DALLAS, TX — The prevalence and severity of coronary artery calcium (CAC) after 14 years of metformin therapy were significantly lower in men, but not women, who started on the drug for prediabetes, in a longitudinal cohort study[1].
The finding based on >2000 persons with serial CAC measurements in the Diabetes Prevention Program (DPP) and its DPP Outcomes Study (DPPOS), if backed up in appropriate clinical trials, suggests metformin might well be able to join other drugs given primarily for diabetes that also reduce the risk of cardiovascular disease.
“I think we have to be very careful about saying that represents a clinically relevant impact of metformin. But it could,” Dr Ronald B Goldberg (George Washington University Biostatistics Center, Rockville, MD) told heartwire from Medscape.
The metformin effect “occurred despite large numbers of individuals being on antihypertensive therapy and statin therapy,” Goldberg said. “There is a background of information indicating that metformin might protect against heart disease in people with diabetes,” but this is the first time an effect has been seen in nondiabetic individuals.
Metformin “seemed to be affecting the smallest lesions, and that might imply that the effect was on early atherosclerosis,” he said.
“If there is a preventive effect, it may mean that this would require long-term metformin usage, and that it’s not something that could necessarily have clinical impact after a few years, for example.”
Recently, other diabetes drugs have been associated with reductions in cardiovascular disease events, including the glucagonlike peptide 1 (GLP-1) receptor agonists liraglutide (Victoza, Novo Nordisk) and semaglutide (Novo Nordisk), and sodium glucose cotransporter-2 (SGLT-2) inhibitors including empagliflozin (Jardiance, Boehringer Ingelheim/Lilly).
While the direct effects on cardiovascular disease and atherosclerosis of each of these drugs “might be relatively small,” according to Goldberg, the current results for metformin fit “into that general category of potential beneficial effects.”
He said: “It raises the possibility that using multiple agents, as so often is required in diabetes management, may have additive effects that could amount to something quite significant.”
The new analysis was published May 5, 2017 in Circulation.
Published about 15 years ago, the DPP tracked 3234 individuals with prediabetes and saw reductions in incidence of new diabetes of 31% for those treated with metformin only and of 58% for those treated with lifestyle intervention.
Subsequently, 2776 participants in DPP followed for subclinical atherosclerosis took part in DDPOS by continuing with maintenance group lifestyle-intervention sessions, with those originally randomized to metformin continuing with the drug if they remained eligible.
Clinical and metabolic variables were assessed at baseline and annually, and coronary calcium scans were obtained at year 10 of the DDPOS in 2029 participants, representing 74% of the cohort.
The scans were performed at a mean of 13.7 years after randomization, when the average ages of the participants were 67 years for men and 63 years for women.
The mean duration of treatment was 9.6 years in the metformin group and 1.7 years and 1.3 years in the placebo and lifestyle groups, respectively. Diabetes developed in 54%, 59%, and 51% of the patients, respectively.
The researchers found that were no differences between the lifestyle and placebo groups in terms of the severity and presence of CAC in either sex.
However, in men, CAC severity was significantly lower in those given metformin vs the placebo group, at an age-adjusted 39.5 Agatston units (AU) vs 66.9 AU (p=0.04). The effect was greatest in the 25-to-44-year age group, at 3.0 AU vs 17.6 AU (p<0.05).
Furthermore, CAC was significantly less prevalent in males given metformin, at 75% vs 84% in the placebo group (P=0.02) and 84% in the lifestyle group (P<0.05).
On multivariate analysis, the metformin effect was unaffected by demographic, anthropometric, and metabolic factors, by the development of diabetes, or by the use of statin therapy.
In contrast, no metformin effect on CAC was seen in women. The authors speculate that women may have less coronary calcification than men, making it harder to observe a benefit from metformin.
Goldberg also pointed out that, although it is “hard to be sure” why the metformin effect is lacking in women, previous studies have shown that metformin reduces testosterone levels in women but not in men. “Whether there’s a metabolic difference between women and men that might count for a differential effect of metformin is a possibility, but we really don’t know the answer.”
Bristol-Myers Squibb and Parke-Davis provided funding and material support during the DPP; Lipha (Merck-Santé) provided medication and LifeScan donated materials during the DPP and DPPOS. Goldberg declared no relevant financial relationships; disclosures for the coauthors are listed in the paper.
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