The Pharmaceutical Journal
Vol 272 No 7303 p733
12 June 2004

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Diabetes drug may lower weight as well as HbA_1c

Exenatide, the first of a new class of incretin-mimetic antidiabetes drugs lowers glycated haemoglobin (HbA_1c) and body weight, according to a phase III study presented to the American Diabetes Association by Ralph DeFronzo, University of Texas. It also appears to elicit a short-term beta-cell response to glucose infusion.

The study of 336 patients with type 2 diabetes randomised three groups of patients following a four-week placebo run-in to placebo or 5µg exenatide administered by subcutaneous injection twice daily for four weeks. One group subsequently doubled the dose to 10µg. All patients received maximally effective doses of metformin.

After 30 weeks, 81 per cent had completed the study. “Participants receiving exenatide had dose-dependent and progressive weight loss with significant reduction in blood glucose levels,” said Professor DeFronzo. In the 10µg arm, 46 per cent with an initial HbA1c exceeding 7 per cent reduced this to below threshold. Average weight loss was 2.8kg and average HbA_1c reduction was 0.8 per cent. In the 5µg arm, 32 per cent achieved the below 7 per cent HbA_1c threshold compared with 13 per cent given placebo. HbA_1c fell 0.4 per cent in the 5µg group compared with no change in the placebo arm.

Average weight loss for the 5µg dose was 1.6kg compared with 0.3kg for placebo. The most common side effect was mild to moderate nausea. Incidence of mild to moderate hypoglycaemia was 5.3 per cent for the 10µg and placebo groups and 4.5 per cent in the 5µg group. An open-label one-year extension phase showed HbA_1c and weight changes were sustained.

In a 25-subject (12 healthy controls and 13 patients) cross-over study, patients with type 2 diabetes showed a beta-cell response following exenatide treatment but not placebo, according to blood glucose, insulin and C-peptide blood concentrations.

Exenatide, in development by Amylin and Eli Lilly, is claimed to mimic the human incretin hormone GLP-1. The product is a synthetic version of exendin-4, a hormone produced in the gut of the Gila monster, a lizard found in the US that eats only four times a year and turns off its pancreas between meals. It secretes exendin-4 to restart pancreatic function.