Results of 2 years of data were presented at the International Diabetes Federation (IDF) 20th World Diabetes Congress.

Presenter and lead author Alan J. Garber, MD, PhD, FACE, stated that, Liraglutide (Novo Nordisk) is a human glucagon-like peptide-1 analogue that "has insulin stimulatory effects in the presence of glucose, has glucagon-suppressive effects in the absence of hypoglycemia, retards gastric emptying, and diminishes appetite."

"It sounds like an ideal combination for overweight people with Type 2 diabetes, and it is. They lose weight, they don't get hypoglycemic, and their sugars come down," said Dr. Garber, who is from the Baylor College of Medicine Faculty Center in Houston, Texas, and is secretary of the American Association of Clinical Endocrinologists.

In the Liraglutide Effect and Action in Diabetes-3 (LEAD-3) study, 746 patients with Type 2 diabetes and a body mass index (BMI) of 45 kg/m² or less were randomized to receive once-daily liraglutide (1.2 mg or 1.8 mg) or the sulfonylurea drug glimepiride (8 mg) for 52 weeks. The primary end point was change in proportion of glycosylated hemoglobin (Hb_A1c). At the outset of the trial, all patients had their diabetes controlled with diet and exercise alone or by taking oral diabetic agents at half or less of the maximal dose.

After 20 weeks, those on liraglutide lost more weight than those on the placebo. Participants on the highest dose of liraglutide lost 15 pounds, compared with 6 pounds on the placebo and 9 pounds on orlistat. Three-quarters of the subjects on the highest dosage of liraglutide lost 5% or more of their body weight.

The medication also reduced blood pressure at all dosages. At the three highest dosages, liraglutide reduced symptoms of pre-diabetes -- blood glucose levels above normal but not yet high enough to qualify as diabetes. The most common side effects of liraglutide were nausea and vomiting. Patients did not seem to mind injecting the drug, the authors noted.

"The original 1-year randomized trial that appeared in The Lancet earlier this year [2009;373(9662):473-481] showed [that liraglutide] was about twice as effective as a traditional means of stimulating insulin secretion using a sulfonylurea, and [the response] was fairly durable over the full year of the randomized trial," said Dr. Garber.

At the IDF meeting, Dr. Garber presented data on a 2-year follow-up that was conducted in 440 of the 473 patients who completed LEAD-3.

Overall, 321 patients completed a full 2 years of treatment. Compared with glimepiride, treatment with liraglutide resulted in significantly greater reductions in Hb_A1c and a lower final Hb_A1c (6.9% with 1.2 mg of liraglutide and 7.1% with 1.6 mg of liraglutide vs 7.5% with glimepiride). Liraglutide therapy was also associated with a greater proportion of patients achieving Hb_A1c levels of less than 7% or of 6.5% or more without hypoglycemia or weight gain, greater reductions in fasting plasma glucose (FPG), and lower final FPG values (7.45 and 7.58 vs 8.54 mmol/L, respectively), greater reductions in mean daily postprandial glucose, and weight loss. Patients receiving glimepiride actually gained a mean of 1.0 kg.

"In the second-year extension that we're showing here, you get the same persistent A1c control at full dose as what you saw at 1 year," said Dr. Garber. "So, it appears to be a very, very stable, durable effect. There is no weight regain while on drug, and it's very well tolerated."

Despite lower Hb_A1c values with liraglutide, this therapy actually caused fewer hypoglycemic events than glimepiride. There were 0.21 hypoglycemic events per patient-year with 1.2 mg of liraglutide and 0.22 events with 1.8 mg of the drug, compared with 1.75 events per patient-year with glimepiride. The most frequently occurring adverse events with liraglutide were nausea and diarrhea.

IDF delegate I. George Fantus, MD, FRCPC, associate dean of research at the University of Toronto and professor of medicine at Mount Sinai Hospital in Toronto, Ontario, stated that the key issue with incretin-based therapies, such as liraglutide, will be whether they truly protect beta cells.

"That's the key issue with the incretins: whether over the long term there is going to be more success and less progression to require insulin using these drugs as opposed to sulfonylureas," he said. "The weight loss is expected and has been demonstrated previously. Less hypoglycemia is expected because its [actions of] lowering glucose and [promoting] insulin secretion are glucose-dependent. Sulfonylureas, it's well known, are not glucose dependent, so there is hypoglycemia."

"The other question is about the [risk for] complications," said Dr. Fantus. "There's a hint of pancreatitis or thyroid problems, which [might] be significant. It's too early to say.... I think these things usually come out in postmarketing, with large, large numbers of people in the real world."

International Diabetes Federation (IDF) 20th World Diabetes Congress: Abstract P-1397. Presented October 21, 2009.