News · Heart & Metabolic
Lifestyle cut chronic disease. Metformin did not.
Two decades after the Diabetes Prevention Program, 1,173 participants were checked for accumulated illness. The lifestyle arm came out ahead. The drug arm matched placebo.
Based on a peer-reviewed long-term follow-up of a randomized trial in JAMA
- Researchers followed 1,173 participants from the Diabetes Prevention Program and its long-term follow-up study, publishing in JAMA.
- All had prediabetes at baseline and were randomized to an intensive lifestyle program, metformin, or placebo.
- Median age at this analysis was 74 and 68% were female.
- The outcome was multimorbidity: having at least 2 of 15 chronic conditions defined in Medicare's Chronic Condition Data Warehouse.
- By the end of follow-up, 997 participants (85%) had 2 or more conditions, with a median of 5.
- The lifestyle group had lower risk than placebo (HR, 0.79; 95% CI, 0.68-0.93).
- Metformin showed no difference from placebo (HR, 0.91; 95% CI, 0.78-1.07).
- Restricted to the costliest condition pairs, the lifestyle advantage widened (HR, 0.57; 95% CI, 0.38-0.85).
- The result held when diabetes itself was removed from the definition, so it is not just diabetes prevention counted twice.
Metformin is the most-discussed candidate anti-aging drug in the world, largely on the strength of observational data. A study in JAMA had something better: two decades of randomized follow-up in people who were actually assigned to take it. Over that horizon, the diet-and-exercise arm pulled ahead and the drug arm did not.
What was being counted
The endpoint was not diabetes. It was the accumulation of illness generally.
The primary outcome was multimorbidity, defined as presence of 2 or more of 15 prevalent conditions, defined in the Chronic Condition Data Warehouse run by the US Centers for Medicare and Medicaid Services, adapted for Medicare Advantage records.
That is the outcome that shapes later life. Two conditions means two specialists, two sets of medications and the interactions between them.
The participants had all started with prediabetes and been randomized decades earlier to an intensive lifestyle program, to metformin, or to placebo. This analysis caught up with 1,173 participants at a median age of 74 years, of whom 795 (68%) were female.
Almost everyone accumulated something
The first finding is a reminder of what aging looks like at scale.
By the end of follow-up, 997 (85%) of participants experienced 2 or more conditions, with a median of 5.
Eighty-five percent, with a median of five conditions each. The question was never whether people would accumulate chronic illness. It was how fast, and whether either intervention slowed it.
The group totals hint at the answer. Reaching that mark were 316 of 385, 327 of 385, and 350 of 403 respectively, among lifestyle, metformin, and placebo groups - 82%, 85% and 87%.
Lifestyle moved the needle
The risk of multimorbidity was lower among lifestyle compared with placebo participants, at 0.79 with a range from 0.68 to 0.93.
Roughly a fifth lower, in a comparison that starts from random assignment rather than from self-selected healthy behavior. That distinction is what makes this different from the usual observational finding that people who exercise are healthier.
The authors then narrowed to the combinations that cost the most. When restricted to dyads of the costliest conditions, the lifestyle-versus-placebo estimate fell to 0.57, with a range from 0.38 to 0.85.
The benefit was largest exactly where it matters most.
Metformin did not
There was no difference between participants in the metformin and placebo groups, at 0.91 with a range running from 0.78 to 1.07.
That range crosses 1.00, which means no effect remains a live possibility. The point estimate leans favorable and the study cannot distinguish it from nothing.
This is not a failure of metformin at its actual job. The original trial showed it delays type 2 diabetes, and that finding stands. What it did not do was change the wider trajectory of chronic illness over the following two decades.
The check that makes it interesting
An obvious objection: if lifestyle prevented diabetes, and diabetes is one of the 15 conditions, the result might be diabetes prevention counted twice.
The researchers tested that. These relationships persisted when diabetes was excluded from the multimorbidity definition.
So the lifestyle advantage extends beyond the disease the program was designed to prevent, into conditions it was never aimed at.
What to hold back
This is 1,173 people, a subset of the original trial with linked Medicare records rather than the full cohort. That subset is older, US-based and insured, and the uncertainty around each estimate is correspondingly wide - the lifestyle benefit could be as small as 7% or as large as 32%.
The multimorbidity definition is administrative, built from billing categories rather than clinical assessment. It counts conditions equally whether they are well controlled or disabling.
And the comparison is between an intensive, supported, resourced lifestyle program and a pill. Real-world lifestyle advice is rarely delivered with that level of support, which is a large part of why drugs remain attractive.
The conclusion
Among adults with prediabetes at baseline, lifestyle intervention, but not metformin, was associated with a lower burden of multimorbidity, and lifestyle programs may persistently lower the development of chronic conditions.
Persistently is the word carrying the weight. The intervention finished decades ago. Something about it was still visible in the medical records at 74.
People also ask
What was the Diabetes Prevention Program?
A landmark US trial that randomized adults with prediabetes to an intensive lifestyle program targeting 7% weight loss and 150 minutes of activity a week, to metformin, or to placebo. It reported in 2002 that lifestyle cut progression to type 2 diabetes by 58% and metformin by 31%. Participants have been followed ever since in the DPP Outcomes Study, which is what makes an analysis at median age 74 possible.
What is multimorbidity and why measure it?
Having two or more chronic conditions at once. It matters more than any single diagnosis because it drives most healthcare cost, most medication burden, and most of the loss of independence in later life. This study used a 15-condition list from Medicare data, so the definition is administrative rather than clinical, but it is applied identically across the three groups.
Why did metformin not work here when it prevented diabetes?
Because those are different questions. Metformin does delay type 2 diabetes, which the original trial showed. What this analysis asks is whether it reduces the wider accumulation of chronic illness two decades on, and the answer was no. The estimate sat at 0.91 with a range from 0.78 to 1.07, which includes no effect. Preventing one condition is not the same as changing the overall trajectory.
Does this settle the metformin longevity question?
Not on its own, though it is relevant. Metformin has been promoted as an anti-aging drug on the strength of observational data and mechanistic reasoning, and dedicated trials are underway. What this adds is long-term randomized evidence in people who took it for prediabetes: over that horizon and in that population, it did not reduce accumulated chronic disease. That is the kind of evidence the enthusiasm has generally lacked.
How much can 1,173 people tell us?
Less than the original trial, which enrolled over 3,000. This analysis covers the subset with linked Medicare records, so it is a slice rather than the whole cohort, and that slice is older and US-insured. The randomization still holds within it, which is the main protection, but the uncertainty ranges are wide enough that the lifestyle estimate could be anywhere from a 7% to a 32% reduction.
References
- Salive ME, Tjaden AH, Ames J, et al. Lifestyle and Metformin Interventions and Risk of Multimorbidity in Adults With Prediabetes. JAMA (2026).
- National Institute of Diabetes and Digestive and Kidney Diseases. Diabetes Prevention Program (DPP).
- Centers for Disease Control and Prevention. National Diabetes Prevention Program.