Practice Update: DIABETES

EDITOR’S PICKS 5

Effect of metformin and lifestyle on coronary artery calcium in the Diabetes Prevention Program Circulation Take-home message

significantly lower among men in the metformin versus the placebo group (age-adjusted mean CAC severity: 39.5 vs 66.9 AU, p=0.04; CAC presence: 75% vs 84%, p=0.02), but no metformin effect was seen inwomen. Inmultivariate analysis, the metformin effect in men was not influenced by demographic, anthropometric or metabolic factors, by the development of diabetes, or by use/non-use of statin therapy. CONCLUSIONS Metformin may protect against coronary atherosclerosis in prediabetes and early diabetes among men. Effect of long-term metformin and lifestyle in the Diabetes Prevention Program and its outcome study on coronary artery calcium. Circulation 2017 May 05;[EPub Ahead of Print], RB Goldberg, VR Aroda, DA Bluemke, et al. raising the possibility of both direct glucose-dependent and independent vascular protective benefit of metformin. This observation is particularly relevant because, in contrast to the recent experience with empagliflozin and liraglutide, there are no contemporary data supporting a cardioprotective role of metformin. Metformin remains the first-line therapy for diabetes, and also a reasonable treatment for patients with prediabetes, but its “pole-position” should be tested in contemporary management strategies against other new agents. Metformin remains the first- line therapy for diabetes, and also a reasonable treatment for patients with prediabetes, but its “pole-position” should be tested in contemporary management strategies against other new agents.

• This long-term intervention study investigated the incidence of coronary heart disease (CHD) among 3234 individuals with prediabetes. After an average 14 years of follow-up, 2029 participants had subclinical atherosclerosis based on coronary artery calcium (CAC) measurement. Participants with lifestyle interventions did not have a significant difference in CAC from the placebo group. Men in the metformin group had a significant reduction in the presence and severity of CAC compared with the placebo group. However, there was no significant difference between women in the metformin and placebo groups. • Among men with prediabetes or early diabetes, metformin may protect against coronary atherosclerosis.

Abstract BACKGROUND Despite the reduced incidence of coronary heart disease (CHD) with intensive risk factor management, people with diabetes and prediabetes remain at increased CHD risk. Dia- betes prevention interventions may be needed to reduce CHD risk. This approach was exam- ined in the Diabetes Prevention Program (DPP) and its Outcome Study (DPPOS), a long-term intervention study in 3234 subjects with predia- betes (mean [±SD] age 64±10 yrs) which showed reduced diabetes risk with lifestyle and met- formin compared to placebo over 3.2 years. METHODS The DPPOS offered periodic group COMMENT By Benjamin Morgan Scirica MD T he DPP study, published in 2002, demonstrated that, compared with placebo, an intensive lifestyle modi- fication program or metformin significantly reduced the risk of developing diabetes and improved cardiometabolic risk factors over an average follow-up of 3.2 years. In this publication, the investigators from the follow-up extension study (named DPPOS) report the long-term effect on coronary artery calcium (CAC) measurements of the initial randomization to metformin or life- style compared with placebo. After 10 additional years of follow-up, CAC was measured in 2029 patients. Overall, CAC severity was greater in men than in women. And, in men, those patients originally randomized to metformin had less severe CAC than those randomized to placebo (age-adjusted mean CAC severity: 39.5 vs 66.9 AU, P = 0.04; CAC

lifestyle sessions to all participants and con- tinued metformin in the originally randomized metformin group. Subclinical atherosclerosis was assessed in 2029 participants using coro- nary artery calcium (CAC) measurements after 14 years of average followup. The CAC scores were analyzed continuously as CAC sever- ity, and categorically as CAC presence (CAC score>0), and reported separately in men and women. RESULTS Therewere no CAC differences between lifestyle and placebo intervention groups, in either sex. CAC severity and presence were

presence: 75% vs 84%, P = 0.02). There was no difference in CAC between the group assigned to lifestyle modifica- tion compared with those assigned to placebo, or between any treatment in women. It is reasonable to hypothesize that the degree of CAC in women in this study was low enough that there was no opportunity to prevent calcifications, but it could also signal a potential differentia- tion in treatment effect. It is disappointing to see no difference in men assigned to the lifestyle modification arm, although CAC can be modulated (worsened) with intense exercise. In the original DPP study, intensive lifestyle intervention was more effective than metformin for glucose control and prevention of diabetes; yet, in this long- term follow-up, metformin was the only strategy to reduce CAC therapy, thus

Dr Scirica is Cardiologist and Director at Inovation, Cardiovascular Division, Brigham and Women’s Hospital, and Associate Professor of Medicine at Harvard Medical School.

VOL. 1 • NO. 1 • 2017