The effective management of type 2

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1 Approximately two thirds of patients with type 2 diabetes mellitus (T2DM) are unable to reach the hemoglobin A 1c target set by the American Diabetes Association ( 7.0%). Therefore, T2DM continues to be a major public health concern. Incretin mimetics and dipeptidyl peptidase IV inhibitors are medications that have the potential to improve patients glycemic control, as well as to result in beneficial socioeconomic effects. Research suggests that significant benefits are to be gained from incretin mimetics and dipeptidyl peptidase IV inhibitors, either one used as monotherapy or used together as combination therapy. However, the benefits and risks of these agents need to be evaluated more thoroughly, with emphasis on such adverse effects as edema, hypoglycemia, and weight gain. J Am Osteopath Assoc. 2007;107(suppl 3):S10-S16 Application of Incretin Mimetics and Dipeptidyl Peptidase IV Inhibitors in Managing Type 2 Diabetes Mellitus Patrick J. Boyle, MD Jeffrey S. Freeman, DO The effective management of type 2 diabetes mellitus (T2DM) continues to pose a challenge to physicians. Despite the development and use of several medications to control patients blood glucose levels, two thirds of patients with T2DM remain unable to reach the hemoglobin A 1c ( ) target of less than 7.0% set by the American Diabetes Association. 1,2 Thus, T2DM continues to be a major public health concern. Newer treatment agents, such as incretin mimetics and dipeptidyl peptidase IV (DPP-IV) inhibitors, have the potential to improve patients glycemic control, as well as to result in beneficial socioeconomic effects. 3-7 Dr Boyle is a professor of medicine at the University of New Mexico in Albuquerque, and Dr Freeman is chair and course director in the Division of Endocrinology at the Philadelphia College of Osteopathic Medicine in Philadelphia, Pa. Dr Boyle serves on the speakers bureaus of Amylin Pharmaceuticals Inc, Eli Lilly and Company, Pfizer Inc, and Takeda Pharmaceuticals North America Inc. Dr Freeman serves on the speakers bureaus of Glaxo- SmithKline Inc, Novartis International AG, Novo Nordisk Inc, and sanofi-aventis US, and he has received grants and research support from AstraZeneca Pharmaceuticals LP, and Bristol-Myers Squibb Company. Presented in part by Dr Boyle at the 111th Annual American Osteopathic Association Convention and Scientific Seminar in Las Vegas, Nev, on October 16, Address correspondence to Patrick J. Boyle, MD, Professor of Medicine, University of New Mexico, Albuquerque, NM pboyle@salud.unm.edu This continuing medical education supplement is supported by an educational grant from Merck & Co., Inc., to the American College of Osteopathic Family Physicians. Targets for Management of Type 2 Diabetes Mellitus Although the American Diabetes Association recommends a target level of less than 7%, it notes that a level of 6% would be preferable if safely achievable. 8 In order to achieve such targets, patients must also reach desirable fasting glucose levels (90 mg/dl-130 mg/dl) and postprandial glucose levels ( 180 mg/dl). 8 A primary clinical target is to control the fasting glucose concentration. The National Health and Nutrition Examination Survey (NHANES) analyzed T2DM targets in two patient populations one with 1215 patients studied from 1988 to 1994 and another with 372 patients studied from 1999 to ,2 After treatment with insulin, oral antidiabetic drugs, or diet, less than 45% of the combined patient population achieved the target of less than 7%. The low-density cholesterol (LDL-C) targets of less than 100 mg/dl in both and women were achieved by about 36% of the patients, while the high-density lipoprotein (HDL- C) targets of 40 mg/dl in men and 55 mg/dl in women were reached by 30% of the patients. Triglyceride concentrations reaching the target of less than 150 mg/dl were achieved by about 65% of the patients. The blood pressure target of 130/80 mm Hg was achieved in about 40% of the population treated with blood pressure lowering agents. 1,2 Therefore, the NHANES study showed that many patients with T2DM have trouble achieving healthcare targets beyond just those associated with glycemic control. Pharmacologic Interventions The availability of new drugs for hypertension steadily increased between the 1950s and the year The advent of vasodilator compounds was followed by adrenergic neuronal blocking agents and diuretics. Centrally acting 2 -agonists, such as clonidine, became available before blockers and -agonists and -antagonists in the 1970s. Calcium channel blockers, angiotensin-converting enzyme inhibitors, and angiotensin-receptor blockers began to appear in the 1980s and 1990s, later followed by the renin inhibitors. For T2DM, the development of new drugs remained relatively flat from the 1960s to the 1980s, with sulfonylureas S10 JAOA Supplement 3 Vol 107 No 5 May 2007

2 Figure 1. Effects of exenatide on glycemic control of patients with type 2 diabetes mellitus who were also using currently available oral medications (metformin and/or sulfonylurea). *P.001 versus placebo; P.001 versus placebo. Abbreviations: BID, twice a day;, hemoglobin A 1c. (Reprinted with permission of the National Diabetes Education Initiative [NDEI]. Sources: 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. Diabetes Care. 2005;28: ; Buse JB, Henry RR, Han J, Kim DD, Fineman MS, Baron AD; for the Exenatide-113 Clinical Study Group. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in sulfonylurea-treated patients with type 2 diabetes. Diabetes Care. 2004;27: ; Kendall DM, Riddle MC, Rosenstock J, Zhuang D, Kim DD, Fineman MS, 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. Diabetes Care. 2005;28: ) being the main medication available to patients. Since the 1990s, there has been an exponential rise in research and development, with the resulting availability of several new agents for T2DM. In the United States, the introduction of the biguanide compound metformin was followed by -glucosidase inhibitors, thiazolidinediones, glinide compounds, incretin mimetics (including glucagon-like peptide 1 [GLP-1] agonists), amylin analogs, and, most recently, DPP-IV inhibitors. All these agents are currently available, providing physicians and patients with several options for the management of hypertension and T2DM. Targets for Managing Hyperglycemia Healthy blood glucose levels are dependent on the dynamic processes of hepatic production of glucose and skeletal muscle use of glucose. These dynamic processes include the suppression by insulin of glucose production in the liver, and the secretion of glucagon by the cells of the pancreas. Thus, there are three potential targets in the management of hyperglycemia in patients: excessive hepatic production of glucose, insufficient skeletal muscle disposal of glucose, and excessive pancreatic production of glucagon. Treatment strategies designed to improve these processes will result in improvements in a patient s glycemic status. Managing Glucose Production and Use Data from the Diabetes Prevention Program were used by the US Department of Health and Human Services to recommend that adults exercise for a minimum of 30 minutes per day. Such an exercise program will improve skeletal muscle mass, the capacity for clearing glucose, and, ultimately, insulin sensitivity Insulin secretagogues (ie, releasers) include sulfonylureas, which directly stimulate insulin secretion through sulfonylurea receptors on cells, and repaglinide and nateglinide, which work through a somewhat different mechanism. The glitinides cause a similar closure of the potassium channel on the cell but not directly through the sulfonylurea receptor. The biguanide compound metformin is the only available medication that suppresses hepatic glucose production by inhibiting hepatic gluconeogenesis and glycogenolysis. The amino glucosidase inhibitors, though not widely used in the United States, have been much used in Europe. These drugs inhibit the hydrolysis of complex starch. When administered to the large intestine, they encourage carbohydrate fermentation by bacteria, resulting in flatus. The thiazolidinediones compounds pioglitazone and rosiglitazone predominantly increase glucose uptake by skeletal muscle. These agents all culminate in the lowering of glucose levels, but from different mechanisms of action. Incretin Mimetics: Exenatide The incretin mimetics are medications that mimic the action of incretins, peptide hormones that originate in the gastrointestinal tract. 3-7 The two major incretins in humans are GLP-1 and glucose-dependent insulinotropic peptide (GIP). Incretins are released during nutrient absorption, augmenting insulin secretion. Incretin mimetics also reduce postprandial glucagon secretion and delay gastric emptying time. As a result, patients using these medications can have improved postprandial glucose excursions and early satiety. 3-7 The improved sense of satiety is most likely a separate effect induced by activation of GLP-1 receptors in the brain. 5 Exenatide, a synthetic GLP-1 agonist and polypeptide originally isolated from the salivary secretions of the Gila monster, has approximately 53% homology to human GLP Unlike natural incretins, however, exenatide is resistant to degradation by DPP- IV. Thus, it shows much promise for treating patients with T2DM. JAOA Supplement 3 Vol 107 No 5 May 2007 S11

3 Figure 1 displays results of three 30- week clinical trials that examined the effects of exenatide in patients with T2DM who were also using metformin (N 336), 12 sulfonylurea (N 377), 13 or metformin plus sulfonylurea (N 733). 14 Exenatide was given to patients 15 to 60 minutes before two large meals. Patients using metformin who were also treated with 10 g of exenatide twice a day had a further reduction of of approximately 0.8%, compared with patients using metformin and placebo (P.001). 12 The sulfonylurea-exenatide group 13 and the metformin-sulfonylureaexenatide group 14 also had further reductions in their levels of about 0.8% compared with their corresponding placebo groups (P.001). The percentages of patients who completed the study using 10 g of exenatide and who reached the target level of less than 7.0% were the following: approximately 46% in the metformin-exenatide group, 41% in the sulfonylurea-exenatide group, and 34% in the metformin-sulfonylurea-exenatide group (Figure 2) The lesser reduction in the latter, combined group might be explained by the fact that T2DM was longer standing in those patients, thereby resulting in greater loss of endogenous insulin secretion. Blonde et al 15 studied 314 overweight patients with T2DM who used exenatide for 82 weeks. The first 30 weeks of the study were placebo-controlled. Fifty-two additional weeks were an openlabel uncontrolled extension. At week 30, patients using 10 g of exenatide twice a day had an average reduction in body weight of 2 kg from baseline, in conjunction with an improvement in levels. At week 82, these patients had an average weight reduction of 4.4 kg. Approximately 50% of the patients using exenatide had a weight-neutral response. Therefore, this study suggests that about half of the patients using exenatide can expect to achieve a significant weight loss with the drug. Blonde et al 15 also demonstrated that the body mass index (BMI) of patients with T2DM predicts their degree of weight loss when using exenatide. Patients with the greatest BMI ( 40) also had the greatest weight loss during the Figure 2. Proportion of patients with type 2 diabetes mellitus using exenatide and other medications who achieved the hemoglobin A 1c target set by the American Diabetes Association ( 7.0%). Abbreviations: BID, twice a day; Ex, exenatide; Met, metformin; SU, sulfonylurea. (Reprinted with permission of the National Diabetes Education Initiative [NDEI]. Sources: 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. Diabetes Care. 2005;28: ; Buse JB, Henry RR, Han J, Kim DD, Fineman MS, Baron AD; for the Exenatide-113 Clinical Study Group. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in sulfonylurea-treated patients with type 2 diabetes. Diabetes Care. 2004;27: ; Kendall DM, Riddle MC, Rosenstock J, Zhuang D, Kim DD, Fineman MS, 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. Diabetes Care. 2005;28: ) 82-week course of the study approximately 8 kg. Heine et al 16 conducted a 26-week randomized controlled trial to compare glargine insulin (one daily dose to maintain fasting glucose levels) with exenatide (10 g twice a day). Patients with suboptimally controlled T2DM and a mean baseline level of 8.2% were randomly assigned to receive either glargine insulin (n 260) or exenatide (n 275). At week 26, the average dose of glargine insulin was 25 units per day, a relatively small dose of insulin for most patients with T2DM. Heine et al 16 found that the patients average levels fell to just above 7% in both groups (1.1% drop from the baseline). The body weight of patients using glargine insulin increased an average of 1.8 kg during the study, while that of patients using exenatide decreased an average of 2.3 kg. Thus, the study suggested that glargine insulin and exenatide produce similar benefits in levels, but exenatide has the added benefit of weight loss. In addition, measurements of preprandial glycemic and postprandial glycemic excursions indicated a tendency for patients using exenatide to have reduced postprandial glycemic excursions. The differences in adverse effects between glargine insulin and exenatide are striking. Heine et al 16 found that nausea occurred in about 9% of patients using glargine insulin, while it occurred in 57% of patients using exenatide. Vomiting occurred in about 4% of patients using glargine insulin and 17% of patients using exenatide (P.001). The hypoglycemia rate in both groups was comparable, with 6.3 events per patientyear in the glargine group and 7.3 events S12 JAOA Supplement 3 Vol 107 No 5 May 2007

4 per patient-year in the group using exenatide. However, the occurrence of nocturnal hypoglycemia was slightly higher in the group using glargine. Incretin Mimetics: Liraglutide Liraglutide is a long-lasting incretin mimetic that is currently under investigation. 17,18 It is a receptor agonist like exenatide; it is an analog of GLP-1 that is DPP-IV resistant. In a 12-week controlled trial by Madsbad et al, patients with T2DM were evenly randomly assigned to receive one of five dosages of liraglutide (0.045 mg once a day to 0.75 mg once a day), the sulfonylurea glimepiride, or placebo. Both liraglutide and glimepiride produced comparable reductions in and fasting glucose levels. However, glimepiride use led to increases in body weight, while liraglutide led to decreases in weight. The reduction in level by liraglutide was dosedependent, with the lowest dosage failing to lead to a decrease in level. Dipeptidyl Peptidase IV Inhibitors Glucagon-like peptide 1 is synthesized in the villi of the epithelium of the small intestine. Immediately after synthesis, GLP-1 can be acted on by DPP-IV. The DPP-IV inactivation process causes greater than 50% inactivation of GLP-1 within 1 to 2 minutes before the GLP- 1 reaches general circulation Dipeptidyl peptidase IV inhibitors are drugs that block the action of this degradation pathway. By blocking this action, DPP-IV inhibitors can lead to an increase in endogenous GLP-1 concentration, benefiting patients with T2DM. Several DPP- IV inhibitors are under development Table 1 presents the results of an 18- week trial by Raz et al 24 in which 521 patients with T2DM were randomly assigned to receive monotherapy with one of two different dosages of the DPP- IV inhibitor sitagliptin (100 mg once a day or 200 mg once a day) or placebo. At week 18, the placebo-subtracted reductions in patients taking sitagliptin were 0.6% in the group assigned to 100 mg once a day and 0.48% in the group assigned to 200 mg once a day (P.001). Approximately 33% of the patients with T2DM achieved the target of less than 7%. Patients with higher baseline levels Table 1 Improvement in Glycemic Control and -Cell Function in Patients With Type 2 Diabetes After 18 Weeks of Sitagliptin Monotherapy* Parameter and Placebo-Subtracted Change Sitagliptin Dosage by Week 18, Mean (95% CI) P, % 100 mg once daily 0.60 ( 0.82 to 0.39) mg once daily 0.48 ( 0.70 to 0.26).001 Fasting Plasma Glucose, mmol/l 100 mg once daily 1.1 ( 1.7 to 0.5) mg once daily 0.9 ( 1.5 to 0.3).01 Proinsulin-Insulin Ratio 100 mg once daily 0.12 ( 0.23 to 0.01) mg once daily 0.09 ( 0.20 to 0.12) HOMA- 100 mg once daily 11.2 (0.3 to 22.0) mg once daily 12.0 (1.2 to 22.9).05 Two-Hour Postmeal Glucose (mmol/l) 100 mg once daily 2.6 ( 4.2 to 1.0) mg once daily 2.9 ( 4.6 to 1.3).001 Abbreviations: CI, confidence interval; HOMA, homeostasis model assessment * Adapted with permission from National Diabetes Education Initiative, for which slide was created from data in Raz I, Hanefeld M, Xu L, Caria C, Williams-Herman D, Khatami H; for the Sitagliptin Study 023 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy in patients with type 2 diabetes mellitus. Diabetologia. 2006;49: Epub 2006 Sep 26. had greater reductions with sitagliptin. If the patients baseline levels were less than 8%, the reductions of were 0.44% in the group assigned to 100 mg once a day and 0.33% in the group assigned to 200 mg once a day. If the baseline levels were greater than 9%, the reductions of were 1.2% in the group assigned to 100 mg once a day and 1.04% in the group assigned to 200 mg once a day). Postprandial glucose levels in patients with T2DM taking sitagliptin for 18 weeks were reduced approximately 40 mg/dl in the group using 100 mg once a day and 50 mg/dl in the group using 200 mg once a day. 24 The 2- hour postprandial glucose reduction in patients taking sitagliptin reached statistical significance compared with placebo (P.001). This result was most likely caused by a reduction in postprandial hyperglucagonemia. Research into using sitagliptin is influenced by current concepts regarding cells. The cells of the pancreas are believed to have a lifespan of approximately 7 years. Precursors to cells are stem cells. If these precursor cells fail to differentiate into new cells, T2DM may develop in patients at an age of approximately 30 years. 24 Table 1 shows a reduction in the proinsulin-insulin ratio a marker of insulin secretion and -cell function in patients who received either dosage of sitagliptin for 18 weeks. 24 In addition, the results of the homeostasis model assessment (HOMA) also indicated an increase in -cell function with both dosages of sitagliptin (Table 1). Therefore, the 18-week study by Raz et al 24 demonstrated significant benefits of sitagliptin in improving -cell function; levels; postprandial glucose excursions; postprandial insulin levels; and the proinsulin-insulin ratio. Charbonnel et al 25 reported on 701 patients who were randomly assigned to receive either sitagliptin (100 mg once a day) or placebo in addition to their JAOA Supplement 3 Vol 107 No 5 May 2007 S13

5 ongoing regimen of metformin. This 24- week add-on study showed that patients taking sitagliptin had an additional decline of 0.65%, an additional fasting plasma glucose decline of about 25 mg/dl, and an additional 2- hour postprandial glucose reduction of about 50 mg/dl, compared with placebo (P.001) (Table 2). The patients using sitagliptin also had reductions in their proinsulin-insulin ratio; increases in their C-peptide, fasting insulin, and postprandial insulin; and increases in their ( )-cell function as indicated by the HOMA (Table 2). 25 In a 24-week trial reported by Rosenstock at al 26, 30 mg to 45 mg of sitagliptin added to a regimen of pioglitazone led to a reduction in of 0.7% in patients with inadequately controlled T2DM, compared with placebo. Approximately 45% of the patients using sitagliptin sustained an level of less than 7% through the duration of study. A second DPP-IV inhibitor that has been investigated is vildagliptin. A 12- week monotherapy study by Pratley et al 27 compared patients with T2DM receiving 25 mg of vildagliptin twice a day (n 70) with those receiving placebo (n 28). The group receiving vildagliptin had a reduction in of approximately 0.6% compared with the group receiving placebo (P.001). The fasting glucose levels of the group using vildagliptin were also improved over those in the group using placebo. According to Schweizer et al, 28 drugnaïve patients with T2DM who received 1 year of treatment with 50 mg of vildagliptin twice a day (n 526) and patients receiving metformin had a significant sustained decrease in of about 1%, compared with patients receiving metformin (n 254). The group using vildagliptin had a 1.0%- reduction in compared with baseline (P.001), and the group receiving metformin had a 1.4% decrease from baseline (P.001). 28 Rosenstock et al 29 compared dosages of 50 mg of vildagliptin twice a day (n 459) with 8 mg of rosiglitazone once a day (n 238) in a 24-week trial of patients with T2DM. Both vildagliptin and rosiglitazone resulted in comparable reductions in of more than 1% from baseline. Patients using rosiglitazone, however, had an average increase in body weight of 1.5 kg at the end of the study, while patients using vildagliptin had an average decrease in weight of 0.3 kg. Rosenstock et al 29 noted that the loss in body weight with vildagliptin was not statistically significant. According to them, the gliptins will most likely remain weight-neutral medications with glucose-lowering properties, providing a probable advantage over existing thiazolidinedones. Treatment of patients with T2DM with a vildagliptin-metformin combination (50 mg of vildagliptin once daily, 1500 mg-3000 mg of metformin once daily) was compared with a placebometformin combination in a 12-week open-label feasibility study and 40-week extension by Ahren et al. 30 During the first 12 weeks, the group treated with the vildagliptin-metformin combination (n 56) showed a reduction in levels. This reduction continued throughout the extension. By contrast, the group using the placebo-metformin combination (n 51) showed a sustained increase in levels after week 4. Table 2 Sitagliptin-Enhanced Glycemic Control, -Cell Function In Patients With Type 2 Diabetes Mellitus Not Controlled With Metformin (N 701)* Placebo-Subtracted Change With Sitagliptin Other Effects of Parameter Plus Metformin P Sitagliptin Treatment P, % Decreased proinsulin-.05 insulin ratio Fasting plasma glucose, mg/dl Increased fasting.05 insulin, C-peptide, postmeal insulin Two-hour postmeal plasma Increased HOMA-.05 glucose, mg/dl (measure of -cell function) Abbreviation: HOMA, homeostasis model assessment. * Patients were randomly assigned (1:2) to receive addition of placebo or 100 mg of sitagliptin once a day to ongoing metformin therapy for 24 weeks. Adapted with permission from National Diabetes Education Initiative; table created from data in Charbonnel B, Karasik A, Liu J, Wu M, Meininger G; Sitagliptin Study 020 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes inadequately controlled with metformin. Diabetes Care. 2006;29: S14 JAOA Supplement 3 Vol 107 No 5 May 2007

6 This study provided an opportunity to assess and compare the durability of vildagliptin and metformin in patients. At the end of 1 year of treatment, the patients using vildagliptin with metformin had a decline of approximately 1.1% in their levels compared with the patients using placebo with metformin (P.001). The reduction in compared with baseline was 0.6% in the group treated with the vildagliptin-metformin combination. Fonseca et al 31 studied 125 patients with T2DM who were given 50 mg of vildagliptin twice a day in addition to insulin for a 24-week core study, which was followed by a 28-week extension. This group was compared with 131 patients with T2DM receiving placebo and insulin. The group receiving vildagliptin had a reduction in levels from approximately 8.5% at baseline to 7.9% at week 52. Furthermore, adding 50 mg of vildagliptin once a day to the placebo arm during the extension period also produced a reduction in levels. The study indicated that using vildagliptin once a day may be more efficacious in reducing levels Incretin Modulators GLP-1 Analogs Administration Route Injection Oral DPP-IV Inhibitors Increased GLP-1 Sustained Meal-related Effect Reduced 1.0% Reduced 0.5% to 0.8% Effects on Body Weight Weight loss Weight neutral Side Effects Nausea? -Cell Mass?Increased*?Increased* than using it twice a day, though the difference in results between the two dosages was not statistically significant. Incretin Mimetics Compared With Dipeptidyl Peptidase IV Inhibitors The administration routes and physiologic effects of incretin modulators (ie, incretin mimetics and DPP-IV inhibitors) are compared in Figure 3. The major difference between incretin mimetics and DPP-IV inhibitors is that incretin mimetics are administered by injection, whereas DPP-IV inhibitors are administered orally. After the injection of incretin mimetics, there is an increased and sustained level of GLP-1 in the patient s circulation, but after the oral administration of DPP-IV inhibitors, the level of GLP-1 increases only at mealtime. Incretin mimetics and DPP-IV inhibitors have similar effects in reducing levels. Incretin mimetics produce weight loss in patients, whereas DPP-IV inhibitors are weight neutral. No nausea is associated with DPP-IV inhibitors, but research indicates that 13% to 19% of patients using incretin mimetics have Figure 3. Comparison of the administration routes and physiologic effects of the incretin modulators incretin mimetics and dipeptidyl peptidase IV inhibitors in patients with type 2 diabetes mellitus based on compilation of overall incretin studies by the National Diabetes Education Initiative (NDEI). *Data from animal studies. Abbreviations: DPP-IV, dipeptidyl peptidase IV; GLP-1, glucagon-like peptide 1. (Reprinted with permission from the NDEI.) vomiting during 1 to 2 months after beginning treatment. Comment The incretins and DPP-IV inhibitors are integral parts of the metabolic machinery in patients with T2DM, regulating their postprandial glucose excursions. Research in the development of drugs in the incretin field is focused on compounds that exogenously replace GLP-1 peptides and compounds that inhibit the degradation of endogenous GLP-1. The available data suggest that patients with T2DM potentially may benefit from use of incretin mimetics and DPP-IV inhibitors, both as monotherapy and in combination therapy. However, the benefits and risks of these agents require further evaluation. References 1. Koro CE, Bowlin SJ, Bourgeois N, Fedder DO. Glycemic control from 1988 to 2000 among US adults diagnosed with type 2 diabetes: a preliminary report. Diabetes Care. 2004;27: Available at: /27/1/17. Accessed January 8, Fan T, Koro CE, Fedder DO, Bowlin SJ. Ethnic disparities and trends in glycemic control among adults with type 2 diabetes in the U.S. from 1988 to Diabetes Care. 2006;29: Available at: /content/full/29/8/1924. Accessed March 19, Nauck MA, Homberger E, Siegel EG, Allen RC, Eaton RP, Ebert R, et al. Incretin effects of increasing glucose loads in man calculated from venous insulin and C-peptide responses. J Clin Endocrinol Metab. 1986;63: Drucker DJ. Enhancing incretin action for the treatment of type 2 diabetes. Diabetes Care. 2003;26: Available at: Accessed January 8, Drucker DJ. Incretin-based therapies: a clinical need filled by unique metabolic effects. Diabetes Educ. 2006;32(Suppl 2);65S-71S. (continued) JAOA Supplement 3 Vol 107 No 5 May 2007 S15

7 6. Visboll T, Holst JJ. Incretins, insulin secretion and type 2 diabetes mellitus [review]. Diabetologia. 2004;47: Epub 2004 Nov 24. Available at: kth9/fulltext.html. Accessed January 9, Brandt I, Joossens J, Chen X, Maes MB, Scharpe S, De Meester I, et al. Inhibition of dipeptidyl-peptidase IV catalyzed peptide truncation by Vildagliptin ((2S)-{[(3-hydroxyadamantan-1-yl) amino]acetyl}-pyrrolidine-2-carbonitrile). Biochem Pharmacol. 2005;70: American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2006;29(Suppl 1):S43-S48. Available at: Accessed January 8, Orchard TJ, Temprosa M, Goldberg R, Haffner S, Ratner R, Marcovina S, et al. The effect of metformin and intensive lifestyle intervention on the metabolic syndrome: the Diabetes Prevention Program randomized trial. Ann Intern Med. 2005:142: Available at: /reprint/142/8/611.pdf. Accessed March 3, Ratner RE, The Diabetes Prevention Program Research. An update on the Diabetes Prevention Program. Endocr Pract. 2006;12(Suppl 1): Available at: /articlerender.fcgi?tool=pubmed&pubmedid = Accessed March 3, US Department of Health and Human Services, US Department of Agriculture. Dietary Guidelines for Americans, Washington, DC: US Department of Health and Human Services, US Department of Agriculture; January 12, Available at: Accessed March 3, 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. Diabetes Care. 2005;28: Available at: /reprint/28/5/1092. Accessed February 28, Buse JB, Henry RR, Han J, Kim DD, Fineman MS, Baron AD; for the Exenatide-113 Clinical Study Group. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in sulfonylurea-treated patients with type 2 diabetes. Diabetes Care. 2004;27: Available at: Accessed February 28, Kendall DM, Riddle MC, Rosenstock J, Zhuang D, Kim DD, Fineman MS, 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. Diabetes Care. 2005; 28: Available at: journals.org/cgi/reprint/28/5/1083. Accessed February 28, Blonde L, Klein EJ, Han J, Zhang B, Mac SM, Poon TH, et al. Interim analysis of the effects of exenatide treatment on A1C, weight and cardiovascular risk factors over 82 weeks in 314 overweight patients with type 2 diabetes. Diabetes Obes Metab. 2006; 8: Heine RJ, Van Gaal LF, Johns D, Mihm MJ, Widel MH, Brodows RG; for the GWAA Study Group. Exenatide versus insulin glargine in patients with suboptimally controlled type 2 diabetes: a randomized trial. Ann Intern Med. 2005;143: Available at: /cgi/reprint/143/8/559.pdf. 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Accessed February 28, Fonseca V, Schweizer A, Albrecht D, Baron MA, Chang I, Dejager S. Addition of vildagliptin to insulin to improve glycaemic control in type 2 diabetes. Diabetologia. 2007;50: Epub Mar 27, Cover Credits Blood sugar test: photograph Jorgeantonio, Dreamstime.com; medicine bottle and pills: photograph Kenhurst, Dreamstime.com; target created by Rachel Lindsey-Miliotto. (Cover design by Leslie M. Huzyk, Creative Director.) S16 JAOA Supplement 3 Vol 107 No 5 May 2007