Incretin hormones in the treatment of type 2 diabetes

•Abstract

Type 2 diabetes mellitus is a progressive disease affecting more than 18 million Americans. Incretin mimetics and DPP-IV inhibitors are new classes of antihyperglycemic agents that may improve glycemic control in patients with type 2 diabetes. The incretin hormone, glucagon-like peptide 1 (GLP-1), stimulates glucose-dependent insulin secretion, suppresses inappropriate glucagon secretion, and slows gastric motility. GLP-1 levels are decreased in type 2 diabetes. GLP-1 is rapidly inactivated by the enzyme dipeptidyl peptidase-IV (DPP-IV), resulting in a half-life of <2 minutes. Strategies to increase GLP-1 activity include the development of incretin mimetics that are resistant to DPP-IV degradation and the development of DPP-IV inhibitors. Clinical trials have demonstrated that the incretin mimetics exenatide and liraglutide, as well as the DPP-IV inhibitor vildagliptin, improve glycemic control, reduce weight, and are fairly well tolerated. Exenatide (Byetta, Amylin/Lilly) was approved by FDA in April 2005 and liraglutide (Novo Nordisk) and vildagliptin (Novartis) are investigational agents. The diverse mechanisms of action and the clinical efficacy of these agents make them promising therapeutic options in the management of type 2 diabetes. (Formulary. 2006;41:130–141.)

Diabetes mellitus is a devastating disease and its prevalence is on the rise. An estimated 18.2 million people in the United States have diabetes, with type 2 diabetes accounting for 90% to 95% of all diagnosed cases. The direct and indirect medical costs associated with diabetes were estimated at $132 billion in 2002.¹

Type 2 diabetes is characterized by a combination of insulin resistance and diminished insulin secretion from pancreatic beta-cells. Early in the disease process, cells do not use insulin properly (insulin resistance) and more insulin is required for glucose uptake. Insulin resistance also results in increased glucose production in the liver. Initially, the pancreas compensates for this resistance by secreting more insulin to meet the cells' demands. Gradually, the pancreas loses its ability to produce insulin and hyperglycemia ensues. In particular, the first, rapid phase of insulin secretion is blunted.² The net result of these pathophysiologic defects is hyperglycemia which, if left untreated oruncontrolled, can lead to complications such as heart disease, stroke, blindness, kidney disease, neuropathy, and amputations.

Diabetes progressively worsens over time. The UKPDS demonstrated a progressive deterioration in beta-cell function and glycemic control over time, even in patients randomized to intensive treatment regimens.^3,5 Eventually, many people will require insulin to successfully control their blood glucose levels. Despite the availability of several treatment options, achieving goal blood glucose and HbA_1c levels remains a challenge for many patients with type 2 diabetes. The incretin mimetics and DPP-IV inhibitors are new classes of drugs that may offer the potential for better glucose control in patients with type 2 diabetes.

THE INCRETIN EFFECT

Incretin hormones are peptide hormones secreted by enteroendocrine cells that line the gastrointestinal (GI) tract. The potential role of incretin hormones in glucose metabolism is based on an observation that glucose given orally provoked a far greater insulin response compared with similar amounts of glucose given intravenously. This discovery was termed the "incretin effect" and suggests that signals from the gut promote insulin secretion from pancreatic beta-cells in response to oral nutrient intake.⁶ Two dominant incretin hormones have been identified; glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). These peptides play an important role in nutrient-related insulin secretion, as GIP and GLP-1 levels increase in response to meals, thus stimulating insulin secretion.⁷

Patients with type 2 diabetes have a decreased incretin effect, or an "incretin defect."⁸ Although circulating levels of GIP are near normal in patients with type 2 diabetes, the peptide loses its ability to stimulate insulin secretion.⁷ In contrast, while GLP-1 levels are decreased in patients with type 2 diabetes, the ability of GLP-1 to solicit an insulinotropic response remains preserved.⁸ In a study by Toft-Nielsen et al,⁹ GLP-1 secretion in response to meals was significantly impaired in patients with type 2 diabetes, probably as a consequence of the disease. Because GLP-1 secretion is decreased in type 2 diabetes yet maintains its ability to stimulate insulin secretion, researchers have focused their efforts on increasing GLP-1 levels.

CLINICAL EFFECTS OF GLP-1

GLP-1 possesses several properties that make it a potentially attractive antihyperglycemic agent. GLP-1 stimulates glucose-dependent insulin secretion.¹⁰ In other words, GLP-1 causes beta-cells to increase insulin secretion only when glucose levels are high in response to meals, thus minimizing the risk of hypoglycemia commonly associated with other agents that stimulate insulin secretion. GLP-1 also suppresses inappropriate glucagon secretion, which in turn suppresses glucose production in the liver.¹¹ This action, which is also glucose-dependent, is favorable because it does not interfere with the counter-regulatory response of glucagon to hypoglycemia. GLP-1 slows gastric emptying, which delays the absorption of nutrients into the bloodstream and inhibits appetite.¹²

GLP-1 has been demonstrated to be effective in patients with type 2 diabetes. In a study by Zander et al,¹³ 20 patients were alternately assigned to continuous subcutaneous infusion of GLP-1 or saline for 6 weeks. For patients in the GLP-1 group, FPG decreased by 77 mg/dL (P<.0001), mean plasma glucose decreased by 99 mg/dL (P<.0001), HbA_1c decreased by 1.3% (P=.003), body weight decreased by 1.9 kg (P=.02), and insulin sensitivity improved by 77% (P=.002).

Although GLP-1 has many attractive properties and clinical evidence supports its potential effectiveness, the therapeutic usefulness of GLP-1 is limited by its short half-life of 1 to 2 minutes. GLP-1 is rapidly inactivated by the enzyme dipeptidyl peptidase-IV (DPP-IV), and thus requires administration via continuous infusion.¹² To avoid using continuous infusions of GLP-1, researchers have proposed alternate therapeutic strategies. The 2 primary areas of interest are the development of incretin mimetic agents or GLP-1 analogues that are resistant to DPP-IV degradation and the development of DPP-IV inhibitors.⁷

INCRETIN MIMETICS

Exenatide. Exenatide injection (Byetta, Amylin/Lilly) is the first of the incretin mimetic agents to be approved by FDA. A new drug application was submitted in June 2004, and exenatide was approved in April 2005. Exenatide is a synthetic version of exendin-4, which was originally isolated from the venom of the Gila monster. It is a GLP-1 receptor agonist and shares 53% amino acid identity with GLP-1.¹⁴ It is resistant to DPP-IV and therefore has a longer half-life (26 minutes in humans) compared with GLP-1.¹⁵

Exenatide produces similar clinical effects to GLP-1, including increased glucose-dependent insulin secretion,^16–18 suppression of inappropriate glucagon secretion,¹⁹ and slowed gastric emptying.²⁰ Fehse et al²¹ demonstrated that exenatide increased insulin AUC during both the first and second phases of insulin secretion after glucose administration in patients with type 2 diabetes, illustrating its ability to improve beta-cell function and restore phase 1 insulin secretion. Exenatide is indicated as adjunctive therapy in patients with type 2 diabetes mellitus who are taking metformin and/or a sulfonylurea who have not achieved adequate glycemic control.²²

Fineman et al²³ conducted a phase 2 study evaluating the effects of exenatide in patients with type 2 diabetes who were treated with sulfonylureas and/or metformin. Males and females aged 18 to 65 years who were stable for at least 6 months on a diabetes regimen containing a sulfonylurea and/or metformin were eligible. A total of 109 patients were randomized to 1 of 4 treatment groups; exenatide 0.08 mcg/kg subcutaneously twice daily at breakfast and dinner (BIDbd), twice daily at breakfast and bedtime (BIDbs), 3 times daily at breakfast, dinner, and bedtime (TIDbds), or placebo 3 times daily for 28 days. To maintain blinding, patients in the twice-daily groups received a third placebo injection each day. Study end points included serum fructosamine, postprandial glucose (PPG), HbA_1c, FPG, body weight, and fasting and postprandial lipids.

At Day 28, all exenatide treatment groups resulted in significant reductions in fructosamine compared with placebo (45, 39, 46, and 5 mcmol/L for BIDbd, BIDbs, TIDbds, and placebo, respectively; P≤.003) and significant reductions in HbA_1c compared with placebo (1.1%, 0.7%, 1.0%, and 0.3% for BIDbd, BIDbs, TIDbds, and placebo, respectively, P≤.006). Fifteen percent of patients receiving exenatide achieved HbA_1c <7%, compared with 4% of patients taking placebo (no P value reported). Significant reductions in postprandial glucose levels were also noted in all exenatide groups compared with placebo (79, 58, 61, and 11 mg/dL for BIDbd, BIDbs, TIDbds, and placebo, respectively, P≤.004). While the beta-cell function, or beta-cell index, in patients taking placebo remained unchanged, an increase from baseline occurred in all exenatide groups at Days 14 and 28, ranging from 50% to 100% (no P value reported). No significant differences were seen in fasting glucose levels, body weight, or lipids between exenatide groups and placebo. The most common adverse effects were nausea (31% overall) and hypoglycemia (15% overall). Nausea was more pronounced during the first week of the study, with the incidence decreasing to 13% at the end of the study. Four patients withdrew from the study due to nausea. All hypoglycemic events were deemed mild-to-moderate, did not require assistance of another individual, and occurred in patients also taking sulfonylureas. This trial demonstrated for the first time that exenatide administered either twice or three time daily for 28 days resulted in significantly decreased HbA_1c levels in patients not achieving target HbA_1c levels on sulfonylureas and/or metformin.

The second AMIGO trial evaluated the effects of exenatide on glycemic control over 30 weeks in patients with type 2 diabetes treated with sulfonylureas.²⁵ Similarly to the previous AMIGO study, 377 patients were randomized to exenatide 5 mcg subcutaneously twice daily, 10 mcg twice daily, or placebo after a 4-week placebo lead-in phase. All patients continued sulfonylurea treatment. Primary end points of the study were HbA_1c levels and safety. Secondary end points included FPG, body weight, fasting concentrations of insulin, proinsulin, and lipids.

Sixty-nine percent of subjects completed the study. At baseline, the average age of the study population was 55 years, BMI was 33 kg/m² , and HbA_1c was 8.6%. At Week 30, both exenatide treatment groups experienced significant changes from baseline in HbA_1c compared with placebo (–0.86%, –0.46%, and +0.12% for 10 mcg, 5 mcg, and placebo, respectively; P=.0002). Of patients with baseline HbA_1c >7% (n=353), 34% and 27% of patients receiving exenatide 10 mcg and 5 mcg achieved HbA_1c levels ≤7%, compared with 8% of patients receiving placebo (P<.0001). Fasting glucose levels decreased in the 10 mcg exenatide group compared with placebo (P<.05). Significant weight loss occurred in the 10 mcg group compared with placebo (–1.6 kg vs –0.6 kg, P<.05). The most common adverse effects were nausea and hypoglycemia. Nausea was reported in 39% of patients receiving 5 mcg, 51% receiving 10 mcg, and 7% receiving placebo. Nausea was generally mild-to-moderate and more pronounced during the initial weeks of the study. Severe nausea was reported in 5% of the 10 mcg group, 6% in the 5 mcg group, and 0% in the placebo group. Study withdrawal due to nausea occurred at a rate of 4% in the 10 mcg group, 2% in the 5 mcg group, and 0% in the placebo group. There were no cases of severe hypoglycemia. Mild-to-moderate hypoglycemia occurred in 36%, 14%, and 3% of the 10 mcg, 5 mcg, and placebo groups, respectively. One subject withdrew from the study due to hypoglycemia (5 mcg group). This trial demonstrated that exenatide administered subcutaneously twice daily resulted in decreased HbA_1c and glucose levels and decreased weight in patients with type 2 diabetes insufficiently controlled on a sulfonylurea.

The third AMIGO trial evaluated the effects of exenatide on glycemic control over 30 weeks in patients with type 2 diabetes treated with metformin and sulfonylureas.²⁶ The treatment randomization of this trial was identical to the previous AMIGO trials. All patients continued metformin and were randomized to receive either maximally effective or minimum-recommended sulfonylurea doses. Primary end points of the study were HbA_1c, weight, and safety. Eighty-one percent of subjects completed the study. At baseline, the average age of the study population was 55 years, BMI was 33.6 kg/m² , and HbA_1c was 8.5%. At Week 30, both exenatide treatment groups experienced significant changes from baseline in HbA_1c compared with placebo (–0.8%, –0.6%, and +0.2% for 10 mcg, 5 mcg, and placebo, respectively, P<.0001). Thirty-four percent and 27% of patients receiving exenatide 10 mcg and 5 mcg achieved HbA_1c levels ≤7%, compared with 9% of patients receiving placebo (P<.001). Significant weight loss occurred in both exenatide groups compared with placebo (–1.6 kg in both treatment groups vs –0.9 kg in the placebo group; P<.01). The most common adverse effect was nausea, occurring in 49% of patients receiving 10 mcg, 39% receiving 5 mcg, and 21% receiving placebo. Mild or moderate hypoglycemia occurred in 28% of patients receiving 10 mcg, 19% receiving 5 mcg, and 13% receiving placebo. There was 1 episode of severe hypoglycemia in the 5 mcg group. Hypoglycemia occurred less often with the minimum-recommended sulfonylurea doses. This trial demonstrated that exenatide administered subcutaneously twice daily resulted in decreased HbA_1c levels and decreased weight in patients with type 2 diabetes insufficiently controlled on combined metformin/sulfonylurea therapy.

An important distinction to note among the AMIGO trials is the differing rates of hypoglycemia (see Table 2). This is most likely explained by the concomitant therapy. The addition of exenatide to metformin, which does not cause hypoglycemia, resulted in no significant hypoglycemia compared with placebo. However, when exenatide was added to sulfonylureas, which cause hypoglycemia, rates of hypoglycemia ranged from 14% to 36%.

Subjects completing the 30-week AMIGO trials could participate in a 52-week open-label extension. A post-hoc analysis examining the effect of exenatide on HbA_1c and weight after 82 weeks of treatment indicated that the reduction in HbA_1c from baseline was sustained (–1.1%; 95% CI, –1.3 to –0.9%) and the reduction in weight was progressive (–4.5 kg; 95% CI, –5.5 to –3.5).²⁷ An additional post-hoc analysis found that the reductions in HbA_1c and body weight after 82 weeks of treatment are not explained by the gastrointestinal side effects.²⁸

Heine et al²⁹ conducted a 26-week, open-label, randomized, controlled trial evaluating the effects of exenatide versus insulin glargine on glycemic control in patients with type 2 diabetes mellitus who were not controlled with metformin or a sulfonylurea. Five hundred sixty-six patients were randomized to exenatide 10 mcg twice daily or insulin glargine once daily, titrated to maintain a FPG level <100 mg/dL. All patients continued metformin or the sulfonylurea. End points of the study included HbA_1c, fasting and postprandial glucose, body weight, and safety. At Week 26, both exenatide and insulin glargine reduced HbA_1c levels by 1.11% (difference 0.017; 95% CI, –0.123 to 0.157). Insulin glargine reduced glucose levels significantly more than exenatide (51.5 mg/dL vs 25.7 mg/dL, P<.001), and 21.6% of patients taking insulin glargine achieved FPG <100 mg/dL, compared with 8.6% of patients taking exenatide (P<.001). Body weight decreased (–2.3 kg) in patients taking exenatide but increased (+1.8 kg) in patients taking insulin glargine (difference –4.1 kg; 95% CI, –4.6 to –3.5). Gastrointestinal adverse effects were significantly more common in patients taking exenatide compared with insulin glargine, including nausea (57.1% vs 8.6%, P<.001), vomiting (17.4% vs 3.7%, P<.001), and diarrhea (8.5% vs 3.0%, P=.006). Overall rates of hypoglycemia were similar between the exenatide and insulin glargine groups (7.3 vs. 6.3 events per patient year; 95% CI, –1.3 to 3.4). Nocturnal hypoglycemia was lower in the exenatide group compared with the insulin glargine group (0.9 vs. 2.4 events per patient year; 95% CI, –2.3 to –0.9) but daytime hypoglycemia was higher (6.6 vs 3.9 events per patient year; 95% CI, 0.4 to 4.9). Four patients in each group experienced severe hypoglycemia. This trial demonstrated that exenatide and insulin glargine achieved similar reductions in HbA_1c in patients with type 2 diabetes uncontrolled on metformin or a sulfonylurea. Exenatide achieved a significant reduction in weight but was associated with a high incidence of GI adverse effects.

The use of exenatide in combination with insulin, thiazolidinediones, meglitinides, or alpha-glucosidase inhibitors has not been studied. In addition, exenatide is not recommended for use in patients with end-stage renal disease or severe renal dysfunction (creatinine clearance <30 mL/min) or in patients with severe gastrointestinal disease.²²

Liraglutide. Liraglutide (Novo Nordisk), an investigational agent, is a synthetic derivative of GLP-1 that exhibits 97% homology with GLP-1. Liraglutide is an acylated GLP-1 analog that binds to albumin. This decreases its sensitivity to DPP-IV and delays its absorption from the injection site, thus extending its half-life.³⁰ After SC injection, the half-life is approximately 12 hours, allowing for once-daily administration.^31,32

Madsbad et al³³ conducted a 12-week, double-blind, randomized, dosage-response trial evaluating the efficacy and safety of once-daily liraglutide in patients with type 2 diabetes. After a 4-week wash-out period, 193 subjects were randomized to 1 of 6 treatment groups: liraglutide 0.045, 0.225, 0.45, 0.60, or 0.75 mg, or placebo, all administered as a once-daily SC injection before breakfast. An open-label sulfonylurea group was included as a reference group. The primary end point of the study was HbA_1c levels. Secondary end points included fasting serum glucose, C-peptide, glucagon, insulin, and beta-cell function. At baseline, the average age of the study population was 57 years, BMI was 30 kg/m² , and HbA_1c was 7.6%. After 12 weeks of treatment, treatment with the 2 highest doses of liraglutide reduced HbA_1c significantly compared with placebo (–0.70% in the 0.60 mg group, P=.0002; –0.75% in the 0.75 mg group, P<.0001). The HbA_1c reductions seen with these 2 doses were similar to the sulfonylurea reference group (–0.74%). Fasting serum glucose levels decreased significantly in the 0.225 mg (P=.009), 0.60 mg (P<.0001), and 0.75 mg (P<.0001) liraglutide groups compared with placebo. Body weight significantly decreased by 1.2 kg in the 0.45 mg liraglutide group compared with placebo (P=.0184). Adverse effects were reported in 60% of patients taking liraglutide and 55% of patients taking placebo. The most common adverse effects were nausea and headache. Nausea was reported in 7.4% of patients taking liraglutide compared with 3.4% of patients taking placebo, with the incidence highest in the 0.75 mg group (18%). One patient (0.60 mg group) experienced minor hypoglycemia (blood glucose <50 mg/dL) and 7 reported symptoms of hypoglycemia. This trial demonstrated that liraglutide administered subcutaneously once daily resulted in decreased HbA_1c levels in patients with type 2 diabetes.

CJC-1131. CJC-1131, an investigational agent, is a DPP-IV resistant GLP-1 analog that binds covalently to albumin in vivo following SC injection. The half-life of CJC-1131 in humans is approximately 10 days.³⁴

Ratner et al³⁵ conducted a 12-week, randomized, placebo-controlled study evaluating the effects of CJC-1131 on glycemic control and weight in patients with type 2 diabetes treated with metformin. After a 4-week wash-out period, 81 subjects were randomized to low-dose CJC-1131, high-dose CJC-1131, or placebo. All subjects continued metformin. The primary end point of the study was HbA_1c levels. At Week 12, both CJC-1131 groups experienced significant changes from baseline in HbA_1c compared with placebo (–1.1%, P<.001; and 0.6, P<.03, respectively). Weight was reduced more in the CJC-1131 groups compared with placebo (–2.5 kg vs –1.6 kg, P<.05). The most frequent adverse effects were GI intolerance, which occurred more often in the first 4 weeks of treatment. This trial demonstrated that CJC-1131 significantly reduced HbA_1c and weight in patients uncontrolled with metformin.

DPP-IV INHIBITORS

Vildagliptin. Pratley et al³⁶ conducted a 12-week, randomized, double-blind, placebo-controlled trial evaluating the effects of vildagliptin (Novartis), an investigational DPP-IV inhibitor, in treatment-naïve patients with type 2 diabetes. One hundred patients were randomized to receive vildagliptin 25 mg po bid or placebo. The primary end point was HbA_1c levels. At baseline, the average age of the study population was 56.9 years in the vildagliptin group and 52.8 years in the placebo group, BMI was 29.9 kg/m² , and HbA_1c was 8.0%. During the 12-week study, HbA_1c decreased 0.6% in the vildagliptin group compared with no change from baseline in the placebo group (P=.0012). The HbA_1c decrease was more notable (1.2%) in patients with higher baseline HbA_1c levels (8.0%–9.5%). Forty-seven percent of patients taking vildagliptin achieved HbA_1c levels <7%. Both FPG and PPG decreased in patients receiving vildagliptin compared with placebo (P=.0043 and P<.0001, respectively). Adverse effects were reported in 55.7% and 71.4% of patients in the vildagliptin and placebo groups, respectively. The most common adverse effect was mild hypoglycemia, occurring in 10% of the vildagliptin group. This trial demonstrated that the DPP-IV inhibitor vildagliptin administered orally twice daily as monotherapy resulted in decreases in HbA_1c, FPG, and PPG in patients with type 2 diabetes.

Ahren et al³⁷ conducted a 12-week, randomized, double-blind, placebo-controlled trial evaluating the effects of vildagliptin in patients with type 2 diabetes treated with metformin. Patients completing the initial 12-week study had the option to participate in a 40-week extension study. After a 4-week run-in period, 107 patients were randomized to vildagliptin 50 mg po qd or placebo. All patients continued metformin. The primary end point was HbA_1c. Secondary end points included FPG and PPG, body weight, lipids, and beta-cell function. Ninety-one percent of patients completed the study. At baseline, the average age of the study population was 57 years, BMI was 30 kg/m² , and HbA_1c was 7.7%. During the 12-week study, HbA_1c decreased 0.6% in the vildagliptin group, compared with a 0.1% increase in the placebo group (P<.0001). In the 40-week extension study, the between-group difference in the HbA_1c change from baseline was –1.1% (P<.0001). An HbA_1c level <7% was achieved in 41.7% of patients taking vildagliptin compared with 10.7% of patients taking placebo. In the 12-week study, fasting glucose levels decreased by 18 mg/dL in the vildagliptin group compared with a slight increase by 3.6 mg/dL in the placebo group (P=.0057). In the 40-week extension study, fasting glucose levels decreased by 10.8 mg/dL in the vildagliptin group compared with an increase of 9 mg/dL in the placebo group (P=.0312). PPG levels also decreased in the vildagliptin group compared with placebo in both the 12-week study (P=.0001) and the 40-week extension (P=.0153). Body weight decreased by 0.4 kg in patients receiving vildagliptin and by 0.5 kg in patients receiving placebo. Adverse event rates were similar between groups during the 12-week study (51.8% vildagliptin vs 54.9% placebo) and the 40-week extension (69.0% vildagliptin vs 58.6% placebo). This trial demonstrated that vildagliptin administered orally once daily resulted in a sustained decrease in HbA_1c, FPG, and PPG levels in type 2 diabetes patients insufficiently controlled on metformin.

MK-0431. Scott et al³⁸ conducted a 12-week, randomized, double-blind, placebo-controlled trial evaluating the effects of MK-0431, an investigational agent, on glycemic control in patients with type 2 diabetes. After a wash-out period, 743 patients were randomized to 1 of 6 treatment groups: MK-0431 5, 12.5, 25, or 50 mg twice daily, glipizide 5 mg once daily (titrated to 20 mg once daily), or placebo. End points included HbA_1c, FPG, weight, and safety. At baseline, patient age ranged from 21 to 76 years and HbA_1c levels ranged from 6.3% to 11% (mean 7.8%–7.9%). At Week 12, HbA_1c was significantly reduced from baseline in all treatment groups compared with placebo, with the largest reduction observed in the 50 mg twice daily group (–0.4% to –0.8%). MK-0431 did not result in any weight change and was generally well tolerated. Hypoglycemic events occurred in 2 patients taking MK-0431, 0 patients taking placebo, and 21 patients (17.1%) taking glipizide. This study demonstrated that the DPP-IV MK-0431 administered orally twice daily resulted in a decrease in HbA_1c in type 2 diabetes.

Herman et al³⁹ conducted a 12-week, randomized, double-blind, placebo-controlled trial evaluating the effects of MK-0431 on glycemic control in patients with type 2 diabetes. After a wash-out period, 552 patients were randomized to 1 of 5 treatment groups: MK-0431 25, 50, or 100 mg once daily, 50 mg twice daily, or placebo. End points included HbA_1c, FPG, weight, and safety. At baseline, patient age ranged from 30 to 74 years and HbA_1c levels ranged from 5.8% to 10.4% (mean 7.6%–7.8%). At Week 12, HbA_1c levels were significantly reduced from baseline in all treatment groups compared with placebo, with the largest reduction observed in the 100 mg qd group (–0.4% to –0.6%). MK-0431 was generally well tolerated, with only 1 hypoglycemic event reported in each MK-0431 group. No mean change in body weight was observed. This trial demonstrated that MK-0431 administered orally once daily or twice daily resulted in a decrease in HbA_1c in patients with type 2 diabetes and was generally well tolerated.

Brazg et al⁴⁰ conducted an 8-week, randomized, double-blind, placebo-controlled crossover study evaluating the effects of MK-0431 on glycemic control in patients with type 2 diabetes treated with metformin. After a 5-week run-in period, 28 patients were randomized to MK-0431 50 mg twice daily for 4 weeks followed by placebo for 4 weeks, or vice versa. All patients continued metformin therapy. Results from the first 4 weeks indicated that FPG levels decreased more in patients receiving MK-0431 compared with placebo (–23.8 vs –3.4 mg/dL, P<.001). Weight gain, GI adverse effects, and hypoglycemic events were not observed. This trial demonstrated that MK-0431 administered orally twice daily in addition to metformin therapy resulted in a decrease in FPG in patients with type 2 diabetes and was generally well tolerated.

ADVERSE EFFECTS

Incretin mimetics and DPP-IV inhibitors are generally well tolerated with the most common adverse effects being nausea and hypoglycemia (when used in combination with a sulfonylurea or other insulin secretagogue). DPP-IV inhibitors appear to be better tolerated than incretin mimetics or analogs. Ninety-one percent of patients in the vildagliptin study³⁷ completed the study, while study completion rates in the AMIGO trials (exenatide) ranged from 69% to 81%.^24–26 While not a predominant adverse effect reported in the trials evaluating vildagliptin, nausea was frequently reported in the exenatide and liraglutide studies.

DRUG INTERACTIONS

Currently there are no published data regarding drug interactions with these agents. However, care should be taken when using these drugs in combination with drugs that can cause hypoglycemia, such as sulfonylureas.

DOSING, ADMINISTRATION, AND COST

Since most of these agents are currently investigational, dosing, administration, and cost information are not available.

With exenatide, the only currently FDA-approved agent, therapy should be initiated at 5 mcg subcutaneously twice daily within 60 minutes before the morning and evening meal. The dose can be increased to 10 mcg twice daily after 1 month. The average wholesale price (AWP) for exenatide per month is $183.75 for 5 mcg twice daily and $215.63 for 10 mcg twice daily.⁴¹

Based on clinical trials, liraglutide may potentially be dosed at 0.6 to 0.75 mg subcutaneously once daily, and vildagliptin at 50 mg orally once daily.

CONCLUSION

Incretin mimetic agents and DPP-IV inhibitors are promising agents in the management of type 2 diabetes. Their diverse mechanisms of action include increased glucose-dependent insulin secretion, suppression of inappropriate glucagon secretion, and slowed gastric emptying. Clinical studies demonstrate that they improve glycemic control in both treatment-naïve patients and in patients receiving sulfonylureas and/or metformin.

These agents are generally well tolerated, with the most common adverse effects being nausea and hypoglycemia (when used in combination with a sulfonylurea or other insulin secretagogue). Incretin mimetics and DPP-IV inhibitors will potentially be used as monotherapy or in combination with sulfonylureas, metformin, or both. Further studies are needed to evaluate their role in combination with thiazolidinediones, insulin, and other antihyperglycemic agents.

Dr Trujillo is assistant dean for academic affairs and associate clinical specialist at Northeastern University School of Pharmacy, Boston, Mass. She can be reached at j.trujillo@neu.edu

Disclosure information: The author reports no financial disclosures as related to products discussed in this article.

REFERENCES

1. American Diabetes Association. National Diabetes Fact Sheet. Available at http:// http://www.diabetes.org/uedocuments/NationalDiabetesFactSheetRev.pdf. Accessed February 27, 2006.

2. Ward WK, Beard JC, Halter JB, et al. Pathophysiology of insulin secretion in non-insulin-dependent diabetes mellitus. Diabetes Care. 1984;7:491–502.

3. UKPDS Group. Intensive blood-glucose control with sulfonylureas or insulin compared with conventional treatment and risk of complications in subjects with type 2 diabetes (UKPDS 33). Lancet. 1998;352:837–853.

4. American Diabetes Association. Standards of medical care in diabetes. Diabetes Care. 2005;28:S4–S36.

5. UKPDS Group. Overview of 6 years' therapy of type 2 diabetes; a progressive disease (UKPDS 16). Diabetes. 1995;44:1249–1258.

6. Perley M, Kipnis DM. Plasma insulin responses to oral and intravenous glucose: studies in normal and diabetic subjects. J Clin Invest. 1967;46:1954–1962.

7. Drucker DJ. Enhancing incretin action for the treatment of type 2 diabetes. Diabetes Care. 2003;26:2929–2940.

8. Holst JJ, Orskov C. The incretin approach for diabetes treatment: modulation of islet hormone release by GLP-1 agonism. Diabetes. 2004;53 (suppl 3):S197–S204.

9. 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 Endocrinol Metab. 2001;86: 3717–3723.

10. Nauck MA, Kleine N, Orskov C, et al. Normalization of fasting hyperglycemia by exogenous glucagon-like peptide 1 (7-36 amide) in type 2 (non-insulin-dependent) diabetic patients. Diabetologia. 1993;36:741–744.

11. Nauck MA, Heimesaat MM, Behle K, et al. Effects of glucagon-like peptide 1 on counterregulatory hormone response, cognitive functions, and insulin secretion during hyperinsulinemic, stepped hypoglycemic clamp experiments in healthy volunteers. J Clin Endocrinol Metab. 2002;87:1239–1246.

12. Deacon CF. Therapeutic strategies based on glucagons-like peptide 1. Diabetes. 2004;53: 2181–2189.

13. Zander M, Madsbad S, Madsen JL, Holst JJ. Effect of a 6-week course of glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and beta-cell function in type 2 diabetes: a parallel-group study. Lancet. 2002;359:824–830.

14. Gryskiewicz KA, Coleman CI. Exenatide: a novel incretin mimetic hormone for the treatment of type 2 diabetes. Formulary. 2005;40:86–90.

15. Edward CM, Stanley SA, Davis R, et al. Exendin-4 reduces fasting and postprandial glucose and decreases energy intake in healthy volunteers. Am J Physiol. 2001;281:E155–E161.

16. Young AA, Gedulin BR, Bhavsar S, et al. Glucose-lowering and insulin-sensitizing actions of exendin-4; studies in obese diabetic (ob/ob, db/db) mice, diabetic fatty Zucker rats, and diabetic rhesus monkeys (Macaca mulatta). Diabetes. 1999;48:1026–1034.

17. Parkes DG, Pittner R, Jodka C, et al. Insulinotropic actions of exendin-4 and glucagons-like peptide-1 in vivo and in vitro. Metabolism. 2001;50:583–589.

18. Egan JM, Clocquet AR, Elahi D. The insulinotropic effect of acute exendin-4 administered to humans: comparison of nondiabetic state to type 2 diabetes. J Clin Endocrinol Metab. 2002;87:1282–1290.

19. Gedulin B, Jodka C, Hoyt J. Exendin-4 (AC2993) decreased glucagons secretion during hyperglycemic clamps in diabetic fatty Zucker rats (abstract). Diabetes. 1999;48 (suppl 1):A199.

20. Jodka C, Gedulin B, Young A. Exendin-4 potentially regulates gastric emptying in rats (abstract). Diabetes. 1998;47 (suppl 1):A403.

21. Fehse FC, Trautmann ME, Holst JJ, et al. Exenatide augments first- and second-phase insulin secretion in response to intravenous glucose in subjects with type 2 diabetes. J Clin Endocrinol Metab. 2005;90:5991–5997.

22. Byetta [package insert]. San Diego, Calif: Amylin Pharmaceuticals, Inc; 2005.

23. Fineman MS, Bicsak TA, Shen LZ, et al. Effect on glycemic control of exenatide (synthetic exendin-4) additive to existing metformin and/or sulfonylurea treatment in patients with type 2 diabetes. Diabetes Care. 2003;26:2370–2377.

24. Defronzo RA, Ratner RE, Han J, et al. Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes. Diabetes Care. 2005;28:1092–1100.

25. Buse JB, Henry RR, Han J, et al. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in sulfonylurea-treated patients with type 2 diabetes. Diabetes Care. 2004;27:2628–2635.

26. 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. Diabetes Care. 2005;28:1083–1091.

27. Blonde L, Han J, Mac S, et al. Exenatide (Exendin-4) reduced A_1c and weight over 82 weeks in overweight patients with type 2 diabetes (abstract). Presented at: American Diabetes Association 65th Annual Scientific Sessions; June 10–14, 2005; San Diego, Calif. Abstract 477-P.

28. Maggs D, Kim D, Holcombe J, et al. Exenatide-induced reductions in A_1c and body weight in long-term trials are not explained by gastrointestinal side effects (abstract). Presented at: American Diabetes Association 65th Annual Scientific Sessions; June 10–14, 2005; San Diego, Calif. Abstract 485-P.

29. Heine RJ, Van Gall LF, Johns D, et al. Exenatide versus insulin glargine in patients with suboptimally controlled type 2 diabetes. Ann Intern Med. 2005;143:559-569.

30. Degn KB, Juhl CB, Sturis J, et al. One week's treatment with the long-acting glucagons-like peptide 1 derivative liraglutide (NN2211) markedly improves 24-h glycemia and alpha- and beta-cell function and reduces endogenous glucose release in patients with type 2 diabetes. Diabetes. 2004;53:1187–1194.

31. Agerso H, Jensen LB, Elbrond B, et al. The pharmacokinetics, pharmacodynamics, safety, and tolerability of NN2211, a new long-acting GLP-1 derivative, in healthy men. Diabetologia. 2002;45:195–202.

32. Juhl CB, Hollingdal M, Sturis J, et al. Bedtime administration of NN2211, a long-acting GLP-1 derivative, substantially reduces fasting and postprandial glycemia in type 2 diabetes. Diabetes. 2002;51:424–429.

33. 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 glucagon-like peptide 1 analog liraglutide (NN2211). Diabetes Care. 2004;1335–1342.

34. Giannoukakis N. CJC-1131. ConjuChem. Curr Opin Invest Drugs. 2003;4:1245–1249.

35. Ratner RE, Guivarc PH, Dreyfus JF, et al. Effects of DAC-GLP:1 (CJC-1131) on glycemic control and weight over 12 weeks in metformin-treated patients with type 2 diabetes (abstract). Presented at: American Diabetes Association 65th Annual Scientific Sessions; June 10–14, 2005; San Diego, Calif. Abstract 10-OR.

36. Pratley R, Galbreath E. Twelve-week monotherapy with the DPP-4 inhibitor LAF237 improves glycemic control in patients with type 2 diabetes (T2DM) (abstract). Presented at: American Diabetes Association 64th Annual Scientific Sessions; June 4-8, 2004. Orlando, Fla. Abstract 355-OR.

37. Ahren B, Gomis R, Standl E, et al. Twelve- and 52-week efficacy of the dipeptidyl peptidase IV inhibitor LAF237 in metformin-treated patients with type 2 diabetes. Diabetes Care. 2004;27:2874–2880.

38. Scott R, Herman G, Zhao P, et al. Twelve-week efficacy and tolerability of MK-0431, a dipeptidyl peptidase IV (DPP-IV) inhibitor, in the treatment of type 2 diabetes (T2D). Presented at: American Diabetes Association 65th Annual Scientific Sessions; June 10–14, 2005; San Diego, Calif. Abstract 41-OR.

39. Herman G, Hanefeld M, Wu M, et al. Effect of MK-0431, a dipeptidyl peptidase IV (DPP-IV) inhibitor, on glycemic control after 12 weeks in patients with type 2 diabetes. Presented at: American Diabetes Association 65th Annual Scientific Sessions; June 10–14, 2005; San Diego, Calif. Abstract 541-P.

40. Brazg R, Thomas K, Zhao P, et al. Effect of adding MK-0431 to on-going metformin therapy in type 2 diabetic patients who have inadequate glycemic control on metformin. Presented at: American Diabetes Association 65th Annual Scientific Sessions; June 10–14, 2005; San Diego, Calif. Abstract 11-OR.

41. First DataBank. Available at: http:// http://www.firstdatabank.com/. Accessed February 22, 2006.

42. DiPiro JT, Talbert RL, Yee GC, et al. Pharmacotherapy: A Pathophysiologic Approach. 6th ed. 2005; New York: McGraw-Hill Companies, Inc.