Metformin to Decrease Mortality in Patients With Prediabetes

In patients with prediabetes, does metformin decrease the mortality rate compared with placebo?

A large, multicenter, randomized controlled trial (RCT) with extended follow-up showed that metformin does not decrease the mortality rate in patients with prediabetes. (Strength of Recommendation [SOR]: A, review of prospective cohort studies, RCTs, systematic reviews, and meta-analyses.) In patients with prediabetes, metformin reduces progression to diabetes. (SOR: B, systematic review with disease-oriented outcomes.) Metformin does not reduce the rate of cardiovascular deaths compared with placebo. (SOR: B, single RCT.)

In a 2023 systematic review of 110 studies that included prospective cohort studies, RCTs, systematic reviews, and meta-analyses, lifestyle modification and medication use were compared with placebo in adults with prediabetes.¹ Of the studies, three RCTs specifically focused on metformin (n = 3,972). Measured outcomes included incidence of progression to diabetes, cardiovascular events, and mortality after the studied interventions. Lifestyle modification consisted of caloric restriction, increased physical activity (150 min/week or more), self-monitoring, and motivational support. Trials included at least 2 years of follow-up.

The patients had a fasting glucose level between 100 and 125 mg/dL, (5.55 and 6.94 mmol/L) a glucose level of 140 to 190 mg/dL (7.77 and 10.54 mmol/L) 2 hours after a 75-g glucose load, or an A1C in the prediabetes range of 5.7% to 6.4% per the American Diabetes Association or 6.0% to 6.4% per the International Expert Committee. Patients enrolled in the US Diabetes Prevention Program (DPP) were included in several studies in which the mean age was 51 years and mean body mass index was 34 kg/m².

Studies were reviewed to compare the effects of lifestyle modification or diabetes medications with those of placebo. In the DPP, after an average of 2.8 years, outcomes such as progression to diabetes, cardiovascular events, and mortality were evaluated. Lifestyle modification (n = 1,079) was shown to reduce mortality from 0.16% to 0.10% per 100 person-years in the placebo group (n = 1,082). The effect of metformin on mortality was not assessed. However, metformin (n = 1,073) reduced progression to diabetes by 20% (relative risk reduction = 0.31) compared with a reduction of 40% with lifestyle modification (relative risk reduction = 0.58). The main limitations were that not all studies were formally evaluated for quality, and many had relatively short durations.

The DPP/DPP Outcomes Study (DPPOS) RCT compared the effect of metformin, lifestyle changes, or placebo in 3,234 patients with prediabetes.² Patients had a mean age of 51 years, mean body mass index of 34 kg/m², and a fasting blood glucose level between 95 and 125 mg/dL. Patients self-identified their sex, race, and ethnicity, with 68% identifying as female and 55% as non-Hispanic White. Forty-one percent were former or current smokers, 29% had hypertension or were treated for hypertension, and 69% had hyperlipidemia or were on lipid-lowering medications. Patients with significant health issues (eg, cardiovascular or kidney disease, cancer requiring treatment in the past 5 years, hepatitis, other medical conditions) were excluded.

Participants were randomized into two intervention groups and one placebo group. One intervention group received metformin, 850 mg twice daily, with standard diet and exercise recommendations. The second intervention group received an intensive lifestyle intervention focused on at least 150 min/week of physical activity and a 7% or greater body weight loss. The placebo group was given a placebo twice daily with standard diet and exercise recommendations. The median follow-up period was 21 years.