Contrave Boosts Weight Loss in Diabetes Patients on Incretins

Marlene Busko

June 30, 2020

An exploratory analysis suggests that the obesity drug naltrexone/bupropion (Contrave, Orexigen Therapeutics) is safe and effective for patients with type 2 diabetes who are overweight or obese being treated with an incretin for their diabetes and who wish to lose weight.

Notably, early responders who lost at least 5% of their initial weight at 16 weeks and completed a year of treatment with naltrexone/bupropion weighed 8.8% less than their starting weight.

Researchers examined data from more than 1000 patients with type 2 diabetes who had participated in two older double-blind, placebo-controlled, phase 3 studies conducted before sodium-glucose cotransporter-2 (SGLT2) inhibitors became available.

Patients were taking a dipeptidyl peptidase-4 (DPP-4) inhibitor or a glucagon-like peptide-1 (GLP-1) receptor agonist, and had stable weight before also being prescribed naltrexone/bupropion; they were followed for 1 year.

Sean Wharton, MD, PharmD, from the Wharton Medical Clinic in Toronto, and McMaster University in Hamilton, Ontario, Canada, delivered the findings in an oral presentation during the virtual American Diabetes Association (ADA) 80th Scientific Sessions.

There is a message for clinicians, he told Medscape Medical News.

"If you have a patient with diabetes and they are on the best regimen of a GLP-1 receptor agonist and their A1c comes down and their weight comes down," but they still say they would like to lose a little more weight, "you can add on Contrave and get further weight loss...in people who stay on it."

The side effects, he said, were similar to patients taking Contrave alone.

Similarly, Contrave could be added to a DPP-4 inhibitor, which is weight neutral, for weight loss in patients with overweight or obesity.

Scott Kahan, MD, MPH, director of the National Center for Weight and Wellness, George Washington University, Washington, DC, who was not involved in the study, said: "This is a valuable preliminary outcome that deserves to be extended."

"The results are in line with prior research on naltrexone/bupropion for weight loss, generally, as well as for weight loss treatment in patients with diabetes," he told Medscape Medical News in an email.

So it is perhaps not surprising, but "good news," that naltrexone/bupropion was safe when used this way.

However, "overall, weight loss with incretins is small," he pointed out.

Taken together, this study supports that naltrexone/bupropion added to a GLP-1 agonist or other incretin "should be considered a reasonable option in patients with obesity and type 2 diabetes," Kahan summarized.

Safety and Efficacy of Naltrexone/Bupropion Added to an Incretin

A "whopping" 42% of US adults currently have obesity and around 13% have diabetes, Wharton noted.

In addition to their glucose-lowering effect, DPP-4 inhibitors and GLP-1 agonists have a neutral or favorable effect on weight, respectively.

And naltrexone/bupropion therapy acts to suppress appetite and decrease cravings and is approved for chronic weight management.

But the safety and efficacy of adding naltrexone/bupropion for weight loss in patients already on incretin therapy were unknown.

To investigate this, the researchers performed a retrospective analysis of data from the COR-DM study (Diabetes Care. 2013;36:4022-4029), conducted in 2007-2009, and the LIGHT study (JAMA. 2016;315:990-1004), conducted in 2012-2015.

As previously reported, the LIGHT study — which was to evaluate cardiovascular disease rates with naltrexone/bupropion — was controversially stopped in May 2015 due to leaked results from 25% of planned enrollment. The phase 4 CONVENE trial, set to replace the LIGHT study, was also ended, in April 2016, after Takeda sold the US rights for Contrave to Orexigen.

Most patients in the current study were drawn from the patients with diabetes who took part in the LIGHT study.

Few patients came from COR-DM, which excluded patients taking GLP-1 agonists.

The researchers identified four patient groups:

  • DPP-4 inhibitors and naltrexone/bupropion: 362 patients (345 from LIGHT)

  • DPP-4 inhibitors and placebo: 329 patients (317 from LIGHT)

  • GLP-1 agonist and naltrexone/bupropion: 339 patients (all from LIGHT)

  • GLP-1 agonist and placebo: 316 patients (all from LIGHT)

Patients were a mean age of 60 years, had a mean body mass index of 37-38 kg/m2, were a mean weight of 105-109 kg (231-240 lb), and had a mean A1c of 7.4%-7.5%.

The efficacy outcome was percentage change in weight from baseline to 1 year.

At 1 year, patients in the DPP-4 inhibitor and naltrexone/bupropion group had lost 5.9% of their initial weight, and those in the DPP-4 inhibitor and placebo group had lost 1.5% of their weight (P < .0001).

Similarly, patients in the GLP-1 agonist and naltrexone/bupropion group lost 5.4% of their initial weight and those in the GLP-1 agonist and placebo group had lost 0.2% of their weight (P < .0001).

Results were better in "early responders" and "completers."

There was no significant difference in weight change between patients receiving a DPP-4 inhibitor or a GLP-1 agonist — but patients taking a GLP-1 agonist had already lost weight and had a stable weight at study entry.

The efficacy and safety of naltrexone/bupropion in the current study were similar to that in studies of participants without diabetes.

The most common adverse events leading to discontinuation of naltrexone/bupropion were nausea (6.6% and 9.4%) and vomiting and constipation (each less than 3%).  

COR-DM was funded by Orexigen Therapeutics and LIGHT was funded by Orexigen Therapeutics and Takeda Pharmaceuticals. The current study was funded by Bausch Health Canada. Wharton has reported being on advisory panels for Bausch Health and Novo Nordisk and receiving research support from the Canadian Institutes of Health Research and Novo Nordisk. Disclosures for the other authors are listed in the abstract. Kahan has reported being a consultant for Novo Nordisk and Vivus.

ADA 2020 Scientific Sessions. June 13, 2020. Abstract 141-OR.

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