Exenatide Added to Thiazolidinediones Helpful in Type 2 Diabetes

Exenatide added to thiazolidinediones improved glycemic control and reduced body weight in some patients with type 2 diabetes, according to the results of a randomized, double-blind, placebo-controlled trial. "Exenatide therapy is effective in combination with metformin or sulfonylureas for treating type 2 diabetes," write Bernard Zinman, MD, from the University of Toronto in Ontario, Canada, and colleagues. "Thiazolidinediones (TZDs) also are commonly used, but the efficacy of exenatide with a TZD has not been reported."

From May 2004 to August 2005 at 490 sites in Canada, Spain, and the United States, 233 patients with type 2 diabetes suboptimally controlled with thiazolidinedione treatment (with or without metformin) were randomized to receive additional exenatide (n = 121) or placebo (n = 112). At baseline, mean glycated hemoglobin A1c (HbA1c) level was 7.9% ± 0.1%.
Patients received subcutaneous abdominal injections of 10 μg of exenatide or placebo twice daily, added to thiazolidinedione (with or without metformin), for 16 weeks. The main endpoint was change from baseline in HbA1c level, and other outcomes were fasting serum glucose level, body weight, self-monitored blood glucose level, and adverse events.

The exenatide group had reductions in HbA1c level (mean difference, -0.98%;  -1.21% to -0.74%), serum fasting glucose level (mean difference, -1.69 mmol/L [-30.5 mg/dL -2.22 to -1.17 mmol/L [-40.0 to -21.1 mg/dL]), and body weight (mean difference, -1.51 kg; ,-2.15 to -0.88 kg).

Adverse events led to treatment discontinuation in 16% of patients in the placebo group. In the exenatide group, 48 patients (40%) reported nausea (mostly mild [n = 21] or moderate [n = 19]), 13% reported vomiting, and 11% had hypoglycemia. In the placebo group, 15% of patients reported nausea, 1% reported vomiting, and 7% had hypoglycemia.

"Exenatide therapy improved glycemic control, reduced body weight, and caused gastrointestinal symptoms more than placebo in patients with type 2 diabetes that was suboptimally controlled with TZD therapy," the authors write.

In an accompanying editorial, Saul Malozowski, MD, PhD, MBA, from the National Institute of Diabetes and Digestive and Kidney Diseases in Bethesda, Maryland, raises concerns about the study. He notes that study patients may not have been receiving maximal conventional therapy when the study began, that lifestyle interventions were not used to maximize diabetes control at baseline, and that data were not provided about subgroups prone to develop adverse drug reactions.

"By virtue of FDA [Food and Drug Administration] approval for the combination of exenatide and TZDs, the data obtained in the study can lead to enormous financial benefits to the sponsor," Dr. Malozowski writes. "Millions of patients receive TZDs and metformin — now physicians may consider adding exenatide. Great power requires greater responsibility. Physicians and patients need answers to the many questions raised by this small study."

Practice Pearls

• Addition of exenatide to oral hypoglycemic agents in patients with diabetes with suboptimal control is associated with improved HbA1c levels, reduced glucose levels, and weight loss.
• Exenatide added to thiazolidinedione for 16 weeks with or without metformin is associated with higher rates of nausea and vomiting and of dropout vs placebo.

Ann Intern Med. 2007;146:477-485, 527-528.
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Peripheral Arterial Disease (PAD) is a serious, under-diagnosed, under-treated disease, often referred to as a silent killer because most people show no symptoms. A type of Peripheral Vascular Disease (PVD) characterized by the narrowing of the arteries in the legs caused by plaque build-up, it is a common condition that affects 8-12 million people in the U.S. every year.  For patients with PAD, the risk of heart attack or stroke is increased 7-10 times. And over 160,000 amputations in the U.S. annually are caused from PAD. The most common symptom is leg pain when exercising, referred to as claudication, which subsides with rest. Unfortunately, most people attribute pain while walking or exercising to the aging process and don’t get properly diagnosed; leg pain is not normal.  Risk factors include patients with diabetes, high blood pressure, high cholesterol, a family history of heart disease, or previous heart disease, or patients who smoke or are obese.  The most common test to diagnose pad is a simple non-invasive test called the Ankle Brachial Index (ABI)