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ADA: Exenatide Benefit Not Always Sustained in Type 2 Diabetes

Nearly half of patients taking exenatide (Byetta) for type 2 diabetes for more than a year in a small study discontinued it because of loss of efficacy, although many were combining it with insulin off-label. See Publisher’s Comments Among 30 patients in an academic clinical practice who started on exenatide and were followed for two years, 18 eventually discontinued the drug, reported Jennifer A. Loh, M.D., of Georgetown University in Washington, at the American Diabetes Association meeting.

Twelve of the discontinuations were for loss of efficacy, mainly in patients who were prescribed it in combination with insulin, she said. "In a real-world clinical practice, the efficacy of exenatide is not sustained in all patients," Dr. Loh said. In addition, she said, "off-label use of exenatide with basal insulin does not appear to be effective."

Superficially, the loss of efficacy appears to contrast with other clinical trial findings that found relatively stable efficacy with exenatide for up to three years, she said.

Dr. Loh said those were typically open-label extensions of 30-week randomized trials. Patients recruited for such studies are chosen carefully with many exclusion criteria, and there is typically selection bias in which participants choose to continue in the extensions.

Even in those studies, she said, discontinuations for various reasons were common. She cited one ongoing open-label extension in which only 36% of eligible patients remained on the drug.

Moreover, those studies have not addressed exenatide’s off-label use in conjunction with insulin. Such use is not uncommon, she said. She and a Georgetown colleague, Stephen Clement, M.D., reviewed records of the first 47 patients at their clinic to begin taking exenatide in 2005, immediately after the drug was approved. Of these, records were complete in 30 for body weight and hemoglobin A1c levels for the following two years.

Half the patients were taking insulin, even though exenatide is only approved for use with oral diabetes drugs. Most were also taking metformin and sulfonylurea drugs, and 12 were on thiazolidinediones.

Dr. Loh reported that 15 patients had discontinued exenatide within one year, and three more stopped the drug in the following year. Six of these discontinued because of adverse effects, nausea being the most common. These discontinuations all occurred during the first nine months after starting exenatide, with nausea the most common side effect. Most of the 12 discontinuations for loss of efficacy occurred from nine to 20 months after starting the drug. For nine of the discontinuations, patients made the decision entirely by themselves. In five cases it was a joint patient-physician decision, and in four cases the physician decided unilaterally to stop exenatide.

Specific efficacy measures that signaled failure were lack of appetite suppression, lack of weight loss, and lack or improvement or worsening in glycemic control. Mean weight loss for all 30 patients reached a maximum of 3.47 kg after six months on the drug, after which patients tended to begin regaining weight, she said. At one year, the mean weight loss from baseline was 2.09 kg, and at two years, it was 1.66 kg. The latter value was not statistically significant from baseline, Dr. Loh said.

Exenatide had the least benefit in patients also taking insulin, both in weight gain and in glycemic control, she said. Among the 12 patients still taking exenatide after two years, those taking only oral medications as concurrent therapy had a mean weight loss from baseline of 4.9 kg, versus 0.36 kg for those taking insulin. Similarly, those on oral drugs showed a decrease in hemoglobin A1c of 1.07 percentage points from baseline. Patients taking insulin plus exenatide had a reduction of 0.22 points.

Overall, Dr. Loh said, about 30% of the patients showed sustained efficacy with exenatide over two years. She said the small number of patients in the study, the retrospective design, and the lack of a control group were significant limitations to the analysis.

On the other hand, Dr. Loh said their results for weight loss and glycemic control "perfectly mirror" what has been reported in larger, prospective open-label trials when their discontinuation rates are considered.

Christopher Sorli, M.D., a diabetologist at the Billings Clinic in Billings, Mont., said the findings did not jibe with his own clinical experience. "We have a data repository, and I would almost guarantee you that if we presented ours, it would be different," he said.

He said dropouts from exenatide therapy are much less common in his clinic, about 8% to 9%, primarily because of nausea early on. "Part of it is picking appropriate patients," he added. "All incretin therapies [including exenatide] are not drugs to be used late in the disease."

Exenatide and similar drugs act to preserve beta cells, most of which are already lost when type 2 diabetes is diagnosed, he said. "If you’re going to preserve them with incretin therapy, you’ve got to do it right away. People who have lack of efficacy, I think you’ll see that much higher percentage in people who are further down in the disease process," Dr. Sorli said
A merican Diabetes Association meeting – Loh J, et al "Efficacy of exenatide therapy over two years in a ‘real world’ setting" ADA Meeting 2008; Abstract 32.

Publisher’s Comments: I agree with Dr. Sorli. I can’t believe a retrospective study like this with only 30 patients, some of whom were using it off label, was even presented when so many clinicians have so much more experience with exenatide. With the patients that I have worked with the discontinuation rate is low.  The main reason for discontinuation in my patient population is payor restrictions. Most patients can get through any nausea if they are told about it up front. I agree that off label use with insulin is often less effective because these patients have less remaining beta cell function if they are requiring insulin. Efficacy is better when used earlier in the disease process. To get the best benefit from glucose reduction and weight loss exenatide should be used second line after metformin. If used properly the experience mimics that of the published studies. Looking forward to the once a week version.

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