DPP-4 Inhibitors: Strategies for PPG Control

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1 Issue 2 Clinical Use o f In c r e t i n-based Therapies to Tr e at Type 2 Diabetes Term of Approval Release date: August 2009 Expiration date: August 31, 2010 DPP-4 Inhibitors: Strategies for PPG Control IN THIS ISSUE: Page 1 Current unmet therapeutic needs in diabetes 2 Hormonal dysregulation in diabetes 2 The incretin system as a therapeutic target 2 Biological basis for the mechanism of DPP-4 inhibitors 3 Overview of DPP-4 inhibitors (approved or in late-stage development) 9 Novel DPP-4 inhibitors 9 Current recommendations for the clinical use of DPP-4 inhibitors 10 Literature reviews 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 increased risk of both microvascular and macrovascular complications. Optimal glycemic control is vital to managing these risks in patients with type 2 diabetes. However, recent estimates indicate that only 57% of type 2 diabetes patients reach the American Diabetes Association glycemic target of A1C < 7%. Historically, glycemic control efforts have emphasized achievement of A1C and fasting plasma glucose (FPG) targets. It has recently become increasingly evident that postprandial increases in blood glucose levels also contribute significantly to overall glycemic control and to the development of diabetes complications. Consequently, postprandial plasma glucose (PPG) control is receiving recognition as an essential therapeutic target for optimizing glycemic control in patients with type 2 diabetes. This publication series will explore the science of PPG and its contribution to glycemic control, and 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. Learning Objectives Upon completion of this activity, the participant should be able to: List the mechanisms of action of dipeptidyl peptidase-4 (DPP-4) inhibitors, paying specific attention to how they affect PPG levels Discuss the clinical efficacy of DPP-4 inhibitors for the treatment of type 2 diabetes Describe the safety profile of DPP-4 inhibitors Explain how DPP-4 inhibitors can be incorporated into the treatment algorithm for 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: Faculty David D Alessio, MD Formal Advisor: Takeda Pharmaceuticals North America, Inc; Merck & Co, Inc Research Activities: Amylin Pharmaceuticals, Inc; Eli Lilly and Company; ETHICON, Inc Consultant: Amylin Pharmaceuticals, Inc; MannKind Corporation CME and Educational Partner Staff Steve Weinman, RN Executive Director IMNE Disclosures: Nothing to disclose Sheryl Torr-Brown, PhD Scientific Director IMNE Disclosures: Nothing to disclose Amy Groves Director, Program Development IMNE Disclosures: Nothing to disclose Katie Fidanza Program Development Executive IMNE Disclosures: Nothing to disclose Megan Stephan, PhD Freelance Science and Medical Writer Disclosures: Nothing to disclose 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 decision-making 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 com, 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. 2

3 Current unmet therapeutic needs in diabetes Type 2 diabetes mellitus (T2DM) is characterized by chronic hyperglycemia, inappropriate fluctuations of blood glucose, and metabolic abnormalities that can predispose patients to both microvascular and macrovascular complications. 1 Diabetes is the leading cause of end-stage renal disease (ESRD) in the US, as well as new cases of blindness among adults aged 20 to 74 years and nontraumatic lower limb amputations in the United States. 2 Heart disease rates and stroke risk in adults with diabetes are 2 to 4 times higher than in adults without diabetes. 3,4 The mechanisms by which persistently elevated plasma glucose mediates the various micro- and macrovascular diseases associated with diabetes are still under investigation, as are the relative benefits of treating hyperglycemia. However, current standards of diabetes treatment put forth by the American Diabetes Association (ADA) recommend glycosylated hemoglobin (A1C) levels of < 7% in general and advocate reaching lower, nondiabetic levels on a patient-by-patient basis. 5 Despite these recommendations, a recent analysis by the National Committee for Quality Assurance has shown that between 29.4% (commercially insured or Medicare) and 47.9% (Medicaid) of patients do not achieve adequate glycemic control as determined by A1C. 6 Current approaches to achieving glycemic control include the use of oral agents, such as metformin, sulfonylureas (SUs), thiazolidinediones (TZDs), and α-glucosidase inhibitors. These drugs act by reducing hepatic glucose production, increasing insulin secretion, improving insulin sensitivity, or delaying the absorption of carbohydrates, respectively. However, for most patients, diabetes is a progressive disease that usually requires increased multidrug therapy, eventuating in insulin treatment to maintain some semblance of metabolic control. The progression of diabetes is thought to be due to gradual β-cell loss, and insulin replacement therapy is common for most patients within 7 to 10 years after diagnosis. While the range of drug choices to treat diabetes has advanced over the past 2 decades, therapeutics are still hampered by unwanted side effects such as weight gain, hypoglycemia, and gastrointestinal (GI) toxicity. Moreover, commonly used therapies like metformin, TZDs, and long-acting insulins are not particularly effective at maintaining postprandial plasma glucose (PPG) levels. This shortcoming has important implications because PPG levels are thought to contribute disproportionately to A1C levels near the target range (A1C of 7.0%-7.5%) and can limit the number of patients reaching the recommended A1C goal on these therapies. 7 In addition, elevated PPG levels have been associated with the development of macrovascular complications The need for new diabetes drugs with unique mechanisms of action and the potential to act on PPG control has been addressed recently with the introduction of incretin-based therapies. 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 Hormonal dysregulation in diabetes Viewed broadly, blood glucose levels are controlled by the regulation of hepatic glucose production to appropriate levels and the clearance of blood glucose into tissues such as liver, muscle, and adipose. These processes are regulated in large part by the actions of the islet hormones insulin and glucagon. Insulin suppresses, and glucagon stimulates, glycogenolysis and gluconeogenesis in the liver, the 2 processes that contribute to hepatic glucose production. Insulin is the primary signal to promote transport of glucose into cells that express the insulin receptor. The regulation of islet hormone secretion is thus of critical importance in controlling blood glucose. An increase in blood glucose is the key signal to stimulate insulin release and, in fact, most other nutrients and neural or endocrine factors acting on the β cell have limited impact at normoglycemia. Furthermore, glucagon release is inhibited during hyperglycemia and stimulated during hypoglycemia. The α cell is also regulated by β-cell secretory products. When meals are consumed, the GI tract releases a number of hormones that aid in the absorption and disposition of nutrients. Among these, the hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) are of particular importance because of their regulation of islet hormone secretion. GLP-1 and GIP augment glucose-stimulated insulin secretion, a process termed the incretin effect (Figure 1). The incretin effect accounts for approximately 50% of the insulin secreted after meals and therefore has a prominent role in postprandial metabolism. Incretin signaling is essential for normal glucose tolerance. 11 In addition to stimulating insulin secretion, GLP-1 also inhibits glucagon secretion. Importantly, the incretin effect is impaired in subjects with T2DM, and this likely contributes to the abnormal control of postmeal glucose levels that is a hallmark of this condition. Figure 1. The Incretin Effect Is Blunted in Type 2 Diabetes 12 IR Insulin (mu/l) Control Subjects (n = 8) Time (min) IR Insulin, insulin immunoreactivity. Intravenous Glucose Incretin effect nmol/l IR Insulin (mu/l) Oral Glucose Patients With Type 2 Diabetes (n = 14) 0 Incretin effect diminished in type 2 diabetes Time (min) Adapted from Nauck MA, et al. Diabetologia. 1986;29: Copyright 1986 Springer-Verlag. 0 nmol/l The reason for the abnormal incretin effect in diabetes has not been fully explained. It appears that most diabetic patients have a greatly attenuated response to GIP, and while they respond to pharmacologic levels of GLP-1, compared with nondiabetic subjects, they have reduced sensitivity to this incretin. 13 The secretion of GIP is normal in diabetic subjects and although some reports have noted modest reductions of GLP-1 in those with T2DM, this finding has not been uniform 14 and probably cannot account for the loss of the incretin effect. The incretin system as a therapeutic target Pharmacologic administration of GLP-1 normalizes fasting plasma glucose (FPG) and PPG, 15,16 at least in part by stimulating insulin and reducing glucagon levels. These findings have led to efforts to harness the incretin system for therapeutics. A key finding shaping this endeavor was the discovery that the incretins, particularly GLP-1, were rapidly metabolized in the circulation by the enzyme dipeptidyl peptidase-4 (DPP-4). This ubiquitous protease cleaves the first 2 amino acids from GLP-1 (and GIP), leaving a metabolite that does not stimulate insulin secretion or glucose clearance. 17 The very short half-lives of the incretins in the circulation (1-2 minutes for GLP-1 and 7 minutes for GIP) make the use of these native peptides as drugs impractical, and have led to alternative approaches. Two strategies have been pursued to overcome the rapid metabolism of the incretins. First, the development of DPP-4 resistant GLP-1 receptor agonists has allowed pharmacologic administration of compounds that activate this signaling system for a few to several hours. Second, small molecules that inactivate DPP-4, called DPP-4 inhibitors, extend the levels of active GLP-1 in the plasma, enhancing its effect. A number of novel therapeutics has been developed from these strategies. GLP-1 agonists that have been approved or are in late-stage development include exenatide (approved by the US Food and Drug Administration [FDA] in 2005), exenatide LAR*, liraglutide*, and taspoglutide*. These agents will be the subject of the next publication in this series. DPP-4 inhibitors that have been approved or are in late-stage development include sitagliptin (approved by the FDA in 2006), saxagliptin (FDAapproved in July 2009), vildagliptin*, and alogliptin*. These agents are described in further detail in the following pages. Biological basis for the mechanism of DPP-4 inhibitors DPP-4 is a ubiquitous enzyme that is found bound to endothelial and lymphocyte cell membranes, and in a soluble, circulating form. Levels of DPP-4 vary among tissues, with high activity in the liver, lungs, kidneys, intestines, and components of the immune system. In addition to GI hormones, many neuropeptides and cytokines are substrates for, and thus are regulated by, this enzyme. In the immune system, DPP-4 acts as a co-stimulator of T-cells. These immunoregulatory roles 2 *Not currently FDA approved.

5 have made it important to monitor for the possible effects of DPP-4 specific inhibitors on immune function during preclinical and clinical development. 18 The physiological actions of GLP-1, mostly elucidated in preclinical animal models (Figure 2), suggest a range of potential therapeutic benefits of DPP-4 inhibition in patients with diabetes. GLP-1 has a number of effects in addition to its stimulation of glucose-dependent insulin secretion as part of the incretin effect that modulates PPG. It inhibits glucagon secretion, reducing glucose production by the liver, thereby contributing to the regulation of both PPG and FPG levels. GLP-1 has effects on β-cell mass, improving pancreatic insulin secretion capacity by stimulating islet cell neogenesis and inhibiting apoptosis. It also increases satiety by acting as a neurotransmitter in the hypothalamus. Additionally, GLP-1 reduces PPG levels by inhibiting further ingestion and slows gastric emptying to provide a more gradual increase in PPG. 19 Figure 2. Antidiabetic Activities of GLP-1 21 DPP-4 inhibition enhances some of these actions of GLP-1. The proximal effect of DPP-4 inhibitors in animal studies and humans is an increase in the concentration of GLP-1 in the blood, by 2- to 3-fold, to high physiologic levels This increase in GLP-1 works to counteract hormonal dysregulation in patients with diabetes. The most well-studied DPP-4 inhibitors, vildagliptin and sitagliptin, are associated with increased postprandial insulin secretion in both drug-naïve and previously treated patients with diabetes Vildagliptin also reduces plasma glucagon levels in diabetes patients 21,24,28 and enhances pancreatic α-cell responsiveness to both hyper- and hypoglycemia. 29 Clinical studies have shown that together, these effects reduce the glucose profile following meals, blunting the inappropriate rise in PPG experienced by patients with diabetes. 24,30,31 increases β-cell mass and improves pancreatic islet architecture, as might be expected from the effects of GLP-1 on islet cell neogenesis and apoptosis. 38 It is well established that diabetes patients experience a gradual decline in β-cell function, leading to the need for increasingly aggressive pharmacotherapy. 39,40 By promoting GLP-1 mediated effects on β-cell mass, DPP-4 inhibitors may slow or even halt this decline, thereby reducing the need for additional therapies and improving outcomes in patients with diabetes. While there is significant evidence to show that DPP-4 inhibitors can restore many of the effects of GLP-1 in patients with diabetes, preliminary results suggest that this does not extend to the central nervous system mediated effects of GLP-1. A recent study in patients with type 2 diabetes showed that vildagliptin does not alter gastric emptying or the rate of entry of ingested glucose into the systemic circulation in humans, despite the role of GLP-1 in these processes. 23 Moreover, there is no evidence that DPP-4 inhibition alone has any impact on food intake or body weight. Overview of DPP-4 inhibitors (approved or in late-stage development) Four DPP-4 inhibitors have been approved or are currently in late-stage development (Figure 3). Sitagliptin has been approved in both the US and Europe. Saxagliptin has recently received approval from the FDA. 41 Vildagliptin has been approved in Europe but is undergoing further clinical trials to meet the requirements of the US FDA. 42 Alogliptin has been submitted for FDA approval and is undergoing additional clinical trials. 43 Figure 3. Structure of DPP-4 Inhibitors Approved or In Development 44 Sitagliptin Vildagliptin DPP-4 inhibitors have also been shown to improve β-cell function in patients with diabetes, as measured by the homeostasis model assessment of β-cell function (HOMA-B) 25,26,29,32-34 and by a number of measures of insulin production and processing. 26,31,32,35-37 Although such direct measures of β-cell function are impractical in humans, animal studies have shown that the DPP-4 inhibitor sitagliptin Alogliptin Saxagliptin 3

6 Pharmacologic properties of DPP-4 inhibitors Sitagliptin Sitagliptin is a competitive inhibitor of DPP-4 that is rapidly absorbed following oral intake. It inhibits plasma DPP-4 activity in a dose-dependent manner, with approximately 80% or greater inhibition occurring with doses 50 mg over 12 hours; doses 100 mg inhibit DPP-4 over a 24-hour period The pharmacokinetics (PK) of sitagliptin are generally similar in healthy subjects and in patients with type 2 diabetes, 46,48 with no requirement to adjust for body mass index (BMI). 46,49 Approximately 70% to 80% of sitagliptin is excreted unchanged in the urine, with an apparent terminal half-life ranging from 8 to 14 hours. 46 Limited oxidative metabolism of sitagliptin does occur and is primarily mediated by cytochrome P450 CYP3A4. 50 Several studies have examined the effects of sitagliptin on the PK of other antidiabetic agents. Co-administration of sitagliptin and metformin does not meaningfully alter the PK of either agent in patients with diabetes. 51 Other studies have found that sitagliptin does not alter the PK of 2 commonly used oral antidiabetic agents, rosiglitazone and glyburide, in healthy subjects. 52,53 Saxagliptin Saxagliptin is a potent, selective DPP-4 inhibitor designed for extended DPP-4 inhibition. A recent study examined the PK and pharmacodynamics of saxagliptin in healthy subjects and in patients with type 2 diabetes. Saxagliptin inhibited plasma DPP-4 at doses ranging from 2.5 to 400 mg, with maximal inhibition occurring at doses of 150 mg or greater. 54 There are little published data on the elimination of saxagliptin in humans, but animal studies in rats, dogs, and monkeys have been used to predict that human plasma clearance of saxagliptin is low to moderate. 55 Saxagliptin is eliminated through both metabolism and renal excretion. The principal metabolite of saxagliptin, which is generated by cytochrome P450 CYP3A, is also pharmacologically active. A study in healthy subjects of different ages and genders found slight differences in the metabolism of saxagliptin in older subjects ( 65 years old), but these differences were not large enough to necessitate changes in dosage. 56 Alogliptin A study of alogliptin doses ranging from 25 to 800 mg in healthy male subjects showed rapid absorption (median time to reach maximum concentration of 1 to 2 hours) and slow elimination (mean terminal elimination half-life ranging from about 12 to 21 hours). Approximately 60% to 70% of alogliptin was excreted unchanged in the urine. Mean peak DPP-4 inhibition ranged from 93% to 99%, and mean inhibition at 24 hours after dosing ranged from 74% to 97%, depending on the dose. 57 Like sitagliptin, alogliptin is not significantly metabolized and is primarily excreted by the kidneys. 58 Vildagliptin Vildagliptin binds covalently to DPP-4 and provides irreversible inhibition of the enzyme. The PK of vildagliptin were studied in patients with diabetes at doses ranging from 10 to 100 mg, taken twice daily for 28 days. Vildagliptin was rapidly absorbed (median time to reach maximum concentration of 1 hour) and had a mean terminal elimination half-life ranging from about 1.5 to 3.0 hours. In this study, vildagliptin inhibited over 90% of DPP-4 activity at all doses, with the duration of effect dependent on dose. 59 Further studies have shown that age, gender, and BMI have no clinically relevant effects on the PK or pharmacodynamics of vildagliptin. 60 Clinical efficacy, safety, and tolerability of DPP-4 inhibitors DPP-4 inhibitors as monotherapy in comparison to placebo Multiple clinical trials examining the efficacy and safety of DPP-4 inhibitors as monotherapies in drug-naïve or previously treated diabetes patients have been performed for sitagliptin, 27,30,61 saxagliptin, 31 alogliptin, 62 and vildagliptin. 25,26,63,64 Most of these trials have examined the efficacy of these agents using the parameters of A1C and FPG, while several have also measured PPG levels in 1-hour or 2-hour postmeal testing (Table 1). Reductions in A1C. Richter et al 18 recently conducted a meta-analysis of available efficacy and safety data for sitagliptin and vildagliptin that included 25 clinical studies of 12 weeks or longer duration with a total enrollment of approximately 12,000 patients. Most patients were white, obese, and had been diagnosed with T2DM within the previous 3 to 5 years. A substantial proportion had been treated with diet and/or exercise, but none had received prior pharmacotherapy. Mean baseline A1C was 8.0% and 8.2% in the intervention arms of the sitagliptin and vildagliptin trials, respectively, vs 8.5% and 8.4% for the corresponding control arms. Analysis of the sitagliptin studies showed a mean A1C reduction of 0.7% in the intervention population (P < compared with placebo), while vildagliptin showed a mean A1C reduction of 0.6% (P < compared with placebo). 18,65 Recent studies of saxagliptin and alogliptin have yielded similar results. Two studies investigated the efficacy of saxagliptin and alogliptin monotherapy over 12 and 26 weeks, respectively. 31,65 A1C reductions with saxagliptin ranged from 0.62% to 0.73%, while A1C reductions with alogliptin ranged from 0.56% to 0.59%. 31,65 Reductions in FPG. A number of studies have reported reductions in FPG levels with DPP-4 inhibitor monotherapy compared with placebo. Sitagliptin treatment (100 mg once daily) was associated with mean FPG changes from baseline of 0.96 mmol/l 60 and 1.0 mmol/l (placebo-subtracted). 30 Similar reductions in FPG have been observed for saxagliptin ( 0.78 to 1.39 mmol/l placebo-subtracted) 31 and alogliptin ( 1.2 to 1.54 mmol/l, placebo-subtracted). 66 A study of different dosing schedules for vildagliptin showed mean FPG reductions ranging from 0.6 ± 0.6 mmol/l to 1.2 ± 0.6 mmol/l in drug-naïve patients with diabetes. 63 Similar changes have been observed in other vildagliptin studies. 24,67 4

7 Table 1. Summary of Efficacy Data: DPP-4 Inhibitor Monotherapy 25,30,31,33,34,61-63,67,73-75,77 Therapy Drug dose (mg) Trial duration (weeks) Monotherapy trials a Mean Reduction in: A1C (%) FPG (mmol/l) PPG (mmol/l) Sitagliptin 100 mg QD or 50 mg BID to to Saxagliptin mg QD to to to 2.2 b Alogliptin 12.5 mg QD or 25 mg QD to to 1.5 ND Vildagliptin Head-to-head trials d 25 mg BID, 50 mg QD, 50 mg BID, or 100 mg QD to to c Sitagliptin 5-50 mg BID to to 1.4 ND morning Glipizide 5-20 mg/d ND Sitagliptin 100 mg per 2 ND metformin NR Exenatide + metformin 5 mcg BID first week, 10 mcg BID second week NR 2 ND Vildagliptin d 100 mg/d ND Metformin d 2000 mg/d ND Vildagliptin d 100 mg QD ND Pioglitazone d 30 mg QD ND Vildagliptin d 100 mg BID ND Rosiglitazone d 8 mg QD ND ND, not determined; NR, not reported; A1C, hemoglobin HbA 1c ; FPG, fasting plasma glucose; PPG, postprandial plasma glucose. a All parameters are reported as placebo-subtracted changes from baseline and rounded to 1 decimal place; 2-h PPG unless otherwise specified; b 1-h PPG; c 4-h PPG; d All parameters are reported relative to active comparator. Reductions in PPG. A major assumption underlying the development of DPP-4 inhibitors was that they would be particularly effective in correcting PPG in patients with diabetes because incretin secretion is highest after meals. Indeed, a 24-week study of sitagliptin showed a mean PPG reduction of 2.6 mmol/l compared to placebo in patients with T2DM. 30 Shorter 12-week studies of saxagliptin 31 and vildagliptin have shown similar reductions ( 1.33 to 2.28 mmol/l and 1.9 mmol/l, respectively). 24 Safety and tolerability. Most studies have found DPP-4 inhibitors to be safe and well tolerated. In the meta-analysis by Richter et al, 18 headache and an increased risk of all-cause infections (ie, nasopharyngitis, sinusitis, upper respiratory tract infection, urinary tract infection, and viral infection) were listed as the most common adverse events (AEs). In another meta-analysis, Amori and colleagues found that treatment with sitagliptin or vildagliptin was associated with a slightly higher rate of urinary tract infections but a lower rate of sinusitis. 68 In both meta-analyses, GI AEs were similar to placebo. As expected, no episodes of severe hypoglycemia defined as those requiring third-party assistance were reported in patients taking sitagliptin or vildagliptin. 18,68 Saxagliptin and alogliptin have been shown to be similarly well tolerated with a favorable AE profile, including a lack of serious episodes of hypoglycemia. 31,62 The effects of saxagliptin on cardiovascular (CV) risk have been evaluated in an analysis that included 5000 patientyears of clinical trial experience, with data from 8 randomized double-blind clinical trials with saxagliptin and various comparators. Saxagliptin showed no increase in CV risk parameters, and the data suggest that a study on the potential cardioprotective effects of saxagliptin may be warranted. 69 Because DPP-4 inhibitors are eliminated primarily by renal excretion, multiple studies have examined the need for dose reduction in patients with renal impairment or ESRD. Sitagliptin has been found to be well tolerated in patients with type 2 diabetes and moderate to severe renal insufficiency, including patients with ESRD on dialysis, 70 although dosage adjustments are recommended. 46,49 A study of alogliptin in patients with mild to severe renal insufficiency or ESRD found that the alogliptin dose should be reduced to one-half of the standard dose in subjects with moderate renal insufficiency, and to onequarter in subjects with severe renal insufficiency or ESRD. No dose adjustment was necessary for patients with mild renal insufficiency. 57 5

8 The effects of DPP-4 inhibitors in patients with hepatic impairment have also been studied. A recent report of saxagliptin PK in patients with hepatic impairment showed slight differences in metabolism compared with healthy subjects, but they were not sufficient to warrant dose adjustment. 71 Vildagliptin has been tested in patients with mild, moderate, and severe hepatic impairment and, again, no dose adjustment was found necessary. 72 The approved labeling for sitagliptin notes that there is currently no clinical experience regarding the use of this agent in patients with severe hepatic insufficiency. 47 DPP-4 inhibitors compared to other antiglycemic therapies Sitagliptin Sitagliptin monotherapy has been compared in head-to-head trials with the sulfonylurea glipizide and the GLP-1 agonist exenatide. In the sitagliptin-glipizide study, drug-naïve patients with type 2 diabetes were treated for 12 weeks with sitagliptin doses ranging from 5 to 50 mg twice daily, or with 5 mg/day glipizide electively titrated up to 20 mg/day. A1C reductions with sitagliptin ranged from 0.38% to 0.77% in a dosedependent manner compared to placebo, while the glipizide group showed a reduction of 1.00% compared to placebo. 73 The higher rate of A1C reduction with glipizide was achieved at the cost of a much higher incidence of hypoglycemia AEs, which were reported in 17% of the glipizide patients compared with 2% for placebo and 0% to 4% in the sitagliptin patients. 73 Exenatide and sitagliptin were compared in a 2-week study that examined 2-hour PPG, insulin and glucagon secretion, gastric emptying, and caloric intake in T2DM. FPG reduction was comparable between exenatide and sitagliptin ( 15 ± 4 mg/dl vs 19 ± 4 mg/dl), while exenatide had a greater effect on PPG with a greater reduction in postprandial glucose excursions (Figure 4). 74 Exenatide also slowed gastric emptying and reduced caloric intake, while sitagliptin did not. AEs were mild to moderate with both therapies. 74 Figure 4. Comparison a of Sitagliptin Monotherapy, Sitagliptin-Glimepiride Combination Therapy, and Exenatide on PPG and FPG in Patients With Diabetes 36, Sitagliptin Sitagliptin + Glimepiride Exenatide FPG, fasting plasma glucose; PPG, postprandial plasma glucose. a Comparison of data from 2 different studies Reduction in 2-hour PPG in response to standard meal (mg/dl) Reduction in FPG (mg/dl) Vildagliptin Vildagliptin monotherapy has been compared in head-to-head studies with metformin, pioglitazone, and rosiglitazone. A 1-year study compared vildagliptin and metformin in drugnaïve patients with type 2 diabetes and found similar effects on A1C. 75 Vildagliptin and metformin reduced A1C by 1.0% ± 0.1% (P <.001) and 1.4% ± 0.1% (P <.001), respectively, compared with control. However, the study was not powered to demonstrate statistical noninferiority of vildagliptin. 75 A 1-year extension of this study showed that these A1C reductions were maintained at similar levels for a total of 2 years. 76 AEs were similar in the 2 groups, although patients taking metformin experienced a 2-fold increase in GI AEs compared to those taking vildagliptin. This increase was driven by a 3- to 4-fold increase in the incidence of diarrhea, nausea, and abdominal pain. Hypoglycemic events were low in both groups. 75,76 Two studies have compared vildagliptin to the TZDs rosiglitazone and pioglitazone. 67,77 A 24-week study of vildagliptin and rosiglitazone monotherapies in drug-naïve patients with T2DM showed that both therapies reduced A1C to a similar extent from a mean baseline of 8.7%. Vildagliptin was as effective as rosiglitazone, improving A1C by 1.1% ± 0.1% (P <.001) compared to 1.3% ± 0.1% (P <.001), meeting the statistical criterion for demonstrating noninferiority. 67 However, rosiglitazone was associated with a larger reduction of FPG than vildagliptin ( 2.3 mmol/l vs 1.3 mmol/l, respectively). 67 Similar results were obtained in a 24-week study that compared vildagliptin to pioglitazone. 77 In addition, both studies showed similar rates of AEs for vildagliptin compared to either TZD, with the exception of edema, which was experienced by 4.1% of patients taking rosiglitazone compared to 2.1% of those taking vildagliptin. 67 Pioglitazone monotherapy was also associated with a higher rate of edema. 77 Incidence of hypoglycemic events was low with all 3 therapies. 67,77 DPP-4 inhibitors as part of combination therapies for diabetes Most patients with diabetes require combination therapy over time to maintain glucose homeostasis. Despite the addition of multiple agents with differing modes of action, blood glucose is still not adequately controlled in many patients. To determine whether DPP-4 inhibition offers an effective adjunct option with other agents, a number of clinical trials have focused on the addition of DPP-4 inhibitors to other antiglycemic therapies, including metformin, sulfonylureas, insulin, and TZDs (Table 2). Several studies have looked at sitagliptin, alogliptin, and vildagliptin as add-on therapies to metformin in patients whose diabetes was inadequately controlled on metformin alone, or as initial combination therapy in drug-naïve patients. 37,78-85 A recent 24-week study of initial combination therapy with sitagliptin and metformin in drug-naïve patients with diabetes demonstrated that the use of DPP-4 inhibitors can produce an additive effect on hyperglycemia. 81 This study compared a number of different sitagliptin-metformin dosage combinations. From a mean baseline of 8.8%, combination therapy reduced 6

9 A1C levels by 2.07% for the sitagliptin 100 mg + metformin 2000 mg group and by 1.57% for the sitagliptin 100 mg + metformin 1000 mg group, compared to 1.30% for metformin 2000 mg alone, 0.99% for metformin 1000 mg alone, and 0.83% for sitagliptin 100 mg alone (P <.001 for all comparisons). Combination therapy was well tolerated, and the incidence of GI events was similar between each combination and the corresponding dose of metformin alone. Hypoglycemia incidence was low across the active treatment groups and did not significantly differ from that for placebo. 81 A study of alogliptin added to metformin in patients with type 2 diabetes whose A1C levels were inadequately controlled with metformin alone similarly found that the addition of alogliptin improved A1C levels without increasing the incidence of AEs. 85 A recent 24-week study examined the effects of adding sitagliptin to glimepiride or glimepiride + metformin in patients with inadequately controlled T2DM. 36 The addition of sitagliptin reduced A1C levels by 0.74% compared to placebo from a mean combined baseline of 8.34%. The addition of sitagliptin also reduced FPG and PPG, and increased pancreatic β-cell function (HOMA-B) relative to placebo. This study found higher rates of AEs with the addition of sitagliptin, largely due to an increase in hypoglycemia with the addition of the DPP-4 inhibitor (12% incidence rate vs 2% for placebo). 36 Garber et al 86 studied the effects of vildagliptin in a 24-week study of patients whose diabetes was inadequately controlled with sulfonylurea monotherapy. Vildagliptin (50 mg once or twice daily) or placebo was added to glimepiride (4 mg once daily). Adding vildagliptin reduced A1C levels by 0.6% ± 0.1% in patients receiving vildagliptin 50 mg daily and by 0.7% ± 0.1% in those receiving 100 mg daily, compared to adding placebo (P <.001). Patients receiving vildagliptin also showed improvements in β-cell function and PPG levels. The incidence of hypoglycemic events was higher in patients receiving vildagliptin 100 mg (3.6%) compared to those receiving vildagliptin 50 mg (1.2%) or placebo (0.6%). 86 Similar results were seen in a study combining alogliptin with glyburide monotherapy. 87 Vildagliptin was added to insulin therapy in a 24-week study of patients with inadequately controlled T2DM. 88 Patients receiving vildagliptin in addition to insulin experienced a 0.5% ± 0.1% reduction in A1C compared to 0.2% ± 0.1% in those receiving placebo. The addition of vildagliptin to insulin therapy also had the beneficial effect of reducing both the frequency and severity of hypoglycemic events in these patients. 88 A recent study of alogliptin added to insulin therapy also showed improvements in A1C but no significant effect on the incidence or severity of hypoglycemia. 89 Sitagliptin, alogliptin, and vildagliptin were all added to monotherapy with the TZD pioglitazone in 4 separate studies. 35,77,90,91 The addition of a DPP-4 inhibitor was associated with improvements in A1C, 35,77,90,91 FPG, 35 and PPG 91 levels. All 4 of these studies found that the combination therapies were well tolerated, with no increased risk of hypoglycemia. 35,77,90,91 One study 77 found that the incidence of peripheral edema was highest in patients receiving pioglitazone monotherapy (9.3%) and lowest in those receiving low-dose combination therapy with vildagliptin and pioglitazone (3.5%), although this result was not replicated in the other studies. Triple therapy with metformin, a TZD, and a DPP-4 inhibitor has also been shown to be associated with substantial improvements in glycemic control, including PPG, without a significant increase in the incidence of AEs. 92 Table 2. Summary of Efficacy Data: DPP-4 Inhibitor Combination Therapies 35,36,77,79,85,86,88,89,91 Mean Reduction in: Therapy Treatment dose (mg) Comparator Comparator dose (mg) Trial Duration (weeks) A1C (%) FPG (mmol/l) PPG (mmol/l) Sitagliptin + metformin a 50 mg QD Metformin monotherapy 500 or 1000 mg QD to to to 2.2 Alogliptin + metformin a 12.5 or 25 mg QD Metformin monotherapy 1500 mg/d ND Vildagliptin + metformin a 50 mg QD Metformin monotherapy 1500 to 3000 mg/d c Sitagliptin + glimepiride b 12.5 or 25 mg/d Glimepiride monotherapy 4 mg/d Alogliptin + glyburide b 50 mg QD or 50 mg BID Glyburide monotherapy 5 mg/d to to 0.6 ND Vildagliptin + glimepiride b 50 mg QD or 50 mg BID Glimepiride monotherapy 4 mg QD to to to -0.9 Alogliptin + insulin b 50 mg BID Placebo to to 1.0 ND Vildagliptin + insulin b Placebo ND ND Sitagliptin + pioglitazone b 100 mg QD Pioglitazone monotherapy 30 or 45 mg/d ND Alogliptin + pioglitazone b 12.5 or 25 mg QD Pioglitazone monotherapy, pioglitazone + metformin, or pioglitazone + a sulfonylurea pioglitazone 35 mg/d (mean dose), metformin and sulfonylurea doses NR to ND Vildagliptin + pioglitazone b 50 or 100 mg QD Pioglitazone monotherapy 15 or 30 mg QD to to to 5.2 c ND, not determined; NR, not reported; A1C, hemoglobin HbA1c; FPG, fasting plasma glucose; PPG, postprandial plasma glucose a Parameters are reported as mean change from metformin monotherapy rounded to 1 decimal place, 2-h PPG unless otherwise specified. b Parameters are reported as between-treatment differences rounded to 1 decimal place, 2-h PPG unless otherwise specified. c 4-h PPG. 7

10 Effects of DPP-4 inhibitors on clinical parameters related to macrovascular complications of diabetes In addition to glucose-lowering effects, current diabetes therapies have effects on clinical parameters that may affect the risk of CV disease. Insulin and pioglitazone, for example, have been associated with improvements in lipid profiles. On the other hand, insulin, sulfonylureas, and TZDs have all been associated with weight gain and higher BMI, both of which are well-established risk factors for CV disease. Of the incretinbased therapies, GLP-1 agonists have been associated with weight loss, while DPP-4 inhibitors are generally considered to be weight neutral, similar to metformin. 93 Figure 5. Comparison of Vildagliptin and Rosiglitazone Monotherapy on Lipids in Patients With Type 2 Diabetes 67 Summary of clinical evidence regarding DPP-4 inhibitors DPP-4 inhibitors have been studied extensively in clinical trials and seem to reduce A1C levels by a range of about 0.5% to 0.8% in diabetic patients who have moderate glycemic control, with concomitant reductions in FPG and PPG (Table 3). These reductions have been shown to be additive when DPP-4 inhibitors are used together with insulin, TZDs, metformin, and sulfonylureas, without a significant increase in AEs. DPP-4 inhibitors are well tolerated, with AEs consisting primarily of headaches and occasionally non life-threatening infections. As expected, due to their glucose-dependent mechanism, DPP-4 inhibitors do not generally increase episodes of hypoglycemia. They are also not associated with GI adverse effects. Overall, these characteristics suggest that DPP-4 inhibitors are a moderately efficacious, well-tolerated addition to the armamentarium of therapies against hyperglycemia in T2DM. These therapies may be particularly useful in older patients or in patients with reduced renal function, for whom some other currently used antiglycemic therapies are inappropriate. Adjusted Mean Change (%) Vildagliptin 100 mg daily Rosiglitazone 8 mg daily b a c c c c TG TC LDL Non-HDL HDL TC/HDL Table 3. Summary: Clinical Properties of DPP-4 Inhibitors A1C reduction (%) 0.5 to 0.8 FPG reduction (mmol/l) 0.6 to 1.4 PPG reduction (mmol/l) 1.2 to 3.0 Safety and tolerability Generally well tolerated Associated with headaches and occasional non life-threatening infections Adjusted mean change from baseline to end point in fasting lipid parameters in the primary ITT population. a P <.05; b P <.01; c P <.001 vs rosiglitazone. TG, triglycerides; TC, total cholesterol; LDL, low-density lipoprotein; HDL, high-density lipoprotein. Several studies have examined the effects of vildagliptin on other CV parameters, including blood lipid profiles. A small study by Matikainen et al examined the effects of 4-week treatment with vildagliptin on triglyceride, cholesterol, and lipoprotein responses to a fat-rich mixed meal. 23 They found that vildagliptin led to an attenuation of the postprandial plasma triglyceride rich lipoprotein response, although the mechanistic and clinical implications of this are unclear. 23 A study by Rosenstock et al compared vildagliptin with rosiglitazone monotherapy and found that vildagliptin significantly decreased triglycerides, total cholesterol, low-density lipoprotein (LDL), non-high density lipoprotein (HDL), and total/hdl cholesterol (HDL-C: 9% to 16%; all P.01), but produced a smaller increase in HDL-C (4% vs 9%; P =.003) compared to rosiglitazone (Figure 5). 67 While these studies suggest some potential benefit, longer and more detailed studies will be needed to determine the overall CV impact of DPP-4 inhibitors. Cardiovascular parameters Not associated with an increase in hypoglycemia Not associated with gastrointestinal adverse effects Generally safe for patients with renal insufficiency (with appropriate dose reductions) Weight neutral Small positive changes in lipid parameters Study warranted on potential cardioprotective effect of saxagliptin DPP-4, dipeptidyl peptidase-4; FPG, fasting plasma glucose; PPG, postprandial plasma glucose. 8

11 Novel DPP-4 inhibitors The development pipeline for DPP-4 inhibitors shows future promise for this therapeutic class. There are several novel DPP-4 inhibitors in preclinical and clinical testing. Linagliptin is a phase 3 compound that has been shown to be effective in patients with T2DM who are poorly controlled with metformin. 94 A second compound, gosogliptin (PF ), was reported to be safe and effective in a phase 2b study in patients with T2DM when added to metformin in a placebo-controlled 12- week trial. 95 However, PK studies have revealed a need for dose reduction in patients with renal failure. 96 An experimental dual DPP-4 inhibitor and GPR119 agonist, SN-IV/119-1, has been shown to exhibit greater glucose-lowering activity than sitagliptin after an acute oral glucose tolerance test in a rat model of T2DM. 97 A second preclinical compound, MP-513, has been shown to prevent visceral obesity induced by a high-fat diet in an obese mouse model. 98 Finally, DSP-7238, a novel non-cyanopyrrolidine, orally available DPP-4 inhibitor, has been demonstrated to be safe and well tolerated in a single ascending dose study in healthy volunteers, 99 with a favorable PK profile in vivo. In addition, this compound has been shown to exhibit higher selectivity than vildagliptin or sitagliptin in rats and monkeys. 100 Current recommendations for the clinical use of DPP-4 inhibitors One of the reasons for targeting the incretin system in diabetes is the potential to reduce PPG excursions, which have been implicated in disproportionately affecting A1C at or near a level of 7% as well as increasing CV risk in patients with diabetes. 7,9,10 Current ADA guidelines recommend a peak postprandial capillary plasma glucose level of < 180 mg/dl for nonpregnant adults with diabetes, although reducing A1C levels is still recommended as the primary goal of antiglycemic therapy. 5 The ADA recommends that specific attention be paid to PPG in individuals whose FPG levels are within the goal range ( mg/dl) but whose A1C levels are still above goal. This approach includes self-monitoring of PPG for 1 to 2 hours after the start of a meal and administration of therapy intended to reduce PPG, ultimately as a means of reducing A1C levels. 5 The most recent consensus algorithm issued by the ADA and the European Association for the Study of Diabetes includes DPP-4 inhibitors, along with α-glucosidase inhibitors, glinide and pramlintide as other therapies outside of the 2 tiers of preferred agents due to their smaller efficacies, limited clinical data, and increased expense. 93 However, the authors of the algorithm note that these agents may be appropriate choices in selected patients. 93 The American College of Endocrinology/American Association of Clinical Endocrinologists most recent diabetes roadmaps for treatment-naïve and previously treated patients 101 include DPP-4 inhibitors as both monotherapy and in combination with other agents in a variety of clinical settings. In treatment-naïve patients whose initial A1C is less than 9%, DPP-4 inhibitors are recommended similarly to other, more established therapies to address A1C, FPG, and PPG targets. In previously treated patients, DPP-4 inhibitors are recommended in those whose current A1C levels range from 6.5% to 8.5%, including patients receiving insulin therapy. 102 Several clinical studies of vildagliptin have detected enhanced reduction of A1C levels in older patients, 86,88 suggesting that DPP-4 inhibitors may be particularly useful in this patient group. These therapies might be used in place of those that are less suitable for older patients, including insulin and sulfonylureas, which are associated with higher rates of hypoglycemia, and TZDs, which are associated with bone fractures. 102 DPP-4 inhibitors can also be used in patients with renal insufficiency, with appropriate dose reductions, suggesting that they could be used instead of metformin, which is contraindicated in patients with renal insufficiency. 50,58,70,102 This consideration is particularly important, since 20% to 40% of patients with diabetes eventually develop diabetic nephropathy and many progress to ESRD. 5 Overall, the key strengths of DPP-4 inhibitors are ease of administration, tolerability, and lack of important contraindications. While it seems appropriate for newer agents, such as DPP-4 inhibitors, to fall lower in consensus algorithms, they may eventually advance to a role as a second-line therapy. Important in the ultimate positioning of these drugs in therapeutic recommendations for T2DM are the results from ongoing trials of CV effects and the durability of response in A1C (David D Alessio, MD. Personal communication). Overall, the key strengths of DPP-4 inhibitors are ease of administration, tolerability, and lack of important Contraindications. 9

12 Literature Reviews The following information is not certified for CME credit. (Figure 1b) concentrations were not significantly different between the metformin and placebo groups after the SMM. DPP-4 activity did not change significantly after the SMM in either group (Figure 1b). Cuthbertson J, Patterson S, O Harte FPM, Bell PM. Investigation of the effects of oral metformin on dipeptidyl peptidase-4 (DPP-4) activity in type 2 diabetes. Diabet Med. 2009;26: Whereas modulation of the incretin system through dipeptidyl peptidase-4 (DPP-4) inhibition is usually achieved with specifically designed agents, controversy exists regarding the effect of the traditional antidiabetic agent metformin on DPP-4 activity and circulating glucagon-like peptide-1 (GLP-1). This study is a continuation of a previous study by the same authors that showed DPP-4 to be suppressed under fasting conditions after oral metformin administration. The current study determined the effect of an acute dose of metformin on DPP-4 activity during a standard mixed meal (SMM) and then after fasting in patients with type 2 diabetes mellitus (TD2M). The study included 10 subjects with a mean (± SEM) age of 65.8 ± 2.6 years and body mass index (BMI) of 30.0 ± 1.2 kg/m 2. Baseline A1C was 6.3 ± 0.2% (mean ± SEM). All patients had met the World Health Organization criteria for T2DM at the time of diagnosis. Patients with a fasting A1C > 7.5% or with significant renal impairment were excluded from the study. Of the initial 10 patients, 6 agreed to return for the fasting portion of the study. Subjects discontinued their oral antidiabetic agents 3 weeks before the study began and fasted from 11:00 PM the night before the study to 8:00 am on the day of the study. Subjects received 1 g oral metformin or placebo at 0 minutes in a randomized crossover design, which was followed immediately by an SMM (450 kcal, 50 g carbohydrate, 18 g protein, 20 g fat) that they consumed within 5 minutes. Venous blood was collected via an antecubital catheter at 10, 0, 15, 30, 60, 120, 180, and 240 minutes for the measurement of plasma glucose (glucose oxidase method), metformin (high performance liquid chromatography [HPLC]), insulin (standard commercial kit), C-peptide (standard commercial kit), DPP-4 (fluorometric method), and GLP-1 (enzyme-linked immunosorbent assay [ELISA]). Figure 1. Comparison of the effects of 1 g oral metformin ( ) with those of placebo (r) on glucose and insulin (a) and on dipeptidyl peptidase-4 (DPP-4) and glucagon-like peptide-1 (GLP-1) (b) after a standard mixed meal in patients with type 2 diabetes. The effects of metformin on the test variables were then compared between the fasting group and the SMM group. Patients ingested metformin and were then monitored for 240 minutes in either a fasting state or after the SMM at 0 minutes. The results are shown in Table 1. Postprandial glucose excursions were seen in the SMM group; glucose concentrations were significantly higher in the SMM group than in the fasting group at 30 and 60 minutes. By 120 minutes, glucose had decreased to fasting concentrations, and no significant differences were observed between the SMM and fasting groups. Similarly, serum insulin concentrations increased in response to the SMM and were significantly higher in the SMM group than in the fasting group at 60 and 120 minutes. Plasma GLP-1 was significantly higher in the SMM group than in the fasting group at 30 minutes, but not at any other time point. DPP-4 activity was significantly lower in the fasting group than in the SMM group at 30, 60, and 120 minutes. The effects of metformin on the measured variables were analyzed. As expected, plasma glucose was significantly lower after metformin than after placebo after the SMM (P <.05 at 240 minutes; Figure 1a). The increases in serum insulin (Figure 1a) and plasma GLP-1 Metformin concentrations were higher in the fasting group than in the SMM group, as indicated by the area under the curve (AUC) when plasma metformin was plotted against time over 4 hours in both groups (350 ± 66 vs 457 ± 55 mg ml -1 min -1 ; P <.001) Table 1. Effects of metformin (1 g orally) on glucose, insulin, glucagon-like peptide-1 (GLP-1), and dipeptidyl peptidase-4 (DPP-4) after a standard mixed meal (SMM) or in a fasting state Time (min) SMM 8.1 ± ± 0.7 Fasting 7.0 ± ± 0.4 P value <.02 <.01 Plasma Glucose (mmol/l) Serum Insulin (pmol/l) GLP-1 (pmol/l) DPP-4 (µmol/l) SMM ± ± 53.5 Fasting 99.3 ± ± 10.4 P value <.001 <.005 SMM 13.6 ± 0.3 Fasting 8.4 ± 0.2 P value <.0001 SMM 6.6 ± ± ± 0.02 Fasting 6.4 ± ± ± 0.03 P value <.001 <.0001 <.01 For clarity, only data reflecting significant differences between the fasting and SMM groups are shown. Data are expressed as mean ± SEM. 10

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