapy, it is particularly appropriate in type 2 diabetes. Ultimately, it is patients who make the final decisions regarding their lifestyle choices and, to some degree, the pharmaceutical interventions they use; their implementation occurs in the context of the patients’ real lives and relies on the consumption of resources (both public and private). Patient involvement in the medical decision making constitutes one of the core principles of evidence-based medicine, which mandates the synthesis of best available evidence from the literature with the clinician's expertise and patient's own inclinations (26). During the clinical encounter, the patient's preferred level of involvement should be gauged and therapeutic choices explored, potentially with the utilization of decision aids (21). In a shared decision-making approach, clinician and patient act as partners, mutually exchanging information and deliberating on options, in order to reach a consensus on the therapeutic course of action (27). There is good evidence supporting the effectiveness of this approach (28). Importantly, engaging patients in health care decisions may enhance adherence to therapy. BACKGROUND Epidemiology and health care impact Both the prevalence and incidence of type 2 diabetes are increasing worldwide, particularly in developing countries, in conjunction with increased obesity rates and westernization of lifestyle. The attendant economic burden for health care systems is skyrocketing, owing to the costs associated with treatment and diabetes complications. Type 2 diabetes remains a leading cause of cardiovascular disorders, blindness, end-stage renal failure, amputations, and hospitalizations. It is also associated with increased risk of cancer, serious psychiatric illness, cognitive decline, chronic liver disease, accelerated arthritis, and other disabling or deadly conditions. Effective management strategies are of obvious importance. Relationship of glycemic control to outcomes It is well established that the risk of microvascular and macrovascular complications is related to glycemia, as measured by HbA1c; this remains a major focus of therapy (29). Prospective randomized trials have documented reduced rates of microvascular complications in type 2 diabetic patients treated to lower glycemic targets. In the UK Prospective Diabetes Study (UKPDS) (30,31), patients with newly diagnosed type 2 diabetes were randomized to two treatment policies. In the standard group, lifestyle intervention was the mainstay with pharmacological therapy used only if hyperglycemia became severe. In the more intensive treatment arm, patients were randomly assigned to either a sulfonylurea or insulin, with a subset of overweight patients randomized to metformin. The overall HbA1c achieved was 0.9% lower in the intensive policy group compared with the conventional policy arm (7.0% vs. 7.9%). Associated with this difference in glycemic control was a reduction in the risk of microvascular complications (retinopathy, nephropathy, neuropathy) with intensive therapy. A trend toward reduced rates of myocardial infarction in this group did not reach statistical significance (30). By contrast, substantially fewer metformin-treated patients experienced myocardial infarction, diabetes-related and all-cause mortality (32), despite a mean HbA1c only 0.6% lower than the conventional policy group. The UKPDS 10-year follow-up demonstrated that the relative benefit of having been in the intensive management policy group was maintained over a decade, resulting in the emergence of statistically significant benefits on cardiovascular disease (CVD) end points and total mortality in those initially assigned to sulfonylurea/insulin, and persistence of CVD benefits with metformin (33), in spite of the fact that the mean HbA1c levels between the groups converged soon after the randomized component of the trial had concluded. In 2008, three shorter-term studies [Action to Control Cardiovascular Risk in Diabetes (ACCORD) (34), Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified-Release Controlled Evaluation (ADVANCE) (35), Veterans Affairs Diabetes Trial (VADT) (36)] reported the effects of two levels of glycemic control on cardiovascular end points in middle-aged and older individuals with well-established type 2 diabetes at high risk for cardiovascular events. ACCORD and VADT aimed for an HbA1c 16.7–19.4 mmol/L [>300–350 mg/dL]) or HbA1c (e.g., ≥10.0–12.0%), insulin therapy should be strongly considered from the outset. Such treatment is mandatory when catabolic features are exhibited or, of course, if ketonuria is demonstrated, the latter reflecting profound insulin deficiency. Importantly, unless there is evidence of type 1 diabetes, once symptoms are relieved, glucotoxicity resolved, and the metabolic state stabilized, it may be possible to taper insulin partially or entirely, transferring to noninsulin antihyperglycemic agents, perhaps in combination. Figure 2 Antihyperglycemic therapy in type 2 diabetes: general recommendations. Moving from the top to the bottom of the figure, potential sequences of antihyperglycemic therapy. In most patients, begin with lifestyle changes; metformin monotherapy is added at, or soon after, diagnosis (unless there are explicit contraindications). If the HbA1c target is not achieved after ∼3 months, consider one of the five treatment options combined with metformin: a sulfonylurea, TZD, DPP-4 inhibitor, GLP-1 receptor agonist, or basal insulin. (The order in the chart is determined by historical introduction and route of administration and is not meant to denote any specific preference.) Choice is based on patient and drug characteristics, with the over-riding goal of improving glycemic control while minimizing side effects. Shared decision making with the patient may help in the selection of therapeutic options. The figure displays drugs commonly used both in the U.S. and/or Europe. Rapid-acting secretagogues (meglitinides) may be used in place of sulfonylureas. Other drugs not shown (α-glucosidase inhibitors, colesevelam, dopamine agonists, pramlintide) may be used where available in selected patients but have modest efficacy and/or limiting side effects. In patients intolerant of, or with contraindications for, metformin, select initial drug from other classes depicted and proceed accordingly. In this circumstance, while published trials are generally lacking, it is reasonable to consider three-drug combinations other than metformin. Insulin is likely to be more effective than most other agents as a third-line therapy, especially when HbA1c is very high (e.g., ≥9.0%). The therapeutic regimen should include some basal insulin before moving to more complex insulin strategies (Fig. 3). Dashed arrow line on the left-hand side of the figure denotes the option of a more rapid progression from a two-drug combination directly to multiple daily insulin doses, in those patients with severe hyperglycemia (e.g., HbA1c ≥10.0–12.0%). DPP-4-i, DPP-4 inhibitor; Fx's, bone fractures; GI, gastrointestinal; GLP-1-RA, GLP-1 receptor agonist; HF, heart failure; SU, sulfonylurea. aConsider beginning at this stage in patients with very high HbA1c (e.g., ≥9%). b Consider rapid-acting, nonsulfonylurea secretagogues (meglitinides) in patients with irregular meal schedules or who develop late postprandial hypoglycemia on sulfonylureas. c See Table 1 for additional potential adverse effects and risks, under “Disadvantages.” d Usually a basal insulin (NPH, glargine, detemir) in combination with noninsulin agents. e Certain noninsulin agents may be continued with insulin (see text). Refer to Fig. 3 for details on regimens. Consider beginning at this stage if patient presents with severe hyperglycemia (≥16.7–19.4 mmol/L [≥300–350 mg/dL]; HbA1c ≥10.0–12.0%) with or without catabolic features (weight loss, ketosis, etc.). If metformin cannot be used, another oral agent could be chosen, such as a sulfonylurea/glinide, pioglitazone, or a DPP-4 inhibitor; in occasional cases where weight loss is seen as an essential aspect of therapy, initial treatment with a GLP-1 receptor agonist might be useful. Where available, less commonly used drugs (AGIs, colesevelam, bromocriptine) might also be considered in selected patients, but their modest glycemic effects and side-effect profiles make them less attractive candidates. Specific patient preferences, characteristics, susceptibilities to side effects, potential for weight gain and hypoglycemia should play a major role in drug selection (20,21). (See Supplementary Figs. for adaptations of Fig. 2 that address specific patient scenarios.) Advancing to dual combination therapy. Figure 2 (and Supplementary Figs.) also depicts potential sequences of escalating glucose-lowering therapy beyond metformin. If monotherapy alone does not achieve/maintain an HbA1c target over ∼3 months, the next step would be to add a second oral agent, a GLP-1 receptor agonist, or basal insulin (5,10). Notably, the higher the HbA1c, the more likely insulin will be required. On average, any second agent is typically associated with an approximate further reduction in HbA1c of ∼1% (70,79). If no clinically meaningful glycemic reduction (i.e., “nonresponder”) is demonstrated, then, adherence having been investigated, that agent should be discontinued, and another with a different mechanism of action substituted. With a distinct paucity of long-term comparative-effectiveness trials available, uniform recommendations on the best agent to be combined with metformin cannot be made (80). Thus, advantages and disadvantages of specific drugs for each patient should be considered (Table 1). Some antihyperglycemic medications lead to weight gain. This may be associated with worsening markers of insulin resistance and cardiovascular risk. One exception may be TZDs (57); weight gain associated with this class occurs in association with decreased insulin resistance. Although there is no uniform evidence that increases in weight in the range observed with certain therapies translate into a substantially increased cardiovascular risk, it remains important to avoid unnecessary weight gain by optimal medication selection and dose titration. For all medications, consideration should also be given to overall tolerability. Even occasional hypoglycemia may be devastating, if severe, or merely irritating, if mild (81). Gastrointestinal side effects may be tolerated by some, but not others. Fluid retention may pose a clinical or merely an aesthetic problem (82). The risk of bone fractures may be a specific concern in postmenopausal women (57). It must be acknowledged that costs are a critical issue driving the selection of glucose-lowering agents in many environments. For resource-limited settings, less expensive agents should be chosen. However, due consideration should be also given to side effects and any necessary monitoring, with their own cost implications. Moreover, prevention of morbid long-term complications will likely reduce long-term expenses attributed to the disease. Advancing to triple combination therapy. Some studies have shown advantages of adding a third noninsulin agent to a two-drug combination that is not yet or no longer achieving the glycemic target (83–86). Not surprisingly, however, at this juncture, the most robust response will usually be with insulin. Indeed, since diabetes is associated with progressive β-cell loss, many patients, especially those with long-standing disease, will eventually need to be transitioned to insulin, which should be favored in circumstances where the degree of hyperglycemia (e.g., ≥8.5%) makes it unlikely that another drug will be of sufficient benefit (87). If triple combination therapy exclusive of insulin is tried, the patient should be monitored closely, with the approach promptly reconsidered if it proves to be unsuccessful. Many months of uncontrolled hyperglycemia should specifically be avoided. In using triple combinations the essential consideration is obviously to use agents with complementary mechanisms of action (Fig. 2 and Supplementary Figs.). Increasing the number of drugs heightens the potential for side effects and drug–drug interactions, raises costs, and negatively impacts patient adherence. The rationale, benefits, and side effects of each new medication should be discussed with the patient. The clinical characteristics of patients more or less likely to respond to specific combinations are, unfortunately, not well defined. Transitions to and titrations of insulin. Most patients express reluctance to beginning injectable therapy, but, if the practitioner feels that such a transition is important, encouragement and education can usually overcome such reticence. Insulin is typically begun at a low dose (e.g., 0.1–0.2 U kg−1 day−1), although larger amounts (0.3–0.4 U kg−1 day−1) are reasonable in the more severely hyperglycemic. The most convenient strategy is with a single injection of a basal insulin, with the timing of administration dependent on the patient's schedule and overall glucose profile (Fig. 3). Figure 3 Sequential insulin strategies in type 2 diabetes. Basal insulin alone is usually the optimal initial regimen, beginning at 0.1–0.2 units/kg body weight, depending on the degree of hyperglycemia. It is usually prescribed in conjunction with one to two noninsulin agents. In patients willing to take more than one injection and who have higher HbA1c levels (≥9.0%), twice-daily premixed insulin or a more advanced basal plus mealtime insulin regimen could also be considered (curved dashed arrow lines). When basal insulin has been titrated to an acceptable fasting glucose but HbA1c remains above target, consider proceeding to basal plus mealtime insulin, consisting of one to three injections of rapid-acting analogs (see text for details). A less studied alternative—progression from basal insulin to a twice-daily premixed insulin—could be also considered (straight dashed arrow line); if this is unsuccessful, move to basal plus mealtime insulin. The figure describes the number of injections required at each stage, together with the relative complexity and flexibility. Once a strategy is initiated, titration of the insulin dose is important, with dose adjustments made based on the prevailing glucose levels as reported by the patient. Noninsulin agents may be continued, although insulin secretagogues (sulfonylureas, meglitinides) are typically stopped once more complex regimens beyond basal insulin are utilized. Comprehensive education regarding self-monitoring of blood glucose, diet, exercise, and the avoidance of, and response to, hypoglycemia are critical in any patient on insulin therapy. Mod., moderate. Although extensive dosing instructions for insulin are beyond the scope of this statement, most patients can be taught to uptitrate their own insulin dose based on several algorithms, each essentially involving the addition of a small dose increase if hyperglycemia persists (74,76,88). For example, the addition of 1–2 units (or, in those already on higher doses, increments of 5–10%) to the daily dose once or twice weekly if the fasting glucose levels are above the preagreed target is a reasonable approach (89). As the target is neared, dosage adjustments should be more modest and occur less frequently. Downward adjustment is advisable if any hypoglycemia occurs. During self-titration, frequent contact (telephone, e-mail) with the clinician may be necessary. Practitioners themselves can, of course, also titrate basal insulin, but this would involve more intensive contact with the patient than typically available in routine clinical practice. Daily self-monitoring of blood glucose is of obvious importance during this phase. After the insulin dose is stabilized, the frequency of monitoring should be reviewed (90). Consideration should be given to the addition of prandial or mealtime insulin coverage when significant postprandial glucose excursions (e.g., to >10.0 mmol/L [>180 mg/dL]) occur. This is suggested when the fasting glucose is at target but the HbA1c remains above goal after 3–6 months of basal insulin titration (91). The same would apply if large drops in glucose occur during overnight hours or in between meals, as the basal insulin dose is increased. In this scenario, the basal insulin dose would obviously need to be simultaneously decreased as prandial insulin is initiated. Although basal insulin is titrated primarily against the fasting glucose, generally irrespective of the total dose, practitioners should be aware that the need for prandial insulin therapy will become likely the more the daily dose exceeds 0.5 U kg−1 day−1, especially as it approaches 1 U kg−1 day−1. The aim with mealtime insulin is to blunt postprandial glycemic excursions, which can be extreme in some individuals, resulting in poor control during the day. Such coverage may be provided by one of two methods. The most precise and flexible prandial coverage is possible with “basal-bolus” therapy, involving the addition of premeal rapid-acting insulin analog to ongoing basal insulin. One graduated approach is to add prandial insulin before the meal responsible for the largest glucose excursion—typically that with the greatest carbohydrate content, often, but not always, the evening meal (92). Subsequently, a second injection can be administered before the meal with the next largest excursion (often breakfast). Ultimately, a third injection may be added before the smallest meal (often lunch) (93). The actual glycemic benefits of these more advanced regimens after basal insulin are generally modest in typical patients (92). So, again, individualization of therapy is key, incorporating the degree of hyperglycemia needing to be addressed and the overall capacities of the patient. Importantly, data trends from self-monitoring may be particularly helpful in titrating insulins and their doses within these more advanced regimens to optimize control. A second, perhaps more convenient but less adaptable method involves “premixed” insulin, consisting of a fixed combination of an intermediate insulin with regular insulin or a rapid analog. Traditionally, this is administered twice daily, before morning and evening meals. In general, when compared with basal insulin alone, premixed regimens tend to lower HbA1c to a larger degree, but often at the expense of slightly more hypoglycemia and weight gain (94). Disadvantages include the inability to titrate the shorter- from the longer-acting component of these formulations. Therefore, this strategy is somewhat inflexible but may be appropriate for certain patients who eat regularly and may be in need of a simplified approach beyond basal insulin (92,93). (An older and less commonly used variation of this two-injection strategy is known as “split-mixed,” involving a fixed amount of intermediate insulin mixed by the patient with a variable amount of regular insulin or a rapid analog. This allows for greater flexibility in dosing.) The key messages from dozens of comparative insulin trials in type 2 diabetes include the following: 1. Any insulin will lower glucose and HbA1c. 2. All insulins are associated with some weight gain and some risk of hypoglycemia. 3. The larger the doses and the more aggressive the titration, the lower the HbA1c, but often with a greater likelihood of adverse effects. 4. Generally, long-acting insulin analogs reduce the incidence of overnight hypoglycemia, and rapid-acting insulin analogs reduce postprandial glucose excursions as compared with corresponding human insulins (NPH, Regular), but they generally do not result in clinically significantly lower HbA1c. Metformin is often continued when basal insulin is added, with studies demonstrating less weight gain when the two are used together (95). Insulin secretagogues do not seem to provide for additional HbA1c reduction or prevention of hypoglycemia or weight gain after insulin is started, especially after the dose is titrated and stabilized. When basal insulin is used, continuing the secretagogue may minimize initial deterioration of glycemic control. However, secretagogues should be avoided once prandial insulin regimens are employed. TZDs should be reduced in dose (or stopped) to avoid edema and excessive weight gain, although in certain individuals with large insulin requirements from severe insulin resistance, these insulin sensitizers may be very helpful in lowering HbA1c and minimizing the required insulin dose (96). Data concerning the glycemic benefits of incretin-based therapy combined with basal insulin are accumulating; combination with GLP-1 receptor agonists may be helpful in some patients (97,98). Once again, the costs of these more elaborate combined regimens must be carefully considered. OTHER CONSIDERATIONS Age Older adults (>65–70 years) often have a higher atherosclerotic disease burden, reduced renal function, and more comorbidities (99,100). Many are at risk for adverse events from polypharmacy and may be both socially and economically disadvantaged. Life expectancy is reduced, especially in the presence of long-term complications. They are also more likely to be compromised by hypoglycemia; for example, unsteadiness may result in falls and fractures (101), and a tenuous cardiac status may deteriorate into catastrophic events. It follows that glycemic targets for elderly with long-standing or more complicated disease should be less ambitious than for the younger, healthier individuals (20). If lower targets cannot be achieved with simple interventions, an HbA1c of <7.5–8.0% may be acceptable, transitioning upward as age increases and capacity for self-care, cognitive, psychological and economic status, and support systems decline. While lifestyle modification can be successfully implemented across all age-groups, in the aged, the choice of antihyperglycemic agent should focus on drug safety, especially protecting against hypoglycemia, heart failure, renal dysfunction, bone fractures, and drug–drug interactions. Strategies specifically minimizing the risk of low blood glucose may be preferred. In contrast, healthier patients with long life expectancy accrue risk for vascular complications over time. Therefore, lower glycemic targets (e.g., an HbA1c <6.5–7.0%) and tighter control of body weight, blood pressure, and circulating lipids should be achieved to prevent or delay such complications. This usually requires combination therapy, the early institution of which may have the best chance of modifying the disease process and preserving quality of life. Weight The majority of individuals with type 2 diabetes are overweight or obese (∼80%) (102). In these, intensive lifestyle intervention can improve fitness, glycemic control, and cardiovascular risk factors for relatively small changes in body weight (103). Although insulin resistance is thought of as the predominate driver of diabetes in obese patients, they actually have a similar degree of islet dysfunction to leaner patients (37). Perhaps as a result, the obese may be more likely to require combination drug therapy (20,104). While common practice has favored metformin in heavier patients, because of weight loss/weight neutrality, this drug is as efficacious in lean individuals (75). TZDs, on the other hand, appear to be more effective in those with higher BMIs, although their associated weight gain makes them, paradoxically, a less attractive option here. GLP-1 receptor agonists are associated with weight reduction (38), which in some patients may be substantial. Bariatric surgery is an increasingly popular option in severe obesity. Type 2 diabetes frequently resolves rapidly after these procedures. The majority of patients are able to stop some, or even all, of their antihyperglycemic medications, although the durability of this effect is not known (105). In lean patients, consideration should be given to the possibility of latent autoimmune diabetes in adults (LADA), a slowly progressive form of type 1 diabetes. These individuals, while presenting with mild hyperglycemia, often responsive to oral agents, eventually develop more severe hyperglycemia and require intensive insulin regimens (106). Measuring titres of islet-associated autoantibodies (e.g., anti-GAD) may aid their identification, encouraging a more rapid transition to insulin therapy. Sex/racial/ethnic/genetic differences While certain racial/ethnic features that increase the risk of diabetes are well recognized [greater insulin resistance in Latinos (107), more β-cell dysfunction in East Asians (108)], using this information to craft optimal therapeutic strategies is in its infancy. This is not surprising given the polygenic inheritance pattern of the disease. Indeed, while matching a drug's mechanism of action to the underlying causes of hyperglycemia in a specific patient seems logical, there are few data that compare strategies based on this approach (109). There are few exceptions, mainly involving diabetes monogenic variants often confused with type 2 diabetes, such as maturity-onset diabetes of the young (MODY), several forms of which respond preferentially to sulfonylureas (110). While there are no prominent sex differences in the response to various antihyperglycemic drugs, certain side effects (e.g., bone loss with TZDs) may be of greater concern in women. Comorbidities Coronary artery disease. Given the frequency with which type 2 diabetic patients develop atherosclerosis, optimal management strategies for those with or at high risk for coronary artery disease (CAD) are important. Since hypoglycemia may exacerbate myocardial ischemia and may cause dysrhythmias (111), it follows that medications that predispose patients to this adverse effect should be avoided, if possible. If they are required, however, to achieve glycemic targets, patients should be educated to minimize risk. Because of possible effects on potassium channels in the heart, certain sulfonylureas have been proposed to aggravate myocardial ischemia through effects on ischemic preconditioning (112), but the actual clinical relevance of this remains unproven. Metformin may have some cardiovascular benefits and would appear to be a useful drug in the setting of CAD, barring prevalent contraindications (32). In a single study, pioglitazone was shown to reduce modestly major adverse cardiovascular events in patients with established macrovascular disease. It may therefore also be considered, unless heart failure is present (60). In very preliminary reports, therapy with GLP-1 receptor agonists and DPP-4 inhibitors has been associated with improvement in either cardiovascular risk or risk factors, but there are no long-term data regarding clinical outcomes (113). There are very limited data suggesting that AGIs (114) and bromocriptine (115) may reduce cardiovascular events. Heart failure. With an aging population and recent decreases in mortality after myocardial infarction, the diabetic patient with progressive heart failure is an increasingly common scenario (116). This population presents unique challenges given their polypharmacy, frequent hospitalizations, and contraindications to various agents. TZDs should be avoided (117,118). Metformin, previously contraindicated in heart failure, can now be used if the ventricular dysfunction is not severe, if patient's cardiovascular status is stable, and if renal function is normal (119). As mentioned, cardiovascular effects of incretin-based therapies, including those on ventricular function, are currently under investigation (120). Chronic kidney disease. Kidney disease is highly prevalent in type 2 diabetes, and moderate to severe renal functional impairment (eGFR <60 mL/min) occurs in approximately 20–30% of patients (121,122). The individual with progressive renal dysfunction is at increased risk for hypoglycemia, which is multifactorial. Insulin and, to some degree, the incretin hormones are eliminated more slowly, as are antihyperglycemic drugs with renal excretion. Thus, dose reduction may be necessary, contraindications need to be observed, and consequences (hypoglycemia, fluid retention, etc.) require careful evaluation. Current U.S. prescribing guidelines warn against the use of metformin in patients with a serum creatinine ≥133 mmol/L (≥1.5 mg/dL) in men or 124 mmol/L (≥1.4 mg/dL) in women. Metformin is eliminated renally, and cases of lactic acidosis have been described in patients with renal failure (123). There is an ongoing debate, however, as to whether these thresholds are too restrictive and that those with mild–moderate renal impairment would gain more benefit than harm from using metformin (124,125). In the U.K., the National Institute for Health and Clinical Excellence (NICE) guidelines are less proscriptive and more evidence-based than those in the U.S., generally allowing use down to a GFR of 30 mL/min, with dose reduction advised at 45 mL/min (14). Given the current widespread reporting of estimated GFR, these guidelines appear very reasonable. Most insulin secretagogues undergo significant renal clearance (exceptions include repaglinide and nateglinide) and the risk of hypoglycemia is therefore higher in patients with chronic kidney disease (CKD). For most of these agents, extreme caution is imperative at more severe degrees of renal dysfunction. Glyburide (known as glibenclamide in Europe), which has a prolonged duration of action and active metabolites, should be specifically avoided in this group. Pioglitazone is not eliminated renally, and therefore there are no restrictions for use in CKD. Fluid retention may be a concern, however. Among the DPP-4 inhibitors, sitagliptin, vildagliptin, and saxagliptin share prominent renal elimination. In the face of advanced CKD, dose reduction is necessary. One exception is linagliptin, which is predominantly eliminated enterohepatically. For the GLP-1 receptor agonists exenatide is contraindicated in stage 4–5 CKD (GFR <30 mL/min) as it is renally eliminated; the safety of liraglutide is not established in CKD though pharmacokinetic studies suggest that drug levels are unaffected as it does not require renal function for clearance. More severe renal functional impairment is associated with slower elimination of all insulins. Thus doses need to be titrated carefully, with some awareness for the potential for more prolonged activity profiles. Liver dysfunction. Individuals with type 2 diabetes frequently have hepatosteatosis as well as other types of liver disease (126). There is preliminary evidence that patients with fatty liver may benefit from treatment with pioglitazone (45,127,128). It should not be used in an individual with active liver disease or an alanine transaminase level above 2.5 times the upper limit of normal. In those with steatosis but milder liver test abnormalities, this insulin sensitizer may be advantageous. Sulfonylureas can rarely cause abnormalities in liver tests but are not specifically contraindicated; meglitinides can also be used. If hepatic disease is severe, secretagogues should be avoided because of the increased risk of hypoglycemia. In patients with mild hepatic disease, incretin-based drugs can be prescribed, except if there is a coexisting history of pancreatitis. Insulin has no restrictions for use in patients with liver impairment and is indeed the preferred choice in those with advanced disease. Hypoglycemia. Hypoglycemia in type 2 diabetes was long thought to be a trivial issue, as it occurs less commonly than in type 1 diabetes. However, there is emerging concern based mainly on the results of recent clinical trials and some cross-sectional evidence of increased risk of brain dysfunction in those with repeated episodes. In the ACCORD trial, the frequency of both minor and major hypoglycemia was high in intensively managed patients—threefold that associated with conventional therapy (129). It remains unknown whether hypoglycemia was the cause of the increased mortality in the intensive group (130,131). Clearly, however, hypoglycemia is more dangerous in the elderly and occurs consistently more often as glycemic targets are lowered. Hypoglycemia may lead to dysrhythmias, but can also lead to accidents and falls (which are more likely to be dangerous in the elderly) (132), dizziness (leading to falls), confusion (so other therapies may not be taken or taken incorrectly), or infection (such as aspiration during sleep, leading to pneumonia). Hypoglycemia may be systematically under-reported as a cause of death, so the true incidence may not be fully appreciated. Perhaps just as importantly, additional consequences of frequent hypoglycemia include work disability and erosion of the confidence of the patient (and that of family or caregivers) to live independently. Accordingly, in at-risk individuals, drug selection should favor agents that do not precipitate such events and, in general, blood glucose targets may need to be moderated. FUTURE DIRECTIONS/RESEARCH NEEDS For antihyperglycemic management of type 2 diabetes, the comparative evidence basis to date is relatively lean, especially beyond metformin monotherapy (70). There is a significant need for high-quality comparative-effectiveness research, not only regarding glycemic control, but also costs and those outcomes that matter most to patients—quality of life and the avoidance of morbid and life-limiting complications, especially CVD (19,23,70). Another issue about which more data are needed is the concept of durability of effectiveness (often ascribed to β-cell preservation), which would serve to stabilize metabolic control and decrease the future treatment burden for patients. Pharmacogenetics may very well inform treatment decisions in the future, guiding the clinician to recommend a therapy for an individual patient based on predictors of response and susceptibility to adverse effects. We need more clinical data on how phenotype and other patient/disease characteristics should drive drug choices. As new medications are introduced to the type 2 diabetes pharmacopeia, their benefit and safety should be demonstrated in studies versus best current treatment, substantial enough both in size and duration to provide meaningful data on meaningful outcomes. It is appreciated, however, that head-to-head comparisons of all combinations and permutations would be impossibly large (133). Informed judgment and the expertise of experienced clinicians will therefore always be necessary.
        Bookmark
        • Record: found
        • Abstract: found
        • Article: not found

        Economic costs of diabetes in the U.S. In 2007.

          (2008)
        The prevalence of diabetes continues to grow, with the number of people in the U.S. with diagnosed diabetes now reaching 17.5 million. The objectives of this study are to quantify the economic burden of diabetes caused by increased health resource use and lost productivity, and to provide a detailed breakdown of the costs attributed to diabetes. This study uses a prevalence-based approach that combines the demographics of the population in 2007 with diabetes prevalence rates and other epidemiological data, health care costs, and economic data into a Cost of Diabetes Model. Health resource use and associated medical costs are analyzed by age, sex, type of medical condition, and health resource category. Data sources include national surveys and claims databases, as well as a proprietary database that contains annual medical claims for 16.3 million people in 2006. The total estimated cost of diabetes in 2007 is $174 billion, including $116 billion in excess medical expenditures and $58 billion in reduced national productivity. Medical costs attributed to diabetes include $27 billion for care to directly treat diabetes, $58 billion to treat the portion of diabetes-related chronic complications that are attributed to diabetes, and $31 billon in excess general medical costs. The largest components of medical expenditures attributed to diabetes are hospital inpatient care (50% of total cost), diabetes medication and supplies (12%), retail prescriptions to treat complications of diabetes (11%), and physician office visits (9%). People with diagnosed diabetes incur average expenditures of $11,744 per year, of which $6,649 is attributed to diabetes. People with diagnosed diabetes, on average, have medical expenditures that are approximately 2.3 times higher than what expenditures would be in the absence of diabetes. For the cost categories analyzed, approximately $1 in $5 health care dollars in the U.S. is spent caring for someone with diagnosed diabetes, while approximately $1 in $10 health care dollars is attributed to diabetes. Indirect costs include increased absenteeism ($2.6 billion) and reduced productivity while at work ($20.0 billion) for the employed population, reduced productivity for those not in the labor force ($0.8 billion), unemployment from disease-related disability ($7.9 billion), and lost productive capacity due to early mortality ($26.9 billion). The actual national burden of diabetes is likely to exceed the $174 billion estimate because it omits the social cost of intangibles such as pain and suffering, care provided by nonpaid caregivers, excess medical costs associated with undiagnosed diabetes, and diabetes-attributed costs for health care expenditures categories omitted from this study. Omitted from this analysis are expenditure categories such as health care system administrative costs, over-the-counter medications, clinician training programs, and research and infrastructure development. The burden of diabetes is imposed on all sectors of society-higher insurance premiums paid by employees and employers, reduced earnings through productivity loss, and reduced overall quality of life for people with diabetes and their families and friends.
          Bookmark
          • Record: found
          • Abstract: found
          • Article: not found

          Impact of medication adherence on hospitalization risk and healthcare cost.

          The objective of this study was to evaluate the impact of medication adherence on healthcare utilization and cost for 4 chronic conditions that are major drivers of drug spending: diabetes, hypertension, hypercholesterolemia, and congestive heart failure. The authors conducted a retrospective cohort observation of patients who were continuously enrolled in medical and prescription benefit plans from June 1997 through May 1999. Patients were identified for disease-specific analysis based on claims for outpatient, emergency room, or inpatient services during the first 12 months of the study. Using an integrated analysis of administrative claims data, medical and drug utilization were measured during the 12-month period after patient identification. Medication adherence was defined by days' supply of maintenance medications for each condition. The study consisted of a population-based sample of 137,277 patients under age 65. Disease-related and all-cause medical costs, drug costs, and hospitalization risk were measured. Using regression analysis, these measures were modeled at varying levels of medication adherence. For diabetes and hypercholesterolemia, a high level of medication adherence was associated with lower disease-related medical costs. For these conditions, higher medication costs were more than offset by medical cost reductions, producing a net reduction in overall healthcare costs. For diabetes, hypercholesterolemia, and hypertension, cost offsets were observed for all-cause medical costs at high levels of medication adherence. For all 4 conditions, hospitalization rates were significantly lower for patients with high medication adherence. For some chronic conditions, increased drug utilization can provide a net economic return when it is driven by improved adherence with guidelines-based therapy.
            Bookmark

            Author and article information

            Affiliations
            [1 ]STATinMED Research , Ann Arbor, Michigan, USA
            [2 ]Sanofi-aventis US , Bridgewater, New Jersey, USA
            [3 ]The University of Michigan , Ann Arbor, Michigan, USA
            Author notes
            [Correspondence to ] Dr Onur Baser; obaser@ 123456statinmed.com
            Journal
            BMJ Open
            BMJ Open
            bmjopen
            bmjopen
            BMJ Open
            BMJ Publishing Group (BMA House, Tavistock Square, London, WC1H 9JR )
            2044-6055
            2013
            30 April 2013
            : 3
            : 4
            23633415
            3641450
            bmjopen-2012-002348
            10.1136/bmjopen-2012-002348
            Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions

            This is an open-access article distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited, the use is non commercial and is otherwise in compliance with the license. See: http://creativecommons.org/licenses/by-nc/3.0/ and http://creativecommons.org/licenses/by-nc/3.0/legalcode

            Product
            Categories
            Diabetes and Endocrinology
            Research
            1506
            1688
            1701
            1723

            Medicine

            diabetes costs, healthcare utilization, employee productivity

            Comments

            Comment on this article