KEYSTONE, COLO. – Colesevelam and the incretin-enhancing gliptins are drugs with established roots in the treatment of type 2 diabetes but also with preliminary evidence of clinical benefit in type 1 disease.
"I think a lot of the medications we’re using in type 2 we’re going to be using in type 1," Dr. Steven V. Edelman said at a conference on practical ways to achieve targets in diabetes care.
Dr. Steven V. Edelman
Colesevelam (Welchol) is a bile acid sequestrant. It’s the only agent approved by the Food and Drug Administration both for treatment of dyslipidemia and for improving glycemic control in type 2 diabetes. Colesevelam is a nonabsorbed polymer that reduces LDL cholesterol levels by binding bile acids in the intestine. It is not widely prescribed, having been overshadowed by the enormously popular statins. But it has been on the market for a long while and has proved to be a safe, effective agent deserving of broader use, according to Dr. Edelman, professor of medicine at the University of California, San Diego.
Clinical trials indicate that colesevelam reduces LDL levels by 12%-16% in hyperlipidemic patients while lowering glycosylated hemoglobin by about 0.5% in patients with type 2 diabetes. The main side effect is constipation.
"This agent is especially valuable, I think, for the many patients who complain of muscle aches on statins. It gives us another option there," the endocrinologist said. "It also benefits especially those diabetic patients who are not far from both their [hemoglobin A1c] and LDL goals."
Data on colesevelam in type 1 diabetes thus far basically consist of a recent pilot study by Dr. Satish K. Garg and his coworkers at the University of Colorado, Aurora. They studied 40 patients in a 12-week, randomized, double-blind pilot trial. Participants averaged 36 years of age with a 20-year history of diabetes. They were assigned to take either placebo or six 625-mg tablets of colesevelam daily, either all at once or in two divided doses; most opted for the latter. The compliance rate was 89%.
The primary study end point was at least a 10% drop in LDL from baseline after 12 weeks on colesevelam. This goal was met, as LDL levels in the active-treatment arm dropped from a baseline mean 108 mg/dL to 95.7 mg/dL at 4 weeks and 98.3 mg/dL at week 12.
The mean HbA1c in the colesevelam arm dropped significantly from 7.6% at baseline to 7.41%; however, this benefit was not sustained as, by week 12, the HbA1c had climbed back to 7.54%.
While the investigators indicated further studies are planned, their tentative conclusion was that colesevelam’s effects on glycemic control in type 1 diabetes may be mediated through a postprandial rise in glucagonlike peptide1 (GLP-1) levels documented during a 4-hour standardized meal challenge test administered at baseline. When the meal challenge was repeated at week 12, however, there was no postprandial increase in GLP-1 (Diabetes Obes. Metab. 2011;13:137-43).
Dr. Edelman noted that the incretin-enhancing gliptins have quickly become popular in clinical practice. Three are on the market, all with an indication for improvement of glycemic control in type 2 diabetes. They are sitagliptin (Januvia), saxagliptin (Onglyza), and linagliptin (Tradjenta). They are once-daily oral drugs with a minimal side effect profile. The gliptins lower HbA1c by 0.5%-1% without causing hypoglycemia. Their mechanism of action in type 2 diabetes involves rapid inhibition of dipeptidyl peptidase-4 (DPP-4), the enzyme that inactivates GLP-1 and other incretins.
A scenario in which a gliptin is an excellent treatment option is in an obese patient with type 2 diabetes whose HbA1c is in the range of 7.6% on maximum-dose metformin and who is adamant about trying to reach the target HbA1c of 7.0% or less without gaining weight or taking injections.
"Although these drugs are not weight-loss agents, the data consistently show that patients lose a little bit of weight on them," Dr. Edelman said at the conference, sponsored by the University of Colorado and the Children’s Diabetes Foundation at Denver.
The gliptins are particularly effective in combination with metformin. In one placebo-controlled study of 117 patients with type 2 diabetes and an HbA1c greater than 11% at baseline, patients assigned to sitagliptin at 50 mg once daily plus metformin at 1,000 mg BID had a mean 2.9% reduction in HbA1c at 24 weeks.
Dr. Edelman noted that Dr. Garg and coworkers recently performed a double-blind, crossover, randomized trial of sitagliptin in 20 patients with type 1 diabetes and a baseline HbA1c of 8.5%-12%. Participants were assigned to either sitagliptin at 100 mg/day or placebo for 1 month, then crossed over to the other arm for another month. Blinded continuous glucose monitoring was carried out throughout the 2-month study.