Key takeaways:

 Metformin, FDA-approved to treat type 2 diabetes, may have CV benefits.

 The ongoing VA-IMPACT trial will assess metformin for people with prediabetes and

ASCVD.

ARLINGTON, Texas — Experimental and clinical evidence suggest the diabetes

drug metformin may offer CV benefits that do not depend on the presence of diabetes, and an

ongoing trial will help researchers learn more, according to a speaker.

A traditional view of separate therapies for diabetes and CVD was challenged after large

randomized controlled trials demonstrated CV benefits for two classes of drugs, SGLT2

inhibitors and GLP-1 receptor agonists, which are “arguably both diabetes and cardiovascular

drugs,” Gregory G. Schwartz, MD, PhD, professor of medicine at the University of Colorado

School of Medicine and chief of the cardiology section at Rocky Mountain Regional VA

Medical Center in Aurora, Colorado, said during a presentation at the American Society for

Preventive Cardiology Congress on CVD Prevention.

Metformin, FDA-approved to treat type 2 diabetes, may have CV benefits.
Image: Adobe Stock

“The question I am going to put before us is whether metformin belongs in the

same category,” Schwartz said during a presentation.

To answer that question, researchers designed a new study, VA-IMPACT, to

assess whether metformin is associated with reduced major adverse CV events for
people with prediabetes and atherosclerotic CVD. The ongoing trial is the first
placebo-controlled CV outcomes trial assessing metformin, which is now an
inexpensive generic drug, Schwartz said.
“Metformin has been supplanted at the top of treatment guidelines for patients with
type 2 diabetes and established CVD by GLP-1 receptor agonists and SGLT2
inhibitors because of the high-quality evidence that has emerged for
these categories,” Schwartz said. “Hopefully, this trial provide the
same kind of high-quality evidence, whether positive or negative, for
metformin.”

Evidence of possible heart benefits

Schwartz said it may seem contradictory that metformin, a metabolic inhibitor,
could afford CV protection; however, experimental evidence suggest metformin
activates adenosine monophosphate-activated protein kinase, which promotes cell
protection, energy conservation and survival, without degrading adenosine
triphosphate (ATP) levels. Data from animal models without diabetes also show
metformin maintains myocardial ATP levels under stress, prevents ischemic
arrhythmias, reduces infarct size and is antiatherogenic.

Clinical evidence from some human studies suggest CV and other benefits. In the
unmasked United Kingdom Prospective Diabetes Study (UKPDS) study, which
formed the basis for metformin’s prevalent use, researchers compared metformin
(n = 342) with usual care (n = 411) in people with new-onset type 2 diabetes and
observed a reduction in CV events, diabetes-related complications and all-cause
mortality in the metformin arm.

Observational data from the Reduction of Atherothrombosis for Continued Health

(REACH) French registry also suggest that metformin may reduce all-cause
mortality for people with diabetes and atherosclerosis compared with nonusers.
Data from the landmark Diabetes Prevention Program study demonstrated
metformin reduced progression from prediabetes to type 2 diabetes compared with
placebo; however, even long-term follow-up data did not show a reduction in CV
events.

“There was a lot of crossover within the groups between metformin and physical
activity and lifestyle, so it is hard to draw an inference,” Schwartz said. “Does
metformin reduce death and CV morbidity? I would say based on the data I shared,
we have equipoise on this question, despite 65 years of use of this drug. When we
have equipoise, we need a randomized, placebo-controlled clinical trial to tell us:
Is this drug worth using in our patients or not?”

New study designed for answers

Researchers designed VA-IMPACT to assess whether metformin reduces death
and major adverse CV events in 7,410 people with prediabetes, established
ASCVD and normal kidney function. Researchers will randomly assign
participants metformin extended release, titrated to a target dose of 2,000 mg per
day or matching placebo. The primary outcome is a five-part composite of major
adverse CV events, including all-cause death, nonfatal MI, stroke, unstable angina
and symptom-driven revascularization. The study began in April and expected
median follow-up is approximately 4 years, Schwartz said.

“The rationale for this group is that people with prediabetes and ASCVD have a
high risk and, unlike placebo-controlled trials in patients with established diabetes,
there is less need to use an alternative agent in the control group when you study
people with prediabetes,” Schwartz said. “The confounding that is potentially
present in most diabetes trials by the differential use of non-test agents is
diminished when a prediabetes population is studied.”

A second study is also assessing metformin’s use as a potential CV drug. In a

registry-based study in Sweden, MIMET, which began in 2022, researchers are
assessing data from 5,150 patients with prediabetes and acute MI who were
randomly assigned to metformin or usual care in an unmasked fashion. The
primary outcome is CV death, MI, HF and stroke; median follow-up is 2 years.

“Hopefully we will have two new sets of data to answer the question at hand,”
Schwartz said. “Is metformin a CV drug? Stay tuned and hopefully we will have
the answer in a few years.”

References:

 Investigation of Metformin in Prediabetes on Atherosclerotic Cardiovascular Outcomes

(VA-IMPACT). Available at: https://classic.clinicaltrials.gov/ct2/show/NCT02915198.
Updated July 6, 2023. Accessed July 24, 2023.

 Knowler WC, et al. N Engl J Med. 2002;doi:10.1056/NEJMoa012512.

 Metformin and Prevention of Cardiovascular Events in Patients with Acute Myocardial

Infarction and Prediabetes (MIMET). Available
at: https://classic.clinicaltrials.gov/ct2/show/NCT05182970. Posted Jan. 10, 2022.
Accessed July 24, 2023.

 Roussel R, et al. Arch Intern Med. 2010;doi:10.1001/archinternmed.2010.409.

 UKPDS Group. Lancet. 1998;doi:10.1016/S0140-6736(98)07019-6.