Multiple Agent Therapy for Type 2 Diabetes

Oral Presentations:
Fri June 10, 2005

Co-chairs:
Philip Raskin, CDE, MD
Matthew Riddle, MD

Report by Joelle Escoffery, PhD

The United Kingdom Prospective Diabetes Study (UKPDS) clearly demonstrated that patients with type 2 diabetes will require multiple therapies over time due to the progressive decline in beta-cell function. Research assessing the efficacy of a wide array of therapeutic approaches for the treatment of type 2 diabetes was presented, and a variety of treatment combinations were tested.

The first presentation discussed research comparing the incretin mimetic, exenatide, with insulin glargine among patients not adequately controlled with metformin and/or sulfonylurea. Results of this randomized study (N = 551) demonstrated that patients who had exenatide added to existing oral therapy achieved reductions in A1C comparable to patients who received insulin glargine in addition to existing oral therapy. Further, the addition of exenatide was associated with better postprandial glycemic control than was the addition of insulin glargine. Patients in the exenatide arm also lost weight, whereas patients in the glargine group gained weight. Patients in the exenatide group experienced more mild-to-moderate nausea, whereas patients in the glargine group experienced more nocturnal hypoglycemia. Results of this study suggest that exenatide may be an effective alternative to insulin glargine among type 2 patients not controlled with oral therapy.

The GLP-1 analogue, CJC-1131, was the topic of the second presentation. This randomized, double-blind, placebo-controlled trial (N = 57) tested the efficacy of CJC-1131 in patients inadequately controlled with metformin or metformin plus sulfonylurea (SU). Patients taking an SU underwent a 4-week washout period, after which, patients were randomized to either a low or high dose of CJC-1131 or placebo. All patients continued on their existing dose of metformin. Results demonstrated that once-daily dosing with either a low dose or high dose of CJC-1131 achieved statistically significant reductions in A1C, fasting plasma glucose, and weight. Like treatment with exenatide, most common side effects were mild to moderate and gastrointestinal in nature.

Another incretin-based therapy that uses a different mechanism of action is the selective dipeptidyl peptidase inhibitor MK-0431 (now called sitagliptin). This study tested the effect of sitagliptin among patients inadequately controlled with metformin (N = 28). Sitagliptin treatment of 4-weeks’ duration was associated with improvements in weighted mean glucose, fructosamine, and mean daily glucose, compared with placebo. The short duration of this study made A1C an unsuitable endpoint.

Moving to a different therapeutic class, this study reported the effect of low doses of rosiglitazone among patients inadequately controlled with insulin (N = 630). Results of this 24-week study demonstrated that the addition of rosiglitazone to insulin resulted in improvements in A1C and C-reactive protein. Further, the addition of rosiglitazone was not associated with an increase in edema, congestive heart failure, or weight gain compared with controls, suggesting that the addition of low dose rosiglitazone may be an effective way to improve glycemic control among patients inadequately controlled with insulin therapy.

Although it is commonly accepted that many antihyperglycemic therapies are associated with changes in body weight, data from patients undergoing routine clinical care (as opposed to those enrolled in clinical trials) is lacking. This retrospective study (N = 9546) used electronic medical records from Kaiser Permanente to track body weight among patients who initiated antihyperglycemic therapy. Even after controlling for numerous demographic characteristics, the results remained similar, which suggests that the effects were very robust. Results demonstrated a weight gain of 3.94 pounds among sulfonylurea-treated patients, 7.32 pounds among insulin-treated patients, and 10.84 pounds in patients treated with a thiazoladinedione. Conversely, metformin treatment was associated with a loss of 5.29 pounds.

The novel dual alpha/gamma PPAR agonist, muraglitazar, was evaluated for efficacy in patients inadequately treated with metformin. In this active placebo-controlled trial, patients were randomized to treatment with either muraglitazar or pioglitazone while continuing on stable doses of metformin. The muraglitazar group showed a substantial improvement in A1C and fasting plasma glucose compared with the pioglitzaone group, with no difference in adverse events. Additional research has demonstrated that pioglitazone can have an impact on disease progression in type 2 diabetes.

The last presentation addressed data from an open-label extension of 3 pivotal trials testing the efficacy of exenatide. This study examined the durability of A1C reduction and weight reduction seen in the 30-week pivotal trials in this 82-week extension. Cardiovascular endpoints were also considered. Results showed that the effect of A1C was indeed durable over 82 weeks, and the effect on weight continued to decline. Further, statistically significant improvements in lipids and blood pressure were also observed.