Off-Label Metformin for Prediabetes With High BMI Improves Cardiovascular Outcomes

Researchers analyzed data taken from EHR insurance claims of 149,654 patients aged 25 years and older between January 2016 and September 2020.

Patients with a body mass index (BMI) of 35 or greater with prediabetes, including Black patients aged over 65 years, showed a lower incidence of cardiovascular disease (CVD) with metformin use vs patients whose BMIs were less than 35, according to study findings presented at the American Heart Association (AHA) Scientific Sessions, held virtually from November 13 to 15, 2021.

Although metformin is not approved by the US Food and Drug Administration (FDA) to treat prediabetes, it is frequently used as an off-label prescription for patients with this condition, according to researchers. The American Diabetes Association (ADA) recommends considering metformin for patients with prediabetes whose BMIs are greater than 35. Because prediabetes is associated with an increased risk of CVD, investigators designed their study to report on the association between real-world, off-label use of metformin for prediabetes and a lowered incidence of CVD by age, race, and BMI.

Researchers analyzed data analyzed taken from electronic health record insurance claims of patients aged 25 years and older between January 2016 and September 2020. In the metformin cohort, patients had more than a 180-day supply — more than 90 days prior to the diagnosis of prediabetes and more than 90 days after diagnosis of prediabetes, and all had continuous enrollment for more than 24 months. Patients were excluded if they had type 1 diabetes mellitus, FDA-approved indications for metformin, CVD, chronic kidney disease, or gestational diabetes. To be included, patients had to have a diagnosis of prediabetes (ICD-10 code R73); and a hemoglobin A1c (HbA1c) level of 5.7% to 6.4%, or a fasting glucose level of 100-125 mg/dL, or oral glucose tolerance test (OGTT) results of 140-199 mg/dL.

Of the 149,654 patients with prediabetes included for analysis, 5.8% (n=8624; average age, 65.9 years; 57.3% female; average BMI 33.1; all P <.001) were prescribed metformin. At a mean follow-up of 2.8 years, 24% of these patients had developed CVD.

In the metformin cohort overall (n=8624), participants with BMIs of 35 or greater had a lower prevalence of CVD: 21.2% compared with 28% among those with BMIs less than 35 (P <.001).

Results by sex showed similar associations between metformin use, BMI, and CVD. Among female participants (n=4945), 25.2% with a BMI less than 35 had new CVD; among those with a BMI of 35 or greater, 18.5% had new CVD (P <.001). Among male participants (n=3679), new CVD was noted 31.5% with a BMI less than 35 and in 26% with a BMI of 35 or greater (P <.001). A similar effect was seen when the analysis was limited to results in Black patients over 65 years of age (n=762): new CVD was noted in 34% with a BMI less than 35 vs 23.1% of those with a BMI of 35 or greater (P <.018).

The investigators concluded, “Patients with BMI [of] 35 [or greater] showed an association between metformin use and lower incidence of CVD, including African Americans older than age 65. The data suggest that morbidly obese patients with prediabetes may benefit from the use of metformin as recommended by the ADA.”

Disclosure: Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.


Murillo JE, McNeil C, Van Nest K, et al. Real world data: Off-label metformin in patients with prediabetes is associated with improved cardiovascular outcomes. Presented at: AHA Scientific Sessions 2021; November 13-15, 2021. Poster P339.