Metformin tied to lower coronary calcium in prediabetes
Long-term metformin was associated with a significantly lower coronary artery calcium (CAC) than placebo or lifestyle modification in men, but not in women, with prediabetes, according to data from the DPP* and DPPOS** cohort.
“[The study suggests that] metformin treatment … within a few years before or after diabetes development … may have reduced early stages of plaque development in men,” according to the researchers.
The DPP randomized 2,061 participants (aged ≥25 years, body mass index ≥24 kg/m2) with prediabetes to one of three arms: metformin 850 mg twice daily, an intensive lifestyle modification programme, or placebo twice daily. After treatment has been unmasked at the end of DPP, 2,029 (regardless of diabetes status) joined the DPPOS which offered maintenance group lifestyle sessions to all participants quarterly, of which the original lifestyle group in DPP received supplementary group programmes twice a year and the metformin group continued with the drug.
CAC─a marker of subclinical coronary atherosclerosis─was 41 percent less severe among men who continued with metformin at 14 years after DPP study than those randomized to the placebo group in the original study (mean CAC severity, 39.5 vs 66.9 arbitary unit [AU]; p=0.04 after adjusting for age). [Circulation 2017;doi:10.1161/CIRCULATIONAHA.116.025483]
Similarly, mean CAC severity was lower among men in the metformin vs the lifestyle groups (39.5 vs 58.3 AU), although the difference was not statistically significant in the age-adjusted analysis.
There were also fewer men with CAC>0 in the metformin group than the placebo group (75 percent vs 84 percent; p=0.02) and the lifestyle group (75 percent vs 85 percent; p<0.05).
However, the beneficial effects of metformin on CAC were not seen among women.
“CAC severity was considerably lower in women than in men in our study, making it more difficult to identify an effect of metformin in women,” observed the researchers. They also believed that premenopause might have contributed to the absence of metformin effect in women since atherogenesis progresses more slowly in premenopausal women, which made up 36 percent of the women in the study.
Stratifying the analysis by age showed that CAC severity (3.0 vs 17.6 AU; p<0.05) and CAC>0 (40 percent vs 71 percent; p<0.05) were both significantly lower with metformin than with placebo among men in the age group of 25–44 years. Similar trends toward lower CAC severity and prevalence among men taking metformin were seen in the older age groups, although these did not reach statistical significance.
According to the authors, the observation that metformin effect on CAC was most evident in younger men aged 25–44 years “who would be expected to have atherosclerotic lesions earlier in their development than among older men… [implies] that the effect of metformin involves smaller and more recently calcifying plaques, rather than well-established lesions.”
Besides age, differences in CAC severity (but not CAC>0) between the treatment groups were also observed regardless of race/ethnic subgroups, statin use and diabetes status, which according to the authors, suggests that “the effect of metformin on CAC in men does not depend on diabetes prevention.”
Since participants weighing >350 lbs were excluded from the analyses because CAC could not be accurately quantified in these individuals, the researchers cautioned against generalizing the results to the entire population with prediabetes.
“Whether these findings translate into beneficial effects on CVD events will require ongoing follow-up,” said the researchers.