September 26, 2013

BARCELONA, SPAIN — The use of a bile-acid sequestrant in patients with type 2 diabetes significantly improves glycemic control, in addition to reducing LDL cholesterol, and does so without any increase in weight, according to the results of a new meta-analysis.

Presenting the results at the European Association for the Study of Diabetes (EASD) 2013 Meeting , lead investigator Dr Morten Hansen (University of Copenhagen, Denmark) said the newest-generation bile-acid sequestrants are better tolerated than older drugs and have fewer gastrointestinal side effects. In the present study, the most common side effect was constipation, which has been reported with the drug class previously.

"When we looked at the data briefly, all of the studies tended to point in the same direction," Hansen told heartwire . "But we wanted to see the magnitude of the reduction in HbA1c levels. We felt that by including a lot of studies, not only the large trials from the US, we would get a better idea of the benefit of treatment."

In total, the researchers included 10 randomized clinical trials, including patients treated with colesevelam and colestimide. The trials were two weeks to 52 weeks in duration and included 2118 patients. At the end of treatment, the weighted mean difference in HbA1c levels when compared against placebo-treated patients was 0.52%, favoring treating with the bile-acid sequestrants. Assessed as a mean reduction in HbA1c, the drugs reduced HbA1c levels 0.50%. When one study that compared bile-acid sequestrants with sitagliptin was included in the analysis, the mean change in HbA1c was attenuated slightly.

In addition to the reduction in HbA1c levels, fasting plasma glucose levels were reduced 0.45% and LDL-cholesterol levels reduced 0.33 mmol/L, or approximately 13 mg/dL. There was no change in the subjects' weight. Across the studies, triglyceride levels rose with treatment, ranging from 4.7 mg/dL to 21.5 mg/dL in the trials. As noted, constipation was the most commonly reported side effect, occurring three times more frequently in patients treated with bile-acid sequestrants.

To heartwire , Hansen said the 0.52% reduction is "clinically relevant" and that the US Food and Administration (FDA) would want any antidiabetic drug to lower HbA1c levels at least this much. "We get that reduction, and not more, but the effects on LDL make this more relevant because we're getting dual action," he said.

Because the drugs are not absorbed, constipation and other gastrointestinal side effects are not unexpected. However, this aspect of the drug is also beneficial, especially when treating diabetics with comorbid disease such as renal impairment or fatty-liver disease. "They'll have issues with most drugs that are metabolized in the liver or in the kidneys, so that's another plus," said Hansen.

In 2008, the FDA approved the use of colesevelam in combination with a sulfonylurea, metformin, and/or insulin therapy in patients with type 2 diabetes. The drugs, however, are not approved for a diabetic indication in Europe. Although prescribed for diabetic patients in the US, the exact role of bile-acid sequestrants in the treatment of diabetics is not fully clear, explained Hansen. Further studies will be needed, including a cardiovascular study, to determine whether reducing HbA1c with the agents can have an impact on important clinical end points.

In the US, there are three bile-acid sequestrants, colestipol, cholestyramine, and colesevelam, approved for the treatment of hypercholesterolemia.

Hansen reported funding from Novo Nordisk.

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