Lifestyle Change in Prediabetes Cuts Risk of Multimorbidity

Adults with prediabetes randomized to a lifestyle intervention had a significantly lower risk of developing multiple chronic conditions over time compared with a placebo group, a benefit not seen among those assigned to metformin, long-term data from the Diabetes Prevention Program (DPP) trial showed.

At 21 years, the risk of multimorbidity — the presence of two or more chronic conditions — was 21% lower among those who received lifestyle interventions compared with those who received placebo (HR 0.79, 95% CI 0.68-0.93).

However, there was no difference in multimorbidity risk between participants who received metformin versus those randomized to placebo (HR 0.91, 95% CI 0.78-1.07), reported Marcel Salive, MD, of the National Institute on Aging in Bethesda, Maryland, and colleagues in JAMA.

“These findings are highly encouraging, reinforcing that lifestyle programs focused on diet and exercise may persistently lower the risk of developing multiple chronic conditions, beyond diabetes,” Griffin Rodgers, MD, director of the National Institute of Diabetes and Digestive and Kidney Diseases, said in a statement.

“Furthermore, because lifestyle modifications can be safe and cost-effective, sustaining these healthy behaviors among people at risk of diabetes may help reduce not only the individual health burden, but also broader healthcare spending,” Rodgers continued.

By the end of follow-up, 82% of the lifestyle group, 85% of the metformin group, and 87% of the placebo group developed at least two chronic conditions from a list that included hypertension, heart failure, coronary artery or ischemic heart disease, cardiac arrhythmias, hyperlipidemia, stroke, arthritis, asthma, cancer, chronic kidney disease, chronic obstructive pulmonary disease, dementia or Alzheimer’s disease, depression, diabetes, and osteoporosis.

The apparent benefits of lifestyle interventions make sense since they can improve inflammation, metabolic regulation, and cellular aging, noted Hermes Florez, MD, PhD, MPH, MA, of the Medical University of South Carolina in Charleston, and co-authors in an accompanying editorial.

The latest American Diabetes Association guidelines still recommend pharmacotherapy for weight management and cardiovascular risk reduction, supporting person-centered goals through more intensive preventive strategies, Florez and colleagues noted.

Although data on diabetes risk reduction with GLP-1 receptor agonists like semaglutide (Ozempic, Wegovy) and dual agonists like tirzepatide (Mounjaro, Zepbound) remain limited, attention is shifting to the long-term health effects of these drugs, the editorialists noted. “Their potential to reduce multimorbidity burden in individuals with or at risk for diabetes remains an area of active research,” they wrote.

Original findings of the landmark DPP trial showed that lifestyle interventions reduced diabetes incidence by 58% and metformin reduced it by 31% in the first 3 years compared with placebo. This risk reduction fell to 24% and 17%, respectively, after 21 years.

“Given the success of metformin and lifestyle interventions at preventing or delaying diabetes and metabolic syndrome in both the short and long term, we sought to determine whether these interventions could prevent or delay multimorbidity in addition to diabetes alone,” Salive and team noted.

“Although DPP interventions have not shown significant long-term associations with microvascular or cardiovascular disease, cancer, or mortality, the odds of frailty were found to be 37% lower for lifestyle compared with metformin and placebo 12 to 14 years after randomization,” they added.

From June 1996 to May 1999, 3,234 adults at high risk for diabetes were enrolled in the DPP trial at 27 U.S. sites; after 3 years, some entered the DPP Outcomes Study. CMS morbidity data were available for 1,173 participants through 2021. At study entry, median age was 51 years, BMI was 32.1, and 68% were female.

Participants randomized to lifestyle interventions were offered 16 individual sessions followed by monthly sessions for approximately 2 years, with a goal of at least a 7% weight loss. Participants on metformin received 850 mg twice daily.

At 21 years, the lifestyle group had a lower risk of having high-cost multimorbidity dyad conditions compared with the placebo group (HR 0.57, 95% CI 0.38-0.85), Salive and co-authors noted.

Participants who progressed to diabetes had a 33% higher risk of multimorbidity, independent of treatment group, reinforcing how chronic conditions tend to cluster around the disease, the researchers said.

DPP participants may not reflect the general prediabetes population, they acknowledged, as this cohort had less baseline hypertension but a higher BMI compared with national data. Adherence to metformin waned throughout the study.

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