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Certain interventions didn't help to keep cardiovascular (CV) events at bay among those with prediabetes, even when long-term diabetes prevention strategies were in place, according to the Diabetes Prevention Program (DPP) Outcomes Study.

During an 18-year follow-up to the landmark trial, treatment with metformin was no better than placebo at reducing the risk of major CV events (MACE; HR 1.03, 95% CI 0.78-1.37, P=0.81), reported Ronald B. Goldberg, MD, of the University of Miami's Miller School of Medicine, and colleagues.

In addition, engaging in lifestyle intervention was no boon for cutting the risk of MACE versus placebo (HR 1.14, 95% CI 0.87-1.50, P=0.34), they wrote in .

Even after adjusting for participants' heart risk factors, both prevention strategies fell short for preventing nonfatal myocardial infarction (MI), stroke, or CV death.

"The fact that neither a lifestyle intervention program nor metformin led to a decrease in cardiovascular disease among people with prediabetes may mean that these interventions have limited or no effectiveness in preventing cardiovascular disease, even though they are highly effective in preventing or delaying the development of type 2 diabetes," said Goldberg in a statement. "It's important to note that most study participants also received treatment with cholesterol and blood pressure medications, which are known to reduce [cardiovascular disease] risk."

"Therefore, the low rate of development of cardiovascular disease found overall may have been due to these medications, which would make it difficult to identify a beneficial effect of lifestyle or metformin intervention," he added.

The original DPP randomized clinical trial kicked off in 1996 and ran for about 3 years. It included 3,234 individuals with prediabetes, defined as impaired glucose tolerance with a fasting plasma glucose 95 to 125 mg/dL (5.27 to 6.94 mmol/L) and BMI 24 or higher. Those who experienced a CV event within the prior 6 months were excluded.

Participants were then randomized to receive 850 mg of metformin twice-daily, placebo twice daily, or lifestyle intervention. The latter program was aimed as a goal of 7% or greater initial body weight reduction with a minimum of 150 minutes per week of moderate intensity physical activity.

After DPP wrapped, all surviving patients were invited to participate in the follow-up DPP Outcomes Study, regardless of their diabetes status. At this point, 68% of the DPP Outcomes Study participants were women with an average age of 51; more than half were white. These participants were followed for an additional 18 years, amounting to a combined median follow-up of 21 years. During this study, unmasked metformin was continued in the metformin group and all participants were offered a less intensive group lifestyle intervention.

Over the course of the 21-year follow-up, 310 of the 3,234 participants experienced a MACE. There tended to be fewer nonfatal strokes in the metformin than in the placebo group, though this wasn't statistically significant. On the other hand, the opposite trend was seen for the lifestyle intervention group, where there tended to be a slightly higher rate of nonfatal strokes, but this also was not statistically significant.

There appeared to be a trend for a higher risk of CV death in both the metformin and lifestyle groups versus placebo, but this finding didn't reach statistical significance.

Neither prevention strategy significantly reduced the risk for an extended CV events outcome composite, that included the primary outcome or hospitalization for heart failure or unstable angina, coronary or peripheral revascularization, coronary heart disease diagnosed by angiography, or silent MI by ECG.

Of note, adherence among metformin users fell throughout the study, down to only 41% at the last check-in.

"Future research to identify higher risk subgroups is needed to develop a more targeted approach to cardiovascular disease prevention in people with prediabetes and type 2 diabetes," Goldberg stated.

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