Metformin for diabetes prevention: insights gained from the Diabetes Prevention Program/Diabetes Prevention Program Outcomes Study

Abstract

The largest and longest clinical trial of metformin for the prevention of diabetes is the Diabetes Prevention Program/Diabetes Prevention Program Outcomes Study (DPP/DPPOS). In this review, we summarise data from the DPP/DPPOS, focusing on metformin for diabetes prevention, as well as its long-term glycaemic and cardiometabolic effects and safety in people at high-risk of developing diabetes. The DPP (1996-2001) was a RCT of 3234 adults who, at baseline, were at high-risk of developing diabetes. Participants were assigned to masked placebo (n = 1082) or metformin (n = 1073) 850 mg twice daily, or intensive lifestyle intervention (n = 1079). The masked metformin/placebo intervention phase ended approximately 1 year ahead of schedule because of demonstrated efficacy. Primary outcome was reported at 2.8 years. At the end of the DPP, all participants were offered lifestyle education and 88% (n = 2776) of the surviving DPP cohort continued follow-up in the DPPOS. Participants originally assigned to metformin continued to receive metformin, unmasked. The DPP/DPPOS cohort has now been followed for over 15 years with prospective assessment of glycaemic, cardiometabolic, health economic and safety outcomes. After an average follow-up of 2.8 years, metformin reduced the incidence of diabetes by 31% compared with placebo, with a greater effect in those who were more obese, had a higher fasting glucose or a history of gestational diabetes. The DPPOS addressed the longer-term effects of metformin, showing a risk reduction of 18% over 10 and 15 years post-randomisation. Metformin treatment for diabetes prevention was estimated to be cost-saving. At 15 years, lack of progression to diabetes was associated with a 28% lower risk of microvascular complications across treatment arms, a reduction that was no different among treatment groups. Recent findings suggest metformin may reduce atherosclerosis development in men. Originally used for the treatment of type 2 diabetes, metformin, now proven to prevent or delay diabetes, may serve as an important tool in battling the growing diabetes epidemic. Long-term follow-up, currently underway in the DPP/DPPOS, is now evaluating metformin's potential role, when started early in the spectrum of dysglycaemia, on later-stage comorbidities, including cardiovascular disease and cancer.

Trial registration: ClinicalTrials.gov NCT00038727 and NCT00004992.

Keywords: DPP; DPPOS; Diabetes prevention; Impaired glucose tolerance (IGT); Metformin; Prediabetes; Review.

Fig. 1

Exposure to metformin throughout the DPP/DPPOS. AUCs represent total metformin-years of exposure, including study-provided metformin (blue), non-study-provided metformin for diabetes treatment (green), and non-study-provided metformin prescribed to individuals without diabetes (red)

Fig. 2

(a) Cumulative incidence of diabetes and (b) weight change over 15 years in the DPP/DPPOS, in metformin (blue line) and placebo (red line) groups. (a) Adapted from The Lancet Diabetes & Endocrinology 3:866–875 [9]; Diabetes Prevention Program Research Group, Long-term effects of lifestyle intervention or metformin on diabetes development and microvascular complications over 15-year follow-up: the Diabetes Prevention Program Outcomes Study, Copyright (2015), with permission from Elsevier

Fig. 2

(a) Cumulative incidence of diabetes and (b) weight change over 15 years in the DPP/DPPOS, in metformin (blue line) and placebo (red line) groups. (a) Adapted from The Lancet Diabetes & Endocrinology 3:866–875 [9]; Diabetes Prevention Program Research Group, Long-term effects of lifestyle intervention or metformin on diabetes development and microvascular complications over 15-year follow-up: the Diabetes Prevention Program Outcomes Study, Copyright (2015), with permission from Elsevier