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EASD: Incretin Mimetic Liraglutide When Added, Boosts Glycemic Control

Sep 16, 2008

Type 2 diabetes patients given daily injections of investigational liraglutide atop oral metformin and rosiglitazone (Avandia) achieved significant reductions in plasma glucose by a drop in A1c of 1.5%, with lower blood pressures and weight loss, researchers reported.

In the 26-week LEAD-4 (Liraglutide Effect and Action in Diabetes) trial, hemoglobin A1c was reduced by 1.5% (P<0.0001) in the 178 patients receiving either 1.2 or 1.8 mg of liraglutide, an incretin mimetic, plus metformin and rosiglitazone. This compared with a 0.5% hemoglobin A1c reduction for 177 patients randomized to placebo plus metformin and rosiglitazone.


The total of 533 patients, who had previously been treated with one or more oral agents, had a mean age of 55 years. At baseline mean body mass index was 33.5±5.2 kg/m2 and the mean HbA1c was 8.3%±1%, reported Bernard Zinman, M.D., of the University of Toronto.

Fifty-eight percent of the patients randomized to 1.2 mg and 54% of those receiving the higher dose achieved HbA1c levels of 7% or lower versus 26% of controls, and more than a third of liraglutide patients achieved HbA1c levels of 6.5% or less (P<0.0001 for both doses compared with controls).

The decrease in systolic blood pressure averaged 6.7 mm Hg in the low-dose liraglutide arm and 5.7 mm Hg in the high-dose arm versus 1.1 mm Hg in controls (P<0.0001).

Patients in the low-dose arm lost about 1 kg while those in the higher-dose arm lost a little more than 2 kg, versus a gain of 0.60 kg in the placebo group (P<0.0001).

But as with the incretin mimetic exenatide (Byetta), nausea was a common side effect — reported by 29% of patients treated with 1.2 mg and 40% of patients given the 1.8 mg dose, versus only 9% of controls (P<0.05).

Dr. Zinman said the nausea occurred early in treatment and decreased to placebo levels by week 16.

“All the GLP-1s have the problem of causing nausea,” he said, adding that although it was a common side effect, it was also one that was difficult to measure.

“In some patients, it is, ‘I just can’t finish my plate (of food),'” and in other patients it can be disabling, he said at a press briefing.

Nonetheless, he said that nausea was much higher in this study than in other liraglutide studies, and he theorized that was “because we had to up-titrate the metformin, which also causes nausea, so maybe the maximum dose of both of these led to more nausea.”

Asked whether there was any evidence of increased pancreatitis — a side effect that has been reported with exenatide and has been linked to six deaths — Dr. Zinman said that it was too early to assess. Moreover, he said he doubted there was a true link between exenatide and pancreatitis and he predicted that further study would confirm his view.

Novo Nordisk, maker of liraglutide, which is a human GLP-1 analog, submitted an NDA to the FDA in May.  And a recent news release from NovoNordisk stated that the approval will be delayed until at least June of 2009.

Zinman, B et al “Effect of the GLP-1 analogue liraglutide on glycaemic control and weight reduction in patients on metformin and rosiglitazone: a randomized double-blind placebo-controlled trial” EASD 2008; Abstract 989.


Studies show Januvia and A TZD work better in combination:  Data from five studies showed that a combination of Merck’s drug Januvia and TZD improved blood-sugar levels over two years of treatment and was well-tolerated. The base study looked at 412 patients over a year and then included them in an all-patients-treated analysis of efficacy over the next year. Januvia combined with a TZD  were found to control blood sugar better than either drug alone. Presented at the 44th Annual Meeting of the European Association for the Study of Diabetes
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