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67th Annual Scientific Sessions of the American Diabetes Association

Chicago, Illinois / June 22-26, 2007

In the struggle against type 2 diabetes, a new class of agents, dipeptidyl peptidase IV (DPP IV) inhibitors, has been developed, and were featured here during the scientific sessions. Agents in the DPP IV inhibitor class show particular promise in both their mode of action and in glycemic control outcomes, according to investigators.

The Role of DPP IV and GLP-1

In healthy patients, DPP IV functions to shorten the half-life and therefore limit the action of glucagon-like peptide-1 (GLP-1) and gastric inhibitor polypeptide (GiP), as explained by Dr. Ralph A. DeFronzo, Chief of Diabetes, University of Texas Health Sciences Center in San Antonio. GLP-1, in turn, is an incretin or hormone that acts on the beta cells in the pancreas to stimulate the secretion of glucose-dependent insulin. GiP aids in fat metabolism. As with many physiologic processes, the actions of GLP-1 and GiP have built-in limitations that function in healthy individuals but are dysfunctional in the setting of illness. Because of the action of DPP IV, more than 80% of GLP-1 degenerates before plasma absorption, Dr. DeFronzo indicated. Therefore, in individuals who have or are progressing to type 2 diabetes, the decrease in beta-cell mass incretin function causes DPP-IV’s action on GLP-1 and GiP to become dysfunctional. The rationale for DPP IV inhibitors is to block this action and enable endogenous GLP-1 and GiP to act more effectively, Dr. DeFronzo told delegates.

Clinical Findings

Among the emerging agents of this novel class are sitagliptin and vildagliptin. Both agents work to inhibit DPP IV and therefore to enhance the actions of GLP-1 and GiP by making the peptides bioavailable for longer periods of time. This action, in turn, improves the body’s sensitivity to its own insulin.

In a session here at the ADA conference in which the newest data regarding sitaglipin was presented, clinical research director Dr. Debora Williams-Herman, Rahway, New Jersey, indicated that sitaglipin in combination with metformin results in durable and significant improvements in glycemic control in patients with type 2 diabetes. In a recent study, she and investigators found that when such patients receive this combination as their initial treatment, the improvements in glycemic control persist over 54 weeks and patients tolerate the treatment well. According to Dr. Williams-Herman, “We found that patients treated with this combination have an early, sustained response and that treatment is well tolerated.”

She and her investigative team conducted the study because initial monotherapy for type 2 diabetes often fails to help patients reach glycemic goals. Because of the progressive nature of type 2 diabetes, the quest to achieve and maintain optimal glycemic control often entails increasingly intensive treatment, she noted.

To that end, the investigators sought to assess the long-term efficacy and safety of initial combination therapy with sitagliptin and metformin. All of the patients had type 2 diabetes and had inadequate glycemic control, as defined by a hemoglobin A1c of 7.5% to 11% on a diet and exercise regimen.

The study involved 1091 individuals for an initial 24-week, placebo-controlled phase followed by a 30-week, double-blind, active-controlled phase that involved 748 participants. Patients in the initial phase received one of five treatment doses: sitagliptin 100 mg and metformin 2000 mg (group 1); sitagliptin 100 mg and metformin 1000 mg (group 2); metformin 2000 mg (group 3) or metformin 1000 mg in divided doses twice daily (group 4); or sitagliptin 100 mg q.d. (group 5). The same doses were used in the second phase, without any placebo use in the monotherapy arms.

In the analysis involving all patients treated, the average mean HbA1c decreased by -1.8% in group 1. They decreased in all of the other groups as follows: 1.4% in group 2, 1.3% in group 3, 1.0% in group 4 and -0.8% in group 5. The average baseline HbA1c was 8.7%. The rates for patients achieving HbA1c levels lower than 7% at week 54 were as follows: 67% for group 1; 48% for group 2; 44% for group 3; 25% for group 4; and 23% for group 5.

Exploring Tolerance

In another analysis by Dr. Peter P. Stein, Senior Clinical Director, Rahway, New Jersey, reported that two years of treatment with sitagliptin is well tolerated in patients with type 2 diabetes.

In this analysis, he and co-investigators pooled data from nine completed phase IIb and III studies that included 5141 individuals. The patients had received either sitagliptin 100 mg/day (n=2786) or placebo or an active comparator (n=2355 not exposed to sitagliptin). The studies were of 24 to 104 weeks in duration and assessed the DPP IV inhibitor as monotherapy, as initial combination therapy with metformin, or as an add-on to oral antihyperglycemic therapy across classes.

The investigators analyzed the studies for clinical and laboratory adverse experiences. All patients had a similar overall incidence of adverse events, serious adverse events, and discontinuations due to adverse events in the DPP IV inhibitor group and in the non-exposed groups. Interestingly, the drug-related adverse events and discontinuations due to such events were higher in the non-exposed patients, primarily due to hypoglycemia in the sulfonylurea-treated patients. Investigators reported that the agent was well tolerated.

Post-prandial Glucose Control

In other research, investigators found that patients with mild hyperglycemia can improve their post-prandial glucose control when treated with vildagliptin, according to Dr. Werner Scherbaum, Director, German Diabetes Research Institute, and Professor of Medicine, University of Dusseldorf, Germany.

In a 52-week randomized study, he and colleagues examined its efficacy and tolerability at 50 mg q.d. in 156 patients compared to 150 patients on placebo. All patients had type 2 diabetes and mild hyperglycemia, defined as an HbA1c of 6.2 % to 7.5%.

The investigators conducted standard meal tests at baseline and end point and calculated the ratio of insulin secretion relative to glucose as an index of beta-cell function. At baseline the patients were an average of 63.1 years old and had a body mass index of 30.2 kg/m2. Their average fasting plasma glucose (FPG) was 7.1 mM and their average HbA1c was 6.7%.

Compared to those on placebo, patients on active treatment had significantly increased beta-cell function, consisting of 5.0 pmol/min/m2/mM (P<0.001). Two-hour post-prandial glucose levels fell an average of 0.9 (P=0.012) and FPG decreased an average of -0.4 (P=0.032). In actively treated patients, the placebo-adjusted decrease in HbA1c from baseline to end point averaged 0.3% (P=0.001). End point HbA1c of no more than 6.5% was achieved by 45.1% of those in the active treatment group and 21.6% of those in the placebo groups. One or more adverse events occurred in 73.1% of those on active treatment and in 72.7% of the placebo cohort. Investigators reported one hypoglycemic event in one patient on placebo and none in any patient on vildagliptin.

Summary

Among the new agents being developed to treat type 2 diabetes, those in the DPP IV inhibitor class have attracted attention in demonstrating their ability to restore functionality by impeding the function of endogenous DPP-IV. This action delays the breakdown of endogenous incretins, a group of peptides that facilitate the metabolism of glucose. By making them available longer, the body’s sensitivity to endogenous insulin is enhanced. In sessions focused on DPP-IV inhibitors here at the ADA, leading investigators presented new findings on both sitagliptin and vildagliptin. Sitagliptin is a DPP IV inhibitor that can be used as monotherapy or in combination therapy with oral hypoglycemic agents.Vildagliptin has been shown in phase III clinical trials to have similar benefits. According to investigators who presented at these sessions, these agents are associated with improved glucose control in patients with type 2 diabetes and show particular promise for the future of type 2 diabetes management.