Obesity and Diabetes — 8

Soon after, there was excitement about the anti-obesity drug rimonabant. It was directed against the cannabinoid receptor in the brain—the same receptor that induces the munchies after smoking or ingesting pot. Multiple reports showed that high-dose rimonabant helped people lose fifteen pounds of body weight, and they had better lipid panel results, lower fasting glucose, and less resistance to their insulin. Keen interest led to a major international trial (which I ran) to see if the drug could reduce heart attacks and strokes. Close to nineteen thousand participants from forty-two countries joined to take the active pill or placebo for three years. At the same time the clinical trial was ongoing, rimonabant had already been approved by regulators in some countries to achieve weight loss. Then came the bad news: reports of suicides or suicide attempts were clustering, both in the trial and in several European countries. Rimonabant was withdrawn from the market in 2008, and our trial had to be discontinued after one year of follow-up, with four suicides in the treatment group and one in the placebo group. Sanofi, the company that developed the drug, stopped its production and commercial pursuit. Meridia, an appetite suppressant (sibutramine) anti-obesity drug marketed by Abbott Laboratories, was withdrawn in 2010 because it significantly increased the risk of heart attacks and strokes. Other nondrug strategies in recent decades to reduce obesity, such as the Atkins high-fat diet craze or imposing soda beverage taxes, both failed. At least they didn’t result in heart disease or suicide.

Given that background, the success here is all the more impressive. We have never seen a class of drugs capable of this magnitude of weight loss. That alone would be considered a monumental achievement, but the impact these drugs are having on heart, kidney, and liver disease goes beyond that achievement.

The cardiovascular benefits of GLP-1 drugs in people with obesity have been measured in two ways. In a large randomized trial of 17,600 people with a high BMI (average of 33 kg/m2) and history of heart disease, treated with semaglutide or placebo for three years of treatment, there was a 20 percent relative reduction, or 1.5 percent absolute reduction, of heart attacks, strokes, and cardiovascular deaths. Of note, there was a substantial reduction of inflammation, as reflected by the biomarker high-sensitivity C-reactive protein (hs-CRP), and the adverse cardiovascular events, before there was substantial weight loss. These results emphasize the GLP-1 effect on reducing inflammation that precedes and is independent of weight loss.