LISBON—The investigational anti-obesity compound known as controlled-release (CR) phentermine/topiramate may prevent progression to type 2 diabetes in obese patients who are prediabetic, researchers announced at the 47th annual meeting of the European Association for the Study of Diabetes.

Their study found that obese prediabetic patients who were treated with phentermine-topiramate CR plus lifestyle counseling over two years had a 0.4% annualized incidence rate of diabetes versus a significantly higher 3.5% rate in patients who received placebo plus lifestyle counseling, which translates into an 88% reduction in progression to frank diabetes.

“This means that patients treated with phentermine/topiramate CR saw almost a complete prevention of onset of new diabetes,” said W. Timothy Garvey, MD, Professor of Medicine and Chair of the Department of Nutrition Sciences at the University of Alabama at Birmingham. “Although a secondary endpoint in our study, the extent of reduction in diabetes was probably our most significant finding.”

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Phentermine-topiramate is a combination of two FDA-approved medications. Phentermine is an appetite suppressant and amphetamine-like stimulant of the phenethylamine class. Topiramate is an anticonvulsant that has published weight loss and beneficial metabolic effects.

Dr. Garvey and his colleagues compared the effects of lifestyle changes plus phentermine/topiramate CR versus lifestyle changes plus placebo at 108 weeks in 675 obese or overweight patients, 316 of whom were prediabetic at baseline.

At enrollment, study participants had a mean weight of 101.7 kg, mean body mass index of 36.1 kg/m2, mean fasting glucose of 6.1 mmol/L, and mean hemoglobin A1c of 6.0%. 

All patients in both groups were managed according to the standard of care for their respective comorbidities and received lifestyle modification counseling, including guidance on nutrition and increased physical activity, throughout the two-year treatment period.

“We have good treatments for hyperglycemia, hypertension, and hyperlipidemia,” Dr. Garvey said. “However, with obesity as the root cause of multiple comorbidities, clinically it makes more sense to treat the underlying condition, obesity, which leads to these many other diseases. By treating the obesity, the hope is that we would have concomitant improvements in multiple comorbidities.”

He pointed out that obesity can impair glucose metabolism and that obese patients who are deemed prediabetic because of impaired fasting glucose or impaired glucose tolerance are at a particularly high risk of developing type 2 diabetes. 

Results in the prediabetic cohort showed that phentermine-topiramate at the two doses tested led to sustained weight loss. That is, prediabetic patients who received placebo lost 2.2% of their baseline weight, whereas those who received phentermine/topiramate CR 7.5 mg/46 mg and 15 mg/92 mg lost 11.1% and 12.7% of their baseline weight, respectively.

Investigators observed dose-related improvements A1c, fasting glucose, fasting insulin, and insulin sensitivity.

Phentermine/topiramate CR was generally well tolerated. The most common side effects were constipation and tingling. 

“We expected to see some improvement in the onset of diabetes based on the bariatric surgery experience,” Dr. Garvey said. “It’s known from the bariatric surgery data that you can see a reduction in the progression to diabetes in high risk individuals, and remission of type 2 diabetes in some patients who already have the disease with the weight loss that accompanies bariatric surgery. We were expecting an improvement with phentermine/topiramate CR, but the magnitude of the effect to prevent diabetes exceeded my expectations. Compared to the lifestyle modification plus placebo group, the higher dose of phentermine/topiramate CR reduced the progression to diabetes by 88%.”