Cardio-Protective Benefit of Metformin Falls Short for People with Diabetes

While metformin didn't reduce the risk of atherosclerosis in people with type 1 diabetes as anticipated, secondary outcomes offered more promise, according to findings from the REMOVAL trial.

With John R. Petrie, MD, and Tamara Wexler, MD, PhD

A favorable cardiovascular effect from metformin in patients with type 1 diabetes (T1D) may be less than has been commonly believed,1 according to study findings in The Lancet. In fact, no improvement in either insulin requirements or reduced risk of atherosclerosis, a marker of cardiovascular disease (CVD), were found.

Although the study failed to meet its primary outcome—reduction in atherosclerosis—results of the secondary outcomes were more positive,1 according to John R. Petrie, MD, professor of diabetic medicine at the Institute of Cardiovascular and Medical Sciences at the University of Glasgow, Scotland.

Metformin doesn't provide cardiovascular benefits for people with diabetes.

Findings of the REMOVAL Trial

The findings from the Cardiovascular and Metabolic Effects of Metformin in Patients with Type 1 Diabetes (REMOVAL),1 a double-blind, randomized, placebo-controlled trial, were gathered from an international consortium of 23 medical centers in Canada, Europe, and Australia, following 493 overweight or obese men and women with T1D.

The REMOVAL investigators sought to determine if adding metformin to titrated insulin therapy would reduce atherosclerosis in people with T1D who were deemed at high risk for CVD.1 The primary outcome of the trial, atherosclerosis, was assessed by averaged mean cIMT. Secondary outcomes included hemoglobin A1c levels, LDL, estimated glomerular filtration rate, and body weight.

Patients, aged 40 years and older, were randomly assigned to receive 1 mg of metformin twice daily or placebo, along with titrated insulin therapy, for three years. 

Although metformin was generally safe, more patients who took the drug dropped out of the trial than did those who received placebo (= 0.0002).1  Most of the patients in the treatment arm who left the study reported gastrointestinal complaints. Metformin also was associated with an increased risk of vitamin B12 deficiency (= 0.0094), according to Dr. Petrie.

Metformin May Still Lessen CVD

 “These data may not support the use of metformin to improve glycemic control in adults with long-standing T1D, as suggested by current diabetes management guidelines2 but the results indicate that it might have a wider role in cardiovascular risk management,” according to the researchers.

Metformin did not appear to offer improvements in median far-wall carotid intima-media thickness (cIMT) or to produce sustained reductions in insulin requirements over the three-year study period.However, patients who took metformin did experience reductions in body weight and LDL cholesterol, while their glomerular filtration rates increased, said the authors, and metformin appeared to reduce progression of maximal cIMT, a proxy measure for arteriosclerosis.

The improvements in low-density lipoprotein ( LDL) and maximal far-wall cIMT surprised the study team,” said Dr. Petrie. The use of metformin to control blood glucose is part of treatment guidelines for both T1D and type 2 diabetes (T2D).2 In particular, this medication is prescribed to patients with T1D who are overweight or obese in an effort to lessen the amount of insulin required.

To date, evidence supporting the use of metformin to improve CVD risk in patients with T1D remains relatively weak, based on clinical experience with the drug in T2D and a pair of published studies, one of which involved teens3 and the other a meta-analysis of nine small trials.4  

“However, [the researchers] are not ready to abandon hope that metformin might offer people with diabetes some protection against CVD,” Dr. Petrie said.                              

What's Ahead for Metformin

“REMOVAL was not a cardiovascular outcome trial but it was the first-ever cardiovascular study in T1D, and one of the largest and longest trials following patients with T1D. We think the data justify a larger trial,” Dr. Petrie told EndocrineWeb.

“Guidelines may change to de-emphasize the effect of metformin on glucose-lowering in T1D,” he said, but “the data from REMOVAL were not sufficiently conclusive to lead to a definite cardiovascular guideline recommendation.”

A large [cardiovascular trial] of metformin in T1D is unlikely to occur within the next few years, he said, “In the meantime, individual doctors may decide to prescribe it for specific patients,” said Dr. Petrie.

A Practitioner’s Point-of-View

Tamara Wexler, MD, PhD, a neuroendocrinologist at New York University Langone Medical Center, in New York City, called the study “very carefully done.”

“The methodology of this study suggests that the results are sound,” said Dr. Wexler, “However, subanalyses of the trial data might provide indication that a larger trial of a subpopulation—such as those who can tolerate a maximum dose [of metformin] only, or those within a certain BMI range—might yield a more dramatic effect.”

“Given that 1/3 of patients in the study were taking a reduced dose of metformin, this raises the possibility that higher doses of the drug might have led to more encouraging findings,” Dr. Wexler told EndocrineWeb.

 “That said, the cost and safety profile of metformin are attractive, and even modest effects over time—on top of other maximal CVD therapy—might lead to a difference in actual cardiovascular outcomes for patients with diabetes,” she said.

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