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Effects of Long-Term Metformin and Lifestyle Interventions on Cardiovascular Events in People With Diabetes
TAKE-HOME MESSAGE
- Over a median follow-up period of 21 years, this study examined the incidence of major cardiovascular events in participants from the Diabetes Prevention Program trial and Diabetes Prevention Program Outcome Study. Compared with placebo, neither metformin nor lifestyle intervention reduced the incidence of major cardiovascular events (HR, 1.03 and 1.14, respectively).
- Despite long-term reductions in diabetes development, metformin and lifestyle interventions did not prevent cardiovascular disease in adults with impaired glucose tolerance or early type 2 diabetes. The effects of the interventions might have been overshadowed by the provision of the group lifestyle intervention to all participants, extensive out-of-study use of statin and antihypertensive agents, and reduction in the frequency of the use of study metformin together with out-of-study metformin use over time.
abstract
This abstract is available on the publisher's site.
Access this abstract nowBACKGROUND
Lifestyle intervention and metformin have been shown to prevent diabetes; however, their efficacy in preventing cardiovascular disease associated with the development of diabetes is unclear. We examined whether these interventions reduced the incidence of major cardiovascular events over a 21-year median follow-up of participants in the DPP trial (Diabetes Prevention Program) and DPPOS (Diabetes Prevention Program Outcomes Study).
METHODS
During DPP, 3234 participants with impaired glucose tolerance were randomly assigned to metformin 850 mg twice daily, intensive lifestyle or placebo, and followed for 3 years. During the next 18-year average follow-up in DPPOS, all participants were offered a less intensive group lifestyle intervention, and unmasked metformin was continued in the metformin group. The primary outcome was the first occurrence of nonfatal myocardial infarction, stroke, or cardiovascular death adjudicated by standard criteria. An extended cardiovascular outcome included the primary outcome or hospitalization for heart failure or unstable angina, coronary or peripheral revascularization, coronary heart disease diagnosed by angiography, or silent myocardial infarction by ECG. ECGs and cardiovascular risk factors were measured annually.
RESULTS
Neither metformin nor lifestyle intervention reduced the primary outcome: metformin versus placebo hazard ratio 1.03 (95% CI, 0.78-1.37; P = 0.81) and lifestyle versus placebo hazard ratio 1.14 (95% CI, 0.87-1.50; P = 0.34). Risk factor adjustment did not change these results. No effect of either intervention was seen on the extended cardiovascular outcome.
CONCLUSIONS
Neither metformin nor lifestyle reduced major cardiovascular events in DPPOS over 21 years despite long-term prevention of diabetes. Provision of group lifestyle intervention to all, extensive out-of-study use of statin and antihypertensive agents, and reduction in the use of study metformin together with out-of-study metformin use over time may have diluted the effects of the interventions.
Additional Info
Disclosure statements are available on the authors' profiles:
Effects of Long-term Metformin and Lifestyle Interventions on Cardiovascular Events in the Diabetes Prevention Program and Its Outcome Study
Circulation 2022 May 31;145(22)1632-1641, RB Goldberg, TJ Orchard, JP Crandall, EJ Boyko, M Budoff, D Dabelea, KM Gadde, WC Knowler, CG Lee, DM Nathan, K Watson, M TemprosaFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
The US Diabetes Prevention Program Outcomes Study (DPPOS) is the largest enduring diabetes prevention program in the world. The active interventions—intensive lifestyle modification or metformin (vs placebo)—demonstrated their ability to prevent diabetes during the 3.1-year randomized period, as well as during the 21 years since randomization. The question as to whether preventing diabetes during this time also prevented cardiovascular events was the subject of the current publication. Major findings showed that neither intensive lifestyle modification or metformin reduced the first occurrence of nonfatal myocardial infarction, stroke or cardiovascular death. Extending the definition of the cardiovascular outcome did not change the results.
For many, the results may be disappointing, but there is a major silver lining that should not be overlooked. First, approximately half of the participants have developed diabetes and are receiving multiple risk factor intervention according to guidelines established by the American Diabetes Association. Second, results from the DPPOS put “prediabetes” on the minds of patients and providers to the extent that many are receiving multiple risk factor interventions as if they had diabetes. This is evidenced by most being on metformin (41% receiving study metformin and approximately 35% receiving out-of-study metformin), approximately 70% taking antihypertensive medications, and approximately 60% reporting use of a statin. Hence, the lack of a positive finding in the current publication may reflect successful risk-factor modification for those with diabetes, as well as those with prediabetes, in this trial and possibly well beyond.