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Glucagon receptor antagonists in pipeline for diabetes.


LISBON--New data on two investigational glucagon receptor antagonists suggest that this novel class of drugs has potential to be an effective treatment for type 2 diabetes, but only if safety can be established, according to two presentations at the meeting.

Both Merck's MK-0893 and Eli Lilly's LY2409021 suppress glucagon action via receptor blockade. Dr. Samuel S. Engel, senior director of clinical research, diabetes and endocrinology at Merck, presented phase II study data on the efficacy and safety of MK-0893 in combination with metformin or sitagliptin in 146 patients with type 2 diabetes, and Dr. Melvin J. Prince, senior director of medical diabetes and endocrinology at Eli Lilly, presented phase I dose-finding data on LY2409021 in 47 patients.

Both agents produced significant reductions in hemoglobin [A.sub.1c] However, both also produced small but significant elevations in liver enzymes, and both carry the theoretical potential for hypoglycemia and hyperglucagonemia. "I think there is definitely potential for the glucagon receptor antagonists in diabetes, but there is also a risk of hypoglycemia associated with them. Also, it has been noted in the past that the hyperglucagonemia that results when the alpha cells overproduce glucagon has led to pancreas tumors in animal studies, so that's a risk," said Dr. Finbarr O'Harte, professor of endocrinology and metabolism at the University of Ulster, Derry (Northern Ireland).

At the American Diabetes Association's annual scientific sessions, Dr. Engel presented data from a phase II study in which 342 type 2 diabetes patients were randomized to once-daily MK-0893 in four different dosages, metformin 1,000 mg twice daily, or placebo. At 12 weeks, treatment with MK-0893 resulted in significant, dose-dependent reductions in fasting plasma glucose, ranging from 32 mg/dL with a 20-mg dose to 63 mg/dL with 80 mg, from a baseline of 180-193 mg/dL. Metformin reduced FPG by 37 mg/dL, and placebo by just 2 mg/dL from baseline. For [HbA.sub.1c], reductions at 12 weeks ranged from 0.6 to 1.5 percentage points, compared with 0.8 percentage points with metformin and 0.5 with placebo.

The current study evaluated 40 mg/day MK-0893 in combination with 2,000 mg/day metformin or 100 mg/day sitagliptin, as well as 100 mg of sitagliptin plus 2,000 mg of metformin. The 146 patients had a mean age of 53 years, [HbA.sub.1c] of 8.6%, and mean diabetes duration of 7 years. The MK-0893/metformin combination was superior to sitagliptin/metformin in lowering 24-hour weighted mean glucose, with a reduction of 117 mg/dL compared with 85 mg/dL. However, MK-0893/sitagliptin was significantly less effective than sitagliptin/metformin, which produced a 24-hour WMG reduction of 100 mg/dL. This could be because sitagliptin, a DPP-4 inhibitor, also suppresses glucagon and so there could be a threshold effect, Dr. Engel noted.

All treatments were equally well tolerated. However, there was a significantly higher incidence of diarrhea in the two MK-0893 groups (10% vs. 0%). In addition, the liver enzymes alanine transaminase (ALT) and aspartate aminotransferase (AST) were elevated in the MK-0893/metformin group, and total cholesterol and LDL cholesterol were increased from baseline with MK-0893 /sitagliptin, relative to reductions with MK-0893 / metformin and sitagliptin/metformin, he reported.

In the phase I dose-ranging study of LY-2409021, 47 patients were randomized to one of four doses or metformin. Patients had a mean baseline fasting blood glucose of 148 mg/dL, and a baseline [HbA.sub.1c] of 8.0%. By day 28, mean reductions in [HbA.sub.1c] were statistically significant compared with baseline in all treatment groups, ranging from 1.02 percentage points with 60 mg to 0.69 percentage points with 5 mg. In the placebo group, [HbA.sub.1c] dropped by 0.49 percentage points, Dr. Prince reported.

Fasting glucagon significantly increased by 0.6- to 4.2-fold compared with baseline across the LY dose levels, and fasting active glucagon-like peptide-1 (GLP-1) rose by 59% at the highest dose. Glucagon and GLP-1 returned to baseline levels during follow-up, he said.

The agent was generally well tolerated. Reversible elevations in hepatic transaminases were seen in five of nine patients in the highest-dose group, with no clinical signs or significant elevations in bilirubin or alkaline phosphatase. In the interview, Dr. O'Harte said that these two agents seem to have already exceeded expectations based on previous experience with other small-molecule glucagon antagonists that have been tested and have failed due to toxicity issues.

Dr. Engel and Dr. Prince are employees of Merck and Eli Lilly, respectively. Dr. O'Harte reported having no conflicts.

'The hyperglucagonemia that results when the alpha cells overproduce glucagon has led to pancreas tumors in animal studies, so that's a risk.'
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Title Annotation:ENDOCRINOLOGY
Author:Tucker, Miriam E.
Publication:Internal Medicine News
Date:Oct 15, 2011
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