Effects of Long-term Metformin and Lifestyle Interventions on Cardiovascular Events in the Diabetes Prevention Program and Its Outcome Study

Abstract

Background: 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.

Registration: URL: https://www.

Clinicaltrials: gov; Unique identifiers: DPP (NCT00004992) and DPPOS (NCT00038727).

Keywords: cardiovascular diseases; diabetes mellitus, type 2; metformin.

Figure 1:. Cardiovascular risk factors during follow-up

The figure shows the trajectories of mean low density lipoprotein cholesterol (LDL-C), triglyceride (TG), systolic blood pressure (SBP), body mass index (BMI), high density lipoprotein cholesterol (HDL-C), glycosylated hemoglobin (HbA1c), and percent receiving statin and antihypertensive medications by intervention groups from randomization until the most recent datalock. Metformin is shown in red circles, lifestyle in green diamonds and placebo in blue triangles. (See also Table 1). All participants with data were used in the analyses for all time points either until they developed an event or in the absence of an event until the datalock. The number of participants at each timepoint (n) is as follows: baseline; n=3234, year 5; n=2573, year 10; n=2356, year 15; n=2144, year 20; n=1884.

Figure 2:. Cumulative incidence of total major adverse cardiovascular (MACE) events and individual cardiovascular event components by intervention groups

The figure shows the effects of the interventions on the cumulative incidence (%) of first major adverse cardiovascular events in Panel A. First occurrence of individual major cardiovascular component events shown are: Non-fatal myocardial infarction (Panel B), Non-fatal stroke (Panel C) and Cardiovascular death (Panel D). The metformin group is shown in red circles, the lifestyle group in green diamonds and the placebo group in blue triangles.

Figure 3.. Effect of metformin and lifestyle interventions versus placebo on cumulative incidence of the extended major adverse cardiovascular event (Extended MACE) outcome

The figure shows the effects of the interventions on the cumulative incidence (%) of first occurrence of the extended cardiovascular event outcome. The metformin group is shown in red circles, the lifestyle group in green diamonds and the placebo group in blue triangles.

Figure 4.. Effect of metformin and lifestyle interventions versus placebo on the incidence of major adverse cardiovascular events by age, sex, race/ethnicity and diabetes status subgroups

Panel A shows the effect of metformin versus placebo groups and Panel B the effect of lifestyle versus placebo groups on major cardiovascular events in prespecified age, sex, race/ethnicity and diabetes status subgroups showing hazard ratio (95% CI). The heterogeneity p values reflect the interaction of subgroup x treatment group to assess differences in treatment effect among subgroups. Absence of diabetes is defined as never having diabetes or not yet having developed diabetes. Arrows on the confidence interval indicate lower or upper bounds that extend beyond the axis.

Figure 4.. Effect of metformin and lifestyle interventions versus placebo on the incidence of major adverse cardiovascular events by age, sex, race/ethnicity and diabetes status subgroups

Panel A shows the effect of metformin versus placebo groups and Panel B the effect of lifestyle versus placebo groups on major cardiovascular events in prespecified age, sex, race/ethnicity and diabetes status subgroups showing hazard ratio (95% CI). The heterogeneity p values reflect the interaction of subgroup x treatment group to assess differences in treatment effect among subgroups. Absence of diabetes is defined as never having diabetes or not yet having developed diabetes. Arrows on the confidence interval indicate lower or upper bounds that extend beyond the axis.