SAN DIEGO – Findings from the landmark 3-year REMOVAL trial find that metformin could hold potential as a tool to reduce cardiovascular disease (CVD) risk in patients with type 1 diabetes. But – in a challenge to current British and American guidelines – findings from the study suggest that the drug doesn’t meaningfully improve glycemic control.
“The CVD benefit is suggestive, but it’s by no means conclusive,” Naveed Sattar, MD, PhD, of the University of Glasgow said in a presentation at the scientific meetings of the American Diabetic Association. As for glycemic control, “you should not prescribe metformin if you want a clinical change in hemoglobin A1c,” he said.
The findings don’t examine CVD outcomes, and researchers bemoaned their inability to launch such a project because of limitations in funding. Still, the study, funded by the Juvenile Diabetes Research Foundation, is the largest to examine metformin in type 1 diabetes.
The Food and Drug Administration has not approved metformin for type 1 diabetes. However, the American Diabetes Association’s 2017 Standard of Care guidelines note that “adding metformin to insulin therapy may reduce insulin requirements and improve metabolic control in overweight/obese patients with poorly controlled type 1 diabetes” (Diabetes Care. 2017 Jan;40[Suppl 1]).
“Metformin has known efficacy for reducing HbA1c, and, at the time we did this, it was one of few diabetes drugs with indications of an effect on cardiovascular disease risk,” study coauthor Helen M. Colhoun, MD, of the University of Edinburgh said during the discussion following the presentation.
The REMOVAL (cardiovascular and metabolic effects of metformin in patients with type 1 diabetes) trial took place from 2011 to 2014. Involved researchers at 23 hospital diabetes clinics around the world randomly assigned 428 patients to metformin (n = 219) and placebo (n = 209) arms.
The patients were all 40 years or older, with a mean age of 55 years. All patients had been diagnosed with type 1 diabetes at least five years prior to the study and met at least 3 of 10 criteria for high risk of cardiovascular disease. Men accounted for 59% of the patients, about 98% were white, and about 79% were obese or overweight. Patients had high levels of use of statins (73%), blood pressure medications (73%), and antiplatelet drugs (39%).
Participants took oral metformin 1,000 mg twice daily or placebo. The results were reported at the ADA meeting and simultaneously online on June 11, 2017 in Lancet Diabetes Endocrinology (2017 Jun 11. doi: 10.1016/S2213-8587[17]30194-8).
In regard to CVD indicators, the researchers did not find significant reduction in the progression of average common carotid artery intima-media thickness (cIMT) (–0.005 mm per year; 95% confidence interval, –0.012-0.002; P = .1664) in metformin, vs. placebo.
There was, however, a significant reduction in maximal cIMT (–0.013 mm per year; 95% CI, –0.024 to –0.003; P = .0093). The study describes this as a surrogate measure for atherosclerosis progression, although it’s a tertiary rather than primary outcome.
Researchers saw a slight decline in HbA1c in the metformin group (–0.13%; 95% CI, –0.22 to –0.037; P = .0060), but researchers say this occurred early and was not sustained.
In the metformin group, compared with placebo, researchers also found reductions in body weight (–1.17 kg; 95% CI,–1.66 to –0.69; p less than .0001) and LDL cholesterol (–0.13 mmol/L; 95% CI, –0.24 to –0.03; P = .0117) on average.
Researchers didn’t find a significant average reduction in insulin use in the metformin group, compared with placebo (–0.005 units per kg; 95% CI, –0.022-0.012, P = .545), although they did notice “a small but sustained reduction in patients allocated to metformin (estimated in post-hoc analyses as –0.023 units per kg; 95% CI, –0.045 to –0.0005; P = .045).”
Rates of gastrointestinal problems were higher in the metformin group, and 27% of these patients discontinued treatment, compared with 12% of placebo patients (P = .0002). Five of the metformin patients died (as did two of the placebo patients), but researchers didn’t link the deaths to medication.
The findings were clearly disappointing. “We’re certainly not claiming that this is a positive trial,” said study coauthor Dr. Colhoun.
A member of the audience at the AAD meeting asked another coauthor, Irene Hramiak, MD, of the University of Western Ontario, London, whether she would prescribe metformin to a patient with type 1 diabetes and a high risk of CVD. “Probably not,” she said, but she added that it may have value in adolescents with weight issues. In those cases, she said, there may be a benefit to improving weight control and lowering insulin doses.
In light of the study findings, the authors recommend revising guidelines that suggest the use of metformin in type 1 diabetes: “We identified a transient improvement in glycemia that reverted to baseline with insulin dose reduction and identified no suggestion of greater benefit in overweight or obese patients.”
The study adds, “Rather than a role in glycemic control, our findings suggest that long-term use of metformin in type 1 diabetes might reduce the long-term risk of cardiovascular disease via small but sustained reductions in bodyweight and LDL cholesterol.”
The Juvenile Diabetes Research Foundation funded the study. Merck Germany KGaA provided medication and shipping for free. Itamar Medical donated equipment and services. Dr. Sataar reported consulting fees and/or research support from Amgen, Boehringer Ingelheim, Eli Lilly, Janssen, and Novo Nordisk. Dr. Colhoun and Dr. Hramiak reported multiple disclosures, including advisory panel, research support, and speaker’s bureau and stock/shareholder relationships.
This article was updated June 19, 2017.