ADA 2009: GLP-1 Agonist Outperforms Sulfonylurea in Type 2 Diabetes

Martha Kerr

June 12, 2009

June 12, 2009 (New Orleans, Louisiana) — Monotherapy with liraglutide (Victoza, Novo Nordisk) was associated with a greater reduction in hemoglobin A1C values, with nearly 60% reaching glycemia targets compared with about one third of patients receiving glimepiride, investigators with the LEAD 3 trial announced here this week at the American Diabetes Association (ADA) 69th Scientific Sessions.

LEAD 3 was a 2-year trial of 323 patients with type 2 diabetes randomized to liraglutide 1.8 mg or 1.2 mg daily, or to the sulfonylurea glimepiride (Amaryl, Sanofi-Aventis; Diapride, Micro Labs Ltd), 8 mg daily.

At 2 years, patients receiving liraglutide 1.8 mg experienced a 1.1% decrease in hemoglobin A1C levels over baseline compared with a decrease of 0.9% with 1.2 mg and 0.6% with glimepiride, principal investigator Alan J. Garber, MD, professor of medicine at Baylor College of Medicine in Houston, Texas, told meeting attendees.

More patients receiving liraglutide achieved a target A1C of less than 7% (58% of patients receiving the 1.8 mg dose, 44% of patients taking 1.2 mg, and 37% of those receiving glimepiride) at 2 years.

Liraglutide was associated with sustained weight loss, while glimepiride was associated with weight gain. Mean body weight decreased a significant 2.8 kg with liraglutide 1.8 mg, and decreased 2.1 kg with the 1.2-mg dose, while there was an increase in mean body weight of 1.1 kg after 2 years with glimepiride.

Hypoglycemia (less than 56 mg/dL) was more than 6 times less frequent among patients assigned to either dose of liraglutide compared with glimepiride. There were also significant reductions in A1C and fasting plasma glucose with liraglutide compared with glimepiride.

"Liraglutide has roughly double the efficacy of glimepiride and it is virtually free of hypoglycemic episodes," Dr. Garber told Medscape Diabetes & Endocrinology. "More than half of patients got to treatment goals with liraglutide compared with glimepiride. When you take this into account with the weight loss and the lack of hypoglycemia, the results are really quite impressive."

An FDA advisory committee was split 6-6 over whether to recommend approval of liraglutide because of concerns that the drug might increase the risk for cancer, which it did in rodents, Dr. Garber acknowledged.

Cancer Concerns

"There was some concern over the risk of cancer, which was seen in rodents," Dr. Garber said. Liraglutide stimulates C-cells in rodents, causing an increase in calcitonin and there were few cases of cancer in these animals, but there were none in nonhuman primates nor in any humans.

"Humans lack the C-cell receptors that liraglutide acts on," he asserted. "But we were asked if there is enough evidence to completely answer the question of whether liraglutide causes cancer...and so we are continuing to look at that."

Calcitonin levels remained stable and did not increase during the 2-year period in a subset of 146 randomized patients. "There was absolutely no effect on calcitonin level with treatment," Dr. Garber said. "There does not seem to be any cause for concern with regard to calcitonin as a marker of excess C-cell stimulation."

Lawrence Blonde, MD, director of the Diabetes Clinical Research Unit at the Ochsner Clinic here in New Orleans told Medscape Diabetes & Endocrinology in an interview after the announcement of the LEAD 3 results that "58% of patients on liraglutide achieving target levels of A1C below 7% is impressive...and a 33% improvement in A1C values with liraglutide," Dr. Blonde said. "About 10 times more patients got to goal without any problems compared with glimepiride.

"[The GLP-1 agonist] had a much more durable effect than the sulfonylurea. Blood sugars were really quite constant," he added.

Nausea is a significant albeit transient problem with liraglutide, Dr. Blonde noted, and the drug may prove to be expensive.

However, "a positive indication for approval has just come from Europe and Japan in the past month," Dr. Blonde announced, "so the company is expecting approval in the US soon."

LEAD 3 was supported by funding from Novo Nordisk. Dr. Garber receives research support from Novo Nordisk, Merck, GlaxoSmithKline, and Sankyo. Dr. Blonde receives support from Abbott Pharmaceuticals, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Bristol-Myers Squibb, Eli Lilly & Co, and GlaxoSmithKline, among other sources.

American Diabetes Association (ADA) 69th Scientific Sessions: Abstract 162-OR. Presented June 6, 2009.

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