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No Efficacy or Safety Sacrifice with Weekly Exenatide (Byetta LAR)

Posted: Friday, June 20, 2008

A long-acting version of the injectable diabetes drug exenatide (Byetta) showed efficacy advantages and safety comparable to the standard formulation given twice a day, researchers said.

Hemoglobin A1c values among 148 patients with type 2 diabetes declined a mean of 1.9 percentage points during 30 weeks of treatment with weekly exenatide, compared with a 1.5-point decline in 147 patients receiving twice-a-day doses of the standard drug (P<0.01), reported Daniel Drucker, M.D., of the University of Toronto, at the American Diabetes Association meeting.

Dr. Drucker also reported that 77% of patients receiving the weekly formulation -- not yet approved by the FDA -- ended the 30-week randomized portion with A1c levels of 7% or lower, compared with only 61% who reached that goal in the control arm (P<0.01).

Moreover, control-arm patients who switched to weekly exenatide in a 22-week, open-label extension of the study achieved many of the same improvements in glycemic control, according to John Buse, M.D., Ph.D., of the University of North Carolina in Chapel Hill, N.C., in a separate presentation.

"Exenatide once weekly was associated with durable glycemic improvements and weight loss over 52 weeks," Dr. Buse said.

"I think it's going to change the landscape," said Steven V. Edelman, M.D., of the University of California San Diego, who chaired the session where results from the 30-week randomized phase were presented.

Patients in the study began with mean A1c levels of 8.3% in both arms, with mean duration of diabetes of 6.4 years in the control arm and 7.0 years in the weekly group.

Patients were also taking standard oral drugs at baseline, including thiazolidinediones, sulfonylureas, and/or metformin. They were allowed to continue taking up to two of these agents during the study. Not only did weekly exenatide lead to greater declines in A1c levels, but in fasting plasma glucose as well.

By the end of 30 weeks, patients treated weekly saw declines of 42 mg/dL in fasting plasma glucose, compared with 25 mg/dL in patients receiving the drug twice a day (P<0.05).

Dr. Drucker reported that patients with relatively high baseline A1c values appeared to benefit the most from the weekly drug. Patients with baseline A1c of 9% and higher showed a mean decline of 2.7 percentage points during the randomized phase, significantly greater than the 1.9-point decline seen in control patients with A1c of at least 9%.

Compared with twice-daily exenatide, the weekly formulation showed a trend toward greater improvements in serum lipid levels, including total cholesterol, LDL cholesterol, and triglycerides.

Dr. Drucker said the apparently greater efficacy of the weekly formulation almost certainly results from greater drug exposure, in terms of the area under the curve for blood concentrations over time.

The half-life of the twice-daily version is so short that it is nearly gone from circulation after 12 hours, said Dr. Buse.

No major hypoglycemia episodes occurred in the study. During the extension phase, according to Dr. Buse, there were no episodes of hypoglycemia at all, except in patients also taking sulfonylureas. In both phases of the trial, patients lost a significant amount of weight. The mean weight loss was about 3.7 kg in both arms at the end of 30 weeks, and reached 4 kg during the extension phase. "In general, [weekly exenatide] is better tolerated than exenatide twice a day," Dr. Buse said.

The only significant drawback to weekly exenatide, according to Drs. Drucker and Buse, was that it takes about six weeks to reach optimal blood levels of the drug.

So, Dr. Buse pointed out, patients who switched to weekly exenatide in the extension phase initially showed steep increases in blood glucose. Within a few weeks, blood glucose levels declined to levels similar to those seen in patients maintained continuously on the weekly version of the drug.

Christopher Sorli, M.D., a diabetologist at the Billings Clinic in Billings, Mont., said weekly exenatide would probably be a better choice for almost every patient now taking the twice-daily product.

In the incretin pathway, where exenatide acts, "the benefits of [non-fluctuating] drug action are improved both for glycemic control as well as total body energy homeostasis, [leading to] weight loss," he said.

Practice Pearls:

Explain to interested patients that weekly injections of a long-acting version of exenatide (Byetta) appeared more effective and equally safe compared with twice-a-day dosing with conventional exenatide.
Point out that the long-acting formulation is not FDA-approved and is available only in a clinical trial setting.

Source: Diabetes In Control: American Diabetes Association meeting: Drucker D, et al "Exenatide once weekly results in significantly greater improvements in glycemic control compared to exenatide twice daily in patients with type 2 diabetes" ADA Meeting 2008; Abstract 37. Buse J, et al "Exenatide once weekly elicits sustained glycemic control and weight loss over 52 weeks" ADA Meeting 2008; Abstract 01-D.