SAN ANTONIO – Once-weekly tirzepatide (Zepbound) reduced the risk for progression from prediabetes to type 2 diabetes (T2D) by more than 90% at 3 years and continued to maintain dramatic levels of weight loss achieved earlier, but these benefits began reversing when the drug was stopped.

The findings, from the subset of 1032 individuals with prediabetes in Eli Lilly’s randomized, placebo-controlled SURMOUNT-1 trial, were presented November 4, 2024, at The Obesity Society’s ObesityWeek meeting and are due to be published November 13 in The New England Journal of Medicine. The company released top-line results in August 2024.

“The weight loss was durable for the duration of the study…These are data over 3 years and 4 months, so it’s a very, very long-term dataset…Basically, you could prevent diabetes in 94% of people, and so very, very few people went on to progress to diabetes…It’s absolutely astounding. It’s something that’s never been seen,” study co-investigator Leigh Perreault, MD, associate professor of medicine in the division of endocrinology, metabolism, and diabetes at the University of Colorado Anschutz Medical Campus, Aurora, told Medscape Medical News.

Moreover, Perreault added, “Taking those people all the way back to normal glycemia means they might never see diabetes, or never see the complications of diabetes. This is just a lot of really great news.”

Asked to comment, Susan Z. Yanovski, MD, senior scientific advisor for clinical obesity research in the Division of Digestive Diseases & Nutrition, and co-director of the Office of Obesity Research at the National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, told Medscape Medical News, “What everybody wants to know with these medications, since we’re saying people need to be on them for a long time, is what happens when you take them for a long time. I do think these are very impressive data, the fact that people could maintain that weight loss for so long.”

While Taking Tirzepatide, Very Few Progressed to Diabetes 

In the on-treatment analysis, only 1.2% of those randomly assigned to tirzepatide at any of the subcutaneous 5, 10, or 15 mg doses were diagnosed with T2D over the 176 weeks on study drug, compared with 12.6% of the placebo group, a 94% risk reduction (hazard ratio, 0.06; P < .001). The number needed to treat to prevent one case of T2D was 9. Nearly all on tirzepatide reverted to normoglycemia, vs 60% in the placebo group.

The average 15.4%-22.9% weight losses across the tirzepatide doses achieved initially in the trial were maintained throughout the 176-week treatment period, compared with just a 2.1% loss with placebo. The average weight reduction was between 34.6 and 54.2 lb, from a baseline of about 236.8 lb. Initial improvements in waist circumference, blood pressure, and lipids were also maintained during treatment, as were patient-reported outcomes.

There were no unexpected adverse events. Most were gastrointestinal and were mild to moderate, and the majority occurred during the dose-escalation period.

However, during an off-drug period of 17 weeks following the total 176 weeks spent on the study drug, about 7% of the weight was regained and A1c crept back to baseline. Eight additional participants in the tirzepatide groups developed T2D, nearly doubling the total number with the diagnosis.

To that, Perreault pointed out, “People who use inhalers for asthma, who use antidepressants for depression, people who use diabetes medications — we have a structure of chronic medical management for certain conditions…and it’s time to look at obesity as one of those chronic conditions.”

Of the original 1032 randomly assigned, the proportions completing the study ranged from 69.6% with the 5 mg tirzepatide dose to 72.7% with 15 mg, in contrast to just 50.4% of the placebo group. The study authors presented the data in several ways to account for the dropouts, with similar results.

Moving Toward Precision Medicine 

Also asked to comment, Francesco Rubino, MD, chair of bariatric and metabolic surgery at King’s College London, pointed out that not everyone with prediabetes will progress to T2D, even without any medication. “It’s a significant amount of the American population. So, yes, you’re going to prevent some certain number of cases, but there may be some who will probably not need it….We know there are effective treatments. That’s good news. I think the next step is to fine-tune what are the right indications, and how you prioritize among those indications. That’s probably not a trivial amount of work that needs to be done.”

Yanovski is optimistic. “We’re in early stages with these new medications…There are so many obesity-related illnesses now that we’re seeing positive effects on, and it’s very gratifying. I think we’re going to get to a point where we’ll have better ideas of what medication to start for what patient, based on the idea of precision medicine, and knowing why they develop their obesity. How much food noise do they have? Do they get hungry all the time? Then we’ll be able to tailor our medications better to the individual patient. The GLP-1 drugs do seem to work for many, many patients and seem to have many health benefits. I think that’s something that clinicians will certainly take into account, if their patients can get them.”

Perreault has received person fees for speaking and/or consulting from Novo Nordisk, Elli Lilly, Boehringer Ingelheim, NeuroBo, Medscape, WebMD, and UpToDate. Rubino is an advisor to GT Metabolic Solutions, receives research funds and/or speaker fees from Johnson & Johnson (Ethicon), Medtronic, Novo Nordisk, Amgen, and Eli Lilly. Yanovski has no disclosures. 

Miriam E. Tucker is a freelance journalist based in the Washington, DC, area. She is a regular contributor to Medscape, with other work appearing in the Washington Post, NPR’s Shots blog, and Diatribe. She is on X (formerly Twitter) @MiriamETucker.