PART ONE: A (small) alarm on the GLP-1s

Yes, they help people lose lots of weight and improve diabetes symptoms. But a big new trial suggests those findings may not translate to better overall cardiovascular health.

(First of two parts)

In July, I asked UT readers about your experiences with GLP-1 obesity drugs, now the top-selling medicines in the world, taken by millions of Americans a month.

And many of you were very positive, saying GLPs had helped you lose significant weight after years of diligent but failed diet and exercise.

So I don’t want to overstate the level of concern here.

This news is more about what we don’t know than what we do.

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(Telling you what I know. And what I don’t.)

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Still, it’s worth explaining.

After those pieces ran, Eli Lilly, which makes the most popular GLP-1, tirzepatide (sold as Mounjaro and Zepbound), announced clinical trial results from its next-generation GLP-1, retatrutide. The Food and Drug Administration has not yet okayed retatrutide for sale, but Lilly expects to ask for approval early in 2027.

The trials showed retatrutide is even more powerful than tirzepatide and its top competitor, semaglutide (sold by Novo Nordisk as Ozempic and Wegovy). Patients lost over 20 percent of their weight on average. Patients with diabetes also had big drops in blood sugar, with glucose levels down from 7.7 percent to just over 6 percent.

Great news.

There was just one problem.

The larger of the two trials, called TRIUMPH-3, tested retatrutide at two doses against placebo in 1946 people with severe obesity and cardiovascular disease. On average, trial participants were 5’5” and weighed 246 pounds when the trial began.

Patients on retatrutide lost roughly 52 to 55 pounds, on average, compared to about eight pounds for those who received placebo. The retatrutide patients also showed major decreases like blood pressure and triglyceride levels.

Obesity, high blood pressure, and triglycerides are known to raise heart risks, one would have expected the retatrutide patients to have fewer heart attacks, strokes, or cardiovascular deaths.

They didn’t. They had more. Twenty-seven people on retatrutide suffered those cardiac events, compared to 23 on placebo, a 12 percent difference.

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(Rapper Fat Joe then… rapper not-so-Fat Joe now.)

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The difference was not statistically significant, meaning that the extra deaths and other problems in the retratrutide patients could have been due to chance.

But it was puzzling and disappointing. At a minimum, it suggests that retatrutide’s heart benefits are marginal, for whatever reason. Worse, it raises a question if the drug (and other GLPs) are somehow causing direct cardiovascular harm in a way that undoes the indirect benefits from their weight loss.

Lilly did not offer any additional details in its press release, including how many of the events were deaths and whether patients who received a higher retatrutide dose were at higher risk. It has promised to publish the trial’s full results in a peer-reviewed journal.

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(I work for you, not Big Pharma. Support independent reporting, for pennies a day.)

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And, again, retatrutide is not even approved right now (although some people, including my fellow Substacker Eugyppius, are buying it from international pharmacies and taking it).

So, for now, the trial results are more a head-scratcher than reason to panic.

But they point to an even more serious problem with the way Lilly and Novo Nordisk have researched these massively profitable and highly prescribed drugs.

(First of two parts)