, Volume 60, Issue 9, pp 1601–1611 | Cite as

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

  • Vanita R. ArodaEmail author
  • William C. Knowler
  • Jill P. Crandall
  • Leigh Perreault
  • Sharon L. Edelstein
  • Susan L. Jeffries
  • Mark E. Molitch
  • Xavier Pi-Sunyer
  • Christine Darwin
  • Brandy M. Heckman-Stoddard
  • Marinella Temprosa
  • Steven E. Kahn
  • David M. Nathan
  • for the Diabetes Prevention Program Research Group


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: NCT00038727 and NCT00004992.


Diabetes prevention DPP DPPOS Impaired glucose tolerance (IGT) Metformin Prediabetes Review 



Albumin:creatinine ratio


Coronary artery calcium


Cardiovascular disease


Diabetes Prevention Program


Diabetes Prevention Program Outcomes Study


Fasting plasma glucose


Gestational diabetes


2-h plasma glucose


Intensive lifestyle


The Diabetes Prevention Program (DPP; 1996–2001), an RCT to prevent or delay the onset of type 2 diabetes, was designed in the mid 1990s. Metformin was selected as one of the interventions, based on its mechanism of action and acceptable safety and tolerability profiles, with lifestyle intervention or placebo comprising the other treatment arms [1, 2]. The possibility of preventing or delaying diabetes in adults without diabetes but at high risk had been hypothesised for decades. Small randomised clinical trials using type 2 diabetes treatment drugs (phenformin or tolbutamide) for diabetes prevention were performed in the 1960s/70s, but were inconclusive [3, 4, 5]. They were followed by larger clinical trials testing lifestyle interventions that proved to be effective [6, 7]. The DPP was the first major diabetes prevention trial using metformin [2].

The DPP/Diabetes Prevention Program Outcomes Study (DPPOS) represents the largest controlled clinical trial of metformin in a population at high-risk of developing diabetes, and also the longest trial of metformin for any indication. The effects of intensive lifestyle (ILS) intervention in the DPP and several other major trials, and the effects of other medications have been described elsewhere and are summarised in Table 1 [2, 8, 9, 10]. In this review, we focus on the effects of metformin on diabetes prevention, its long-term glycaemic and cardiometabolic effects, and its safety in the DPP/DPPOS.
Table 1

Summary of select RCTs evaluating the prevention of progression to diabetes

Study title (country of conduct, year of publication, n)

Risk eligibility criteria

Duration of follow-up


Incidence/100 person-years (events) or cumulative incidence (%) at study end

Risk reduction in diabetes incidence compared with control/placebo

Da Qing Study [6] (China, 1997, n = 577)

IGT; age >25 years

6.0 years







Diet and exercise





Finnish Diabetes Prevention Study [7] (Finland, 2001, n = 522)

IGT; age 40–65 years; BMI >25 kg/m2

3.2 years

Diet and activity





DPP [2] (USA, 2002, n = 3234)

IGT; FPG 5.3–6.9 mmol/l (<6.9 mmol/l for Native American ancestry); age ≥25 years; BMI ≥24 kg/m2 (≥22 kg/m2 in Asians)

2.8 years




Metformin 850 mg BID





STOP-NIDDM [41] (multiple countries, 2002, n = 1429)

IGT; FPG 5.6–7.7 mmol/l; age 40–70 years; BMI 25–40 kg/m2

3.3 years

Acarbose 100 mg TID





XENDOS [42] (Sweden, 2004, n = 3305)

BMI ≥30 kg/m2; age 30–60 years

4.0 years

Orlistat 120 mg TID





Japanese IGT study [43] (Japan, 2005, n = 458)

Men with IGT

4.0 years

Diet and exercise





Indian Diabetes Prevention Programme [44] (India, 2006, n = 531)

IGT; age 35–55 years

30 months

Lifestyle modification



Metformin 250 mg BID



Lifestyle modification + metformin 250 mg BID





DREAM (rosiglitazone) [45] (multiple countries, 2006, n = 5269)

IFG and/or IGT; age ≥30 years

3.0 years

Rosiglitazone 8 mg daily





DREAM (ramipril) [46] (multiple countries, 2006, n = 5269)

IFG and/or IGT; age ≥30 years

3.0 years

Ramipril, up to 15 mg per day





Voglibose Ph-3 [47] (Japan, 2009, n = 1780)

IGT; age 30–70 years; with additional risk factor for T2D

48.1 weeks

Voglibose 0.2 mg TID





NAVIGATOR (valsartan) [48] (multiple countries, 2010, n = 9306)

IGT; FPG 5.3–<7.0 mmol/l; with CVD/CVD risk

5.0 years

Valsartan, up to 160 mg daily, and lifestyle modification instruction





NAVIGATOR (nateglinide) [49] (multiple countries, 2010, n = 9306)

IGT; FPG 5.3–<7.0 mmol/l; with CVD/CVD risk

5.0 years

Nateglinide, 60 mg before meals, TID





CANOE [50] (Canada, 2010, n = 207)

IGT; age 30–75 years (18–75 for Native Canadian ancestry); with at least one risk factor for T2D

3.9 years

Rosiglitazone + metformin (2 mg /500 mg, BID)





ACT NOW [51] (USA, 2011, n = 602)

IGT; FPG 5.3–6.9 mmol/l; age ≥18 years; BMI ≥25 kg/m2; at least one risk factor T2D

2.4 years

Pioglitazone 45 mg daily





SCALE Prediabetes [52] (multiple countries, 2017, n = 2254)

Prediabetesb; age ≥18 years; BMI ≥30 kg/m2 or ≥27 kg/m2 with comorbidities

3.0 years

Liraglutide 3.0 mg





Table includes RCTs studying progression to diabetes as a primary outcome with interventions that are currently available. Refer to original referenced studies for details on outcomes measured and reported

aComposite primary outcome of incident diabetes or death from any cause

bPrediabetes was defined as fulfilment of at least one of the three ADA 2010 criteria: 5.7–6.4% HbA1c; FPG between 5.6 and 6.9 mmol/l; or 2-h post-challenge plasma glucose concentration between 7.8 and 11.0 mmol/l

ACT NOW, Actos Now for the prevention of diabetes; BID, twice daily; CANOE, CAnadian Normoglycemia Outcomes Evaluation; DREAM, Diabetes REduction Assessment with ramipril and rosiglitazone Medication; IFG, impaired fasting glucose; IGT, impaired glucose tolerance; NAVIGATOR, Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research; SCALE, Satiety and Clinical Adiposity — Liraglutide Evidence in Nondiabetic and Diabetic Individuals; STOP-NIDDM, Study to Prevent Non-Insulin Dependent Diabetes Mellitus; T2D, type 2 diabetes; TID, thrice daily; XENDOS, XENical in the prevention of Diabetes in Obese Subjects

Overview of the DPP/DPPOS

Design of the DPP/DPPOS

The DPP enrolled 3234 participants aged 25 years or older who were at high risk of developing diabetes, defined as impaired glucose tolerance, with elevated fasting plasma glucose (FPG) (5.3–6.9 mmol/l [≤6.9 mmol/l in Native Americans]) and a BMI of 24 kg/m2 or higher (≥22 kg/m2 in Asian-Americans). Participants were randomly assigned to placebo (n = 1082), metformin (n = 1073) titrated to 850 mg twice daily, or ILS intervention (n = 1079), which aimed for 7% weight loss through a low-energy, low-fat diet (based on recommendations for health) and ≥150 min/week of moderate-intensity physical activity [2]. Interventions were discontinued if there were safety concerns. Diagnosis of diabetes was based on annual OGTTs or semi-annual FPG tests, using the ADA diagnostic criteria, with the diagnosis requiring confirmation with repeat testing [11]. Diagnosis of diabetes and FPG ≥7.8 mmol/l resulted in discontinuation of study medication and referral to the participant’s own physician for further treatment [2].

The DPP was stopped in 2001, 1 year ahead of schedule, owing to demonstrated efficacy of both metformin and the lifestyle intervention [2]. Given the demonstrated effects of ILS, all participants were offered a group-administered version of the lifestyle curriculum at the end of the DPP. Eighty-eight per cent (n = 2776) of eligible DPP participants continued follow-up in the DPPOS, in which placebo was discontinued, those previously assigned to metformin received metformin 850 mg twice daily (now unmasked) and lifestyle messages were intermittently reinforced. The study-provided metformin was discontinued if diabetes was diagnosed and HbA1c was ≥7% (≥53 mmol/mol), hence requiring management by the participant’s physician [8]. Outcomes in the DPPOS from 2002 to 2013 centred on the long-term effects of the interventions on diabetes prevention, diabetes-associated microvascular complications [9] and cardiovascular disease (CVD) risk factors.

Participant characteristics

By intention, the DPP enrolled a heterogeneous population, with 45% from racial or ethnic minorities, 20% aged 60 years or older and 68% women, including 350 women with a history of gestational diabetes (GDM). The mean age at randomisation was 51 years and mean BMI was 34 kg/m2. Mean FPG was 5.9 mmol/l and baseline HbA1c was 5.9% (41 mmol/mol). Sex, ethnic distribution and risk factors for diabetes were similar among the randomised treatment arms [2].

Exposure to metformin

Integral to understanding the effects of metformin over time is the separation of study and non-study exposure, keeping in mind that DPP/DPPOS participants who developed diabetes were subsequently managed by their own physicians, often with non-study metformin. By 15 years after randomisation, 37% of the original placebo participants had been treated with metformin by their healthcare providers, the vast majority associated with diabetes diagnosis (Fig. 1). The mean exposure, including study- and non-study metformin, from 1996 to 2013, remained widely separated, at 10.7 vs 2.3 metformin-years in metformin vs placebo groups [9].
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)

Throughout the DPP and DPPOS, pill counts and structured interviews were used to promote adherence [12]. During the DPP, adherence to metformin, defined as taking at least 80% of assigned study pills, was 72% (Fig. 1) [2]. An additional 10–15% of participants took some metformin, albeit at less than 80% of pills assigned. Adherence to metformin (at the >80% threshold) fell to an average of 49% over the DPPOS (2002–2013) [9].


Effects of metformin on diabetes prevention

In 2002, the DPP published its primary findings from the masked-treatment phase, showing that the ILS and metformin groups had a respective 58% and 31% lower incidence of diabetes than the placebo group [2]. Subsequently, the DPPOS addressed the longer-term effects of metformin, showing a decline in risk reduction by 18% compared with placebo over 10 and 15 years post-randomisation (Fig. 2a) [8, 9]. Although the differences in incidence rates over the entire follow-up remained significant, the observed diabetes incidence rates during the DPPOS period (i.e. in the period after the DPP completed) were not significantly different between the original randomised groups. Diabetes incidence rates during the DPP were 7.8 cases per 100 person-years in the metformin group and 11.0 cases per 100 person-years in the placebo group [2], and these decreased in the DPPOS (2002–2008) to 4.9 cases per 100 person-years for metformin and 5.6 cases per 100 person-years for placebo [8], remaining stable thereafter. This reduced diabetes incidence approximates the five cases per 100 person-years rate observed in the lifestyle group during the DPP, which has remained nearly constant throughout the DPP/DPPOS [9]. The average genetic risk score, derived from 34 type 2 diabetes-associated genetic variants, declined over time among participants who remained without diabetes in the DPP/DPPOS, in both the metformin and placebo groups [13]. This suggests that the lower annual incidence rate of diabetes seen in the DPPOS was not entirely due to an effect of the lifestyle intervention offered during the transition to the DPPOS, but, in part, due to ‘exhaustion of susceptibles’, or that diabetes developed in the people who were most susceptible to diabetes during the DPP and that remaining participants in the DPPOS were less susceptible to diabetes [13].
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

Effects of metformin on diabetes prevention/delay in subgroups of interest

The DPP was not powered to assess the significance of effects within subgroups. Nonetheless, examination of treatment effects in cohort subgroups revealed significant heterogeneity. For example, obese participants with a BMI ≥35 kg/m2 were more responsive to metformin than to placebo, with a 53% risk reduction for diabetes but only a 3% reduction in those with BMI 22 to <30 kg/m2. In addition, those with a higher fasting glucose (6.1–6.9 mmol/l) had a greater risk reduction with metformin (48%) compared with those with a fasting glucose of 5.3–6.1 mmol/l (15% risk reduction). Although not significant for heterogeneity across strata, metformin appeared more effective in younger participants compared with placebo, reducing diabetes onset by 44% (95% CI 21%, 60%) in those 25–44 years old vs 11% (95% CI −33%, 41%) for those ≥60 years of age at study entry. Of note, no such differences were observed by sex, race/ethnicity, or tertiles of baseline 2-h plasma glucose (2-hPG) [2].

During the DPP, women with a history of GDM randomised to placebo had a 71% higher risk of diabetes than parous women without such a history, despite similar FPG and 2-hPG values at baseline [14]. Significant heterogeneity was observed in response to metformin with a 50% reduction in incidence of diabetes in women with a history of GDM compared with 14% in parous women with no such history. Ten-year follow-up in the DPPOS confirmed these effects, demonstrating a sustained and relatively greater risk for diabetes in women with a history of GDM, which was reduced by 40% with metformin [15].

Insights from the DPP/DPPOS on how metformin prevents or delays diabetes

Acute pharmacological effect or amelioration of pathophysiology?

During the DPP, evaluations were carried out without interruption of study medication (placebo or metformin), except for withholding study medicine the morning of glycaemic testing. Thus, some (or all) of metformin’s effect could have been a transient pharmacological treatment effect (‘masking of diabetes’), rather than a true delay in the onset of diabetes. The DPP addressed this issue by retesting participants who had not developed diabetes by study end, 1–2 weeks after stopping metformin. After this washout period, the incidence of diabetes was still reduced by 25%, compared with the 31% reduction seen in the primary analysis, suggesting a more durable effect of metformin treatment on glucose metabolism [16].

Explanation of metformin-induced effects

Some of metformin’s diabetes prevention effect is attributed to weight loss, which was durable over time in the DPP/DPPOS (Fig. 2b, Table 2) [2, 8, 9]. Weight loss with metformin explained 64% of the its beneficial effect on diabetes risk at the end of the DPP [17]. Favourable changes were also seen in other measures of adiposity (waist circumference, waist-to-hip ratio), and in fasting insulin and proinsulin [17]. No differences were seen in self-reported physical activity or diet, or insulin secretion measured by the insulinogenic index between the metformin and placebo groups. While no single covariate completely explained the beneficial effect of metformin vs placebo, the combination of weight, fasting insulin and proinsulin levels, and other metabolic factors explained 81% of the beneficial outcomes with metformin [17]. Improvements in FPG and estimated insulin sensitivity with metformin may be owing to a combination of weight loss and other direct effects on the liver and, perhaps, other tissues.
Table 2

Effect of metformin on diabetes risk and CVD risk factors at baseline and at the end of each phase of the DPP and DPPOS


Baseline (1996–1999)

DPP (1996–2001)

3.2 years mean follow-upa

DPPOS 1 (2002–2008)

10 years mean follow-up

DPPOS 2 (2008–2013)

15 years mean follow-up











n = 1082

n = 1073

n = 935

n = 926

n = 924

n = 932

n = 924

n = 932


 Weight (kg)









 BMI (kg/m2)










 Diabetes cases (n)









 Mean diabetes duration (years among cases)







 FPG (mmol/l)









 HbA1c (%)









 HbA1c (mmol/mol)









CVD risk factors


 Systolic BP (mmHg)









 Diastolic BP (mmHg)









 LDL-c (mmol/l)









 HDL-c (mmol/l)









 Triacylglycerol (mmol/l)









 CRP (nmol/l)







 tPA (ng/ml)





 Fibrinogen (μmol/l)







 Coronary calcification (%)b







Data shown as means, unless otherwise indicated

aDPP intervention phase was 3.2 years with primary diabetes incidence analysis completed at 2.8 years owing to demonstrated efficacy

bBased on scan measured at DPPOS year 10, with 14 years of average follow-up

* p < 0.05, metformin vs placebo

CRP, C-reactive protein; HDL-c, HDL-cholesterol; LDL-c, LDL-cholesterol; tPA, tissue plasminogen activator

Effects of metformin on blood glucose measures

The effects of the DPP interventions on FPG and HbA1c were examined in all participants, regardless of whether they had developed diabetes. During the DPP, metformin and ILS were similarly effective in restoring normal FPG values [2]. Despite metformin and ILS having similar effects on FPG, diabetes incidence was more significantly reduced by ILS than by metformin, reflecting the fact that most diabetes diagnoses in the DPP were triggered by the 2-hPG rather than FPG, and that ILS was more effective than metformin at restoring a normal 2-hPG. This latter observation was likely because, while both active interventions improved beta cell function, this effect was greater with ILS [18]. Consistent with metformin’s known ability to suppress hepatic glucose production during fasting [19, 20], its reduction of diabetes incidence compared with placebo was much greater in those entering the study with a FPG 6.1–6.9 mmol/l than in those with a FPG 5.3–6.1 mmol/l [2]. Metformin also lowered HbA1c relative to placebo, but to a lesser extent than did ILS [2].

After the DPP had been completed, an International Expert Committee and the ADA expanded the diagnostic criteria for diabetes to include HbA1c ≥6.5% (≥48 mmol/mol) [21, 22]. Although HbA1c was measured during the DPP/DPPOS, eligibility and diabetes diagnoses were based on fasting and/or 2-hPG. Thus, a secondary analysis using HbA1c ≥6.5% (≥48 mmol/mol) as an alternative definition of diabetes was performed, excluding the 13% of participants with HbA1c ≥6.5% (≥48 mmol/mol) at study entry. Although ILS was more effective than metformin in reducing the incidence of diabetes defined by the FPG and OGTT criteria, the effect of metformin was no longer significantly different from ILS when diabetes was diagnosed based on HbA1c (44% vs 49% reduction in the DPP, 38% vs 29% reduction throughout DPP/DPPOS; metformin vs ILS) [23]. In summary, metformin was as effective as ILS in preventing diabetes by some measures (i.e. HbA1c), but not by 2-hPG, in the DPP/DPPOS population.

Metformin’s interaction with genetic factors

The DPP investigated several genetic variants previously associated with risk of type 2 diabetes or metformin action. For example, homozygosity for the major diabetes risk variant rs7903146 in the TCF7L2 gene was associated with an 81% higher diabetes incidence in the placebo group that was reduced to a 62% increased risk in the metformin group [24]. In addition, a genetic risk score predicted diabetes incidence in the DPP, but with no significant interaction between the score and treatment group. That is, the interventions were equally effective, regardless of genetic susceptibility [25]. There was, however, a nominal interaction with metformin (p = 0.006) with the variant rs8065082 in the metformin transporter gene SLC47A1, with the minor allele being associated with lower incidence of diabetes in the metformin arm (HR 0.78 [95% CI 0.64, 0.96]; p = 0.02) [26].

Effects of metformin on microvascular complications

At the end of the DPP, the only microvascular outcome assessed was microalbuminuria. There was no effect of treatment intervention on the percentage of participants with elevated albumin:creatinine ratio (ACR) levels, although those who developed diabetes had a 59% increased risk of developing an elevated ACR (≥3.39 mg/mmol) [27]. One of the main goals in the longer-term follow-up of the DPPOS is to determine if treatments effective in preventing diabetes also affect the development of microvascular complications, specifically retinopathy, nephropathy and neuropathy. A composite of these microvascular outcomes at 15 years in the DPPOS was 28% less frequent in those who did not progress to diabetes, but there was no difference between the original treatment arms [9]. The very small difference in HbA1c levels among the treatment groups, limited power, and early referral to care providers for treatment of hypertension and dyslipidaemia have been considered reasons for the lack of an effect of the active treatments on microvascular outcomes thus far, despite the reduction in diabetes incidence [9]. It is still possible that treatment effects may emerge with longer follow-up and longer diabetes duration in the cohort.

Effects of metformin on cardiovascular disease risk factors

In the DPP, metformin had favourable effects on several cardiovascular risk factors, including lipoprotein subfractions [28], C-reactive protein and tissue plasminogen activator [29]. It also reduced the incidence of the metabolic syndrome by 17% compared with placebo [30]. No significant effects on lipid levels or blood pressure were seen [31] (Table 2). Over longer-term follow-up (10 years), no significant differences in traditional cardiovascular disease (CVD) risk factors have been noted between the metformin and placebo groups [32] (Table 2).

An average of 14 years after randomisation, subclinical atherosclerosis was assessed in 2029 participants using coronary artery calcium (CAC) measurements, according to the original randomisation group. There was a significant interaction between sex and the effects of metformin vs placebo on CAC presence (p = 0.01) and CAC severity (p = 0.08). Compared with placebo, metformin significantly lowered the presence and severity of CAC in men, with no effect in women. Of interest, no reduction in the prevalence of clinically significant plaque (Agatston score >100) was observed, suggesting the possibility that metformin affects smaller, more recently calcified plaques, rather than well-established plaques. There was no difference in CAC between ILS and placebo groups, suggesting a possible long-term differentiation between metformin and ILS [33]. Longer-term follow-up with ascertainment of CVD outcomes is underway.

Long-term safety and tolerability of metformin in the DPP/DPPOS

The long-term use of metformin within the context of a closely-monitored clinical trial has provided additional information on metformin safety and tolerability. Minor gastrointestinal symptoms were reported by 9.5% of those randomised to metformin, compared with 1.1% in the placebo group, but these were generally mild and tended to wane over time [34]. The risk of lactic acidosis with metformin use has recently been shown to be much lower than previously suspected [35] and there have been no reported cases of lactic acidosis in over 15,000 person-years of exposure to metformin in the DPP/DPPOS.

Metformin use has been associated with impaired intestinal absorption of vitamin B12 and increased risk of vitamin B12 deficiency. This risk was recognised in the design of the DPP and annual testing was performed to detect anaemia as a potential manifestation of low vitamin B12 levels. In addition, vitamin B12 levels were directly measured at two time points in the DPPOS. Biochemical vitamin B12 deficiency levels (<150 pmol/l) occurred more often in individuals in the metformin group than the placebo group at 5 years (4.3% vs 2.3%; p = 0.02); a similar pattern was observed but was not significant at 13 years (7.4% vs 5.4%; p = 0.12) [36]. Low or ‘borderline’ vitamin B12 (defined as levels <220 pmol/l) is accepted by some as evidence of inadequate vitamin B12 stores and was more common in those in the metformin group at 5 years vs placebo (19.1% vs 9.5%; p = 0.01) and 13 years (20.3% vs 15.6%; p = 0.02). In a multivariate model, years of metformin use, including metformin prescribed outside of the study, were associated with increased risk of vitamin B12 deficiency with the odds ratio for vitamin B12 <150 pmol/l per year of metformin use being 1.13 (95% CI 1.06, 1.20). Anaemia prevalence was higher in the metformin group but, importantly, did not differ by vitamin B12 level, suggesting that haematological monitoring may not be sufficient to detect metformin-associated vitamin B12 deficiency [36]. Given these findings in this large cohort, current guidelines now recommend consideration of periodic measurement of vitamin B12 levels and supplementation as needed in patients treated with metformin [37].

Looking to the future

The impact of prediabetes and diabetes worldwide is enormous, with 415 million adults currently having diabetes and a projected increase to 642 million by 2040 [38]. Both lifestyle intervention and metformin are effective in the prevention or delay of diabetes. Originally used for the treatment of type 2 diabetes, metformin, now proven to prevent or delay diabetes, may serve as an important additional tool in battling the growing diabetes epidemic. As detailed in this review, metformin had sustained benefit in preventing/delaying diabetes for at least 15 years. Further, while lifestyle intervention was uniformly effective across subgroups [2], the DPP identified significant benefit from metformin in those who were more obese, had a higher fasting glucose or a history of GDM, and a suggestion of greater effect than lifestyle intervention in those who were younger. Although not specific to treatment assignment, lack of progression to diabetes was associated with lower risk of microvascular complications [9] and, among men, metformin reduced atherosclerosis development [33]. Furthermore over 10 years, metformin treatment was estimated to be cost-saving, decreasing the cumulative costs of medical care received outside the DPP/DPPOS, compared with placebo [39]. Guidelines consistently recommend either lifestyle intervention or metformin therapy for the prevention of diabetes, with considerations for metformin in subgroups in which metformin had a relatively greater effect in the DPP [37, 40]. Given our current understanding of the beneficial effects of metformin to prevent or delay diabetes, a concerted global effort to translate this evidence may help redirect the continuing increase in the prevalence of type 2 diabetes.

The potential for additional benefits of metformin extends beyond diabetes prevention and represents the next phase of study for the DPPOS. As the largest and longest clinical trial of metformin treatment, uniquely in a population initially without diabetes, the DPP/DPPOS is now poised to evaluate whether starting metformin early in high-risk individuals impacts the development and risk for even later-stage comorbidities, notably CVD and cancer. Although decreasing the incidence of diabetes would be expected to decrease CVD risk, the effect of metformin and diabetes delay/prevention on CVD is unproven. In addition, based on experimental and epidemiological data, metformin has recently received attention as a potential anti-cancer agent. Prospective intervention studies with treatment of long duration and follow-up are needed to address these important questions. DPP/DPPOS, with over 15 years of randomised metformin experience, now aims to address this need.

In conclusion, the DPP/DPPOS clearly demonstrated a role for metformin in the prevention of diabetes. Looking to the future, understanding whether translation of these findings into routine clinical care improves current trends in the development of diabetes is of critical importance. The possibility that metformin can further impact additional complications of dysglycaemia that have not yet been investigated remains an exciting area of study.



The Research Group gratefully acknowledges the commitment and dedication of the participants of the DPP and DPPOS. A complete list of Centers, investigators, and staff can be found in the electronic supplementary material (ESM). All members of the Steering Committee had input into the report’s contents. All authors in the writing group had access to all data.

Data availability

DPP and DPPOS data are available in the NIDDK repository ( and can be requested by any researcher.


During the DPP and DPPOS, the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health provided funding to the clinical centers and the Coordinating Center for the design and conduct of the study, and collection, management, analysis, and interpretation of the data (U01 DK048489). The Southwestern American Indian Centers were supported directly by the NIDDK, including its Intramural Research Program, and the Indian Health Service. The General Clinical Research Center Program, National Center for Research Resources, and the Department of Veterans Affairs supported data collection at many of the clinical centers. The sponsor of the DPP/DPPOS study was represented on the Steering Committee and played a part in study design, how the study was done, and publication. Funding was also provided by the National Institute of Child Health and Human Development, the National Institute on Aging, the National Eye Institute, the National Heart Lung and Blood Institute, the Office of Research on Women’s Health, the National Center for Minority Health and Human Disease, the National Cancer Institute, the Centers for Disease Control and Prevention, and the American Diabetes Association. Bristol-Myers Squibb and Parke-Davis provided additional funding and material support during the DPP, Lipha (Merck-Sante) provided medication and LifeScan Inc. donated materials during the DPP and DPPOS. The opinions expressed are those of the investigators and do not necessarily reflect the views of the funding agencies. This material should not be interpreted as representing the viewpoint of the US Department of Health and Human Services, the National Institutes of Health, or the National Cancer Institute.

Duality of interest

The authors declare that there is no duality of interest associated with this manuscript.

Contribution statement

All authors were responsible for drafting the article and revising it critically for important intellectual content. All authors approved the version to be published.

Supplementary material

125_2017_4361_MOESM1_ESM.pdf (119 kb)
ESM DPPOS Research Group Investigators (PDF 118 kb)
125_2017_4361_MOESM2_ESM.pptx (154 kb)
ESM Downloadable slideset (PPTX 154 kb)


  1. 1.
    Diabetes Prevention Program Research Group (1999) The Diabetes Prevention Program. Design and methods for a clinical trial in the prevention of type 2 diabetes. Diabetes Care 22:623–634CrossRefGoogle Scholar
  2. 2.
    Knowler WC, Barrett-Connor E, Fowler SE et al (2002) Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 346:393–403CrossRefPubMedGoogle Scholar
  3. 3.
    Jarrett RJ, Keen H, Fuller JH, McCartney M (1979) Worsening to diabetes in men with impaired glucose tolerance (“borderline diabetes”). Diabetologia 16:25–30CrossRefPubMedGoogle Scholar
  4. 4.
    Sartor G, Schersten B, Carlstrom S, Melander A, Norden A, Persson G (1980) Ten-year follow-up of subjects with impaired glucose tolerance: prevention of diabetes by tolbutamide and diet regulation. Diabetes 29:41–49CrossRefPubMedGoogle Scholar
  5. 5.
    Keen H, Jarrett RJ, McCartney P (1982) The ten-year follow-up of the Bedford survey (1962-1972): glucose tolerance and diabetes. Diabetologia 22:73–78CrossRefPubMedGoogle Scholar
  6. 6.
    Pan XR, Li GW, Hu YH et al (1997) Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance. The Da Qing IGT and Diabetes Study. Diabetes Care 20:537–544CrossRefPubMedGoogle Scholar
  7. 7.
    Tuomilehto J, Lindstrom J, Eriksson JG et al (2001) Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med 344:1343–1350CrossRefPubMedGoogle Scholar
  8. 8.
    Diabetes Prevention Program Research Group, Knowler WC, Fowler SE et al (2009) 10-year follow-up of diabetes incidence and weight loss in the Diabetes Prevention Program Outcomes Study. Lancet 374:1677–1686CrossRefPubMedCentralGoogle Scholar
  9. 9.
    Diabetes Prevention Program Research Group (2015) 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. Lancet Diabetes Endocrinol 3:866–875CrossRefPubMedCentralGoogle Scholar
  10. 10.
    Aroda VR, Ratner RE (2012) Interventional trials to prevent diabetes: diabetes prevention Program. In: LeRoith D (ed) Prevention of type 2 diabetes: from science to therapy. Springer, New York, pp 143–166CrossRefGoogle Scholar
  11. 11.
    American Diabetes Association (1997) Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 20:1183–1197CrossRefGoogle Scholar
  12. 12.
    Walker EA, Molitch M, Kramer MK et al (2006) Adherence to preventive medications: predictors and outcomes in the Diabetes Prevention Program. Diabetes Care 29:1997–2002CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Diabetes Prevention Program Research Group, Hamman RF, Horton E et al (2015) Factors affecting the decline in incidence of diabetes in the Diabetes Prevention Program Outcomes Study (DPPOS). Diabetes 64:989–998CrossRefGoogle Scholar
  14. 14.
    Ratner RE, Christophi CA, Metzger BE et al (2008) Prevention of diabetes in women with a history of gestational diabetes: effects of metformin and lifestyle interventions. J Clin Endocrinol Metab 93:4774–4779CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Aroda VR, Christophi CA, Edelstein SL et al (2015) The effect of lifestyle intervention and metformin on preventing or delaying diabetes among women with and without gestational diabetes: the Diabetes Prevention Program Outcomes Study 10-year follow-up. J Clin Endocrinol Metab 100:1646–1653CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Diabetes Prevention Program Research Group (2003) Effects of withdrawal from metformin on the development of diabetes in the Diabetes Prevention Program. Diabetes Care 26:977–980CrossRefGoogle Scholar
  17. 17.
    Lachin JM, Christophi CA, Edelstein SL et al (2007) Factors associated with diabetes onset during metformin versus placebo therapy in the Diabetes Prevention Program. Diabetes 56:1153–1159CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Kitabchi AE, Temprosa M, Knowler WC et al (2005) Role of insulin secretion and sensitivity in the evolution of type 2 diabetes in the Diabetes Prevention Program: effects of lifestyle intervention and metformin. Diabetes 54:2404–2414CrossRefPubMedGoogle Scholar
  19. 19.
    DeFronzo RA (1999) Pharmacologic therapy for type 2 diabetes mellitus. Ann Intern Med 131:281–303CrossRefPubMedGoogle Scholar
  20. 20.
    Hundal RS, Krssak M, Dufour S et al (2000) Mechanism by which metformin reduces glucose production in type 2 diabetes. Diabetes 49:2063–2069CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    International Expert Committee (2009) International Expert Committee report on the role of the A1C assay in the diagnosis of diabetes. Diabetes Care 32:1327–1334CrossRefGoogle Scholar
  22. 22.
    American Diabetes Association (2010) Diagnosis and classification of diabetes mellitus. Diabetes Care 33(Suppl 1):S62–S69CrossRefPubMedCentralGoogle Scholar
  23. 23.
    Diabetes Prevention Program Research Group (2015) HbA1c as a predictor of diabetes and as an outcome in the Diabetes Prevention Program: a randomized clinical trial. Diabetes Care 38:51–58CrossRefGoogle Scholar
  24. 24.
    Florez JC, Jablonski KA, Bayley N et al (2006) TCF7L2 polymorphisms and progression to diabetes in the Diabetes Prevention Program. N Engl J Med 355:241–250CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Hivert MF, Jablonski KA, Perreault L et al (2011) Updated genetic score based on 34 confirmed type 2 diabetes loci is associated with diabetes incidence and regression to normoglycemia in the Diabetes Prevention Program. Diabetes 60:1340–1348CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Jablonski KA, McAteer JB, de Bakker PI et al (2010) Common variants in 40 genes assessed for diabetes incidence and response to metformin and lifestyle intervention in the Diabetes Prevention Program. Diabetes 59:2672–2681CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Diabetes Prevention Program Research Group (2009) Changes in albumin excretion in the Diabetes Prevention Program. Diabetes Care 32:720–725CrossRefPubMedCentralGoogle Scholar
  28. 28.
    Goldberg R, Temprosa M, Otvos J et al (2013) Lifestyle and metformin treatment favorably influence lipoprotein subfraction distribution in the Diabetes Prevention Program. J Clin Endocrinol Metab 98:3989–3998CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Goldberg RB, Temprosa MG, Mather KJ et al (2014) Lifestyle and metformin interventions have a durable effect to lower CRP and tPA levels in the Diabetes Prevention Program except in those who develop diabetes. Diabetes Care 37:2253–2260CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Orchard TJ, Temprosa M, Goldberg R et al (2005) The effect of metformin and intensive lifestyle intervention on the metabolic syndrome: the Diabetes Prevention Program randomized trial. Ann Intern Med 142:611–619CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Ratner R, Goldberg R, Haffner S et al (2005) Impact of intensive lifestyle and metformin therapy on cardiovascular disease risk factors in the Diabetes Prevention Program. Diabetes Care 28:888–894CrossRefPubMedGoogle Scholar
  32. 32.
    Diabetes Prevention Program Outcomes Study Research Group, Orchard TJ, Temprosa M et al (2013) Long-term effects of the Diabetes Prevention Program interventions on cardiovascular risk factors: a report from the DPP Outcomes Study. Diabet Med 30:46–55CrossRefGoogle Scholar
  33. 33.
    Goldberg RB, Aroda VR, Bluemke DA et al (2017) Effect of long-term metformin and lifestyle in the Diabetes Prevention Program and its outcome study on coronary artery calcium. Circulation doi: 10.1161/CIRCULATIONAHA.116.025483
  34. 34.
    Diabetes Prevention Program Research Group (2012) Long-term safety, tolerability, and weight loss associated with metformin in the Diabetes Prevention Program Outcomes Study. Diabetes Care 35:731–737CrossRefGoogle Scholar
  35. 35.
    Inzucchi SE, Lipska KJ, Mayo H, Bailey CJ, McGuire DK (2014) Metformin in patients with type 2 diabetes and kidney disease: a systematic review. JAMA 312:2668–2675CrossRefPubMedCentralGoogle Scholar
  36. 36.
    Aroda VR, Edelstein SL, Goldberg RB et al (2016) Long-term metformin use and vitamin B12 deficiency in the Diabetes Prevention Program Outcomes Study. J Clin Endocrinol Metab 101:1754–1761CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    American Diabetes Association (2017) Prevention or delay of type 2 diabetes. Diabetes Care 40:S44–S47CrossRefGoogle Scholar
  38. 38.
    International Diabetes Federation (2016) IDF diabetes atlas—7th edition, Accessed 14 Feb 2017
  39. 39.
    Diabetes Prevention Program Research Group (2012) The 10-year cost-effectiveness of lifestyle intervention or metformin for diabetes prevention: an intent-to-treat analysis of the DPP/DPPOS. Diabetes Care 35:723–730CrossRefGoogle Scholar
  40. 40.
    Hostalek U, Gwilt M, Hildemann S (2015) Therapeutic use of metformin in prediabetes and diabetes prevention. Drugs 75:1071–1094CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Chiasson JL, Josse RG, Gomis R et al (2002) Acarbose for prevention of type 2 diabetes mellitus: the STOP-NIDDM randomised trial. Lancet 359:2072–2077CrossRefPubMedGoogle Scholar
  42. 42.
    Torgerson JS, Hauptman J, Boldrin MN, Sjostrom L (2004) XENical in the prevention of diabetes in obese subjects (XENDOS) study: a randomized study of orlistat as an adjunct to lifestyle changes for the prevention of type 2 diabetes in obese patients. Diabetes Care 27:155–161CrossRefPubMedGoogle Scholar
  43. 43.
    Kosaka K, Noda M, Kuzuya T (2005) Prevention of type 2 diabetes by lifestyle intervention: a Japanese trial in IGT males. Diabetes Res Clin Pract 67:152–162CrossRefPubMedGoogle Scholar
  44. 44.
    Ramachandran A, Snehalatha C, Mary S et al (2006) The Indian Diabetes Prevention Programme shows that lifestyle modification and metformin prevent type 2 diabetes in Asian Indian subjects with impaired glucose tolerance (IDPP-1). Diabetologia 49:289–297CrossRefPubMedGoogle Scholar
  45. 45.
    Dream Trial Investigators, Gerstein HC, Yusuf S et al (2006) Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial. Lancet 368:1096–1105CrossRefGoogle Scholar
  46. 46.
    Dream Trial Investigators, Bosch J, Yusuf S et al (2006) Effect of ramipril on the incidence of diabetes. N Engl J Med 355:1551–1562CrossRefGoogle Scholar
  47. 47.
    Kawamori R, Tajima N, Iwamoto Y et al (2009) Voglibose for prevention of type 2 diabetes mellitus: a randomised, double-blind trial in Japanese individuals with impaired glucose tolerance. Lancet 373:1607–1614CrossRefPubMedGoogle Scholar
  48. 48.
    Navigator Study Group, JJ MM, Holman RR et al (2010) Effect of valsartan on the incidence of diabetes and cardiovascular events. N Engl J Med 362:1477–1490CrossRefGoogle Scholar
  49. 49.
    Navigator Study Group, Holman RR, Haffner SM et al (2010) Effect of nateglinide on the incidence of diabetes and cardiovascular events. N Engl J Med 362:1463–1476CrossRefGoogle Scholar
  50. 50.
    Zinman B, Harris SB, Neuman J et al (2010) Low-dose combination therapy with rosiglitazone and metformin to prevent type 2 diabetes mellitus (CANOE trial): a double-blind randomised controlled study. Lancet 376:103–111CrossRefPubMedGoogle Scholar
  51. 51.
    DeFronzo RA, Tripathy D, Schwenke DC et al (2011) Pioglitazone for diabetes prevention in impaired glucose tolerance. N Engl J Med 364:1104–1115CrossRefPubMedGoogle Scholar
  52. 52.
    le Roux CW, Astrup A, Fujioka K et al (2017) 3 years of liraglutide versus placebo for type 2 diabetes risk reduction and weight management in individuals with prediabetes: a randomised, double-blind trial. Lancet 389:1399–1409CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany 2017

Authors and Affiliations

  • Vanita R. Aroda
    • 1
    • 2
    • 3
    Email author
  • William C. Knowler
    • 4
  • Jill P. Crandall
    • 5
  • Leigh Perreault
    • 6
  • Sharon L. Edelstein
    • 3
  • Susan L. Jeffries
    • 7
  • Mark E. Molitch
    • 8
  • Xavier Pi-Sunyer
    • 9
  • Christine Darwin
    • 10
  • Brandy M. Heckman-Stoddard
    • 11
  • Marinella Temprosa
    • 3
  • Steven E. Kahn
    • 12
    • 13
  • David M. Nathan
    • 14
    • 15
  • for the Diabetes Prevention Program Research Group
  1. 1.MedStar Health Research InstituteHyattsvilleUSA
  2. 2.Division of Endocrinology, Diabetes, and MetabolismGeorgetown University School of MedicineWashingtonUSA
  3. 3.The Biostatistics CenterThe George Washington UniversityRockvilleUSA
  4. 4.Diabetes Epidemiology and Clinical Research Section, Phoenix Epidemiology and Clinical Research BranchNational Institute of Diabetes and Digestive and Kidney DiseasesPhoenixUSA
  5. 5.Department of Medicine, Division of EndocrinologyAlbert Einstein College of MedicineNew YorkUSA
  6. 6.Division of Endocrinology, Metabolism and Diabetes, School of MedicineUniversity of Colorado DenverDenverUSA
  7. 7.Department of Epidemiology, Graduate School of Public HealthUniversity of PittsburghPittsburghUSA
  8. 8.Feinberg School of MedicineNorthwestern UniversityChicagoUSA
  9. 9.Columbia University Medical CenterNew YorkUSA
  10. 10.University of California, Los Angeles Medical CenterLos AngelesUSA
  11. 11.Division on Cancer PreventionNational Cancer InstituteBethesdaUSA
  12. 12.VA Puget Sound Health Care SystemSeattleUSA
  13. 13.Division of Metabolism, Endocrinology and Nutrition, Department of MedicineUniversity of WashingtonSeattleUSA
  14. 14.Department of Medicine, Diabetes UnitMassachusetts General HospitalBostonUSA
  15. 15.Harvard Medical SchoolBostonUSA

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