Incretinas mayo clinic 2010 copia


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Incretinas mayo clinic 2010 copia

  1. 1. SUPPLEMENT ARTICLE INCRETIN SYSTEM IN TREATMENT OF TYPE 2 DM Incretins: Clinical Perspectives, Relevance, and Applications for the Primary Care Physician in the Treatment of Patients With Type 2 Diabetes Mellitus Jeff Unger, MD The prevalence of type 2 diabetes mellitus (DM) is increasing substantially in the United States. Almost 24 million people have the disease, with most of these patients treated by primary care physicians. Optimal treatment of type 2 DM requires physicians to understand the pathophysiology of this disorder. Once the physiologic defects are determined, lifestyle interventions and glucoselowering medications can be prescribed to minimize the state of chronic hyperglycemia and to address the pathophysiologic defects associated with type 2 DM. Other metabolic abnormalities, including hyperlipidemia, hypertension, and oxidative stress, must also be addressed to reduce the patient’s risk of cardiovascular disease. The incretin system plays a role in the pathogenesis of type 2 DM. Incretin-based therapies, including glucagon-like peptide 1 receptor agonists and dipeptidyl peptidase 4 inhibitors, have shown efficacy and safety in treating type 2 DM and have been reviewed in consensus treatment algorithms. This article provides an overview of the role of incretin-based therapies in the management of patients with type 2 DM and how primary care physicians can incorporate these agents into their practice. DM decreased from 38% to 28% of treatment visits as several newer classes of antidiabetes medications were introduced.4,5 Currently, at least 10 different medication classes are available for the treatment of patients with type 2 DM. Additional DM treatments that are in various stages of preclinical and clinical development may address DM prevention, novel methods to control hyperglycemia, and reversal of DM-related complications. The purpose of this article is to provide an overview of incretin-based therapies with an emphasis on how PCPs can optimally use these agents for the treatment of patients with type 2 DM. Mayo Clin Proc. 2010;85(12)(suppl):S38-S49 Approximately two-thirds of the insulin response to an oral glucose load is due to the potentiating effect of gut-derived incretin hormones.6 The incretin effect has been mostly attributed to peptide hormones that are released into the bloodstream from intestinal K and L cells in response to a meal. Glucagon-like peptide 1 (GLP-1), secreted by L cells,6 appears to play an important role in the incretin effect. Secretion of GLP-1 in response to meals decreases progressively from normal glucose tolerance to overt DM.7 This is important because GLP-1 facilitates the regulation of postprandial glucose (PPG) control by stimulating insulin secretion in a glucose-dependent manner8,9 and helps regulate the rate of glucose appearance by inhibiting glucagon secretion,10 inhibiting hepatic glucose production,10 AACE = American Association of Clinical Endocrinologists; ACCORD = Action to Control Cardiovascular Risk in Diabetes; ACE = American College of Endocrinology; AE = adverse event; CI = confidence interval; CV = cardiovascular; DM = diabetes mellitus; DPP-4 = dipeptidyl peptidase 4; DURATION-2 = Diabetes Therapy Utilization: Researching Changes in A1c, Weight and Other Factors Through Intervention With Exenatide Once Weekly; FDA = US Food and Drug Administration; FPG = fasting plasma glucose; GIP = glucose-dependent insulinotropic polypeptide; GLP-1 = glucagon-like peptide 1; HbA1c = hemoglobin A1c; HOMA-β = homeostasis model assessment of β-cell function; LEAD = Liraglutide Effect and Action in Diabetes; PCP = primary care physician; PPG = postprandial glucose P rimary care physicians (PCPs) are on the front lines of diabetes mellitus (DM) care in the United States.1,2 An estimated 23.6 million Americans (7.8% of the US population) have DM, approximately 90% to 95% of whom have type 2 DM.3 Approximately 17.9 million patients in the United States have been diagnosed as having DM, and 5.7 million have undiagnosed DM.3 Type 2 DM is characterized by abnormal glucose homeostasis and increased risks of cardiovascular (CV), renal, and other complications. Although type 2 DM is a complex illness, PCPs are well positioned to provide the long-term and comprehensive medical care required to treat patients. During the past 15 years, the prevalence of type 2 DM and the complexity and costs of its treatment have increased substantially. In the United States, the estimated number of visits to officebased physicians for type 2 DM treatment increased from 29 million to 45 million between 1994 and 2007.4 During this same period, insulin use for the treatment of type 2 INCRETIN PHYSIOLOGY From the Catalina Research Institute, Chino, CA. Dr Unger has received royalties from Lippincott Publishing; consulting fees from Roche Pharmaceuticals, Novo Nordisk Inc, Amylin Pharmaceuticals, Inc, KOWA Pharmaceuticals, NicOx Pharmaceuticals, Colcrys Pharmaceuticals, and Takeda Phamaceuticals; speakers’ bureau fees from Novo Nordisk Inc, Amylin Pharmaceuticals, Inc, Lilly Pharmaceuticals, Roche Pharmaceuticals, Takeda Pharmaceuticals, and Solvay Pharmaceuticals; and contracted research fees from Novo Nordisk Inc, GlaxoSmithKline Pharmaceuticals, sanofiaventis Pharmaceuticals, Roche Pharmaceuticals, Forrest Pharmaceuticals, AstraZeneca Pharmaceuticals, Takeda Pharmaceuticals, Daiichi Sankyo Pharmaceuticals, Ortho-McNeil Pharmaceuticals, Arena Pharmaceuticals, Inc, Wyeth Pharmaceuticals, Cephaplon Pharmaceuticals, Proctor & Gamble Pharmaceuticals, Allergan Pharmaceuticals, Abbott Laboratories, Sangamo Pharmaceuticals, Amylin Pharmaceuticals, Inc, Johnson & Johnson Pharmaceuticals, Endo Pharmaceuticals, and MAP Pharmaceuticals. Address correspondence to Jeff Unger, MD, Associate Director of Metabolic Studies, Catalina Research Institute, 14726 Ramona Ave, Ste 110, Chino, CA 91710 ( © 2010 Mayo Foundation for Medical Education and Research S38 For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings. a
  2. 2. INCRETIN SYSTEM IN TREATMENT OF TYPE 2 DM regulating gastric emptying,11,12 and reducing food intake by postulated centrally mediated mechanisms.10,13 Enzymatic inactivation by dipeptidyl peptidase 4 (DPP-4) shortens the biologic activity of GLP-1 to less than 2 minutes.14 Glucagon-like peptide 1 controls fasting and PPG concentrations by multiple actions, primarily by stimulating glucose-dependent insulin secretion from pancreatic β cells while inhibiting glucagon secretion. In addition, GLP-1 enhances satiety and reduces food intake. Among the newest approved classes of antidiabetes medications are incretin-based therapies known as GLP-1 receptor agonists and DPP-4 inhibitors. Several medications in this category that recently have been approved by the US Food and Drug Administration (FDA) have been rapidly adopted into clinical practice.4 Exenatide is a GLP-1 receptor agonist that received FDA approval in 2005 as an adjunct to diet and exercise to improve glycemic control in adults with type 2 DM. Exenatide is indicated for use as monotherapy, but it may also be used in combination with metformin plus a sulfonylurea or metformin plus a thiazolidinedione.15 In January 2010, liraglutide, another GLP-1 receptor agonist, received regulatory approval in the United States as an adjunct to diet and exercise to improve glycemic control in adults with type 2 DM. Although not recommended for use as monotherapy, liraglutide can be prescribed to patients who are metformin intolerant or in whom metformin may be contraindicated. Both exenatide and liraglutide are available for use as subcutaneous injections. Two DPP-4 inhibitors, sitagliptin and saxagliptin, approved in 2006 and 2009, respectively, are available orally for improving glycemic control in patients with type 2 DM. RELATIONSHIP OF GLP-1 DEFICIENCY AND RESISTANCE TO THE PATHOGENESIS OF TYPE 2 DM The fundamental pathophysiologic defects in type 2 DM are β-cell failure and insulin resistance in muscle, the liver, and adipose tissue.16 The metabolic consequences of these deficits include impaired insulin secretion, decreased muscle glucose uptake, unrestrained hepatic glucose production, decreased hepatic glucose uptake, and inappropriate secretion of glucagon. Diminished gastrointestinal production of incretins also plays a key role in the development of hyperglycemia.16 Chronic hyperglycemia is the physiologic hallmark of type 2 DM and may be present before the onset of clinical symptoms, causing pathologic and functional changes in target organs and tissues.17 The 2 most important incretins are GLP-1 and glucosedependent insulinotropic polypeptide (GIP). Together these hormones account for up to 70% of postprandial insulin secretion.18,19 The incretin effect is severely impaired or absent in patients with type 2 DM, and recognition of the important role of this effect in maintaining glucose homeostasis has fueled the current interest in the development of therapies that target the incretin system.18 The impaired incretin effect in patients with type 2 DM occurs in the presence of normal GIP secretion, suggesting a possible loss of β-cell sensitivity to the insulinotropic effects of GIP in type 2 DM in addition to hyposecretion or decreased sensitivity to incretin factors.20 The incretin defect in patients with type 2 DM includes a lack of GIP amplification of the late-phase (ie, 20- to 120-minute postprandial) insulin response to glucose.21 In contrast, there is a moderate degree of GLP-1 hyposecretion in patients with type 2 DM, although the insulinotropic response to GLP-1 is well preserved.22 These observations provide a rationale for the development of therapeutic options for the modulation of the incretin effect via the GLP-1 pathway, including degradation-resistant GLP-1 receptor agonists (incretin mimetics) and inhibitors of DPP-4 activity (incretin enhancers).23 GLP-1 RECEPTOR AGONISTS AND DPP-4 INHIBITORS Exenatide is a GLP-1 receptor agonist that enhances glucose-dependent insulin secretion by the pancreatic β cells, suppresses inappropriately elevated glucagon secretion, and slows gastric emptying. Exenatide is a synthetic form of exendin 4, a naturally occurring GLP-1 receptor agonist found in the salivary secretions of the Gila monster.2 Exendin 4 is 53% homologous with human GLP-1 and binds to the mammalian GLP-1 receptor with affinity equal to that of native GLP-1, producing many of the same glucoregulatory effects.2,24 The amino acid sequence of exenatide partially overlaps that of human GLP-1, allowing the drug to bind and activate human GLP-1 receptors, while delaying DPP-4 degradation. Exenatide is resistant to degradation by DPP-4 and detectable in the circulation for up to 10 hours after administration, allowing for twice-daily administration in the treatment of patients with type 2 DM.2,24 Liraglutide’s structural modifications delay DPP-4 degradation, resulting in a half-life of 13 hours.25 Once bound to the receptor, the GLP-1 receptor agonist increases insulin synthesis and release by mechanisms involving cyclic adenosine monophosphate and other intracellular signaling pathways. Additional GLP-1 analogues are currently undergoing clinical trials in the United States. Pharmaceutical companies are also looking into novel delivery mechanisms by which these drugs might be shown to have better efficacy and tolerability, such as continuous subcutaneous infusion and implantable delivery systems. S39 For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings. a
  3. 3. INCRETIN SYSTEM IN TREATMENT OF TYPE 2 DM The DPP-4 inhibitors inhibit the proteolytic inactivation of GLP-1 by DPP-4. Unlike GLP-1 receptor agonists, which result in pharmacological levels of GLP-1 (6- to 10-fold increase), DPP-4 inhibitors result in physiologic levels of GLP-1 (2- to 3-fold increase).26 Physiologic increases in GLP-1 refer to the increase in hormone release from the intestinal L cells, which would be expected to occur in response to the ingestion of a carbohydrate-rich meal in a euglycemic individual. Pharmacological activation of GLP-1 receptors occurs once agonists bind to them and their actions are expressed by the receptor. The DPP-4 inhibitors prevent the degradation of GIP and a wide range of other peptides, including chemokines, glucagon-secretin family hormones, pancreatic polypeptide proteins, and neuropeptides.24 In contrast to GLP-1 receptor agonists, DPP-4 inhibitors do not affect gastric emptying, as reflected by the lack of effect of DPP-4 inhibition on the rate of increase in circulating glucose after ingestion of a meal.27 After initial animal studies and successful proof-ofconcept and clinical studies in humans, 2 DPP-4 inhibitors have been approved for marketing in the United States. Both sitagliptin and saxagliptin are oral tablet formulations taken once daily. A single-tablet formulation of sitagliptin and metformin was approved in March 2007. In addition, a new drug application has been filed in the United States for a combination of saxagliptin and metformin. Finally, a new drug application has been filed for vildagliptin, which is approved in the European Union and Latin America for the treatment of patients with type 2 DM. Alogliptin is also being developed for use in patients with type 2 DM. The DPP-4 inhibitors do not bind directly to GLP-1 receptors and have less potent pharmacological activity than GLP-1 receptor agonists.2 They also impede the proteolytic degradation of GLP-1 by binding directly to the DPP-4 enzyme, thereby increasing the concentration of endogenous GLP-1 approximately 2-fold.2 In Table 2 of his article (also published in this supplement), Davidson28 reviews the comparative physiologic and clinical effects of GLP-1 receptor agonists and DPP-4 inhibitors. The differences between these 2 groups of compounds have been reflected in their distinct effects on metabolic parameters and clinical end points observed in comparative randomized trials. In a double-blind study, 95 patients with type 2 DM receiving metformin were randomized to receive exenatide or sitagliptin for 2 weeks and were then crossed over to the alternate therapy. After 2 weeks of exenatide, 2-hour PPG levels were lower with exenatide than with sitagliptin (133 vs 208 mg/dL; P<.0001). Switching from exenatide to sitagliptin increased 2-hour PPG by +73 mg/dL, whereas switching from sitagliptin to exenatide further reduced 2-hour PPG by –76 mg/dL. Postprandial insulin secretion was significantly greater with exenatide than sitagliptin (P=.0017), and exenatide suppression of postprandial glucagon secretion was significantly greater with exenatide than with sitagliptin (P=.0011).29 Exenatide demonstrated a significant slowing of gastric emptying compared with baseline and sitagliptin (P<.0001) and significantly reduced caloric intake compared with sitagliptin (–134 vs +130 kcal per meal; P=.02). In the Diabetes Therapy Utilization: Researching Changes in A1c, Weight and Other Factors Through Intervention With Exenatide Once Weekly (DURATION-2),30 491 patients with type 2 DM following a stable regimen of metformin were randomized to once-weekly treatment with exenatide (n=160), sitagliptin (n=166), or pioglitazone (n=165) for 26 weeks. Exenatide produced significantly greater improvements in glucose control with mean reductions in hemoglobin A1c (HbA1c) levels of –1.55%, –0.92%, and –1.23% with exenatide, sitagliptin, and pioglitazone, respectively (P<.05 for both vs exenatide). Also, 66% of patients receiving exenatide achieved an HbA1c level less than 7% compared with 42% who received sitagliptin and 56% who received pioglitazone (P<.05 for both vs exenatide). Exenatide-associated reduction of body weight (–2.7 kg) was significantly greater that that seen with sitagliptin or pioglitazone (–0.9 and +3.2 kg, respectively; P<.05 for both vs exenatide).30 A recent clinical trial compared 2 daily doses of liraglutide, 1.2 mg (n=225) and 1.8 mg (n=221), with 100 mg of sitagliptin (n=219) daily for 26 weeks in a randomized, parallel-group, open-label fashion.31 Patients with type 2 DM inadequately controlled with metformin with a mean baseline HbA1c level of 8.5% were studied. Greater lowering of HbA1c from baseline was seen with liraglutide, 1.2 mg (–1.24%; 95% confidence interval [CI], –1.37% to –1.11%) and 1.8 mg (–1.50%; 95% CI, –1.63% to –1.37%), than with sitagliptin (–0.90%; 95% CI, –1.03% to –0.77%). Estimated mean treatment differences for liraglutide vs sitagliptin were –0.34% for 1.2 mg (P<.0001) and –0.60% for 1.8 mg (P<.0001). Nausea was more common with liraglutide (21% with 1.2 mg and 27% with 1.8 mg) than with sitagliptin (5%), and minor hypoglycemia was observed in approximately 5% of patients in each treatment group.31 Both the DURATION-2 and the liraglutide vs sitagliptin study demonstrate the superiority of GLP-1 receptor agonists favoring reductions in HbA1c, fasting glucose levels, and weight over DPP-4 inhibitors in patients with type 2 DM. EFFECTS OF GLP-1 RECEPTOR AGONISTS ON GLUCOSE CONTROL AND OTHER CV RISK FACTORS Treatment with GLP-1 receptor agonists offers an effective alternative to other currently available hypoglycemic S40 For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings. a
  4. 4. INCRETIN SYSTEM IN TREATMENT OF TYPE 2 DM agents for patients with type 2 DM.32 In pivotal phase 3 studies, exenatide given for 30 weeks significantly reduced HbA1c levels in patients with type 2 DM who were unable to achieve adequate glycemic control with maximally effective doses of a sulfonylurea (exenatide, –0.86% vs +0.12% with placebo; P≤.0001),33 metformin (exenatide, –0.78% vs +0.08% with placebo; P<.002),34 or combined metformin and sulfonylurea therapy (exenatide, –0.8% vs +0.2% with placebo; P<.0001).35 Exenatide also resulted in weight loss in each of the 3 studies in the range of –1.6 to –2.8 kg, which was markedly better than weight loss seen with placebo. The most common adverse events (AEs) reported were mild-to-moderate gastrointestinal disorders and mild-to-moderate hypoglycemia.33-35 In an open-ended, open-label extension trial of the 3 placebo-controlled phase 3 trials noted in this article, 217 patients completed 3 or more years of exenatide therapy.36 Exenatide treatment was associated with sustained improvements in glycemic control and reductions in CV risk factors. Reductions in HbA1c from baseline to week 12 (–1.1%) were maintained for 3 years (–1.0%; P<.0001). Body weight decreased progressively from baseline such that the mean reduction at 3 years was –5.3 kg (P<.0001), with 84% of patients losing weight, and 50% of patients losing 5% or more of their body weight. Total cholesterol levels were significantly reduced (–5%; P=.0007), as were triglyceride levels (–12%; P=.0003) and low-density lipoprotein cholesterol levels (–6%; P<.0001). High-density lipoprotein levels increased by 24% (P<.0001). Also, after 3 years, systolic and diastolic blood pressures were reduced by –2% and –4%, respectively (P=.0063 and P<.0001, respectively).36 Homeostasis model assessment of β-cell function (HOMA-β) was also significantly improved from baseline in 92 patients for whom data were available (baseline HOMA-β, 52.4% with an increase at 3 years to 70.1%; P<.0001). Mild-to-moderate nausea was the most common AE seen in 59% of patients and led to a 5% patient withdrawal rate. Hypoglycemia was the next most frequent AE reported with 1 case of severe hypoglycemia occurring in a patient who also received metformin and a sulfonylurea.36 Exenatide treatment for 52 weeks (n=36) significantly improved β-cell function, as reflected by a 2.46-fold increase (95% CI, 2.09-2.90; P<.0001) in glucose- and arginine-stimulated C-peptide secretion compared with insulin glargine in metformin-treated patients with type 2 DM.37 Both exenatide and insulin glargine reduced HbA1c levels similarly (–0.8% and –0.7%, respectively). Body weight was reduced significantly more with exenatide than with insulin glargine (difference, –4.6 kg; P<.0001). Both agents were generally well tolerated; mild-to-moderate nausea was seen in 50% of exenatide-treated patients, whereas hypoglycemia was seen more frequently with insulin glargine (24% vs 8%). The effects on β-cell function were not sustained after cessation of therapy, with a return to baseline levels within 4 weeks.37 The beneficial effects of exenatide on HbA1c in patients with type 2 DM are similar to those of insulin analogues. However, exenatide has shown greater beneficial effects on PPG excursions and lower risks of nocturnal and overall hypoglycemia. Barnett et al38 evaluated exenatide and insulin glargine in 138 patients with type 2 DM not adequately controlled with metformin or a sulfonylurea. Although both agents reduced HbA1c levels by –1.36%, exenatide therapy resulted in weight loss, whereas patients receiving insulin gained weight (between-group difference, –2.2 kg; P<.001). The PPG excursions (2-hour) were significantly lower with exenatide (P≤.016) as were total daily mean glucose excursions (P<.001).38 Exenatide was compared with insulin glargine in 551 patients with DM not adequately controlled with metformin and a sulfonylurea. Both drugs reduced HbA1c levels by –1.1%, but exenatide reduced PPG excursions more than did insulin.39 Finally, patients with type 2 DM who received metformin and a sulfonylurea were randomized to receive exenatide (n=253) or insulin aspart (n=248) for 52 weeks. There was no difference between the 2 groups in HbA1c reduction (exenatide, –1.04% vs –0.89% for insulin). The PPG excursions were significantly lower for exenatide after morning (P<.001), midday (P<.002), and evening meals (P<.001).40 Exenatide treatment provided an additional benefit of sustained weight loss, whereas insulin analogue therapy was associated with weight gain.38-40 Exenatide once weekly (formulated with exenatide and poly [d,l-lactic-co-glycolic acid] microspheres to extend release; n=148) for 30 weeks provided significantly greater improvements in glycemic control than exenatide twice daily (n=147), with HbA1c reductions of –1.9% vs –1.5% (P=.0023). Exenatide once weekly has yet to be FDA approved for clinical use. Both exenatide once weekly and twice daily resulted in similar reductions in body weight (–3.7 vs –3.6 kg) without increased risk of hypoglycemia (1 case among 186 patients not receiving background sulfonylurea therapy and approximately 15% in each exenatide group receiving background sulfonylurea therapy).41 The improvements in glycemic control, body weight, and cardiometabolic risk factors associated with exenatide once weekly were sustained during 2 years of treatment.42,43 Six large randomized, placebo- and/or active-controlled, multicenter phase 3 trials of 26 or 52 weeks’ duration were performed as part of the Liraglutide Effect and Action in Diabetes (LEAD) program, which included both placebo and active control groups.44-49 Most used double-blind, double-dummy methods; however, LEAD-649 was open label, as was one of the control arms (insulin glargine) in S41 For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings. a
  5. 5. INCRETIN SYSTEM IN TREATMENT OF TYPE 2 DM LEAD-5.46 In the LEAD program, liraglutide in therapeutic doses of 1.2 and 1.8 mg as monotherapy or combination therapy reduced HbA1c levels from baseline by –0.8% to –1.5%. Improvements were also seen in blood pressure and some CV risk factors.48 In LEAD-6, 464 patients were randomized to receive liraglutide (n=233) or exenatide (n=231) for 26 weeks, and their effects on glycemic control, body weight, and safety were evaluated. Liraglutide was associated with better glycemic control (HbA1c reduction of –1.12% with liraglutide compared with –0.79% for exenatide; P<.0001). Both drugs promoted similar weight loss (–3.2 kg with liraglutide and –2.8 kg with exenatide). Nausea was reported in 25.5% of patients receiving liraglutide and 28.0% of patients receiving exenatide. Although the incidence of nausea was similar initially, liraglutide-treated patients had less persistent nausea at week 26 compared with exenatide-treated patients (5 [3%] of 202 vs 16 [9%] of 186). Despite the lower overall reporting of AEs in the liraglutide group compared with the exenatide group (74.9% vs 78.9%), there were more serious (5.1% vs 2.6%) and more severe (7.2% vs 4.7%) AEs in the liraglutide group.49 Interestingly, patients enrolled in the LEAD studies were not permitted to down-titrate the dose of their study medications. If they developed nausea in association with their drug they had to choose between withdrawing consent or continuing with the study and living with their nausea. In clinical practice, patients can be advised to reduce their dose because fewer gastrointestinal adverse effects are associated with lower doses of GLP-1 receptor agonists.35,50 Some investigators believe that nausea can be more prevalent in patients using GLP-1 agonists who eat beyond their point of satiety. Therefore, advising patients to stop eating if they feel full might reduce the frequency of nausea. Adding liraglutide once daily (1.2 or 1.8 mg) to a sulfonylurea for 26 weeks produced greater improvements in glycemic control than rosiglitazone (–1.1% reduction in HbA1c level for liraglutide vs –0.4% for rosiglitazone; P<.0001) and greater weight loss (–0.2 kg with 1.8 mg of liraglutide vs +2.1 kg for rosiglitazone; P<.0001) in patients with type 2 DM.44 In patients with type 2 DM receiving metformin, the addition of liraglutide, 1.2 or 1.8 mg, or glimepiride, 4 mg, once daily provided the same improvements in glycemic control (–1.0% for all groups); body weight decreased in both liraglutide groups in the range of –1.8 to –2.8 kg compared with an increase of +1.0 kg with glimepiride (P<.0001), with a lower incidence of minor hypoglycemia (3% with liraglutide vs 17% with glimepiride; P<.001).45 Finally, liraglutide monotherapy in a dose of 1.8 mg provided greater improvements in HbA1c level (P<.05) and body weight (P<.05), with a lower inci- dence of minor hypoglycemia (P<.05) than glimepiride, 8 mg once daily, monotherapy in patients with type 2 DM treated for 52 weeks47 and 2 years.51 DPP-4 INHIBITORS A number of clinical trials have evaluated the efficacy and safety of the DPP-4 inhibitors in patients with type 2 DM. Overall, such studies have shown that these compounds have favorable effects on glycemic outcomes, have no consistent beneficial effects on lipid profiles, and are weight neutral.26,32 Aschner et al52 studied 741 patients with type 2 DM with a baseline HbA1c level of 8% who were randomized to receive sitagliptin monotherapy (100 or 200 mg/d) or placebo for 24 weeks. Sitagliptin produced significant (P<.001) placebo-subtracted reductions in HbA1c (–0.79% and –0.94% with the 100- and 200-mg doses, respectively) compared with placebo. Measures of β-cell function (HOMA-β and proinsulin-insulin ratio) improved with sitagliptin. No meaningful body weight changes were seen in any of the groups. Sitagliptin was well tolerated after 24 weeks of treatment with no meaningful differences in AEs between treatment groups.52 Nauck et al53 compared the efficacy and safety of sitagliptin with glipizide for 52 weeks in 588 patients with type 2 DM not adequately controlled with metformin. From a mean baseline HbA1c level of 7.5%, both agents reduced HbA1c by –0.67%. Changes in fasting plasma glucose (FPG) from baseline were similar as well: –10 mg/dL with sitagliptin and –7.5 mg/dL with glipizide. Sitagliptintreated patients lost an average of 1.5 kg of body weight during the 52 weeks compared with a weight gain of 1.1 kg in glipizide-treated patients (significant between-group difference, P<.001). More patients experienced hypoglycemic episodes with glipizide (32%) than with sitagliptin (5%; P<.001). Seven patients receiving glipizide (1.2%) and 1 patient receiving sitagliptin (0.2%) had hypoglycemic episodes that required medical assistance.53 When added to ongoing pioglitazone therapy in patients with type 2 DM, sitagliptin significantly reduced the mean change from baseline in between-group difference in HbA1c (–0.7%; P<.001) and FPG (–17.7 mg/dL; P<.001) levels, and more patients achieved a target HbA1c level of less than 7% with sitagliptin (45.4% vs 23.0%; P<.001) than with placebo. Sitagliptin also reduced fasting proinsulin levels (P=.009) and the proinsulin-insulin ratio (P<.001) compared with placebo. Treatment with sitagliptin was generally well tolerated. The incidence of drug-related clinical AEs was similar between the 2 groups (9.1% vs 9.0%). The number of patients discontinuing therapy because of drugrelated AEs was the same in both groups (0.6%).54 S42 For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings. a
  6. 6. INCRETIN SYSTEM IN TREATMENT OF TYPE 2 DM Saxagliptin once daily or placebo was added to ongoing metformin therapy for 24 weeks in 743 patients with type 2 DM inadequately controlled with metformin alone.55 Saxagliptin, compared with placebo, resulted in significant reductions in HbA1c levels (–0.6% for 10 mg/d vs +0.13% for placebo; P<.0001). Improvements in β-cell function (as measured by HOMA-β) were also noted. Finally, improvements in FPG, PPG, insulin, and glucagon areas under the concentration time curve during oral glucose tolerance testing (all P≤.001 vs placebo) were observed with saxagliptin treatment. Monotherapy with saxagliptin once daily produced improvements in HbA1c, FPG, and PPG levels and was generally well tolerated in treatment-naive patients with type 2 DM.56 The addition of alogliptin (12.5 or 25 mg/d) or placebo was studied in 493 patients with type 2 DM not adequately controlled with pioglitazone.57 Background therapy with metformin or a sulfonylurea was continued. Alogliptin in either dose significantly improved glycemic control after 26 weeks (HbA1c reductions of –0.66% and –0.80% for alogliptin vs –0.19% for placebo; P<.001) and was generally well tolerated. The AEs were similar across all treatment groups. Cardiac events occurred more often in the group receiving alogliptin, 25 mg/d (6.5%), than in the group receiving placebo (1.0%) or alogliptin, 12.5 mg/d (3.0%), although these differences were not statistically significant. There was no significant effect on body weight or the incidence of hypoglycemia between the groups.57 When added to ongoing metformin therapy, alogliptin once daily significantly decreased HbA1c (P<.001) and FPG levels (P<.001) for 26 weeks with no increased risk of hypoglycemia or weight gain.58 The effects of vildagliptin monotherapy on glycemic control in patients with type 2 DM were similar to those of acarbose monotherapy at 24 weeks, but vildagliptin had better gastrointestinal tolerability.59 In treatment-naive patients with type 2 DM, vildagliptin monotherapy at dosages of 50 mg once daily, 50 mg twice daily, and 100 mg once daily produced significant decreases in HbA1c compared with placebo (change from baseline, –0.8%, –0.8%, and –0.9% vs –0.3% for placebo, respectively; P<.01 for all active groups vs placebo). Vildagliptin did not cause weight gain and was associated with a low risk of hypoglycemia at 24 weeks.60 The most common AEs with DPP-4 inhibitors were nasopharyngitis, headache, and increased risk of urinary tract infection.32 The DPP-4 inhibitors appeared to improve short-term surrogate measures of β-cell function (eg, HOMA-β and proinsulin-insulin ratio) but did not seem to provide benefits over other agents with respect to β-cell function and activity.61 However, long-term prevention of β-cell dysfunction with these agents needs to be studied. CLINICAL PERSPECTIVES FOR PCPS WHEN TREATING PATIENTS WITH INCRETIN THERAPY The complexity of DM care coupled with the need to tailor treatment recommendations to individual patients produces wide variability in the provision of care.62 Balancing the multiple goals of ideal DM care with the realities of patient adherence, expectations, and circumstances is a major challenge for PCPs. Understanding the basic principles of the pathophysiology of type 2 DM is important for rationale-based management of chronic hyperglycemia. In an online survey of 847 PCPs and specialized care physicians in the United States and several European countries, the proportions of respondents familiar with key aspects of type 2 DM pathophysiologic features and newer treatment options were low.63 In particular, overall familiarity was low for β-cell dysfunction (55%), glucagon (38%), and hepatic glucose output (55%). Among specialized care physicians, 6% were not familiar with the term β . In the United States, familiarity with the incretins and GLP-1 was higher among specialized care physicians (69% and 74%, respectively) than among PCPs (5% and 6%, respectively). This lack of understanding may influence physician prescribing behavior and limit the application of pathophysiologybased therapy in individual patients with type 2 DM.63 Differences in the clinical effects of GLP-1 receptor agonists and DPP-4 inhibitors on glycemic control, body weight, and CV risk factors in patients with type 2 DM may be partially related to differences in the degree of GLP-1 receptor activation achieved with these compounds. The pharmacological concentrations of GLP-1 receptor agonists achieved with therapeutic administration may provide greater levels of GLP-1 receptor activation than the physiologic levels achieved with DPP-4 inhibition.26,29 This difference may explain the greater levels of PPG reduction, stimulation of insulin secretion, and inhibition of glucagon secretion observed with GLP-1 receptor agonists compared with DPP-4 inhibitors, as well as the appetite suppression and weight loss observed in patients treated with GLP-1 receptor agonists.26 SAFETY GLP-1 RECEPTOR AGONISTS The safety of GLP-1 receptor agonists has been examined in clinical trials. Exenatide is associated with an increased risk of hypoglycemia, primarily when used in combination with sulfonylureas. Compared with insulin or used in combination with metformin, exenatide is not associated with an increased risk of hypoglycemia.15,64,65 The most frequently reported AEs with exenatide are nausea and vomitS43 For personal use. 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  7. 7. INCRETIN SYSTEM IN TREATMENT OF TYPE 2 DM ing; however, discontinuation rates of exenatide treatment due to gastrointestinal AEs have been low and consistent across studies.64 Similarly, the most common AEs reported in the liraglutide registry clinical trials were gastrointestinal. Nausea, diarrhea, and vomiting were reported in 10% to 30% of patients. One in 7 patients developed nausea, which was transient and usually decreased to less than 10% between weeks 6 and 12.48 In rats, once-daily subcutaneous administration of liraglutide has been found to induce thyroid C-cell hyperplasia, elevated calcitonin levels, and medullary thyroid cancers after long-term administration of at least 8 times the doses used in humans. In mice, only benign adenomas were found under similar conditions. The findings raised concern at the FDA, and a box warning has been included in the liraglutide prescribing information that alerts physicians to the potential risk of liraglutide-induced thyroid Ccell tumors. However, to date there is no evidence linking liraglutide to medullary thyroid cancers in humans. Investigators think that the differences in the C-cell stimulation observed between nonhuman primates and humans may be due to the absence or very low levels of GLP-1 receptor agonist activity within human C cells.66 Structurally distinct GLP-1 receptor agonists, such as liraglutide and exenatide, are associated with induction of antibodies. Nine percent of liraglutide-treated patients and 38% of twice-daily exenatide–treated patients developed antibodies to the drugs.15,67 In a study of 295 patients with type 2 DM, exenatide once weekly resulted in higher antibody titers than with exenatide twice daily.41 However, development of antibody titers did not interfere with glycemic efficacy, and the antibody titers remained constant for 6 to 14 weeks and then decreased during the remaining 16 weeks of the study (all patients were followed up for 30 weeks).41 In the liraglutide clinical trials, although the presence of antibodies does not seem to be a major determinant of therapeutic effectiveness for most patients, some individuals with very high antibody titers may experience diminished therapeutic efficacy, angioedema, anaphylaxis, urticaria, or generalized pruritus. The elevation in antibody titers does not appear to correlate with a reduction in HbA1c levels over time. A total of 5% of the patients enrolled in the LEAD registry trials developed cross-reacting antibodies to native GLP-1.67 From a clinical standpoint, the true importance of antibody induction is unclear. Antibodies to therapeutic proteins can compromise efficacy by neutralizing the medication and/ or triggering AEs, ranging from mild injection site reactions to life-threatening anaphylaxis. Therapeutic proteins with a higher structural similarity to endogenous proteins generally have a lower risk of both antibody formation and higher antibody titer development. Liraglutide shares 97% homology with human GLP-167 compared with exenatide, which shares 53% homology.15 In the LEAD-6 open-label extension arm comparing the safety and efficacy of liraglutide and exenatide, antibody titers were obtained at weeks 0, 12, 26, 41, 78, and 79 before the daily dosage administration.68 After 78 weeks of liraglutide therapy, 2.6% of patients had low-titer antibodies.69 Four patients who developed neutralizing antibodies to liraglutide had HbA1c levels reduced by up to –1.9% from baseline. However, after 26 weeks of exenatide use, 61% of patients developed antiexenatide antibodies. Those who had high titers of neutralizing antibodies demonstrated a minimal reduction in HbA1c (–0.1%) compared with individuals who had low titers of neutralizing antibodies, who demonstrated a –1% HbA1c reduction. At the conclusion of the study (week 78), only 3% of liraglutide-treated patients had developed antibodies to the GLP-1 analogue. The HbA1c level in this small subset of patients (n=4) decreased by an additional –0.3% to –0.5%. In the LEAD-6 extension, 1% of the liraglutide-treated patients had injection site reactions; 75% of these reactions occurred when the patients were switched from exenatide to liraglutide and had positive exenatide antibody formation present. Only 2% of the patients who switched from exenatide to liraglutide during the extension phase developed mild site reactions. Therefore, the LEAD-6 trial demonstrates that the presence of neutralizing antibodies may minimize the efficacy of medication. However, patients with high antibody titers who were switched to liraglutide did not appear to experience a compromise in their glycemic response. For liraglutidetreated patients, the presence of neutralizing antibodies appears to have minimal clinical importance. Hypoglycemia is a primary factor that limits the success of treatment with insulin and sulfonylureas in patients with type 2 DM.70 Hypoglycemic events may lead to patient dissatisfaction with therapy, and medication adherence may decrease. Patients who are older and those with impaired hepatic or renal function with type 2 DM may be at an increased risk of treatment-related hypoglycemia. Therefore, the use of therapies with a low likelihood of hypoglycemia can be beneficial. Patients with type 2 DM have a nearly 3-fold increased risk of pancreatitis relative to patients without type 2 DM. In younger patients with type 2 DM (age <45 years), the risk of pancreatitis is increased more than 5-fold.71 According to a health insurance claims–based drug safety system analysis, the use of exenatide in previously untreated patients with type 2 DM is not associated with an increased risk of pancreatitis compared with other antidiabetes drugs.72 During 1 year of follow-up, the risk of hospitalization for a primary diagnosis of acute pancreatitis among patients with type 2 DM was similar for initiators of treatment with S44 For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings. a
  8. 8. INCRETIN SYSTEM IN TREATMENT OF TYPE 2 DM exenatide (0.13%), sitagliptin (0.12%), and metformin and glyburide (0.12%-0.13%).73 On the basis of postmarketing data, liraglutide has been associated with pancreatitis, including fatal and nonfatal, hemorrhagic, and necrotizing pancreatitis. A direct link between GLP-1 agonists and pancreatitis has not been established.73 On the basis of postmarketing data, exenatide has been associated with pancreatitis, including fatal and nonfatal hemorrhagic and necrotizing pancreatitis. After initiation of an incretin mimetic agent and after dose increases, physicians are advised to observe patients carefully for signs and symptoms of pancreatitis. Use of incretins should be discontinued if pancreatitis is suspected, and appropriate management should be instituted. Exenatide therapy should not be resumed if pancreatitis is confirmed.15 In phase 3A clinical trials of liraglutide, 8 cases of pancreatitis were reported, 7 of which were in patients treated with liraglutide and 1 of which was in a patient treated with a comparator. Five cases were diagnosed as acute, and 2 were chronic. Some patients had documented risk factors for pancreatitis, including obesity, alcohol use, high triglyceride levels, use of concurrent medications (such as angiotensin-converting enzyme inhibitors and thiazide diuretics), and the presence of cholelithiasis.73 Exenatide has not been shown to be nephrotoxic in preclinical or clinical studies; however, altered renal function in patients taking exenatide has been noted in postmarketing reports. These include increased serum creatinine levels, renal impairment, worsened chronic renal failure, and acute renal failure, sometimes requiring hemodialysis or transplantation. Reversibility of renal dysfunction has been observed in many cases with supportive treatment and discontinuation of use of the potentially causative agents, including exenatide. Exenatide should not be used in patients with severe renal impairment (creatinine clearance <30 mL/min).15 Liraglutide is not metabolized by the kidney or liver. The drug has not been studied specifically in patients with hepatic or renal failure. However, no dose reductions are recommended in these special patient populations.67 Patients with type 2 DM are at an increased risk of CV disease. Consideration of the CV safety of antidiabetes medications is an important aspect of disease management in patients with type 2 DM. Compared with insulin therapy, treatment with exenatide was not associated with an increased risk of CV disease and, in a recent meta-analysis, was associated with a nonsignificant decreased risk of experiencing a CV event.74 The observation is consistent with data from a long-term clinical trial extension demonstrating a beneficial effect of exenatide on CV risk factors.36 Whether the changes in CV risk factors seen with GLP-1 agonists will have a substantial impact on future CV outcomes is uncertain. Exenatide was the only incretin agent used in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study. An initial report of a 75% reduction in mortality in exenatide-treated patients, adjusted for glycemia effect, is compelling because this was the only antihyperglycemic agent that showed a significant improvement in mortality among the various agents used in ACCORD.75 DPP-4 INHIBITORS The DPP-4 inhibitors are generally well tolerated, with low rates of hypoglycemia and other AEs.32 The AEs associated with DPP-4 inhibitors observed in clinical trials include nasopharyngitis, headache, and increased risk of urinary tract infection.32 The AEs reported with sitagliptin include anaphylaxis, angioedema, and exfoliative skin conditions, such as Stevens-Johnson syndrome.70 Dipeptidyl peptidase 4 cleaves multiple substrates in vivo, which may contribute to the rare immunologic adverse effects of sitagliptin.70 From October 2006 through February 2009, 88 postmarketing cases of pancreatitis associated with sitagliptin have been reported through the FDA MedWatch program. As a result, the sponsor has revised the labeling for sitagliptin.76 GUIDELINES, ALGORITHMS, AND CLINICAL RECOMMENDATIONS Expert consensus guidelines, such as those developed by the American Diabetes Association/European Association for the Study of Diabetes,5 the American Diabetes Association,77 and the American Association of Clinical Endocrinologists (AACE)/American College of Endocrinology (ACE),78 provide valuable guidance for the management of patients with type 2 DM. The AACE/ACE guidelines78 specifically address the following therapeutic principles: clinicians should minimize the risk and severity of hypoglycemia; GLP-1 receptor agonists are recognized as having a greater effect on HbA1c and weight reduction than DPP-4 inhibitors; metformin is a cornerstone of therapy because of its efficacy, safety, and cost and is usually the most appropriate choice for initial therapy unless a contraindication (eg, renal failure) exists; sulfonylureas are considered lowpriority drugs because they tend to induce hypoglycemia, favor weight gain, and have relatively short-term efficacy (1-2 years); thiazolidinediones are well validated, effective, and durable agents but have adverse effects that include fluid retention, weight gain, congestive heart failure, and bone fractures with long-term use; and α-glucosidase inhibitors, colesevelam, and glinides have utility in relatively few, well-defined clinical situations based on their limited efficacy and adverse effect profiles. Schwartz and Kohl79 S45 For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings. a
  9. 9. INCRETIN SYSTEM IN TREATMENT OF TYPE 2 DM TABLE. Selection of Incretins Based on Actions and Patient Type Action(s) Patient type GLP-1 receptor agonists DPP-4 inhibitors Fasting hyperglycemia ↑Glucose-stimulated insulin secretion ↓Glucagon secretion ↑Glucose-stimulated insulin secretion ↓Glucagon secretion Postprandial hyperglycemia ↑Glucose-stimulated insulin secretion ↓Glucagon secretion Restoration of biphasic response Slow gastric emptying ↑Glucose-stimulated insulin secretion ↓Glucagon secretion Restoration of biphasic response Overweight ↓Body weight Enhanced early satiety Appetite suppression Delayed satiety Enhanced early satiety Large appetite Appetite suppression Hypoglycemia unawareness Low incidence of hypoglycemia Maintenance of hypoglycemia counterregulation Low incidence of hypoglycemia Maintenance of hypoglycemia counterregulation Hyperlipidemia ↓Total cholesterol ↓Low-density lipoprotein cholesterol ↑High-density lipoprotein cholesterol ↓Triglycerides ↓Total cholesterol ↓Low-density lipoprotein cholesterol ↑High-density lipoprotein cholesterol ↓Triglycerides DPP-4 = dipeptidyl peptidase 4; GLP-1 = glucagon-like peptide 1; ↑ = increased; ↓ = decreased. From ,81 with permission from Quadrant HealthCom. review the approach to the treatment of patients with type 2 DM based on the AACE/ACE algorithm in Figure 5 of their article. Management of patients with type 2 DM requires a comprehensive assessment of lifestyle factors, including nutrition, weight loss goals, and exercise and activity levels. Behavior modifications may be needed to improve glycemic control and to reduce the long-term risk of complications. In addition to other important topics, patients should be taught the importance of flexible meal planning and the effects of caffeine, alcohol, and glycemic index on blood glucose levels. Regular exercise should be encouraged for its beneficial effects on glycemic control, body weight, and CV risk factors.77 Patients should understand the importance of medication adherence, blood glucose monitoring, and other aspects of DM management. Patients facing the prospects of long-term medical treatment and lifestyle changes may benefit from the establishment of highly specific behavior outcome goals and short-term behavior targets.80 Adhering to DM treatment regimens may be enhanced with telephone calls and reminder cards, minimization of delays during office visits, and positive reinforcement from health care professionals.80 Incretin mimetics have been developed to address the direct pathophysiologic defects observed in type 2 DM. Because incretin mimetics work in a glucose-dependent manner, they are likely to reduce hyperglycemia safely without causing hypoglycemia. In the process of restoring β-cell function, these agents can allow patients to achieve an HbA1c level less than 7% (approximately 45%-50% of patients receiving monotherapy and approximately 25%40% of patients receiving incretins in combination therapy achieve an HbA1c level <7%) without experiencing weight gain or hypoglycemia. Implementation of incretin therapy in patients with type 2 DM requires careful consideration of numerous patient factors. Loss of β-cell function is significant in patients with prediabetes conditions and type 2 DM.16 Although the possible long-term beneficial effects of incretins on β-cell function remain uncertain, preservation of remaining β-cell function is a reasonable therapeutic goal in patients at risk of chronic hyperglycemia. Patients unaware of their hypoglycemia may also benefit from treatment with incretins because these agents are associated with a low incidence of hypoglycemia. The weight-reduction potential of GLP-1 receptor agonists and the weight-neutral effects of DPP-4 inhibitors may have important implications for certain patients with type 2 DM and may serve as motivating factors to enhance treatment adherence.81 The AACE/ACE 2009 guidelines recommend that higher priority be given to the use of GLP-1 receptor agonists and DPP-4 inhibitors because of their effectiveness and overall safety profiles.78 Recommendations for selecting incretins based on physiologic actions and patient type are given in the Table.81 CONCLUSION Primary care physicians must be kept informed of evolving concepts in DM pathophysiology and newer therapies for patients with type 2 DM. Understanding the clinical S46 For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings. a
  10. 10. INCRETIN SYSTEM IN TREATMENT OF TYPE 2 DM implications of the similarities and differences between the GLP-1 receptor agonists and DPP-4 inhibitors is an important aspect of therapeutic decision making and provides the best opportunity for successful individualization of therapy in these patients. The GLP-1 receptor agonists target the underlying metabolic defects of type 2 DM and have provided clinical benefits beyond glucose control, including improvements in body weight and CV risk factors and preservation of β-cell function in clinical trials. The DPP-4 inhibitors also work to correct the underlying incretin defect in patients with type 2 DM. The incretinbased therapies are an important addition to the antidiabetes treatment armamentarium for the management of type 2 DM. CLINICAL PEARLS HbA1c levels, effectively help patients reach their targeted HbA1c level, lower FPG and PPG levels, improve β-cell function, reduce weight, and improve markers for CV risk in patients with type 2 DM. most common adverse effect of GLP-1 receptor agonists is mild, transient nausea; patients should also be monitored for the development of pancreatitis. The DPP-4 inhibitors can cause rashes, headaches, and upper respiratory tract infections. The long-term safety profile of these agents has not yet been defined. tions, GLP-1 receptor agonists have a more potent pharmacological effect on lowering HbA1c levels and effecting weight loss than do the DPP-4 inhibitors. abetes agents, such as GLP-1 receptor agonists and DPP-4 inhibitors, that target the pathophysiology of type 2 DM is being investigated for its ability to slow disease progression and prevent long-term complications. REFERENCES 1. Unger J. Introduction. . Philadelphia, PA: Lippincott, Williams and Wilkins; 2007:1-42. 2. Unger J, Parkin CG. Appropriate, timely, and rational treatment of type 2 diabetes mellitus: meeting the challenges of primary care. . 2009;4(3):144-157. 3. Centers for Disease Control and Prevention (CDC). National diabetes fact sheet: general information and national estimates on diabetes in the United States, 2007. Atlanta, GA: US Dept of Health and Human Services, Centers for Disease Control and Prevention; 2008. ndfs_2007.pdf. Accessed October 11, 2010. 4. Alexander GC, Sehgal NL, Moloney RM, Stafford RS. National trends in treatment of type 2 diabetes mellitus, 1994-2007. . 2008;168(19):2088-2094. 5. Nathan DM, Buse JB, Davidson MB, et al; American Diabetes Association; European Association for Study of Diabetes. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. . 2009;32(1):193-203. 6. Holst JJ, Gromada J. Role of incretin hormones in the regulation of insulin secretion in diabetic and nondiabetic humans. . 2004;287(2):E199-E206. 7. Toft-Nielsen MB, Damholt MB, Madsbad S, et al. Determinants of the impaired secretion of glucagon-like peptide-1 in type 2 diabetic patients. J Clin . 2001;86(8):3717-3723. 8. Mojsov S, Weir GC, Habener JF. Insulinotropin: glucagon-like peptide I (7-37) co-encoded in the glucagon gene is a potent stimulator of insulin release in the perfused rat pancreas. . 1987;79(2):616-619. 9. Goke R, Wagner B, Fehmann HC, Goke B. Glucose-dependency of the insulin stimulatory effect of glucagon-like peptide-1 (7-36) amide on the rat pancreas. . 1993;193(2):97-103. 10. Holst JJ. Glucagon-like peptide 1 (GLP-1): an intestinal hormone, signaling nutritional abundance, with an unusual therapeutic potential. . 1999;10(6):229-235. 11. Willms B, Werner J, Holst JJ, Orskov C, Creutzfeldt W, Nauck MA. Gastric emptying, glucose responses, and insulin secretion after a liquid test meal: effects of exogenous glucagon-like peptide-1 (GLP-1)-(7-36) amide in type 2 (noninsulin-dependent) diabetic patients. . 1996;81(1):327-332. 12. Young AA, Gedulin BR, Rink TJ. Dose-responses for the slowing of gastric emptying in a rodent model by glucagon-like peptide (7-36) NH2, amylin, cholecystokinin, and other possible regulators of nutrient uptake. . 1996;45(1):1-3. 13. Turton MD, O’Shea D, Gunn I, et al. A role for glucagon-like peptide-1 in the central regulation of feeding. . 1996;379(6560):69-72. 14. Unger J. Amylin, glucagon-like peptide-1 receptor agonists, and dipeptidyl peptidase IV (DPP-IV) inhibitors as novel treatments for diabetes. In: Unger J, ed. . Philadelphia, PA: Lippincott, Williams and Wilkins; 2007:618-645. 15. Byetta (exenatide BID) [package insert]. San Diego, CA: Amylin Pharmaceuticals Inc; 2009. 16. DeFronzo RA. Banting Lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. . 2009;58(4):773-795. 17. American Association of Clinical Endocrinologists Diabetes Mellitus Clinical Practice Guidelines Task Force. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the management of diabetes mellitus. . 2007;13(suppl 1):S1-S68. 18. Holst JJ, Vilsbøll T, Deacon CF. The incretin system and its role in type 2 diabetes mellitus. . 2009;297(1-2):127-136. 19. Vilsbøll T, Holst JJ. Incretins, insulin secretion and type 2 diabetes mellitus. . 2004;47(3):357-366. 20. Nauck M, Stöckmann F, Ebert R, Creutzfeldt W. Reduced incretin effect in type 2 (non-insulin-dependent) diabetes. . 1986;29(1):4652. 21. Vilsbøll T, Krarup T, Madsbad S, Holst JJ. Defective amplification of the late phase insulin response to glucose by GIP in obese type II diabetic patients. . 2002;45(8):1111-1119. 22. Nauck MA, Baller B, Meier JJ. Gastric inhibitory polypeptide and glucagon-like peptide-1 in the pathogenesis of type 2 diabetes. . 2004; 53(suppl 3):S190-S196. 23. Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lan . 2006;368(9548):1696-1705. 24. Stonehouse A, Okerson T, Kendall D, Maggs D. Emerging incretin based therapies for type 2 diabetes: incretin mimetics and DPP-4 inhibitors. . 2008;4(2):101-109. 25. Croom KF, McCormack PL. Liraglutide: a review of its use in type 2 diabetes mellitus. . 2009;69(14):1985-2004. 26. Nauck MA, Vilsboll T, Gallwitz B, Garber A, Madsbad S. Incretinbased therapies: viewpoints on the way to consensus. . 2009; 32(suppl):S223-S231. 27. Ahren B. Dipeptidyl peptidase-4 inhibitors: clinical data and clinical implications. . 2007;30(6):1344-1350. S47 For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings. a
  11. 11. INCRETIN SYSTEM IN TREATMENT OF TYPE 2 DM 28. Davidson JA. Incorporating incretin-based therapies into clinical practice: differences between glucagon-like peptide 1 receptor agonists and dipeptidyl peptidase 4 inhibitors. Mayo Clin Proc. 2010;85(12)(suppl):S27-S37. 29. DeFronzo RA, Okerson T, Viswanathan P, Guan X, Holcombe JH, MacConell L. Effects of exenatide versus sitagliptin on postprandial glucose, insulin and glucagon secretion, gastric emptying, and caloric intake: a randomized, cross-over study. . 2008;24(10):2943-2952. 30. Bergenstal R, Wysham C, Yan P, MacConell L, Malloy J, Porter L. DURATION-2: exenatide once weekly demonstrated superior glycemic control and weight reduction compared to sitagliptin or pioglitazone after 26 weeks of treatment [abstract 6-LB]. Presented at: American Diabetes Association 69th Annual Meeting; New Orleans, LA; June 5-9, 2009. http://professional %20Abstracts/09%20ADA%20-%20Late%20Breaking%20Handout(1).pdf. Accessed October 11, 2010. 31. Pratley RE, Nauck M, Bailey T, et al; 1860-LIRA-DPP-4 Study Group. Liraglutide versus sitagliptin for patients with type 2 diabetes who did not have adequate glycemic control with metformin: a 26-week, randomized, parallel-group, open-label trial [published correction appears in 2010; 376(9737):234]. . 2010;375(9724):1447-1456. 32. Amori RE, Lau J, Pittas AG. Efficacy and safety of incretin therapy in type 2 diabetes: systematic review and meta-analysis. JAMA. 2007;298(2):194-206. 33. Buse JB, Henry RR, Han J, Kim DD, Fineman MS, Baron AD; Exenatide-113 Clinical Study Group. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in sulfonylurea-treated patients with type 2 diabetes. . 2004;27(11):2628-2635. 34. DeFronzo RA, Ratner RE, Han J, Kim DD, Fineman MS, Baron AD. Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes. . 2005; 28:1092-1100. 35. Kendall DM, Riddle MC, Rosenstock J, et al. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in patients with type 2 diabetes treated with metformin and a sulfonylurea. . 2005;28(5):1083-1091. 36. Klonoff DC, Buse JB, Nielsen LL, et al. Exenatide effects on diabetes, obesity, cardiovascular risk factors and hepatic biomarkers in patients with type 2 diabetes treated for at least 3 years. . 2008; 24(1):275-286. 37. Bunck MC, Diamant M, Cornér A, et al. One-year treatment with exenatide improves beta-cell function, compared with insulin glargine, in metformin-treated type 2 diabetic patients: a randomized, controlled trial. . 2009;32(5):762-768. 38. Barnett AH, Burger J, Johns D, et al. Tolerability and efficacy of exenatide and titrated insulin glargine in adult patients with type 2 diabetes previously uncontrolled with metformin or a sulfonylurea: a multinational, randomized, open-label, two-period, crossover noninferiority trial. . 2007;29(11):2333-2348. 39. Heine RJ, Van Gaal LF, Johns D, Mihm MJ, Widel MH, Brodows RG; GWAA Study Group. Exenatide versus insulin glargine in patients with suboptimally controlled type 2 diabetes: a randomized trial. . 2005; 143(8):559-569. 40. Nauck MA. A comparison of twice-daily exenatide and biphasic insulin aspart in patients with type 2 diabetes who were suboptimally controlled with sulfonylurea and metformin: a non-inferiority study. . 2007;50: 259-267. 41. Drucker DJ, Buse JB, Taylor K, et al; DURATION-1 Study Group. Exenatide once weekly versus twice daily for the treatment of type 2 diabetes: a randomised, open-label, non-inferiority study. . 2008;372(9645):1240-1250. 42. Bergenstal R, Kim T, Yan P, et al. Exenatide once-weekly improved cardiometabolic risk factors in subjects with type 2 diabetes during one year of treatment [abstract 165-OR]. . 2009;58(suppl 1): A43-A44. 43. Kim T, Taylor K, Wilhelm K, Trautman M, Zhuang D, Porter L. Exenatide once weekly treatment effects sustained glycemic control and weight loss over 2 years [abstract 159-OR]. . 2009;58(suppl 1):A42. 44. Marre M, Shaw J, Brändle M, et al; LEAD-1 SU Study Group. Liraglutide, a once daily human GLP-1 analogue, added to sulphonylurea over 26 weeks produces greater improvements in glycaemic and weight control compared with adding rosiglitazone or placebo in subjects with type 2 diabetes (LEAD-1 SU). . 2009;26(3):268-278. 45. Nauck M, Frid A, Hermansen K, et al; LEAD-2 Study Group. Efficacy and safety comparison of liraglutide, glimepiride, and placebo, all in combination with metformin, in type 2 diabetes: the LEAD (Liraglutide Effect and Action in Diabetes)-2 study. . 2009;32(1):84-90. 46. Russell-Jones D, Vaag A, Schmitz O, et al. Liraglutide Effect and Action in Diabetes 5 (LEAD-5) MET+SU Study Group. Liraglutide vs insulin glargine and placebo in combination with metformin and sulfonylurea therapy in type 2 diabetes mellitus (LEAD-5 MET+SU): a randomised controlled trial. . 2009;52:2046-2055. 47. Garber A, Henry R, Ratner R, et al; LEAD-3 (Mono) Study Group. Liraglutide versus glimepiride monotherapy for type 2 diabetes (LEAD-3 Mono): a randomised, 52-week, phase III, double-blind, parallel-treatment trial. . 2009;373(9662):473-481. 48. Madsbad S. Liraglutide Effect and Action in Diabetes (LEAD) trial. . 2009;4(2):119-129. 49. Buse JB, Rosenstock J, Sesti G, et al; LEAD-6 Study Group. Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a 26-week randomised, parallel-group, multinational, open-label trial (LEAD-6). . 2009;374(9683):39-47. 50. Madsbad S, Schmitz O, Ranstam J, et al. Improved glycemic control with no weight increase in patients with type 2 diabetes after once-daily treatment with the long-acting glucagons-like peptide 1 analog liraglutide (NN211). . 2004;27(6):1335-1342. 51. Garber AJ, Henry R, Ratner R, Hale P, Chang CT, Bode B. Monotherapy with liraglutide, a once-daily human GLP-1 analog, provides sustained reductions in A1C, FPG, and weight compared with glimepiride in type 2 diabetes: LEAD-3-Mono 2-year results [abstract 162-OR]. . 2009;58(suppl 1): A42-A43. 52. Aschner P, Kipnes MS, Lunceford JK, Sanchez M, Mickel C, WilliamsHerman DE; Sitagliptin Study 021 Group. Effect of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy on glycemic control in patients with type 2 diabetes. . 2006;29(12):2632-2637. 53. Nauck MA, Meininger G, Sheng D, Terranella L, Stein PP; Sitagliptin Study 024 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, compared with the sulfonylurea, glipizide, in patients with type 2 diabetes inadequately controlled on metformin alone: a randomized, doubleblind, non-inferiority trial. . 2007;9:194-205. 54. Rosenstock J, Brazg R, Andryuk PJ, Lu K, Stein P; Sitagliptin Study 019 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing pioglitazone therapy in patients with type 2 diabetes: a 24-week, multicenter, randomized, double-blind, placebo-controlled, parallelgroup study. . 2006;28(10):1556-1568. 55. DeFronzo RA, Hissa MN, Garber AJ, et al; Saxagliptin 014 Study Group. The efficacy and safety of saxagliptin when added to metformin therapy in patients with inadequately controlled type 2 diabetes with metformin alone. . 2009;32(9):1649-1655. 56. Rosenstock J, Aguilar-Salinas C, Klein E, Nepal S, List J, Chen R; CV181-011 Study Investigators. Effect of saxagliptin monotherapy in treatment-naïve patients with type 2 diabetes. . 2009;25(10): 2401-2411. 57. Pratley RE, Reusch JE, Fleck PR, Wilson CA, Mekki Q; Alogliptin Study 009 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor alogliptin added to pioglitazone in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled study. . 2009;25(10):23612371. 58. Nauck MA, Ellis GC, Fleck PR, Wilson CA, Mekki Q; Alogliptin Study 008 Group. Efficacy and safety of adding the dipeptidyl peptidase-4 inhibitor alogliptin to metformin therapy in patients with type 2 diabetes inadequately controlled with metformin monotherapy: a multicentre, randomised, doubleblind, placebo-controlled study. . 2009;63(1):46-55. 59. Pan C, Yang W, Barona JP, et al. Comparison of vildagliptin and acarbose monotherapy in patients with type 2 diabetes: a 24-week, double-blind, randomized trial. . 2008;25(4):435-441. 60. Dejager S, Razac S, Foley JE, Schweizer A. Vildagliptin in drugnaïve patients with type 2 diabetes: a 24-week, double-blind, randomized, placebo-controlled, multiple-dose study. . 2007;39(3):218223. 61. Riche DM, East HE, Riche KD. Impact of sitagliptin on markers of betacell function: a meta-analysis. . 2009;337(5):321-328. S48 For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings. a
  12. 12. INCRETIN SYSTEM IN TREATMENT OF TYPE 2 DM 62. Helseth LD, Susman JL, Crabtree BF, O’Connor PJ. Primary care physicians’ perceptions of diabetes management: a balancing act. . 1999;48(1):37-42. 63. Busse FP, Denti V, Stumvoll M. Awareness of pathophysiological concepts of type 2 diabetes: a survey in 847 physicians. . 2007;76(3):445-448. 64. Gentilella R, Bianchi C, Rossi A, Rotella CM. Exenatide: a review from pharmacology to clinical practice. . 2009;11(6): 544-556. 65. Monami M, Marchionni N, Mannucci E. Glucagon-like peptide-1 receptor agonists in type 2 diabetes: a meta-analysis of randomized clinical trials. . 2009;160(6):909-917. 66. Bjerre Knudsen L, Madsen LW, Andersen S, et al. Glucagon-like peptide-1 receptor agonists activate rodent thyroid C-cells causing calcitonin release and C-cell proliferation. . 2010;95(4):1473-1486. 67. Victoza (liraglutide) [package insert]. Princeton, NJ: Novo Nordisk Inc; 2010. 68. Buse JB, Sesti G, Schmidt WE, et al. Switching to once-daily liraglutide from twice-daily exenatide further improves glycemic control in patients with type 2 diabetes using oral agents. . 2010;33(6):13001303. 69. Buse J, Montanya D, Sesti G, et al. Frequency and magnitude of antibody formation are lower with liraglutide than exenatide: LEAD-6 results [abstract 0676-P]. Presented at: American Diabetes Association 70th Scientific Sessions; Orlando, FL; June 25-29, 2010. http://professional.diabetes .org/Abstracts_Display.aspx?TYP=1&CID=79621. Accessed October 29, 2010. 70. Bergenstal RM, Bailey CJ, Kendall DM. Type 2 diabetes: assessing the relative risks and benefits of glucose-lowering medications. . 2010; 123(4):374.e9-374.e18. 71. Noel RA, Braun DK, Patterson RE, Bloomgren GL. Increased risk of acute pancreatitis and biliary disease observed in patients with type 2 diabetes: a retrospective cohort study. . 2009;32(5):834-838. 72. Bloomgren G, Dore D, Patterson R, Noel R, Braun D, Seeger J. Incidence of acute pancreatitis in exenatide initiators compared to other antidiabetic drug initiators: a retrospective, cohort study [abstract 158-OR]. . 2009;58(suppl 1):A41. 73. Dore DD, Seeger JD, Arnold Chan K. Use of a claims-based active drug safety surveillance system to assess the risk of acute pancreatitis with exenatide or sitagliptin compared to metformin or glyburide. . 2009;25(4):1019-1027. 74. Shen L, Han J, Yushmanova I, Bruce S, Porter L. Cardiovascular safety of exenatide bid: an integrated analysis from long-term clinical trials in subjects with type 2 diabetes [abstract 366-OR]. . 2009;58(suppl 1):A96-A97. 75. Mafong DD, Henry RR. The role of incretins in cardiovascular control. . 2009;11(1):18-22. 76. US Food and Drug Administration (FDA). Sitagliptin (marketed as Januvia and Janumet)—acute pancreatitis. MedWatch. US Dept of Health and Human Services. September 25, 2009. /SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm183800.htm. Accessed October 11, 2010. 77. American Diabetes Association. Standards of medical care in diabetes—2010. . 2010;33(suppl 1):S11-S61. 78. Rodbard HW, Jellinger PS, Davidson JA, et al. Statement by an American Association of Clinical Endocrinologists/American College of Endocrinology consensus panel on type 2 diabetes mellitus: an algorithm for glycemic control. . 2009;15:540-559. 79. Schwartz SS, Kohl BA. Glycemic control and weight reduction without causing hypoglycemia: the case for continued safe aggressive care of patients with type 2 diabetes mellitus and avoidance of therapeutic inertia. Mayo Clin Proc. 2010;85(12)(suppl):S15-S26. 80. Unger J. Lifestyle interventions for patients with diabetes. In: . Philadelphia, PA: Lippincott, Williams and Wilkins; 2007:405-464. 81. Cobble ME. How to implement incretin therapy. . 2008;57(9) (suppl):S26-S31. S49 For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings. a