Exenatide in Combination Therapy: Small Study, Big Market, and Many Unanswered Questions

In the past decade, many new medications have improved our ability to treat patients with type 2 diabetes (1). The pharmaceutical industry has played a key role in this process. Among these novel medications are newly designed insulins, thiazolidinediones (TZDs), meglitinides, orally active inhibitors of the incretin-degrading enzyme dipeptidyl peptidase-IV, and glucagon-like peptide (GLP) mimetics. Combinations of these drugs, each drug with its distinct pharmacologic mechanism of action, have increased our capacity to manage patients with diabetes.

The latter 2 drug classes mentioned enhance or mimic the effects of endogenous incretins, such as GLP hormones secreted by the gut (2–4). As with most gut peptides, GLP biological activity is exercised locally by inhibiting gastric emptying but also in the pancreas by stimulating glucose-dependent insulin secretion, promoting insulin biosynthesis, and inhibiting glucagon secretion. At the central nervous system level, GLP inhibits food and water intake, promotes satiety and weight loss, and induces nausea and vomiting. These diverse sites of action make GLPs attractive molecules for treating diabetes.

In a randomized trial in this issue (5), we learn about use of a GLP mimetic—exenatide—in combination with a TZD. The study was designed, conducted, and analyzed by employees of the manufacturer in collaboration with academicians from several institutions and “[all] authors participated in interpreting the data and drafting or critically reviewing the manuscript” (5).

Zinman and colleagues report on a relatively small study of patients with type 2 diabetes (n = 233) from 49 centers where exenatide, 10 µg twice daily (n = 121), or placebo (n = 122) was added to rosiglitazone (≥4 mg/d) or pioglitazone (≥30 mg/d) alone or in combination with metformin (79%) for 16 weeks to assess both efficacy and safety. The study results were the basis for the U.S. Food and Drug …