Despite high expectations for the commonly used diabetes drug metformin to improve risk factors for heart disease in people without diabetes, few beneficial effects have been found in a randomized trial of patients with established cardiovascular disease.
There has been a lot of anticipation based on research in diabetic patients suggesting that metformin has cardiovascular benefits beyond its effects on blood glucose, David Preiss, PhD, of the University of Glasgow in the United Kingdom, said in a news release. We were hoping to find that it might also prevent hardening of the arteries in people without diabetes already on a statin.
Metformin is recommended as the first-line treatment for people with type 2 diabetes, according to background information for the study, which was published Nov. 7 on the website of The Lancet Diabetes & Endocrinology. It reduces the overactive glucose production associated with diabetes, and was shown to reduce other related risk factors for heart disease such as cholesterol levels and inflammatory and blood clotting markers in earlier studies conducted before the widespread use of statins.
The landmark UKPDS trial found that metformin treatment led to a 39% reduction in risk of myocardial infarction over 10 years in diabetic patients, but whether its potential cardiovascular benefits could be replicated in individuals without diabetes had not been tested.
The Carotid Atherosclerosis: MEtformin for insulin ResistAnce trial, or CAMERA, was designed to investigate the effect of metformin on changes in carotid intima-media thickness, or cIMT, in non-diabetic individuals with heart disease who were taking statins. A total of 173 patients were randomly assigned to metformin (850 milligrams twice daily) or matching placebo for 18 months.
After 18 months, no improvement in cIMT or the extent of atherosclerotic plaque in the carotid arteries was noted in patients taking metformin. The average cIMT increased significantly in both groups (0.024mm per year for metformin, 0.017mm for placebo).
However, metformin significantly reduced all measures of adiposity body weight, body fat, body mass index and waist circumference compared with placebo. The reduction was similar to what often is achieved on weight-loss drugs, according to the researchers, and improvements in insulin levels and hemoglobin A1c also were apparent.
Overall, 251 adverse events were reported, including 136 in 63 patients taking metformin and 115 in 58 patients given placebo. Gastrointestinal events were more common in patients taking metformin.
Major cardiovascular outcome trials are needed to conclusively assess metformins cardiovascular effects in people without type 2 diabetes; such trials are underway at present, Preiss said. We cannot dismiss the potential cardiovascular benefit of metformin in patients without diabetes, but CAMERA suggests that metformin has limited impact on important cardiovascular risk factors when patients aleready are on a statin.
In a linked commentary, Chris Lexis and Iwan van der Horst, clinicians with University Medical Center Gronigen in the Netherlands, cautioned: The CAMERA study shows that the effect of metformin in addition to current best treatment, including statins on cIMT is probably small or negligible [but] whether the primary endpoint of CAMERA or secondary endpoints such as HbA1c best represent cardiovascular outcome is unclear.
The definitive evidence for the role of metformin in non-diabetic cardiovascular disease will have to be provided by large randomized clinical trials powered for cardiovascular outcomes such as the Glucose Lowering in Non-diabetic hyperglycemia Trial, in which 12,000 patients with high cardiovascular risk and dysglycemia, but without diabetes, will be assigned to metformin or placebo for five years. Until then, the role of metformin for improving cardiovascular outcomes has promise, but is still largely unproven.
Study abstract: http://bit.ly/1aI1Jl9