Lifestyle and Metformin Interventions and Risk of Multimorbidity in Adults With Prediabetes (paper june 15 2026)

#1

https://jamanetwork.com/journals/jama/article-abstract/2850450?utm_campaign=articlePDF&utm_medium=articlePDFlink&utm_source=articlePDF&utm_content=jama.2026.8492

Sadly this is behind a paywall. I have not been a metformin fan as I think the arguments that it had a lifespan advantage came from selection bias. However, this is another nail in its coffin. (although the paywall is a nuisance).

Key Points

Question What are the associations of lifestyle and metformin interventions compared with placebo on the occurrence of multimorbidity in adults with prediabetes?

Findings In 1173 participants enrolled in Medicare and followed up for 21 years after enrolling in a randomized clinical trial, 82%, 85%, and 87% experienced multimorbidity among lifestyle, metformin, and placebo groups, respectively. The risk of multimorbidity was significantly lower in the group randomly assigned to lifestyle intervention compared with the placebo group after adjustment for relevant covariates, and there was no significant difference between the metformin and placebo groups.

Meaning Among adults with prediabetes at baseline, lifestyle intervention, but not metformin, was associated with a lower risk of multimorbidity during 21 years of follow-up.

Abstract

Importance Studying how to prevent or delay not just 1 disease but multiple chronic conditions is of great importance for public health; however, few interventions have demonstrated success during long-term follow-up.

Objective To examine the association of lifestyle or metformin compared with placebo on long-term multimorbidity in adults with prediabetes.

Design, Setting, and Participants Observational follow-up cohort study of a randomized clinical trial conducted at 27 sites in the United States from June 1, 1996, to December 31, 2021. From June 1, 1996, through May 28, 1999, 3234 adults at high risk of diabetes enrolled in the 3-year Diabetes Prevention Program (DPP). They were subsequently enrolled in the DPP Outcomes Study (DPPOS). Of this cohort, Centers for Medicare & Medicaid Services (CMS) morbidity data were available through 2021 for 1173 participants who provided consent. Data were analyzed from June 5, 2024, to November 7, 2025.

Exposures Participants in DPP were randomly assigned to intensive lifestyle intervention, metformin, or placebo. During DPPOS, medications were unmasked with discontinuation of placebo; metformin was continued. Group booster classes were offered to the lifestyle group semiannually and all participants were offered lifestyle classes quarterly until 2014.

Main Outcomes and Measures The primary outcome was multimorbidity (presence of ≥2 of 15 prevalent conditions, defined in CMS’ Chronic Condition Data Warehouse and adapted for Medicare Advantage encounters). Cox proportional hazard models were applied to estimate associations between randomized treatment groups and time to development of outcomes.

Results Of the 1173 participants (median age, 74 years [IQR, 70-80]; 795 [68%] were female), 997 (85%) experienced greater than or equal to 2 conditions (median, 5 [IQR, 3-7]) by the end of follow-up (316 of 385 [82%], 327 of 385 [85%], and 350 of 403 [87%], respectively, among lifestyle, metformin, and placebo groups). The risk of multimorbidity was lower among lifestyle compared with placebo participants (hazard ratio [HR], 0.79; 95% CI, 0.68-0.93) after adjustment for relevant covariates. There was no difference between participants in the metformin and placebo groups (HR, 0.91; 95% CI, 0.78-1.07). These relationships persisted when diabetes was excluded from the multimorbidity definition. When restricted to dyads of the costliest conditions, the association with lifestyle vs placebo yielded an HR of 0.57 (95% CI, 0.38-0.85).

Conclusions and Relevance Among adults with prediabetes at baseline, lifestyle intervention, but not metformin, was associated with a lower burden of multimorbidity. Lifestyle programs may persistently lower the development of chronic conditions.

#2

I think we kind of knew this already. Lifestyle adjustments have been shown to provide superior prevention of prediabetes to diabetes progression and if maintained long term, the effect continued, whereas metformin eventually failed (within a few years) to prevent the progression.

I’m curious as to how this comparison would work substituting imeglimin for metformin.

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#3

Lifestyle and Metformin Interventions and Risk of Multimorbidity in Adults With Prediabetes.pdf (558.4 KB)

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#4

A 21-year follow-up of the landmark Diabetes Prevention Program found that an intensive lifestyle program — not metformin — was associated with a 21% lower risk of accumulating multiple chronic diseases in older adults who started with prediabetes. Metformin showed no measurable benefit over placebo on this outcome.

For decades, the central promise of preventive medicine has been simple: change how you live, and you change how you age. Proving it has been harder. Most trials track a single disease over a few years; almost none follow people long enough to watch chronic illnesses pile up across a lifetime. A new analysis published in JAMA on June 15, 2026, does exactly that, and the answer is encouraging for behaviour and sobering for pharmacology.

Researchers linked participants from the original Diabetes Prevention Program (DPP) — adults with prediabetes randomised in the late 1990s to an intensive lifestyle program, the diabetes drug metformin, or placebo — to their Medicare insurance records. This let them count how many of 15 common chronic conditions each person developed over roughly two decades. The “Big Idea” is multimorbidity: not whether you get one disease, but whether you slide into the tangled cluster of several at once, which is what actually drives disability, cost, and decline in later life.

By the end of follow-up, almost everyone was sick with something — 85% of the cohort had two or more chronic conditions, with a median of five. Aging, it turns out, is relentless. But the lifestyle group fared meaningfully better. Compared with placebo, people originally assigned to diet and exercise had a 21% lower risk of crossing into multimorbidity (two or more conditions) and a 25% lower risk of reaching three or more. For the most expensive disease pairings — combinations involving stroke, kidney disease, heart failure, and lung disease — the lifestyle group’s risk was 43% lower.

The striking null was metformin. Despite its reputation in longevity circles as a candidate “anti-aging” drug, randomisation to metformin produced no significant difference from placebo on multimorbidity. The benefit of lifestyle also persisted after the researchers removed diabetes itself from the disease count, suggesting the effect is broader than just blood-sugar control.

The caveats are real: this is observational follow-up of a trial, the intensive coaching faded after the first few years, and the analysable sample was a self-selected, relatively healthy and affluent slice of the original cohort. But as the longest randomised-origin evidence of its kind, it strengthens a now-familiar message with unusual durability: the early behavioural intervention echoed across 21 years, and the drug did not.

Actionable Insights

The take-home is behavioural, not pharmacological. The original lifestyle program had a concrete, replicable target: at least 150 minutes of moderate physical activity per week, a reduced-calorie and reduced-fat diet (under 25% of calories from fat), and a goal of losing at least 7% of body weight. That protocol — not exotic — is what tracked with less disease two decades on.

Effect-size magnitude, stated plainly:

  • Multimorbidity (2+ conditions): hazard ratio 0.79 (21% relative risk reduction). Absolute prevalence 82% lifestyle vs. 87% placebo — about a 5 percentage-point absolute difference, roughly 1 fewer case per 20 people.
  • 3+ conditions: roughly 25% relative risk reduction; absolute 72% vs. 81%, an 8.4 percentage-point difference (about 1 fewer case per 12 people).
  • High-cost disease dyads: hazard ratio 0.57 (43% relative risk reduction); absolute 10% vs. 16%.
  • Total disease count: about 10% fewer chronic conditions overall (relative mean count 0.90).

What this does not support: taking metformin for general healthy-aging or multimorbidity prevention if you do not have a clinical indication for it. In this dataset it matched placebo. Bottom line: the evidence here favours sustained weight management and physical activity as the durable lever; the drug was not a shortcut. [Confidence: Medium — relative effects are reasonably precise, but absolute differences are modest and the cohort is non-representative.]

Source:

  • Paywalled Paper: Lifestyle and Metformin Interventions and Risk of Multimorbidity in Adults With Prediabetes
  • Institution: DPP Outcomes Study Coordinating Center, George Washington University Biostatistics Center (Milken Institute School of Public Health), Bethesda, Maryland; lead author affiliated with the Division of Geriatrics and Clinical Gerontology, National Institute on Aging (NIH). Multi-site collaboration across 27 U.S. clinical centers.
  • Country: United States.
  • Journal: JAMA (Journal of the American Medical Association), American Medical Association.

Impact Evaluation

The impact score of this journal is 55.0 (2024 Journal Impact Factor; 5-year JIF 64.7), evaluated against a typical high-end range of 0–90+ for top general science and medical journals (for reference, The Lancet ~88, NEJM ~78), therefore this is an Elite impact journal.

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#5

There is evidence that metformin can help prevent the progression of breast ad colorectal cancers because it deprives cancer cells of glucose. I started taking it for that reason and stayed on it for glucose control.

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