Improving Clinical Outcomes: The Role of Incretin-Based Therapies

Transcription

1 Issue 4 Clinical Use of Incretin-Based Therapies to Treat Type 2 Diabetes Term of Approval Release date: April 2010 Expiration date: April 30, 2011 Improving Clinical Outcomes: The Role of Incretin-Based Therapies IN THIS ISSUE: Page 1 Introduction 2 A1C and postprandial plasma glucose: Correlation with patient outcomes 4 Effects of incretin-based therapies on indicators of control 7 Safety and tolerability of incretin-based therapies 9 Successful implementation of incretin-based therapies: Patient characteristics to consider 10 Case Studies Editor David D Alessio, MD Professor of Medicine Director, Division of Endocrinology University of Cincinnati College of Medicine Chief, Endocrinology and Diabetes Clinic VA Medical Center Cincinnati, Ohio Sponsored by the Institute for Medical and Nursing Education, Inc. and brought to you by the Caring for Diabetes Educational Forum. This activity is partially supported by an educational grant from Takeda Pharmaceuticals North America, Inc. 1

2 Program Overview Several landmark clinical studies have demonstrated the relationship between type 2 diabetes and an increased risk of both microvascular and macrovascular complications. Optimal glycemic control can decrease the development of microvascular disease, such as retinopathy and nephropathy, and is the central rationale for current glycemic targets in diabetic patients. Unfortunately, recent estimates indicate that only 57% of type 2 diabetes patients achieve the glycemic target of A1C < 7% recommended by the American Diabetes Association. It is now clear that both fasting and postprandial glucose control contribute to A1C, and reaching glycemic targets may require attention to both components in any given patient. There is now a spectrum of medications that can be used to treat patients with type 2 diabetes, some of which have disproportionate effects on fasting or postprandial glucose. The ability to apply specific therapies to optimize glucose control in individual patients requires familiarity with drugs that control fasting and postprandial glucose. This publication series will explore the science of postprandial plasma glucose (PPG) and its contribution to glycemic control and will highlight recent and emerging therapies that address this important target. Intended Audience This program is intended for endocrinologists, diabetologists, and other healthcare professionals (HCPs) who frequently treat patients with type 2 diabetes. Faculty David D Alessio, MD Research Activities: Amylin Pharmaceuticals, Inc; Eli Lilly and Company; Johnson & Johnson. Consultant: Amylin Pharmaceuticals, Inc; MannKind Corporation; Merck & Co, Inc; Takeda Pharmaceuticals North America, Inc; Wyeth; Sanofi-Aventis; Novo Nordisk. Educational Partner Staff Steve Weinman, RN Executive Director IMNE Disclosures: Nothing to disclose Sheryl Torr-Brown, PhD Scientific Director IMNE Disclosures: Nothing to disclose Robin Devine, DO Medical Writer IMNE Disclosures: Nothing to disclose Amy Groves Director of Program Development IMNE Disclosures: Nothing to disclose 2 Learning Objectives Upon completion of this activity, the participant should be able to: Describe the role of incretin-based therapies in the management of hyperglycemia with particular focus on PPG and improvement of clinical outcomes Compare and contrast the efficacy and safety of the dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists for the treatment of type 2 diabetes Discuss the available evidence in the published guidelines and treatment algorithms pertaining to the importance of PPG monitoring for maintaining glycemic control Explain how the mechanisms of action of the incretin-based therapies address the multi-factorial complexities of type 2 diabetes Accreditation and Credit Designation Statements The Institute for Medical and Nursing Education, Inc (IMNE) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education (CME) for physicians. IMNE designates this educational activity for a maximum of 2.0 AMA PRA Category 1 Credit(s). Physicians should only claim credit commensurate with the extent of their participation in the activity. Disclosures In compliance with the ACCME s Standards for Commercial Support, it is the policy of IMNE to ensure fair balance, independence, objectivity, and scientific rigor in all programming. All individuals involved in planning (eg, CME provider staff, faculty, and planners) are expected to disclose any significant financial relationships with commercial interests over the past 12 months. IMNE also requires that faculty identify and reference off-label or investigational use of pharmaceutical agents and medical devices. In accordance with ACCME Standards for Commercial Support, parallel documents from other accrediting bodies, and IMNE policy, identification and resolution of conflict of interest have been made in the form of external peer review of educational content. The following disclosures have been made: Betsey King Associate Director of Program Development IMNE Disclosures: Nothing to disclose CME Reviewers Robert Hash, MD Texas A&M Health Science Center College of Medicine College Station, Texas Dr Hash has nothing to disclose Martin Quan, MD David Geffen School of Medicine University of California, Los Angeles Los Angeles, California Dr Quan has nothing to disclose Disclaimer This activity is designed for HCPs for educational purposes. Information and opinions offered by the faculty/presenters represent their own viewpoints. Conclusions drawn by the participants should be derived from careful consideration of all available scientific information. While IMNE makes every effort to have accurate information presented, no warranty, expressed or implied, is offered. The participant should use his/her clinical judgment, knowledge, experience, and diagnostic decisionmaking before applying any information, whether provided here or by others, for any professional use. Commercial Support Acknowledgment This activity is partially supported by an educational grant from Takeda Pharmaceuticals North America, Inc. Method of Obtaining CME Credit CME credit/verification is offered upon successful completion of a posttest with a minimum passing score of 70%. CME certificates will be issued to participants after receipt of the CME registration form, evaluation form, and successfully completed posttest. For those taking the test and completing the evaluation online at a printable certificate will be made available upon successful completion of the posttest. Questions or comments can be addressed to steve.weinman@imne.com. If you choose to apply for CME credit by mail or fax, please allow up to 12 weeks for issuance of CME credit.

3 Introduction Type 2 diabetes mellitus (T2DM) contributes substantially to morbidity and mortality in the United States. On the basis of 2007 estimates, the number of Americans with diabetes (types 1 and 2) increased by more than 3 million over approximately 2 years, reaching nearly 24 million. 1,2 Unfortunately, this increase is not an isolated trend. The incidence of diabetes has more than doubled in the last 27 years, with T2DM accounting for up to 95% of all diabetes cases. 1,3 The burden this disease places on the healthcare system is immense. Diabetes leads to increased rates of macrovascular complications, such as heart disease and stroke, as well as microvascular complications, including kidney disease, retinopathy, and neuropathy. Adults with diabetes are up to 4 times more likely to die from heart disease than are adults without diabetes. The stroke rate is up to 4 times higher in the diabetic population than in the nondiabetic population. Diabetes is known to cause nephropathy, accounting for 44% of new cases of kidney failure in the United States as recently as Diabetes also accounts for greater than 60% of nontraumatic lower-limb amputations. Up to 70% of diabetes patients have some type of nervous system damage, ranging from peripheral neuropathy to erectile dysfunction. 2 In addition, diabetes is the seventh leading cause of death in the United States; the risk of death is almost double for a person with diabetes (type 1 and type 2) than for a nondiabetic person of similar age. 2 Estimates of direct and indirect costs of care for diabetes patients in the United States in 2007 were $116 billion and $58 billion, respectively. 2 Therefore, improving diabetes morbidity and mortality has been an important focus of scientific research and clinical practice. Progress in this venue is limited due to the complex nature of T2DM itself, conflicting study outcomes, the effectiveness and adverse events of traditional antidiabetic therapy, and patient-related factors such as compliance and lifestyle. Numerous studies have evaluated the relationship between glycemic control and both microvascular and macrovascular outcomes. Elevated hemoglobin A1C levels have previously been linked with increased rates of cardiovascular (CV) disease as well as microvascular complications. 4 Landmark trials, including the United Kingdom Prospective Diabetes Study (UKPDS) and the Kumamoto study of glycemic control in T2DM, have demonstrated that improved glycemic control decreases microvascular complications. 5,6 This information has led to the development of treatment guidelines from the American Diabetes Association (ADA)/European Association for the Study of Diabetes (EASD), International Diabetes Federation (IDF), and American Association of Clinical Endocrinologists (AACE), which recommend intensive glycemic control (IGC) to reduce the incidence of microvascular complications. 7,8,9 However, the effect of tight glycemic control on macrovascular complications is not as clear. The results of more recent studies, such as the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) study, and the Veterans Affairs Diabetes Trial (VADT), initially appeared to be conflicting regarding IGC and its effect on CV outcomes. The ACCORD trial was designed to investigate the effects of IGC on CV events. However, the study was terminated after a mean of 3.5 years because of higher mortality rates in the intensive therapy group. 10 Interestingly, later subset analyses showed a significant CV risk reduction in subjects in the intensive arm who had no prior CV events and a baseline A1C < 8%. 11 ADVANCE and VADT initially failed to show any CV risk reduction with IGC. 11 However, a further subset analysis with computed tomography measurement of coronary artery calcium levels showed that IGC did reduce CV events in patients with lower levels of calcified coronary atherosclerosis at baseline. 12 Similarly, 10-year follow-up data from the UKPDS indicated a legacy effect for IGC. Those patients who received intensive control experienced a persistent decrease in microvascular risk 5 years after the study ended. In addition, a reduction in CV risk was observed during the follow-up period. 13 Results of the subset analyses of ACCORD, ADVANCE, and VADT raise the possibility that IGC can beneficially lower the risk of CV disease in subjects who do not have established or advanced macrovascular disease. In 2009, 3 meta-analyses examining the effects of glycemic control on macrovascular disease were published. Mannucci et al, in a meta-analysis of 5 studies including over 30,000 patients, found that IGC was associated with a decreased risk of nonfatal myocardial infarction (MI) but not with a decreased risk of cerebrovascular accident or CV mortality. 14 The intensive group, however, exhibited an increased incidence of hypoglycemia associated with Peak Issues is a publication series that focuses on glycemic control in patients with type 2 diabetes, with an emphasis on the regulation of postprandial plasma glucose (PPG) levels through the use of incretin-based therapies and the potential benefits of this approach. 1

4 an increased CV risk. A meta-analysis by Turnbull et al also evaluated the effects of IGC on CV risk. 15 Similarly, they found a decreased risk of CV events in the more intensive arm, but a subset analysis revealed a possible difference in risk for patients with and without established macrovascular disease. Finally, Kelly et al examined 5 trials involving over 27,000 patients to examine the benefits versus the risks of IGC. 16 Similarly to the other 2 meta-analyses, a reduced risk of nonfatal MI was found in the intensive arm, but an increased risk of severe hypoglycemia was found with IGC. These findings suggest that IGC may have a positive long-term effect on CV outcomes, but the relationship between IGC and CV risk is complicated. The risk of hypoglycemia and the associated potential for increased CV events necessitate individualization of treatment plans to avoid hypoglycemia while still improving glycemic control. Additionally, one must consider the patient s current CV state, because data suggest that patients with established CV disease and other comorbidities may not benefit from IGC and, in fact, may be at greater risk of complications from IGC. 11 While fasting plasma glucose (FPG) and A1C are widely used measures of glycemic control, postprandial plasma glucose (PPG) levels may also merit attention in managing T2DM and trying to reduce CV risk. PPG elevations are the consequence of dysfunction in a number of hormonal components. Historically, insulin resistance and declining β-cell function have been targeted in attempts to restore glycemic control. However, a newer understanding of the pathophysiology of T2DM has widened this focus. Increased postprandial glucagon secretion with continued and inappropriate hepatic glucose production, rapid gastric emptying, and an decreased incretin effect may all contribute to postprandial hyperglycemia and insulin resistance in T2DM patients. Incretin-based therapies lower A1C, have specific effects that can improve PPG levels, and may also have beneficial effects on CV disease risk factors such as excessive body weight, dyslipidemia, and elevated blood pressure. This issue is the last in a series of 4 Peak Issues publications to address the role of incretin-based therapies in managing hyperglycemia, with a particular focus on PPG and the improvement of clinical outcomes for patients with T2DM. Previous publications of Peak Issues have explored, in depth, the physiology of incretin hormones as well as the efficacy and tolerability of the dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists. A1C and Postprandial Plasma Glucose: Correlation With Patient Outcomes A1C, Fasting Plasma Glucose, and Postprandial Plasma Glucose Are Related A1C levels provide a measure of average plasma glucose levels, including PPG and FPG, over the previous 2 to 3 months and enable the clinician and patient to more accurately manage glycemic control. 17 Increasing A1C levels have been correlated with an increased risk of microvascular and macrovascular complications. 4 In addition, studies have shown that the risk of retinopathy is more strongly correlated with A1C levels than with FPG. 18 Recently, an expert committee, with members appointed by the ADA, recommended the A1C assay as an acceptable screening tool for the diagnosis of diabetes. 18 According to the ADA s 2010 position statement, the A1C assay is now regarded as an accepted diagnostic tool for those suspected to have diabetes. 19 A1C levels, however, may not adequately reflect the day-to-day variability of glucose levels; therefore, a combination of A1C levels and self-monitoring of blood glucose (SMBG) is still recommended for the management of T2DM. 20 Postprandial Plasma Glucose Dysregulation Occurs Early in the Natural History of Type 2 Diabetes It is also known that abnormal PPG excursions occur early in the development of diabetes, often before FPG levels rise. 21 This is an important observation because, in many patients progressing to T2DM, normal FPG is maintained in the early stages of disease. The sole measurement of FPG levels may result in PPG elevations being missed, and thus delay the diagnosis of T2DM. β-cell dysfunction also starts prior to the onset of diabetes and progresses with time (Figure 1); therefore, early diagnosis and treatment may improve longterm outcomes Figure 1: Natural History of Type 2 Diabetes 24 Glucose (mg/dl) Relative Amount Prediabetes (Obesity, IFG, IGT) Diabetes diagnosis Postmeal Glucose Fasting glucose β-cell failure Insulin resistance Insulin level Onset Years diabetes Clinical Macrovascular changes features Microvascular changes IFG, impaired fasting glucose; IGT, impaired glucose tolerance. Kendall DM, et al. Am J Med. 2009;122:S37-S50. Kendall DM, et al. Am J Manag Care. 2001;7(suppl):S327-S343. PPG levels are known to rise early in the progression toward T2DM, but how they relate to A1C and FPG is still being investigated. 25 Bonora et al studied plasma glucose levels in non-insulin-treated patients with T2DM and found that PPG levels were often high (> 160 mg/dl), even in patients with good glycemic control (A1C < 7%). 26 Similarly, Erlinger and Brancati demonstrated that 39% of non-insulin-treated T2DM patients with optimal glycemic control (A1C < 7%) still could 2

5 be considered to have hyperglycemia when evaluated using an oral glucose tolerance test (OGTT). 27 Of relevance to these findings, Monnier et al evaluated the contribution of FPG and PPG to overall hyperglycemia in 290 non-insulin-treated T2DM patients (Figure 2). 28 Figure 2: Relationship Between Postprandial Glucose (PPG) and Hemoglobin A1C 21,28 Contribution (%) a,b b < > 10.2 A1C (%) a Significant difference between postprandial and fasting plasma glucose. b Significantly different from all other quintiles. A1C = Hemoglobin A1C a a Postprandial hyperglycemia Fasting hyperglycemia Postprandial glycemic control deteriorates before fasting glycemic control as type 2 diabetes progresses. Monnier L, et al. Diabetes Care. 2007;30: Monnier L, et al. Diabetes Care. 2003;26: They found that PPG contributed more substantially to overall hyperglycemia at lower A1C levels and decreased as the A1C levels rose. Conversely, FPG contributed more substantially when the A1C rose above 8.4%. 28 These results are important to our understanding of hyperglycemia and may aid in our ability to provide more focused care, targeting the individual patient s specific glycemic abnormality and improving longterm outcomes. Several trials have examined the effects of lifestyle intervention and medication on the progression of impaired fasting glucose (IFG) or impaired glucose tolerance (IGT) to frank diabetes. In 2001, the Finnish Diabetes Prevention Study evaluated the effects of lifestyle interventions on patients with IGT. The investigators reported a 58% reduction in the risk of developing T2DM in the intervention group. 29 In the United States, the Diabetes Prevention Program (DPP) examined patients at high risk of developing T2DM (overweight, IFG, and IGT). They compared lifestyle intervention or the administration of metformin with placebo. The blinded portion of the study was terminated a year early because of an emerging reduction in risk of progression to T2DM in the intervention arms. Metformin reduced the incidence of T2DM by 31%, whereas lifestyle intervention resulted in a 58% reduction compared with placebo. 30 Additional studies using acarbose, orlistat, rosiglitazone, and liraglutide have shown that intervention can delay or prevent progression to T2DM Impact of Elevated PPG on Cardiovascular Outcomes Recent evidence suggests that PPG levels not only contribute to A1C, but may be an independent risk factor for CV disease even more so than FPG. 25,34 The mechanisms thought to contribute to this increased CV risk are increased oxidative stress, free radical generation, inflammation, endothelial dysfunction, and hypercoagulability. 35 Postmeal hyperglycemia is associated with increased carotid intimamedia thickness as well as decreased myocardial blood volume and blood flow. 25 The Diabetes Epidemiology: Collaborative Analysis of Diagnostic Criteria in Europe (DECODE) meta-analysis examined data from 10 prospective European studies involving more than 20,000 patients between the ages of 30 and 89 years (median follow-up: 8.8 years). They found that FPG alone did not predict CV risk adequately. A 2-hour PPG reading, however, was a better predictor of death than was FPG. 36 In patients with established diabetes, control of PPG levels may afford greater CV performance than A1C reduction alone. Bibra et al evaluated the effects of greater PPG control on myocardial function over 2 years. 37 The investigators randomly assigned patients to 3 treatment groups: conventional therapy with premixed insulin, intensified therapy with insulin lispro at meals and insulin NPH at bedtime, or supplementary insulin therapy with regular human insulin at meals. All patients in the study had relatively good glycemic control on the basis of A1C values (mean A1C during the study: 6.4% ± 0.6%). However, the intensified insulin therapy and supplementary insulin therapy groups achieved tighter postmeal glucose control and had improved myocardial and vascular function. The emerging data regarding PPG and CV disease suggest and support increased attention to the detection and treatment of elevated PPG levels in the absence of IFG. Dysregulation of Multiple Hormones Contributes to Elevated Postprandial Plasma Glucose Levels Elevated PPG levels are the result of several pathophysiologic mechanisms. Traditionally, these excursions have been attributed to insulin deficiency or resistance. In T2DM, it is widely accepted that insulin resistance coupled with impaired pancreatic β-cell function leads to a diminished insulin response to an intravenous glucose load. 22 Recent evidence suggests, however, that elevations in PPG levels are the result of abnormalities in several endocrine signaling systems, not just insulin. These hormones include amylin, glucagon, and the incretin hormones GLP-1 and gastric inhibitory peptide (GIP). 38 Amylin is a peptide secreted from the islet β cell in conjunction with insulin, which probably contributes to glucose regulation by suppressing postprandial glucagon secretion and decreasing gastric emptying. However, the secretion of amylin is impaired in T2DM. 39 Because glucagon, secreted by the 3

6 4 islet α cells primarily to promote hepatic glucose production, is not normally regulated in T2DM, excessive glucose output from the liver contributes to fasting and postprandial hyperglycemia. 40 Abnormalities in amylin signaling may play a role in this process. Incretin hormones, most notably GLP-1 and GIP, are secreted in the gut in response to an oral glucose load. They enhance glucose-dependent insulin secretion from pancreatic β cells. This phenomenon is referred to as the incretin effect, an important factor in the postprandial insulin response that is necessary for normal glucose tolerance. 41 The incretin hormones are thought to contribute to as much as 70% of postprandial insulin secretion GLP-1 also decreases gastric emptying, suppresses inappropriate glucagon secretion, and decreases food intake. These actions may also affect PPG levels. However, the incretin effect is impaired in T2DM (for more information, please refer to Figure 2 in Peak Issues #3). 45 Native GLP-1 secretion may be reduced modestly in a subset of T2DM patients, but its insulinotropic effects remain intact. 46 Infusions of GLP-1 in T2DM have been shown to inhibit gastric emptying, glucagon secretion, and food intake and to increase insulin secretion from pancreatic β cells. 46,47 However, native GLP-1 is rapidly degraded by the enzyme DPP-4, shortening its half-life to only a few minutes. 48 Two therapeutic classes of antidiabetic agents have been developed to increase active GLP-1 levels. First, the GLP-1 receptor agonists are agents that mimic native GLP-1 but are resistant to DPP-4 degradation. Second, the DPP-4 inhibitors are agents that, as implied by the name, inhibit the enzyme DPP-4. Because they increase active levels of GLP-1 and therefore, enhance insulin secretion based on an oral glucose load, they have a beneficial effect not only on A1C levels, but also on PPG levels. 46 Effects of Incretin-Based Therapies on Indicators of Glycemic Control DPP-4 Inhibitors Sitagliptin, the first DPP-4 inhibitor to be marketed in the United States, was approved by the US Food and Drug Administration (FDA) in Recently, saxagliptin was FDA-approved for the treatment of T2DM. 50 Another agent currently in late-stage development is alogliptin*; the FDA has requested additional CV data before considering approval of alogliptin. 51 All DPP-4 inhibitors are orally administered medications with once- or twice-daily dosing. They are weight neutral, ie, they cause neither weight gain nor weight loss. Importantly, these medications exhibit a side effect profile *Agent not currently FDA-approved comparable with that of placebo in randomized clinical trials, with headache and non-life-threatening infections being the most common side effects Numerous studies have examined the effectiveness of DPP-4 inhibitors on glycemic control as monotherapy or in comparison with traditional antidiabetic agents. Similar to standard studies of antidiabetic agents, A1C and FPG are commonly reported markers of glycemic control in trials with DPP-4 inhibitors. However, because incretin hormones have a specific effect on PPG levels, a number of studies have also used PPG levels as a measure of efficacy. Sitagliptin has been studied as monotherapy and as add-on therapy to other antidiabetic agents. Aschner et al studied the effects of sitagliptin as monotherapy in patients with an average A1C of 8.0%. 55 The administration of sitagliptin at a dose of 100 mg daily over a 24-week period resulted in a placebo-subtracted reduction in A1C of 0.79%. FPG reductions of 17.1 mg/dl (P <.001) and 2-hour PPG reductions of 48.9 mg/dl (P <.001) were achieved during this study period. A similar study by Raz et al 56 compared sitagliptin at 100 mg daily with placebo in T2DM patients with a mean baseline A1C of 8.1%. After 18 weeks, the placebo-subtracted A1C reduction in the treatment group was 0.60%, whereas a reduction in FPG of 19.8 mg/dl and a reduction in 2-hour PPG of 46.8 mg/dl were observed. Additional studies have examined the efficacy of sitagliptin as add-on therapy. Sitagliptin combined with metformin, thiazolidinediones (TZDs), or sulfonylureas has been shown to significantly reduce PPG as well as A1C Similar efficacy was achieved in studies of saxagliptin. A 12-week randomized, placebo-controlled study to evaluate the efficacy and safety of saxagliptin in drug-naïve T2DM patients revealed A1C reductions from baseline of 0.7% to 0.9% from an average baseline of 7.9% compared with a 0.3% change in the placebo group. One-hour PPG levels were reduced by 24 to 41 mg/dl in the saxagliptin group compared with the placebo group. 61 A 24-week trial compared placebo with saxagliptin monotherapy at doses of 2.5, 5, and 10 mg once daily in T2DM patients with a mean A1C of 7.9%. 62 The mean adjusted decrease in A1C was greater with all doses of saxagliptin ( 0.43%, 0.46%, and 0.54%, respectively; P <.0001) than with placebo (+0.19%). The postprandial area under the curve (AUC) for glucose was also lower with all doses of saxagliptin ( 6868, 6896, and 8084 mg min/dl) than with placebo ( 647 mg min/dl). The reductions in the 5- and 10-mg saxagliptin group were clinically significant (P =.0002 and P <.0001, respectively). 62 Early studies of alogliptin for the treatment of poorly controlled T2DM showed a significant effect on glycemic parameters. DeFronzo et al examined alogliptin (12.5 and 25 mg daily) compared with placebo in T2DM patients with a baseline A1C of 7.9% over a 26-week period. 63 Mean changes in A1C for the alogliptin groups were 0.56% and 0.59% (P <.001) for the 12.5-mg and 25-mg doses, respectively, whereas the placebo group achieved reductions of 0.2%. FPG reductions were significantly greater in the alogliptin groups than in the placebo group, and hypoglycemic events were more frequent in the placebo group (29%) than in the 12.5-mg (9.8%) and

7 25-mg (7.6%) alogliptin groups. Covington et al evaluated various dosages of alogliptin for effectiveness and safety. 64 A comparison of placebo with alogliptin at doses of 25, 100, or 400 mg once daily for 14 days showed significant decreases in 4-hour PPG levels with 400 mg alogliptin ( 65.6 mg/dl, P <.001) compared with placebo (+8.2 mg/dl). Alogliptin at doses of 25 and 100 mg also resulted in reductions in PPG ( 32.5 and 37.2 mg/dl, respectively). GLP-1 Receptor Agonists While the DPP-4 inhibitors are similar to one another with regard to dosing and administration, the GLP-1 receptor agonists vary greatly. In general, the GLP-1 receptor agonists reduce A1C, FPG, and PPG, and they are capable of promoting weight reductions up to 5 kg. 54 Gastrointestinal (GI) disturbances such as nausea and vomiting are the most common adverse events, but these generally diminish over several weeks of treatment. 54 All GLP-1 receptor agonists currently require administration by subcutaneous injection. New and emerging GLP-1 receptor agonists boast longer half-lives, allowing for once-daily and even once-weekly administration. These dosing regimens may have important implications in noncompliant T2DM patients and in T2DM patients with a large medication burden. Exenatide was the first GLP-1 receptor agonist approved by the FDA. Exenatide is considered a short-acting GLP-1 receptor agonist and is administered twice daily by subcutaneous injection with a preloaded pen. 65,66 Liraglutide, approved in early 2010, is a long-acting GLP-1 receptor agonist that is administered once daily. 67,68 Exenatide long-acting release (LAR)*, another long-acting GLP-1 receptor agonist, is currently awaiting FDA approval and is administered once weekly. Taspoglutide* and albiglutide*, both of which are verylong-acting GLP-1 receptor agonists, are currently in phase 3 clinical trials. Several studies have established GLP-1 receptor agonists as promising antidiabetic therapies because they improve FPG, PPG, and A1C levels in T2DM patients. Exenatide is approved for the treatment of T2DM as adjunctive therapy in patients who do not achieve glycemic control with TZDs, sulfonylureas, metformin, or a combination thereof. 66 Exenatide has also recently been approved by the FDA for monotherapy of T2DM. 69 Moretto et al studied the effectiveness of exenatide as monotherapy compared with placebo over a 24-week period in drug-naive patients with T2DM. 70 A1C reductions of 0.9% (P <.001) were achieved with 10-mcg doses of exenatide, whereas placebo reduced A1C by only 0.2%. In addition, changes in mean PPG excursions from baseline were 24 mg/dl (P <.001) with exenatide compared with 8.3 mg/dl for placebo. A study that compared exenatide with insulin glargine in patients suboptimally controlled with metformin and a sulfonylurea revealed similar A1C reductions over 26 weeks ( 1.11%). However, exenatide resulted in significantly greater reductions in PPG excursions and a 2.3-kg weight loss compared with a 1.8-kg weight gain with insulin. 71 Liraglutide has been studied extensively in a series of clinical trials known as the Liraglutide Effect and Action in Diabetes (LEAD) studies (Table 1). LEAD-3 compared the effects of liraglutide monotherapy with those of glimepiride in T2DM patients over a 2-year period. Reductions in A1C of 1.1% and 0.9% were achieved with 1.8- and 1.2-mg doses of liraglutide, respectively, compared with a reduction of 0.6% with glimepiride over the 2-year period. PPG levels also decreased in all treatment groups. 72 Table 1: Liraglutide Effect and Action in Diabetes (LEAD) Studies and Postprandial Plasma Glucose Levels LEAD-1 LEAD-2 LEAD-3 LEAD-4 LEAD-5 LEAD-6 Reference Marre et al, Nauck et al, Garber et al, Zinman et al, Russell-Jones et al, Buse et al, Comparator Background therapy Duration PPG reductions TZD (rosiglitazone) or placebo SU (glimepiride) or placebo SU (glimepiride) or placebo TZD (rosiglitazone) or placebo SU (glimepiride) Metformin None 26 wk 6-mo + 18-mo extension 52-week + 2-y extension 44.7 mg/dl to 48.2 mg/dl a 30.4 mg/dl to mg/dl b NR Placebo Metformin + TZD (rosiglitazone) Insulin glargine or placebo Metformin + SU (glimepiride) 26 wk 26 wk Exenatide Metformin + SU (glimepiride) 26-wk + 52-wk extension 47 mg/dl to 49 mg/dl c 32.1 mg/dl a NR a Reported as decreased from baseline. b Self-reported as mean decrease from baseline. c Reported as 90 minutes postprandial. NR, not reported. SU = sulfonylurea, TZD = thiazolidinedione *Agent not currently FDA-approved 5

8 Studies of once-weekly exenatide LAR have shown efficacy similar to that of short-acting exenatide. For example, Kim et al examined the efficacy of exenatide LAR compared with that of placebo in T2DM patients with inadequate glycemic control with metformin and/or diet and exercise. 78 A1C reductions of 1.4% ± 0.3% and 1.7% ± 0.3% were achieved with 0.8-mg and 2.0-mg doses, respectively, compared with an increase of 0.4% ± 0.3% with placebo. Exenatide LAR 2.0 mg reduced postprandial excursions by as much as 4-fold compared with placebo. Drucker et al compared a twice-daily formulation of exenatide with exenatide LAR in a 30-week randomized, noninferiority trial. 79 Subjects were administered either exenatide 10 mcg twice daily or 2 mg once weekly. Both agents demonstrated reductions in FPG and PPG levels. FPG decreased by 41 mg/dl with LAR and by 25 mg/dl with twice-daily exenatide. Conversely, the change from baseline in 2-hour PPG levels was 123 mg/dl with twice-daily exenatide and was 95 mg/dl with exenatide LAR (P =.0124). The once-weekly LAR formulation resulted in greater reductions (P =.0023) in A1C ( 1.9%) than did the twice-daily formulation ( 1.5%) over the 30-week time period. Adverse events were similar between groups. Both groups achieved a compliance rate of 98% during the study period. 79 A phase 3 clinical trial examined taspoglutide, administered once weekly or once every 2 weeks, in T2DM patients with inadequate glycemic control with metformin alone. Improvements in A1C up to 1.2% were observed, compared with +0.2% ± 0.1% with placebo. PPG excursions decreased by up to 21% with taspoglutide 20 mg once weekly compared with a 10% reduction with placebo. 80 Preliminary studies of albiglutide, a GLP-1 receptor agonist recently entering phase 3 clinical trials, show promising efficacy. Matthews et al examined the pharmacodynamics and safety of albiglutide in a single-blind dose-escalation study with 9, 16, or 32 mg albiglutide on day 1 and day On day 9, the albiglutide group achieved significant placebo-adjusted least-squares mean differences in postbreakfast glucose AUCs of 18, 46.5, and 65.5 mg/dl, respectively. In summary, the GLP-1 receptor agonists are effective antidiabetic agents that improve A1C, FPG, and PPG levels. In addition, they have a weight-loss effect that sets them apart from many traditional therapies. A thorough review of the efficacy and nonglycemic effects of GLP-1 receptor agonists and DPP-4 inhibitors can be found in earlier publications of this Peak Issues series. Fixed-Dose Combination Therapy Many treatment algorithms recommend early use of combination therapy to achieve glycemic control. 8,9,82 In addition, data from the UKPDS indicate that only 50% of patients can maintain glycemic control (A1C < 7%) with monotherapy. The addition of an agent increases the proportion of patients who achieve glycemic control by 2- to 3-fold compared with diet alone. 83 Whereas many studies have shown that the DPP-4 inhibitors and GLP-1 receptor agonists are safe and effective in combination with other antidiabetic agents, only sitagliptin/metformin is FDA-approved as a fixed-dose combination therapy. 75,78,84-90 Williams-Herman et al compared the effects of initial treatment with sitagliptin and metformin with those of sitagliptin or metformin monotherapy (Table 2). 60 During the 54-week study, 1091 subjects with a mean A1C of 8.7% were randomly assigned to receive either sitagliptin alone, metformin alone, low-dose sitagliptin/ metformin, or high-dose sitagliptin/metformin. The data showed greater efficacy concerning A1C and PPG reductions with combination therapy than with monotherapy, without additional adverse events compared with metformin alone. Sitagliptin/metformin fixed-dose combination tablets are administered twice daily. 91 Table 2: Initial Combination Therapy with Sitagliptin and Metformin 60 Sitagliptin 100 mg QD Metformin 500 mg BID Metformin 1000 mg BID Sitagliptin 50 mg BID + Metformin 500 mg BID Sitagliptin 50 mg BID + Metformin 1000 mg BID A1C from baseline (%) a 0.8 ( 1.0,.6) 1.0 ( 1.2,.8) 1.3 ( 1.5, 1.2) 1.4 ( 1.6, 1.3) 1.8 ( 2.0, 1.7) PPG from baseline 45.9 ( 57.2, (mg/dl) a 34.6) 58.6 ( 69.6, 47.6) 76.3 ( 86.1, 66.5) 89.6 ( 99.2, 80.0) ( 117.1, 98.7) Drug-related adverse events [% (n)] 15 (8) 24 (3) 32 (18) 29 (15) 34 (19) Hypoglycemia [% (n)] 2 (1) 2 (1) 2 (1) 4 (2) 5 (3) a Reported as least-squares mean change (95% CI). A1C, hemoglobin A1C; BID, twice daily; PPG, postprandial glucose; QD, once daily. 6

9 In a poster presentation at the 2009 ADA annual meeting, Rosenstock et al compared the efficacy of alogliptin and pioglitazone with that of either agent alone in T2DM patients with a baseline A1C of 8.8%. In this 26-week study, the subjects were randomly assigned to alogliptin 25 mg daily (ALO), pioglitazone (PIO) 30 mg daily, alogliptin 12.5 mg/ pioglitazone 30 mg daily (ALO PIO), or alogliptin 25 mg/pioglitazone 30 mg daily (ALO 25 + PIO). The leastsquares mean changes in A1C from baseline were 0.96% and 1.15% (P <.001), respectively, for alogliptin and pioglitazone monotherapy. Combination therapy resulted in significantly greater improvements in A1C of 1.56% (ALO PIO) and 1.71% (ALO 25 + PIO). Hypoglycemia occurred in less than 3% of patients. 92 An application for an alogliptin/ pioglitazone fixed-dose combination was submitted to the FDA in mid Safety and Tolerability of Incretin-Based Therapies Numerous studies have evaluated the safety and tolerability of the DPP-4 inhibitors and the GLP-1 receptor agonists. Amori et al reported a meta-analysis of the clinical trials of incretin-based therapies reported through They noted that the DPP-4 inhibitors were well tolerated, with a risk of hypoglycemia similar to that of placebo. GI adverse events were low, and there was a mildly increased risk of nasopharyngitis, headaches, and urinary tract infection (UTI). 54 A more recent review by White found the incidence of hypoglycemia with sitagliptin to range from 0.5% to 2.2%, with rare reports of severe hypoglycemia. 94 Other DPP-4 inhibitors, including saxagliptin and alogliptin, had similarly low incidences of hypoglycemia and mild infection, such as nasopharyngitis and UTI. 88,89,94,95 Because of the glucose-dependent nature of the incretin effects on islet hormone secretion, GLP-1 receptor agonists also boast a low incidence of hypoglycemia. However, the risk of hypoglycemia with these agents increases when used in combination with sulfonylureas. 94 GI adverse events, such as nausea, are the most common adverse events of GLP-1 receptor agonists, but these effects tend to be mild to moderate in severity and transient in nature, with tolerance developing over several weeks of use. 94,96 Antibody formation to GLP-1 receptor agonists has been documented; however, the appearance of these antibodies does not appear to be clinically significant in most patients. 94,97 Postmarketing cases of pancreatitis associated with GLP-1 receptor agonist use have also been reported. However, a recent study by Bloomgren et al evaluated the incidence of acute pancreatitis with exenatide compared with that with other antidiabetic agents. 98 They found no elevation in risk with exenatide use compared with other antidiabetic agents. Dore et al also examined this phenomenon, utilizing claims for hospitalizations associated with a primary diagnosis of acute pancreatitis. 99 The investigators compared exenatide and sitagliptin initiators with metformin or glyburide initiators. They found that the relative risks for exenatide (1.0; 95% CI: ) and sitagliptin (1.0; 95% CI: ) were comparable with the comparison cohorts of metformin and glyburide. However, the prescribing information for exenatide recommends the cessation of treatment with a GLP-1 receptor agonist if acute pancreatitis is suspected, with no reinitiation of therapy. 66 Additionally, GLP-1 agonists are not recommended in individuals at high risk of pancreatitis, including those with alcoholism, gallstones, or a history of pancreatitis. 65 During early studies with GLP-1 receptor agonists, thyroid C-cell tumors were observed in rodents after clinically relevant liraglutide and exenatide exposure. 100 A GLP-1 receptormediated increase in calcitonin levels was observed during these studies and raised the possibility of similar effects in humans. However, a 20-month study of liraglutide (with doses up to 20 times human exposure levels) did not show increased calcitonin levels or C-cell hyperplasia. Additionally, phase 3 human studies showed a decrease in serum calcitonin levels, suggesting there may be species-specific actions of GLP-1 on calcitonin and the thyroid. 77, 100 During clinical trials, 5 cases of thyroid tumors were reported in liraglutide-treated patients. Nine cases of thyroid tumors have been reported in post marketing data. 101 Nevertheless, long-term data regarding thyroid tumors and GLP-1 receptor agonists is needed and at this time, liraglutide is contraindicated in a patient with a personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia 2 syndrome. 67 Overall, the DPP-4 inhibitors and GLP-1 receptor agonists are well tolerated. Their risk profiles have become more apparent and predictable over time with increased clinical use. Although long-term CV outcomes are needed, the studies to date show a promising beneficial effect on CV risk factors In light of their efficacy concerning glycemic control, beneficial nonglycemic effects, and tolerability, the incretin-based therapies offer an attractive option for treatment of T2DM patients. Incretin-Based Therapies in the Treatment Algorithms The major clinical guidelines emphasize the need for achievement of early, aggressive glycemic control. 8,9,82 Additionally, the AACE/ACE guidelines and the IDF guidelines highlight the importance of PPG monitoring and control in the prevention of CV disease. The AACE/ACE guidelines specifically recognize that whereas traditional therapy has addressed FPG levels preferentially, recent advances in our understanding of PPG contributions to A1C levels suggest that clinicians should address both FPG and PPG levels simultaneously. 8,105 7

10 Recently, updates to the AACE/ACE guidelines were published. 105 The authors cite numerous reasons for the update, including the emergence of the incretin class of medications. The general recommendations include stratification of therapy depending on A1C level (Figure 3). For example, in a newly diagnosed patient with an A1C of 6.5%, monotherapy should be initiated. However, if the same new patient presented with an A1C of 8.5%, the guidelines recommend dual therapy with medications that have complementary mechanisms of action. This more aggressive early intervention is thought to increase the likelihood that glycemic goals are achieved and that T2DM complications are prevented, including microvascular and macrovascular complications. The guidelines also recommend individualization of therapy to avoid hypoglycemia, frequent assessments of glycemic control, and if necessary, frequent adjustments of medications to achieve glycemic goals. The authors state that the selection of medication for a particular patient should be based primarily on the efficacy and safety of the agent. Costs of therapy are another important consideration for many patients. However, it has been proposed that higher direct medication costs may result in long-term healthcare savings if a higher-cost medication yields better cardiovascular outcomes (see also Sinha et al, Diabetes Care. 2010; January 7). The GLP-1 receptor agonists are recommended early in the algorithm, as part of the dual/triple therapy regimen because of their efficacy, low-risk of hypoglycemia, and positive nonglycemic effects and as monotherapy when weight is a concern. The authors recommend the GLP-1 receptor agonists over DPP-4 inhibitors because of their somewhat greater effects on PPG excursions. The IDF has published a specific guideline concerning postmeal glucose. It states that optimal glycemic control cannot be achieved without adequate management of postmeal plasma glucose. 9 A regimen targeting both FPG and PPG levels is recommended by the IDF. Both the DPP-4 class and the GLP-1 receptor agonist class are mentioned as plausible choices in the clinician s therapeutic armamentarium. The ADA/EASD consensus algorithm for the management of T2DM recommends an A1C < 7% (with A1C levels as close to normal as possible without hypoglycemia). 7 This algorithm is very specific, suggesting lifestyle interventions and metformin as first-line treatment. Additional medications are added if step one fails to achieve glycemic control. The algorithm recommends the addition of insulin or sulfonylureas when metformin and lifestyle changes fail. However, in situations where hypoglycemia is a concern or weight gain is a problem, GLP-1 receptor agonists should be considered. PPG levels should be monitored when fasting, preprandial, or A1C goals are not achieved. 7 The similarities and differences between the glycemic guidelines are shown in Table 3. Note that the ADA/ EASD guidelines were written after the results of ACCORD and ADVANCE were released. Figure 3: Updated AACE/ACE T2DM Algorithm 105 Lifestyle Modification A1C Goal 6.5%* A1C 6.5%-7.5%** A1C 7.6%-9.0% A1C > 9.0% Monotherapy Dual therapy 8 Drug naive Under treatment MET DPP-4 1 GLP-1 TZD 2 AGI 3 MET TZD MET 2-3 mo*** Dual therapy GLP-1 or DPP-4 1 TZD 2 Glinide or SU 5 GLP-1 or DPP-4 1 Colesevelam AGI mo*** Triple therapy MET + GLP-1 or TZD 2 DPP Glinide or SU 4,7 GLP-1 or DPP-4 1 MET + or TZD 2 SU or glinide 4,5 2-3 mo*** Triple therapy 9 GLP-1 or DPP-4 1 TZD 2 MET + GLP-1 or DPP-4 1 SU 7 TZD mo*** Insulin ± other agents mo*** Symptoms No symptoms Insulin ± other agents 6 MET + GLP-1 or DPP-4 1 TZD 2 GLP-1 or DPP-4 1 ±SU 7 ±TZD 2 Insulin ± other agents 6 *May not be appropriate for all patients. **For diabetes & A1C < 8.5%, pharmacologic Rx may be considered. *** If A1C goal not achieved safely. Preferred initial agent. 1 DPP-4 if PPG and FPG or GLP-1 if PPG. 2 TZD if metabolic syndrome and/or NAFLD. 3 AGI if PPG. 4 Glinide if PPG and SU if FPG. 5 Low-dose secretagogue recommended. 6 a) Discontinue secretagogue with multidose insulin. b) Can use pramlintide with prandial insulin. 7 Decrease secretagogue by 50% when added to GLP-1 or DPP-4. 8 If A1C < 8.5%, combination Rx with agents that cause hypoglycemia should be used with caution. 9 If A1C > 8.5% on dual therapy, insulin should be considered. A1C = hemoglobin A1C, MET = metformin, TZD = thiazolidinedione, DPP-4 = DPP-4 inhibitor, AGI = α-glucosidase inhibitor, GLP-1 = GLP-1 receptor agonist, SU = sulfonylurea 8

11 Table 3: Therapeutic Goals for Glycemic Indicators 8,9,17 AACE/ACE ADA/EASD IDF A1C < 6.5% < 7%* < 6.5% Fasting plasma glucose 2-hour postprandial plasma glucose < 110 mg/dl mg/dl < 100 mg/dl < 140 mg/dl < 180 mg/dl < 140 mg/dl * As close to normal as possible without hypoglycemia. AACE, American Association of Clinical Endocrinologists; ACE, American College of Endocrinology; ADA, American Diabetes Association; EASD, European Association for the Study of Diabetes; IDF, International Diabetes Federation. Successful Implementation of Incretin-Based Therapies: Patient Characteristics to Consider Although the guidelines may differ slightly with regard to glycemic goals, they all agree that therapy must be individualized to the patient. Whereas, at first, this may seem like a daunting task for the clinician, an understanding of the pathophysiology of hyperglycemia makes individualizing therapy easier. The newly revised AACE/ACE guidelines, among other guidelines, address this concern and attempt to simplify the process for clinicians. 105 The introduction of incretin-based therapies has also provided a therapeutic option that contributes to glycemic control in a multitude of clinical situations, giving the clinician more selection when intensifying diabetes care. Because of their diverse actions, incretinbased therapies may improve many abnormalities associated with T2DM and address a much-needed barrier to glycemic control postprandial hyperglycemia. The initial requirement for success with an incretin-based therapy is intact β-cell function. Because incretins enhance insulin secretion from the pancreatic β cells, a patient with functioning β cells should have greater improvements in A1C, FPG, and PPG than a patient without functioning β cells. It has been well established that T2DM is a consequence, in part, of chronic β-cell dysfunction. β-cell dysfunction progresses over time and contributes to poor glycemic control. 22,106 Interestingly, GLP-1 has been shown to increase β-cell proliferation and to decrease β-cell apoptosis in animal models, raising the possibility that early use of incretin-based therapies may have important implications in preventing the long-term progression of T2DM in humans. 42,83 Another compelling reason for using incretin-based therapies early in the treatment of T2DM is the early rise in PPG levels and the efficacy of incretin-based therapies on this aspect of hyperglycemia. As mentioned previously, postprandial hyperglycemia precedes the onset of fasting hyperglycemia. 21 As seen from the UKPDS, achieving early glycemic control may provide a legacy effect regarding CV disease. 13 Incretinbased therapies have been shown to reduce A1C, FPG, and PPG, but their effect on PPG is greater than their effect on FPG because of the action of these agents in the first-phase insulin response. 54 The mechanism for GLP-1 and incretin-based therapies is glucose dependent; therefore, the risk of hypoglycemia is lower than some other agents for T2DM. 43,46 In a patient at high risk of hypoglycemia or one with hypoglycemic unawareness, incretin-based therapy is an attractive choice to help achieve glycemic targets. Hypoglycemic unawareness is an impaired perception of hypoglycemia, which may cause loss of consciousness without warning. 107 Hypoglycemic unawareness is more likely to occur as A1C levels approach the target level; therefore, a medication less likely to result in hypoglycemia should be considered in a T2DM patient approaching near-normal glycemia. 107 Elderly patients are at particularly high risk of developing hypoglycemia as well as hypoglycemic unawareness. 108,109 The new guidelines emphasize the use of agents that minimize hypoglycemia because of their effects on mortality and morbidity. 82,105 GLP-1 receptor agonists and DPP-4 inhibitors have demonstrably lower rates of hypoglycemia than other agents for T2DM. Pratley et al performed a pooled analysis of 6 phase 2 and 3 studies involving alogliptin. 110 They compared efficacy and safety data between individuals < 65 years of age and individuals > 65 years of age. Alogliptin administration (12.5- and 25-mg doses) resulted in greater least-squares mean decreases in A1C from baseline in the older age group ( 0.7% and 0.8%, respectively; P =.70) and in the younger age group ( 0.5% and 0.6%, respectively; P =.70) than did placebo, despite lower baseline A1C levels in the older age group. However, no differences in hypoglycemia were seen with alogliptin between the 2 age groups. Eighty percent of patients in the studies experienced hypoglycemia; all except 1 were in the glyburide or insulin coadministration studies. This information highlights the utility of the incretin-based therapies in specific populations at risk of hypoglycemia, such as the elderly. Weight should be another consideration when choosing an antidiabetic agent. Recent data showed that approximately one-third of Americans 20 years of age or older are obese. 111 More relevant to this discussion, 60%-90% of T2DM patients are overweight, and weight gain tends to progress along with the disease state. 112,113 Not only is obesity a risk factor for the development of T2DM, it is also a risk factor for CV disease. Conversely, weight loss in T2DM is associated with a lower risk of mortality. Williamson et al found a 25% reduction in mortality associated with intentional weight loss in T2DM. 114 Traditional antidiabetic therapies, such as insulin, TZDs, and sulfonylureas, may contribute to weight gain. 115 Data from the UKPDS showed a significantly higher weight gain (2.9 kg, P <.0001) in the intensive treatment group (sulfonylurea or 9

12 insulin) than in the conventional group. 5 Weight is an important factor when selecting an antidiabetic agent; one that lowers weight or is weight-neutral, such as a GLP-1 receptor agonist or DPP-4 inhibitor, would be beneficial. The treatment of T2DM involves more than just glycemic control. Today, clinicians must consider the effects of weight, CV effects, side effect profiles, as well as the risk of hypoglycemia in addition to an antidiabetic agent s effect on A1C, FPG, and PPG. An agent with beneficial glycemic and nonglycemic effects is imperative. GLP-1 receptor agonists and DPP-4 inhibitors are recent additions to the treatment options available for diabetes that offer such benefits. Case Studies Recent advances in diabetes research have introduced promising new agents, altered our understanding of IGC as it relates to CV risk, and shed new light on the contributions of both FPG and PPG levels to A1C levels. However, the task of translating this conflicting information into practical, patientdriven care may be overwhelming to the busy clinician. The following section is intended to aid in the application of this new data directly to patient care. Case Study #1: A 41-year-old female is in your office for a physical exam. She has not seen a healthcare provider in several years. She reports good health. Her medical history is significant for gestational diabetes 5 years previously, appendectomy at age 15 years, and allergic rhinitis. She has never smoked and does not drink alcohol. Her lifestyle is sedentary. Her vital signs are as follows: BP: 140/92 mm Hg P: 82 R: 12 T: 98.4 F Height: 61 inches Weight: 165 lbs BMI: 31.2 kg/m 2 Her fasting laboratory values are as follows: Glucose 98 mg/dl Total Cholesterol 180 mg/dl BUN 11 mg/dl LDL 115 mg/dl Cr 0.8 mg/dl HDL 36 mg/dl K+ 4.1 mmol/l Triglycerides 168 mg/dl Na+ 144 mmol/l TSH 1.7 miu/l Would you screen this patient further for T2DM? If so, with what screening method? A. No, FPG is a sufficient screening method and her level is normal B. Yes, hemoglobin A1C C. Yes, repeat fasting laboratory tests in 3 months D. Yes, 2-hour OGTT E. Yes, more than one of the above would be appropriate Answer: E Answer explanation: The above mentioned patient is a highrisk candidate for developing T2DM and should be screened at this visit. According to the ADA, screening for T2DM should be considered in adults with a BMI 25 kg/m 2 with 1 or more additional risk factors. Additional risk factors include the following: physical inactivity, history of polycystic ovarian syndrome, women with a history of gestational diabetes, impaired FPG or IGT based on a previous test, history of CV disease, or first-degree relative with T2DM. 20 This patient is overweight, sedentary, and has a history of gestational diabetes. She, therefore, has several additional risk factors for T2DM, necessitating screening. Until recently, the only approved means of screening for T2DM was to measure the FPG level or conduct a 2-h OGTT. However, OGTT is a time-consuming test and is not often performed in the primary care clinical setting. As a result, up to one-third of patients with T2DM remain undiagnosed. 20 The A1C assay has been used clinically to manage diabetes for some time, but it has not historically been recommended as a means of diagnosing T2DM because of poor standardization. However, in 2009, the International Expert Committee (made up of members appointed by the ADA, EASD, and IDF) reviewed advances in standardization, the relationship of A1C to glucose levels, as well as disease outcomes and recommended that the A1C assay be used as a primary means of diagnosing diabetes. 18 The ADA, in their updated 2010 guidelines, adopted A1C as a diagnostic tool. 19 Thus, the physician has the choice of using an OGTT or an A1C measurement as a diagnostic tool. Case Study #1 (continued): The A1C level is measured at your request. The result is 6.8%. The patient denies any symptoms of hyperglycemia, such as polyuria or polydipsia. She admits to a poor diet and a lack of exercise. She is concerned about having T2DM. What do you recommend next? A. Refer her to a registered dietitian to discuss the ADArecommended diet, carbohydrate counting, and weight loss. Advise her, based on the normal results from her physical exam and electrocardiogram (ECG), to start exercising and have a repeat A1C measurement in 3 months B. Nothing. Clearly she has a normal FPG the A1C level must be erroneous. Advise her to return to the office in 6 months for a recheck of her cholesterol and blood pressure C. Recommend she begin SMBG D. Begin metformin 500 mg at bedtime for 1 week and then twice daily. Discuss side effects such as diarrhea and GI upset. Refer her to a registered dietitian to discuss the ADA-recommended diet, carbohydrate counting, and weight loss. Advise her, based on the normal results from her physical exam and ECG, to start exercising E. Start her on sitagliptin/metformin 50 mg/500 mg at bedtime for 7 days and then twice daily. Refer her to a registered dietitian to discuss the ADA-recommended diet, carbohydrate counting, and weight loss. Advise her, based 10

13 F. on the normal results from her physical exam and ECG, to start exercising G. More than one option may be correct Answer: F Answer explanation: This patient has an abnormal A1C level. When the patient is without symptoms, the International Expert Committee recommends confirming the diagnosis with repeat testing. 18 However, this patient has numerous risk factors, not only for T2DM but also for CV disease. A regimen of diet and exercise will positively affect both her glycemic indicators and her CV risk. 7 The consensus statement from the ADA/EASD recommends treatment with lifestyle modifications and metformin at the time of diagnosis if the A1C level is between 6% and 7%. Therefore, the addition of metformin would be an appropriate initial therapy, in addition to diet and exercise, once the diagnosis of T2DM is confirmed with a repeat A1C measurement. Once the A1C level rises above 7%, the consensus algorithm dictates the use of combination medication. 7 However, this patient has only a single elevated A1C level and her A1C level at this time is not greater than 7%. SMBG is recommended because the A1C level does not reflect fluctuations in blood sugar. Case Study #1 (continued): The patient is sent home with a blood glucose monitor and instructed to check her sugars twice daily, once fasting and once 2 hours after a meal for the next month. She returns with the following blood sugar readings (mg/dl): 5/3 8:00 am: 96 8:00 pm: 189 5/8 7:30 am: 102 3:00 pm: 152 5/13 10:00 am: 118 8:00 pm: 175 5/ :30 pm: 143 5/26 8:00 am: 99 9:00 pm: 201 5/31 10:00 am: The patient states that she had a hard time remembering to check her blood sugars regularly. She did meet with a registered dietitian and states that she would like to make changes to her diet, but it is challenging because of her busy schedule. She has not started exercising yet. The result of a repeat A1C measurement is 7.0%. She is given a prescription for metformin 500 mg to take in the evening for 1 week and then twice daily. Side effects, such as GI upset and diarrhea, are discussed. Over the next year, the patient is compliant with her metformin therapy, but has minimal success with weight loss or exercise. She returns to your office for a follow-up visit. Her vital signs are as follows: BP: 132/86 mm Hg P: 78 R: 13 Weight: 163 lbs BMI: 30.8 kg/m 2 Her fasting laboratory values are as follows: Glucose 120 mg/dl Total Cholesterol 190 mg/dl BUN 18 mg/dl LDL 131 mg/dl Creatinine 1.0 mg/dl HDL 36 mg/dl TSH 1.3 miu/l Triglycerides 152 mg/dl A1C 7.0% Glucose logs, although not complete, continue to show increased PPG excursions. Glycemic goals, CV risk, and T2DM complications are discussed with the patient. The importance of lifestyle changes and glycemic control are also discussed. The patient states that she understands and has been making an effort to reduce her carbohydrate and calorie intakes, but is frustrated that her weight has not changed significantly. Because of her CV risk and high cholesterol levels, you give her a prescription for a statin at today s visit. Which of the following medications would you add to her T2DM therapy? A. TZD B. Sulfonylurea C. DPP-4 inhibitor D. GLP-1 receptor agonist E. Insulin F. More than one of the above G. None, she is at goal and is making efforts toward lifestyle changes Answer: F Answer explanation: Early glycemic control is important to long-term outcomes. 13 The IDF and AACE/ACE recommend early combination therapy. Whereas all of these choices would affect A1C levels, they are not all appropriate for this patient. With an A1C of 7.0%, she needs a medication that addresses postprandial hyperglycemia. Because she has a short duration of disease, has elevated PPG readings, is overweight, and has several CV risk factors, a GLP-1 receptor agonist or DPP-4 inhibitor would be of benefit. The incretin-based therapies would address this patient s postprandial hyperglycemia, elevated A1C level, and obesity. (DPP-4 inhibitors are weight neutral, whereas GLP-1 receptor agonists have a weight-loss effect.) This, in turn, may have a beneficial effect on her long-term CV risk. A TZD is an effective option for lowering A1C, but it often results in weight gain. Weight gain is not only detrimental to glycemic control, but it increases the risk of CV disease. 7 Insulin and sulfonylureas are also effective at reducing A1C, but, once again, they are associated with significant weight gain. 115 Studies that compared insulin with the GLP-1 receptor agonist exenatide have shown that exenatide offers greater 71, 116 improvements in PPG than insulin. 11

14 Case Study #2: A 72-year-old male returns to your office for a recheck of his T2DM. His comorbid conditions include peripheral vascular disease, coronary artery disease, and hyperlipidemia. He recently had a stent placed, and his cardiologist referred him for optimization of his glycemic control. His diagnosis of T2DM was made 6 years ago. His vital signs are as follows: Height: 70 inches Weight: 198 lbs BP: 128/78 mm Hg P: 64 BMI: 27.6 kg/m 2 Medications used: Metoprolol succinate 50 mg daily, atorvastatin 40 mg daily, acetylsalicylic acid (ASA) 81 mg daily, lisinopril/ hydrochlorothiazide 20/25 mg daily, metformin 1000 mg twice daily, glyburide 5 mg daily His fasting laboratory values are as follows: Glucose 88 mg/dl Total Cholesterol 103 mg/dl BUN 20 mg/dl LDL 62 mg/dl Creatinine 1.2 mg/dl HDL 37mg/dL TSH 2.4 miu/l Triglycerides 99 mg/dl A1C 7.2% Which of the following is likely to contribute more to his elevated A1C level? A. FPG B. PPG Answer: B Answer explanation: Monnier et al have shown that PPG excursions contribute more substantially to overall hyperglycemia at lower A1C levels and decrease as A1C levels rise. 28 Therefore, at an A1C of 7.2%, PPG excursions are more likely to contribute to the mildly elevated A1C. This patient does not monitor his glucose levels. He admits that he does not always take his T2DM medications as instructed. He explains that he has a busy lifestyle and the medications often make him feel foggy. He denies any GI adverse events. He has been to a dietitian and feels that he does pretty good watching his calorie and carbohydrate intakes. He has never been to a diabetes educator and is not able to identify the signs and symptoms of hypoglycemia when asked. He is up-to-date with dilated eye exams. Which of the following is TRUE regarding hypoglycemia? A. Metformin is associated with significant hypoglycemia B. Sulfonylurea agents and incretin-based therapies have similar rates of hypoglycemia C. Hypoglycemia is more likely to occur in a patient with a higher A1C D. Hypoglycemic unawareness increases with tighter glycemic control Answer: D Answer explanation: As glycemic control improves, the risk of hypoglycemia increases. The UKPDS exemplified this concept, with a greater risk of hypoglycemia in the intensive arm than in the control group. 117 Although hypoglycemia can occur with any antidiabetic agent, it is not common with metformin. 30 In addition, hypoglycemia is not common with incretin-based therapies, because they enhance insulin secretion in a glucose-dependent manner. However, hypoglycemia is a common side effect of sulfonylurea therapy. 20,118 Hypoglycemic unawareness is more likely in a patient with advancing age, near-normal glycemic control, β-blocker therapy, and little knowledge about T2DM. 107,108 Although this patient does not express having hypoglycemic episodes, he describes feeling foggy, which may indicate hypoglycemia. In addition to hypoglycemic unawareness, classic symptoms of hypoglycemia may not be reported by a patient with little knowledge of T2DM. Patients with an impaired perception or understanding of hypoglycemia should perform SMBG more frequently. 107 This patient does not perform SMBG; therefore, little information is available regarding daily blood glucose fluctuations. 20 The ADA/EASD, IDF, and AACE/ACE all recommend SMBG in order to improve detection of abnormal PPG excursions and hypoglycemia so that glycemic control can be improved. 8,9,20 Case Study #2 (continued): The patient s sulfonylurea use is discontinued because of the possibility of hypoglycemia. He is referred to a diabetes educator for SMBG instruction. He is asked to monitor his blood sugar levels at least twice daily while continuing to take his other medications. He is instructed regarding symptoms of hypoglycemia as well as treatment. He is asked to call the office if any of his blood sugar levels are < 70 mg/dl and to return to the office in 3 weeks with his blood sugar log. He returns to the office 3 weeks later. He admits that he is feeling much better after having discontinued glyburide use; however, his blood glucose readings have been high. According to his blood glucose monitor, his average glucose reading is 189 mg/dl. His FPG levels range from 85 to 120 mg/dl. His PPG levels, however, range from 140 to 220 mg/dl. What characteristics make this patient a candidate for incretin-based therapy? A. Previous incidence of hypoglycemia B. Postprandial hyperglycemia C. BMI D. CV disease E. All of the above Answer: E Answer explanation: This patient is a candidate for incretinbased therapy for all of the above reasons. First, the patient has experienced symptoms of hypoglycemia and is at risk of 12

15 hypoglycemic unawareness based on his β-blocker therapy, A1C level, and age. In addition, although his FPG values are close to normal, he has significant postprandial hyperglycemia. Incretin-based therapies have a beneficial effect on A1C and FPG, but their effect on PPG is greater. 46 The patient s BMI categorizes him as overweight. Although he is not yet obese, weight gain in T2DM tends to be progressive. 113 Weight loss is associated with improved glycemic control as well as a decreased CV risk. 113 Therefore, a medication with a weightneutral or weight-loss effect, such as metformin or an incretinbased therapy, is ideal for this individual. This patient already has established coronary artery disease. Poor glycemic control, an elevated BMI, and postprandial hyperglycemia are risk factors for CV events. 4,25,34 Incretin-based therapies address these issues and early studies show they may help improve CV disease risk factors such as elevated cholesterol and blood pressure. 119,120 What glycemic goal would you recommend for this patient based on the information provided? A. A1C 6.5% B. A1C 7.0% C. A1C 6.0% D. None of the above E. More than one of the above may be correct for this patient Answer: E Answer explanation: The guidelines differ somewhat regarding the exact glycemic targets desired (see Table 1). Treatment should be individualized to the patient. This patient has CV disease and is elderly. The general consensus, in response to the ACCORD and ADVANCE trial data suggesting no benefit or an increased CV risk with IGC, is to treat T2DM patients with comorbid conditions and increased CV risk less intensively. 7,8,82 Therefore, an A1C 7% would be recommended for this patient unless a lower A1C can be achieved without risk of hypoglycemia. Case Study #3: A 54-year-old female returns to the office for a recheck of her chronic medical problems: hypertension, depression, obesity, and hyperlipidemia. She states that she has been feeling poorly over the last few months. She is fatigued and has blurred vision. She thinks that she might have a UTI. Her vital signs are as follows: Height: 65 inches Weight: 210 lbs BMI: 35 kg/m 2 BP: 146/88 mm Hg P: 86 R: 14 Medications used: Simvastatin 40 mg daily, venlafaxine XR 150 mg daily, lisinopril/hydrochlorothiazide 20/12.5 mg daily, ASA 81 mg daily Her fasting laboratory values are as follows: Glucose 169 mg/dl Total Cholesterol 130 mg/dl BUN 22 mg/dl LDL 74 mg/dl Creatinine 1.2 mg/dl HDL 39 mg/dl TSH 3.2 miu/l Triglycerides 222 mg/dl A1C 7.5% On the basis of this patient s elevated FPG and A1C levels, she has T2DM. What medication(s) are most likely to decrease this patient s A1C level to 7%? A. Metformin 500 mg in the evening, titrate to 1000 mg twice daily B. Metformin/pioglitazone 500 mg/15 mg, titrate to twice daily C. Metformin/sitagliptin 500 mg/50 mg, titrate to twice daily D. None of the above E. B or C may be appropriate options Answer: E Answer explanation: The AACE/ACE and the ADA/EASD guidelines both recommend early initiation of therapy to lower glucose levels. The AACE/ACE guidelines recommend the initiation of combination therapy when A1C levels are 7%-8% and to initiate and intensify combination therapy when A1C levels are 8%-10%. 8 Metformin alone is likely to lower A1C by 1.0%-2.0%, which would not result in this patient achieving the goal of A1C of 7%. 7 In a 54-week study of T2DM patients that compared metformin and sitagliptin monotherapy with combination therapy, 44% of patients who took sitagliptin/ metformin 50 mg BID mg BID achieved an A1C < 7% compared with only 25% and 23% of patients who took metformin 1000 mg and sitagliptin 100 mg, respectively. 60 A study that compared pioglitazone/metformin with metformin alone found an additional 0.89% reduction in A1C with combination therapy than with metformin monotherapy. 121 Either combination therapy would be an appropriate choice to help this patient achieve an A1C of 7%. 13

16 In addition to pharmacotherapy, what other steps would you use to safely improve this patient s PPG values without causing hypoglycemia? A. Diet B. Exercise program C. Diabetes educator D. SMBG E. A and D F. All of the above Answer: F Answer explanation: All of the abovementioned interventions are helpful for lowering A1C levels. In particular, a low glycemic diet provides additional efficacy in reducing PPG values compared with a low-carbohydrate diet alone. 9 SMBG is recommended by all of the guidelines that have been discussed in this article to help monitor daily fluctuations in blood glucose levels and allow for optimization of glycemic control while monitoring for hypoglycemia. 7-9,20 Patients with a lack of knowledge about T2DM are more likely to experience hypoglycemic unawareness than are patients with adequate knowledge about T2DM; therefore, contact with a diabetes educator is important. 107 Posttest Questions 1. Individuals with type 2 diabetes (T2DM) are times more likely to die from heart disease than adults without diabetes. a. 2 b. 3 c. 4 d The ACCORD trial studied the effects of tight glycemic control on cardiovascular risk reduction. The trial showed a significant reduction for cardiovascular risk in the intensive group. a. TRUE b. FALSE 3. In a 2009 meta-analysis, Mannuci et al showed an increased risk of cardiovascular risk associated with this condition in the intensive group: a. Hyperlipidemia b. Hyperglycemia c. Hypoglycemia d. Hypertension 4. Which of the following actions does NOT contribute to postprandial hyperglycemia in T2DM patients? a. Impaired suppression of glucagon b. Impaired incretin effect c. Delayed gastric emptying d. Hepatic glucose production 5. At an A1C of 7.1%, which glycemic indicator contributes most substantially to overall hyperglycemia? a. Fasting plasma glucose (FPG) b. Postprandial glucose (PPG) 14