Type 2 diabetes mellitus (T2DM) is characterized by progressively worsening hyperglycemia that leads to microvascular and macrovascular complications. Optimal management of T2DM aims to simultaneously control hyperglycemia, hypertension, and dyslipidemia to reduce the overall risk. However, a large proportion of patients in clinical practice do not reach treatment targets. Some of the obstacles to achieving treatment targets include high medication costs, costs associated with health insurance, poor patient adherence to medication, patient fear of potential adverse effects, improper patient education, and failure by health care providers to appropriately initiate or intensify therapy (clinical inertia). Possible causes of clinical inertia include the influence exerted on physicians by reluctant patients and the influence of media-driven attention and the negative spin of clinical trial results on physicians’ prescribing behavior and on patients’ attitudes towards treatment. This negative publicity can be disproportionate to the overall body of scientific evidence and may, therefore, prove to be unfounded in the long-term. There is clear evidence of the benefits of the effective management of T2DM to achieve goals. Overcoming the obstacles to achieving treatment targets may include use of strategies such as early intensive treatment and combination therapy with drugs with complementary mechanisms of action.
Type 2 diabetes mellitus (T2DM) is an increasingly prevalent and progressive disease that has a major impact on public health, with total costs in 2007 estimated at $174 billion in the United States alone.1 Over time, the impairment of the normal response to insulin in the liver and peripheral tissues (insulin resistance), a reduced incretin effect, defects in glucagon regulation, and, most importantly, decreased β-cell mass and function all contribute to worsening glycemic control.2 This leads to microvascular complications, such as neuropathy, retinopathy, and nephropathy, as well as macrovascular complications, including cardiovascular disease, stroke, and peripheral vascular disease.3 Hypertension and dyslipidemia also contribute to the risk for cardiovascular disease in patients with T2DM. Therefore, optimal management of T2DM aims to simultaneously control hyperglycemia, hypertension, and dyslipidemia.4,5 In the Steno-2 trial, 130 of the 160 enrolled patients continued on into the follow-up phase, where the comprehensive approach to treating T2DM by controlling hyperglycemia, hypertension, and dyslipidemia was shown to reduce mortality in the intensive therapy group by 46% compared with the conventional therapy group.6,7
As control of hyperglycemia, hypertension, and dyslipidemia declines, combination therapy is required. However, a large proportion of patients in clinical practice do not reach treatment targets even when they receive combination therapy.8,9 Reasons for this include poor adherence to treatment, attributed to complicated drug regimens and/or the risk of adverse effects,3 as well as clinical inertia exhibited by health care providers—an unwillingness to appropriately initiate or intensify therapy.10–12 This review will examine the obstacles to achieving optimal risk factor management in patients with T2DM and discuss potential strategies for overcoming these obstacles, including the importance of early intensive treatment.
As demonstrated in the 1999 to 2004 National Health and Nutrition Examination Survey data, a significant proportion of patients with T2DM fail to achieve glycemic control (hemoglobin A1c [A1C] levels <7.0%; Figure). Although glycemic control rates have improved in recent years, the proportion of adults with T2DM not achieving A1C levels <7.0% is still >40%.8,13 Even fewer patients with T2DM achieve the A1C goal of ≤6.5% recommended by the American Association of Clinical Endocrinologists (AACE) and the American College of Endocrinology (ACE).14 In addition, most patients are unable to achieve simultaneous control of all three major risk factors (hyperglycemia, hypertension, and dyslipidemia). In one study of 5145 patients with T2DM15 and a second study of 1765 patients with T2DM (85%) or type 1 diabetes (15%),16 only about 10% achieved the recommended goals for A1C (<7.0%), blood pressure (BP, <130/80 mm Hg), and low-density lipoprotein cholesterol (LDL-C, <100 mg/dL [to convert from mg/dL to mmol/L, multiply by 0.0259]).
Reasons for Treatment Failure and Obstacles to Risk Factor Management in T2DM
Patient adherence to treatment is a major obstacle to attaining treatment goals. A study in 11,523 patients with T2DM found that patients who were <80% adherent to their treatment regimen (including oral antidiabetes agents, antihypertensive agents, and/or statin therapy) had significantly higher rates of morbidity and hospitalization, coupled with significantly higher A1C, BP, and LDL-C levels, compared with more adherent patients. Importantly, each 25% improvement in adherence was associated with a reduction in A1C (0.05%), systolic BP/diastolic BP (SBP/DBP, 1.0/1.2 mm Hg), and LDL-C (3.8 mg/dL) that correlated with a significant (P<.01) reduction in all-cause hospitalization and mortality.17 Despite this evidence, many patients may be unwilling to adhere to intensive antidiabetes therapy (particularly with insulin) because of the risks of hypoglycemia and weight gain, need for frequent self-monitoring of blood glucose, preconceived cultural fear of insulin, perceived negative effects on lifestyle,3 and complexity of glucose-lowering regimens.18,19 Nonadherence to antihypertensive and/or lipid-lowering therapy may occur due to similar concerns, such as the complexity of the treatment regimen due to polypharmacy. Medication cost also adversely affects patient adherence. Up to one fifth of adults with diabetes underuse prescription medications because of out-of-pocket costs.20 Lower income and higher out-of-pocket costs significantly increase the likelihood of nonadherence.21 For example, two recent studies demonstrated that when higher prescription copayments were required for patients with T2DM, adherence to oral antidiabetes medications decreased significantly, leading to poorer glycemic control and treatment failure.22,23
Another common cause of treatment failure in the management of hyperglycemia,24 hypertension,25 and dyslipidemia26 is unwillingness on the part of health care providers to appropriately initiate or intensify therapy—termed clinical inertia. Decisions regarding intensification of therapy in the management of T2DM and other chronic health problems rest mainly with the physician. Despite the existence of well-defined targets and practice guidelines for the management of hyperglycemia, hypertension, and dyslipidemia in patients with T2DM, clinical inertia still exists in medical practice. In one study, the average A1C level prior to intensification of pharmacologic treatment was 9.6% and 2 to 3 years had passed before treatment was intensified, exposing patients to long periods of uncontrolled hyperglycemia and high risk for adverse events.11 Furthermore, a recent study reported that it can take up to 9 years after initial diagnosis, with mean A1C values of 9.5%, before insulin is initiated.27
One possible cause of clinical inertia is confusion of the health care provider due to the multiple treatment guidelines, algorithms, and goals recommended by different organizations and societies, which are periodically revised as new data emerges.4,5,14 This lack of consensus, specifically for the treatment of T2DM, makes it such that the health care provider needs to “choose sides” without having the proper tools to do so. Interestingly, clinical inertia appears to be more common among primary care physicians than specialists. The rates of initiation or intensification of pharmaceutical therapy were shown to be low among patients in a primary care setting who were above goals for glycemia, BP, and cholesterol.28 In an observational study, patients treated in a primary care clinic had higher A1C levels than patients treated in a specialty clinic, a difference that was associated with less frequent use of insulin and less frequent intensification of therapy when glucose levels were above recommended targets in the primary care clinic.29 In a separate study, 45.1% of patients under the care of a specialist received treatment intensification subsequent to an A1C measurement of >8.0%, compared with only 37.4% of patients treated by a primary care physician; this difference was statistically significant (P=.009).30 This analysis demonstrated that regardless of the health care provider, <50% of patients received the necessary treatment intensification. These results also suggest that primary care physicians should consider referring a patient to a specialist when more intensive therapy is required, particularly if the patient is poorly controlled, has complicating comorbidities, and/or is at high risk for microvascular or macrovascular events. Conversely, in view of the epidemic of T2DM and the reduced availability of specialists in many areas of the country, primary care physicians need to be better educated and provided with the appropriate tools to confidently treat patients with T2DM earlier and more intensely.
Clinical inertia exhibited by physicians can also be influenced by patient adherence. A T2DM study demonstrated that patients with poor medication adherence and elevated A1C levels were less likely to have their treatment regimen intensified compared with patients with good adherence and elevated A1C levels. However, even among the most adherent patients, treatment intensification was generally delayed for almost 2 years.31 Furthermore, a prospective cohort study of adults with T2DM demonstrated that treatment went unchanged, and was even decreased, in a proportion of patients who failed to achieve A1C, SBP, or LDL-C treatment goals (Table).28 Another cause of clinical inertia is overestimation of care by both physicians and patients. For example, a survey of physicians and patients in the United Kingdom, France, Germany, Italy, and Spain revealed that, although 76% of physicians and 95% of patients believed their BP was adequately controlled, only 37% of these patients achieved recommended BP treatment goals.32 Additional causes of clinical inertia include concerns about potential adverse effects and drug interactions, concerns by physicians and patients about whether results from large clinical trials can be used to guide decision making in the clinical setting, and lack of education or training. Furthermore, patients previously experiencing adverse effects may be more reluctant to undergo treatment, and this may adversely influence the physician’s decision to treat aggressively.10
Table TABLE. Changes in Medical Therapy Among Patients With Type 2 Diabetes Mellitus Who Failed to Meet Treatment Goals for A1C, SBP, and LDL-C28
Data are expressed as numbers and proportions. Low-density lipoprotein cholesterol (LDL-C): to convert from mmol/L to mg/dL, divide by 0.0259. aGoal risk factor levels: hemoglobin A1c (A1C) >8.0%, systolic blood pressure (SBP) >130 mm Hg, LDL-C >3.4 mmol/L (or >2.6 mmol/L if coronary artery disease is present). bChi-square tests were used to compare A1C with SBP and A1C with LDL-C. cRelative potencies of 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitors were compared to determine increased vs decreased regimen. N/A, not available. Reproduced with permission from Grant et al.28
Patients above goala at year 1, No.
Untreated at end of year 1, No. (%)
Started on therapy during year 2, No. (%)
On treatment at end of year 1, No. (%)
Change in regimen during year 2, %
Missing dose information
Effect of Direct-to-Consumer Advertising and Negative Publicity Surrounding Clinical Trial Results
Direct-to-consumer advertising (DTCA) can have negative effects on a patient’s willingness to accept new therapeutic regimens. For example, a study on the impact of televised DTCA found that 28% of respondents felt that DTCA caused confusion, and 18% of respondents stopped taking their medication due to concerns about the serious adverse effects mentioned in DTCA.33
Another potential contributor to clinical inertia is the media spin of clinical trial results or meta-analyses, particularly when these results are negative and subsequently shown to be inconclusive and/or subject to reinterpretation. For instance, following a widely criticized meta-analysis suggesting that rosiglitazone was associated with a significant increase in the risk of myocardial infarction,12 many patients discontinued not only rosiglitazone but other antidiabetes medications as well.34 In an analysis of lay media articles on rosiglitazone published subsequent to the meta-analysis, a medical reviewer and a lay reviewer found that 75% of these articles were “worrisome” (vs “neutral” or “not worrisome”).35 When there was disagreement as to tone, the lay reviewer was significantly more likely to give a worrisome appraisal than the medical reviewer (77% vs 3%, respectively; P=.003). Further analysis demonstrated that a substantial number of patients who had discontinued rosiglitazone received less-aggressive therapy, with 13% receiving no substitute agent, leading to no pharmacologic treatment of T2DM in those patients.34 Moreover, the use of combination therapy markedly decreased from 89% to 33%. Only 6% of patients were switched to pioglitazone, alone or in combination, suggesting an increase in physician uncertainty about thiazolidinediones as a class.
The impact of media-driven confusion on clinical inertia was also seen in the reporting of results from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study. In the ACCORD study,36 intensive therapy to reduce A1C to <6.0% was associated with significantly increased all-cause mortality compared with standard therapy targeting A1C to 7.0% to 7.9%, raising doubts about the safety and desirability of attaining low A1C levels. The exact cause of the increased mortality in patients receiving intensive therapy remains unknown, and data from similar studies (the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation [ADVANCE] and the Veterans Affairs Diabetes Trial [VADT]) did not demonstrate an adverse effect of intensive therapy on mortality risk.37,38 Moreover, further analysis of the ACCORD data showed that patients in the intensive therapy treatment group who had higher baseline A1C levels (>8.5%), and presumably higher cardiovascular risk, had a higher risk of mortality, while those with a lower A1C level were more protected.39 Similarly, another analysis demonstrated that patients whose A1C levels remained at >7.0% during intensive treatment had a higher risk of mortality than those with A1C <7.0%.40 A consensus statement by the American Diabetes Association (ADA), the American College of Cardiology Foundation, and the American Heart Association maintains that there is no need for major changes in glycemic control targets because of results from the ACCORD, ADVANCE, and VADT trials.41 However, it appears evident that a lack of nuanced reporting and discussion of these data in the media may have led to confusion in the general public and the medical community regarding the value of intensive glycemic control in T2DM.
A similar situation arose in reports from Germany that seemingly linked the use of insulin glargine with a higher, dose-related incidence of cancer than seen with human insulin.42 However, subsequent large retrospective cohort studies in the United Kingdom,43 Scotland,44 and Sweden45 failed to confirm this association. Subsequently, the US Food and Drug Administration46 released a statement that the data regarding the use of insulin glargine and increased cancer risk were inconclusive, as a result of limitations in study design. How this has affected the treatment of T2DM in patients receiving insulin, and particularly insulin glargine, remains undetermined.
Proposed Solutions to Overcome Obstacles to Risk Factor Management in T2DM
The increased prevalence of T2DM and failure to achieve adequate control of risk factors in the majority of patients have serious implications in terms of the future burden of mortality, morbidity, and health care costs associated with T2DM,9 and further efforts will be required to reduce the large proportion of adults with T2DM who continue to have elevated glucose, BP, and cholesterol levels. Adherence can be improved by conducting open discussions with patients and reviewing the long-term importance of taking medications on a regular basis.20 To prevent nonadherence due to cost, clinicians should attempt to identify medications with the lowest possible out-of-pocket costs, without compromising treatment effectiveness. Nurses, social workers, and pharmacists can assist clinicians by suggesting regimens that are suited to a patient’s health status and financial situation.20 Possible measures for overcoming clinical inertia include ongoing monitoring and measurement of quality of care, building incentives for providing comprehensive care in the health care system, empowering health care providers with medical decision-support tools, and providing patients with information.9 Routine use of the current clinical guidelines4,5,14 (which mandate therapeutic changes every 2 to 3 months if the target A1C level is not achieved) is an important aspect of this process. In addition, improving processes that focus on intensification of therapy can overcome clinical inertia and lead to improved control of glucose,47 BP, and cholesterol levels.
Benefits of Intensive Treatment of T2DM
The lasting benefits of early, intensive antidiabetes treatment have been demonstrated in the United Kingdom Prospective Diabetes Study (UKPDS). Intensive glycemic control with sulfonylureas, metformin, or insulin in patients with newly diagnosed T2DM significantly decreased the risk of microvascular complications compared with conventional treatment. For example, intensive metformin therapy in overweight patients reduced the risk of any diabetes-related end point, diabetes-related death, and all-cause mortality. In addition, the risk of myocardial infarction was reduced by 39% (P=.01).48 Importantly, results from a 10-year follow-up showed that the reduction in the risk of microvascular complications observed among patients treated with sulfonylureas, metformin, or insulin was sustained throughout the post-trial period, and a significant risk reduction for myocardial infarction and death from any cause also emerged during the post-trial period.49
Several other studies have emphasized the clinical benefits of intensive treatment of risk factors in T2DM. In the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) study,50 the rates of death and major cardiovascular events over 5 years in patients with T2DM and coronary artery disease did not differ significantly among patients receiving prompt revascularization plus intensive medical therapy and those receiving intensive medical therapy alone. In addition, there was no difference between insulin-sensitization therapy and insulin-provision therapy aimed at achieving an A1C <7.0%. All patients were also treated to recommended BP and LDL-C targets. At a 3-year follow-up, 47% of patients receiving intensive medical therapy had met A1C targets, 71% had met BP targets, and 83% had met LDL-C targets; all three targets were achieved by 28% of patients. Thus, aggressive treatment of all risk factors resulted in similar clinical outcomes regardless of the approach.50 However, insulin-sensitizing therapy may provide better long-term metabolic effects, which, in turn, could increase patient adherence. For example, patients in the BARI 2D study who received insulin-sensitization therapy had a significantly lower mean body mass index at 3 years, fewer episodes of hypoglycemia, and higher high-density lipoprotein cholesterol (HDL-C) levels compared with those who received insulin-provision therapy.50
To help achieve these benefits, the 2009 AACE/ACE glycemic control algorithm recommends initiating lifestyle modifications and oral antidiabetes monotherapy in patients with an A1C ≥6.5%, dual therapy in patients with an A1C >7.5%, and either triple therapy in asymptomatic or insulin therapy in symptomatic, drug-naïve patients with an A1C >9.0%.14 Pharmacologic treatment may also be considered for some high-risk patients with an A1C <6.5%.14 The ADA guidelines51 recommend starting all patients on lifestyle modifications and metformin monotherapy. Both guidelines recommend instituting more-intense regimens in patients who have not achieved their A1C goal after 2 to 3 months of therapy. These guidelines stress that combining antidiabetes agents with different modes of action is advantageous, since they would be expected to have additive effects and allow lower dosages of each to be used, theoretically lowering the overall risk of adverse effects. In addition, treatment guidelines recommend reducing BP to <130/80 mm Hg in patients with T2DM, as well as using combination therapy if BP is >20/10 mm Hg above BP goal.52 The ADA guidelines support reducing LDL-C levels to <100 mg/dL (<70 mg/dL for high-risk patients) in patients with T2DM to reduce cardiovascular risk.4 Often, combination antihypertensive and lipid-lowering therapy is required to achieve treatment goals.
Several studies have shown that early treatment with combination therapy is more effective than monotherapy for achieving glycemic control.53,54 In patients with uncontrolled T2DM, initial treatment with fixed-dose rosiglitazone and metformin led to significantly greater reductions in A1C after 32 weeks, compared with either agent alone.53 Similarly, in a 2-year study, sitagliptin and metformin as initial combination therapy led to greater reductions in A1C than either monotherapy.54 A study evaluating saxagliptin and metformin as initial combination therapy also demonstrated significantly greater reductions in A1C than either agent alone for up to 76 weeks.55,56 Furthermore, there is no glycemic threshold for reduction in the risk of complications; the better the glycemic control, the lower the risk.40,57 In patients with an A1C of 6.5% to 7.5%, the AACE/ACE glycemic control algorithm recommends dual combination therapy that includes the use of metformin or a thiazolidinedione (if metformin is contraindicated) with an incretin mimetic, a dipeptidyl peptidase-4 inhibitor, or an insulin secretagogue, such as a glinide or sulfonylurea.14 Other recommended combinations include metformin with either the bile acid sequestrant colesevelam (indicated for lowering LDL-C as well as being the only bile acid sequestrant approved by the US Food and Drug Administration as adjunctive therapy to improve glycemic control in adults with T2DM) or an alpha-glucosidase inhibitor; both are associated with a minimal risk of hypoglycemia.14 Intensification to triple therapy algorithms, such as metformin with an incretin mimetic or a dipeptidyl peptidase-4 inhibitor and a thiazolidinedione or an insulin secretagogue, is recommended for patients not controlled on dual therapy.
Current treatment guidelines also recommend continuous management of glycemia, BP, and lipid levels to reduce the long-term risk of complications.4,5 The primary recommendation for lipid management in patients with T2DM is to reduce LDL-C levels and numbers of small LDL particles.58 Combination therapy to manage LDL-C levels (<100 mg/dL [<70 mg/dL for high-risk patients]) in patients with T2DM includes the use of statins with fibrates, niacin, ezetimibe, or bile acid sequestrants.4,5 Combination therapy with a statin and a fibrate leads to reductions in LDL-C and triglyceride levels and a greater increase in HDL-C than with either monotherapy.4,5 In the ACCORD study, adding fenofibrate to simvastatin significantly lowered total cholesterol and triglyceride levels, and significantly increased HDL-C levels, compared with simvastatin alone; both treatment groups had comparable decreases in LDL-C.59 However, the rate of fatal cardiovascular events, nonfatal myocardial infarction, or nonfatal stroke was not reduced with simvastatin plus fenofibrate therapy compared with simvastatin monotherapy.59 Despite this, some patient subgroups appeared to benefit from fenofibrate therapy. Among men, the primary outcome of fatal or nonfatal cardiovascular events was lower in the fenofibrate group than the placebo group (11.2% vs 13.3%; P=.01 for interaction). There was also a nonsignificant decrease in the primary outcome with fenofibrate treatment among patients with high triglyceride levels (≥204 mg/dL) and low HDL-C levels (≤34 mg/dL; 12.4% vs 17.3%; P=.057 for interaction).59 Intensive therapy with simvastatin and fenofibrate was found to significantly reduce the progression of diabetic retinopathy.60 The combination of a statin and niacin also reduces LDL-C and triglyceride levels and has additive effects on HDL-C.5 Combination therapy with a statin and a bile acid sequestrant (colesevelam) results in similar, if not greater, reductions in LDL-C compared with high-dose statin monotherapy.61–63 In addition, colesevelam in combination with a fibrate or niacin may be useful for intensive lipid lowering in certain patients, such as those who are statin intolerant.64,65 Combining colesevelam with ezetimibe is another effective therapeutic option for patients who are intolerant to statins or when statins are contraindicated.66–68
Fixed-dose combination medications to treat hyperglycemia, hypertension, and/or dyslipidemia are often preferred due to a higher level of patient adherence compared with analogous component combination therapy.69,70 The higher patient adherence with fixed-dose combination medications is thought to be largely due to lower pill burden and simplification of the drug regimen.69,70 There are also drawbacks to fixed-dose combination medications, including their reduced dosing flexibility, which may prevent some physicians from prescribing these agents. However, reduced dosing flexibility is unlikely to be a problem for fixed-dose combination medications, as there are many available dose combinations, and therefore the potential for increased adherence with fixed-dose combination medications usually outweighs the drawbacks. The fixed-dose combination of amlodipine and atorvastatin may be used instead of the individual agents to treat both hypertension and dyslipidemia in patients with T2DM, thereby reducing the overall number of medications. Similarly, drugs that target >1 risk factor may be beneficial for patients with T2DM. Colesevelam targets both hyperglycemia and dyslipidemia without producing the additive risk of adverse effects inherent in fixed-dose combinations of distinct pharmacologic agents.71 In clinical trials, colesevelam significantly reduced A1C levels and also decreased LDL-C, total cholesterol, and apolipoprotein B levels in patients with T2DM.72–74 The addition of colesevelam to an antidiabetes agent(s) and/or a lipid-lowering agent(s) may enable patients to get closer to both their glycemic and LDL-C treatment targets without necessitating the addition of separate antidiabetes and lipid-lowering agents. Therefore, drugs that target >1 risk factor, such as atorvastatin/amlodipine and colesevelam, may help to overcome some obstacles to risk management in T2DM.
Maintaining Objectivity Regarding Publicity Around Clinical Trial Results
Opinions expressed in the media should always be considered based on the merits of the individual clinical trial being reported. Thus, health care providers need to be diligent in reviewing published study data and making therapeutic decisions based on these data. While it is natural to err on the side of caution, premature actions based on incomplete or misleading information can potentially have adverse consequences for the ongoing management of T2DM. Conversely, failing to act in the face of compelling evidence can have similar or worse consequences, as highlighted by the events surrounding the cardiovascular complications associated with rofecoxib.75 Therefore, a balance between caution and timely reaction needs to be maintained.
Despite the proven benefits of antidiabetes treatments in clinical trials, a large proportion of patients in clinical practice do not achieve glycemic control, and fewer achieve combined treatment goals for blood glucose, BP, and cholesterol. This is the result of a number of factors, including poor patient adherence; cost of medications; clinical inertia stemming from reluctance by health care providers to initiate intensive treatment regimens; conflicting treatment guidelines and treatment algorithms as well as periodic revisions of these guidelines and algorithms, which can cause uncertainty about appropriate treatment; and confusion surrounding clinical trials results because of media interpretation. Routine and timely use of sensible treatment algorithms and therapies that can address more than one cardiovascular risk factor in patients with T2DM (such as lowering BP and LDL-C or glucose and LDL-C) is one approach that may help overcome obstacles to risk factor management in T2DM by improving patient adherence, simplifying treatment regimens, and improving patient outcomes.
Acknowledgments: Editorial assistance provided by Luana Atherly, PhD, Paul McCormack, PhD, and Lucy Whitehouse of inScience Communications, a Wolters Kluwer business, was funded by Daiichi Sankyo, Inc.
Disclosures: Dr Handelsman has received research grants from Boehringer Ingelheim, Daiichi Sankyo, Inc, GlaxoSmithKline, Novo Nordisk, sanofi-aventis, Takeda Pharmaceuticals, Xoma, and Tolrex; served as a consultant for Abbott, Daiichi Sankyo, Inc, GlaxoSmithKline, Genentech, Merck, and Tolrex; and served as a speaker for AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Inc, GlaxoSmithKline, Merck, and Novo Nordisk. Dr Jellinger has received honoraria for serving on the speakers’ bureau for Amylin, Eli Lilly & Co, Merck, and Novo Nordisk.