Contrary to high expectations, an 18-month trial involving 173 subjects without diabetes has shown that metformin treatment did not reduce the risk factors for cardiovascular disease. This is the first ever large trial undertaken to study the effect of the drug in reducing the cardiovascular risk factors in people without diabetes. The study has been published today (November 7) in The Lancet.
“Metformin had no effect on cIMT [the thickness of the innermost and middle layer of the carotid artery that supplies blood to the brain and which is a measure of hardening of the artery] and little or no effect on several surrogate markers of cardiovascular disease in non-diabetic patients with high cardiovascular risk, taking statins,” David Preiss from the BHF Glasgow Cardiovascular Research Centre and the lead author of the study and others write.
The authors clearly state that more trials are required to asses the cardiovascular benefits of the drug in non-diabetic people who are at high risk of a cardiovascular event.
The results of the first-ever trial CAMERA (Carotid Atherosclerosis MEtformin for insulin ReistAnce) comes as a surprise as the initial 10-year follow-up of UKPDS and the long-term follow-up over 25 years of type-2 diabetic patients who are on metformin treatment had conclusively shown that the drug reduced cardiovascular events. Several meta-analyses had also shown that the drug had a cardiovascular risk-reducing effect.
They state that metformin — a drug already used for patients without type 2 diabetes — did not reduce the plague in the carotid artery and also did not reduce cIMT, which is a measure of hardening of the artery. These two serve as risk markers of a cardiovascular event.
However, the drug given to the subjects who were not diabetic resulted in a “significant reduction in weight together with improvements in other risk factors for development of type 2 diabetes.”
However, metformin significantly reduced all measures of adiposity (body weight by over three kg, body fat, body mass index, and waist circumference) compared with a placebo, along with improvements in other risk factors for the development of type 2 diabetes.
But a related Comment piece notes that proof-of-principal trials such as CAMERA are usually designed to study the markers to assess the outcomes.
Ideally, a strong relationship exists between markers and outcomes.
But in the case of metformin and cardiovascular events the beneficial effects of the drug go beyond the markers studied. “Little evidence exists of a direct association between improvement of cIMT and outcome. Moreover, the experimental evidence for a direct effect of metformin on cIMT is weak,” note Chris P.H. Lexis and Iwan C.C. van der Horst in the Comment piece. Both are from the Department of Cardiology, University of Groningen, The Netherlands.
On the other hand, there is plenty of evidence to prove the beneficial effects of the drug. For instance, several studies have shown that the drug is positively associated with reduced size of a heart attack (myocardial infract).
And if it can produce improved survival of diabetic patients who had had coronary heart disease or even heart failure, it is unclear how the drug failed to produce the same beneficial effects in the trial subjects who did not have diabetes. It therefore remains unclear whether the primary and secondary endpoints measured by the CAMERA trial best represents cardiovascular outcome, the two Netherlands researchers wonder.
The CAMERA was a double-blind, placebo-controlled trial undertaken at the Glasgow Clinical Research Facility.
Of the 173 subjects, 86 were assigned to the metformin arm and the remaining 87 were given a placebo. The trial was carried out over a period of 18 months.