Clinical Perspective
What Is New?
During the 21-year follow-up of the 3234 DPP (Diabetes Prevention Program) participants who began with impaired glucose tolerance and were followed in the DPPOS (Diabetes Prevention Program Outcomes Study), neither metformin nor the lifestyle interventions reduced major adverse cardiovascular events compared with placebo, despite decreasing diabetes development.
Results should be viewed in the context of the modest progression of hyperglycemia, extensive out-of-study use of lipid-lowering and antihypertensive medications, provision of a less intensive lifestyle intervention to all DPPOS participants, and increased out-of-study metformin use over time, which may both have limited the apparent effects of the interventions and have been valuable preventive strategies.
What Are the Clinical Implications?
Despite significant long-term reduction in diabetes development, metformin and lifestyle interventions may not have additional effects on cardiovascular disease prevention in the setting of impaired glucose tolerance or early type 2 diabetes with minimal cardiovascular disease and modern glucose-lowering, lipid-lowering, and antihypertensive treatment strategies.
Metformin and lifestyle intervention reduce the risk of type 2 diabetes, but may not provide additional protection against cardiovascular disease when glycemia, lipids, and blood pressure are well controlled.
Editorial, see p 1642
Type 2 diabetes is associated with a 2- to 3-fold increased risk for cardiovascular disease.1,2 Although glycemia-related mechanisms are a likely contributor,2 attempts to reduce risk with intensive management of glycemia have had variable results3–6 with several long-term follow-up studies of initially negative clinical trials suggesting a benefit,7,8 albeit potentially short-lived,9 and one positive trial demonstrating long-term beneficial effects in myocardial infarction survivors.10 Metformin has been shown to have a beneficial effect in reducing myocardial infarctions and total cardiovascular events in a single study.11
This mixed picture of hyperglycemia predicting cardiovascular events, although glycemia reduction does not consistently lower their incidence, supports a multifactorial pathogenesis of cardiovascular disease in diabetes wherein some of the diabetes-associated cardiovascular risk is mediated by nonglycemic pathways. The diabetes-atherogenesis link may thus have its roots with earlier metabolic disturbances, like insulin resistance12 and prediabetes.13 This concept suggests that intervention in an earlier, prediabetic phase may be of greater benefit regarding cardiovascular disease (CVD) reduction.
Successful diabetes prevention studies14–17 have thus examined the impact of their interventions on CVD risk with no clear benefit emerging except for acarbose,17 which was not subsequently confirmed.18 However, extended follow-up of the Da Qing Diabetes Prevention Study, a lifestyle intervention study, showed benefit for cardiovascular mortality after 23 years19 and for cardiovascular events after 30 years follow-up.20
The randomized interventions in the DPP trial (Diabetes Prevention Program) were highly successful after an average of 2.8 years in reducing cumulative diabetes incidence by 58% with intensive lifestyle and by 31% with metformin compared with placebo.16 The benefits on diabetes prevention have continued for as long as 15 years after randomization during continued follow-up in the DPPOS (DPP Outcomes Study).21 DPPOS has recently focused on the cardiovascular impact of metformin given its suggestive benefit in the UKPDS study (United Kingdom Prospective Diabetes Study),11 and beneficial effects on cardiovascular risk factors,22,23 the arterial wall,24 and coronary calcification.25 The present report’s primary objective is to assess the effect of the original DPP randomization to metformin or lifestyle interventions on major adverse cardiovascular events compared with placebo.
Methods
DPP/DPPOS Design
The DPP randomized clinical trial (1996–2002, with a mean of 3 years of study) compared metformin or lifestyle with placebo to prevent or delay diabetes in 3234 participants with impaired glucose tolerance, fasting plasma glucose 5.27 to 6.94 mmol/L (95–125 mg/dL), and body mass index ≥24 kg/m2, hereafter referred to as prediabetes.16 Individuals who had experienced a cardiovascular event within 6 months of screening were excluded. The methods have been described in detail.26 Written informed consent was obtained from all participants before screening, consistent with the Declaration of Helsinki and the guidelines of each center’s institutional review board, all of which approved the trial. Eligible persons were randomly assigned to metformin 850 mg twice daily, placebo twice daily, or lifestyle intervention aimed at weight reduction of ≥7% of initial body weight and at least 150 minutes per week of moderate intensity physical activity (CONSORT diagram, Figure S1). Treatment assignments were stratified according to clinical center and double-blinded for metformin and placebo. Standardized questionnaires, assessment of systolic and diastolic blood pressure, height and weight, and measurement of glycohemoglobin, insulin, lipid profile, urine albumin/creatinine ratio, and estimation of glomerular filtration rate were performed annually as previously described.16,21,26 Diabetes was diagnosed by an annual oral glucose tolerance test or a semiannual fasting glucose21 and required confirmation by a second test. If confirmed, diabetes management was transferred to the participant’s health care provider. Metformin or placebo was still provided until the fasting plasma glucose level was ≥7.7 mmol/L (≥140 mg/dL) during DPP.
At the end of DPP, all surviving members regardless of diabetes status were invited to participate in DPPOS (2002–2019). In view of the clear evidence of benefit of the lifestyle intervention, all participants were offered the lifestyle intervention in a group format during a 1-year bridge period between DPP and DPPOS. During DPPOS, randomized metformin therapy, now unmasked, was continued until the glycohemoglobin was >7%, at which time the study drug was discontinued. After diabetes diagnosis and cessation of study-supplied metformin, 28% of participants were treated with metformin by their own health care providers. Such use was tracked and called out-of-study metformin in this report. At the end of DPP, all participants were offered lifestyle intervention in a supplementary semiannual group lifestyle program.21 During DPP and DPPOS, treatment of cardiovascular risk factors was left to the participants’ own health care providers.
CVD Outcomes
All fatal and nonfatal cardiovascular events were adjudicated by an Outcomes Classification Committee of physicians masked to treatment assignment using medical records, death certificates, autopsy reports, and research records. The committee membership was largely unchanged throughout the duration of the study, The primary outcome was the first occurrence of a major cardiovascular event defined as nonfatal myocardial infarction (excluding silent myocardial infarction), nonfatal stroke, or fatal CVD. An extended cardiovascular event outcome comprised the first occurrence of a major event as earlier, or hospitalization for congestive heart failure or unstable angina, coronary or peripheral revascularization, coronary heart disease diagnosed by angiography, or silent myocardial infarction. The definitions of the cardiovascular outcomes are tabulated in Table S1.
From DPP inception in 1996 through DPPOS, participants were screened for CVD events at every contact to obtain medical records for adjudication of myocardial infarction and other cardiovascular outcomes on the basis of criteria used in the Women’s Health Initiative27 and in the randomized clinical trial PEACE (Prevention of Events with ACE Inhibition).28,29 Because of advances in laboratory methodology related to troponin levels, and other changes, as well, new criteria for adjudication of myocardial infarction in clinical trials were established by the American Heart Association/American College of Cardiology task force and published in 2015.30 These new criteria were adopted by the DPPOS for adjudication of new cases beginning in November 2016. ECGs were recorded at baseline and annually until DPPOS Year 14 and biennially thereafter in all participants using standardized procedures on identical electrocardiographs (MAC 1200, Marquette Electronics Inc.) at all clinic sites. ECGs were processed centrally at the Epidemiological Cardiology Research Center of Wake Forest School of Medicine (Winston-Salem, NC), where all were visually inspected for technical errors and overall quality. ECGs from hospital records were read by the Epidemiological Cardiology Research Center using Minnesota Code criteria31 and were used in the adjudication process. For participants lost to follow-up, a search was conducted of the National Death Index with deaths reported as of December 31, 2018, and a commercial investigation firm (ASG), as well, to determine more updated vital status as of December 31, 2019. The causes of death indicated on National Death Index reports were reviewed and classified similarly to other deaths. The total follow-up described in this report covers the average 3-year follow-up in DPP plus up to 18 years during DPPOS for a total median follow-up of 21 years.
Statistical Methods
A primary goal of DPPOS was to assess the long-term effects of metformin, in comparison with placebo, on the incidence of major adverse cardiovascular events among participants who had prediabetes at the study entry. To detect a 30% risk reduction in the metformin versus placebo comparison with 85% power and a 2-sided significance level of 0.05 using a log-rank test, it was estimated that 145 events would be required in the placebo group. Although it was projected that we needed to follow the participants until approximately 2025, a prespecified interim analysis of this outcome for the metformin versus placebo group was conducted to assess futility of the major adverse cardiovascular event outcome for the metformin versus placebo comparison. A nonbinding guideline based on a conditional power criterion of <15% and an efficacy interim look using an O’Brien-Fleming alpha spending function to control the type 1 error rate at 0.05 was used. The interim analysis occurred in March 2019 when the Data Safety Monitoring Board declared the futility for the metformin versus placebo comparison of the major adverse cardiovascular event outcome leading to this early report. With 57% of the information, the prespecified futility analysis showed a hazard ratio (95% CI) of 0.91 (0.68–1.23) for the metformin versus placebo comparison with P=0.54 and conditional power (95% CI) of 4.1% (0.1%–32.6%) under the present trend. The data used for this report included results for an additional year to maximize adjudicated data for the analysis. The lifestyle and placebo comparison is considered a secondary analysis.
Primary analyses used the intention-to-treat paradigm including all participants with data at the datalock that was February 23, 2020. Generalized estimating equations (with identity link for continuous and logit link for binary measures) were used to assess time-weighted differences in longitudinal measures to account for within-person correlation and assumed that data are missing at random. Risk factor data before the development of a major cardiovascular event were included in these analyses. The time to first cardiovascular event analysis was based on the first occurrence as adjudicated by the Outcomes Classification Committee. Each participant had 2 censor dates to reflect differences in ascertainment of events, namely, the last contact or visit in DPP or DPPOS for nonfatal events before the datalock in February 2020 and the last survey for deaths in December 2019. Cumulative incidence rates accounted for competing risk attributable to noncardiovascular deaths using Fine-Gray estimates32 in marginal Cox proportional hazards models to assess treatment and covariate effects33 and to accommodate separate ascertainment times for fatal and nonfatal events. Treatment effects are tested and expressed as hazard ratios and 95% confidence limits. Secondary analyses for assessing the effects of metformin and lifestyle compared with placebo according to prespecified subgroups were conducted without adjustment for multiplicity. Extended follow-up increased the likelihood that time-varying confounders attributable to intercurrent events may attenuate the hypothesized effect of randomized metformin compared with placebo.34 Therefore, additional Cox models assessed the effect of lifestyle and metformin compared with placebo after adjustment for cardiovascular risk factors and out-of-study metformin use to explore these potential sources of confounding.
Results
The characteristics of the overall study population at baseline and by treatment group, time-weighted during follow-up, are shown in Table 1. At baseline, the population was middle aged (mean age, 51 years) with more women (68%) than men and was racially diverse with 54.7% being White, 19.9% Black, 15.7% Hispanic, 5.3% American Indian, and 4.4% Asian. All baseline characteristics were similar among the 3 treatment groups, except for significantly lower high-density lipoprotein cholesterol and higher triglyceride concentrations in the placebo compared with the metformin or lifestyle groups. During follow-up, cardiovascular risk factors were generally more favorable in the active intervention than in the placebo groups, except for low-density lipoprotein cholesterol, urine albumin, and glomerular filtration rate that did not differ over time by treatment group. Overall antihypertensive medication and statin use were common at 68% to 74% and 56% to 62%, respectively; however, use of statins was modestly, albeit significantly lower in the lifestyle, but not in the metformin group, compared with the placebo group (Table 1). In general, smoking rates were low at 7% and fell over time in all groups, although to a greater extent in the lifestyle group. It is important to note that the development of diabetes was significantly lower in both the metformin and lifestyle than in the placebo groups. Figure 1 shows the overall improvement in cardiovascular risk factors over time, except for glycohemoglobin and systolic blood pressure that increased in later years.
Table 1. Participant Characteristics at Baseline, and Time-Weighted Mean For 21 Years Follow-up After Randomization by Original Diabetes Prevention Program Randomized Groups
Characteristics during follow-upBaseline (n=3234)Characteristics during follow-up by original randomized groupsPlacebo (n=1073)Metformin (n=1082)Lifestyle (n=1079)Metformin vs placebo P value*Intensive lifestyle vs placebo P value*Time-weighted mean during follow-up† Body mass index (kg/m2)34.0 (33.7–34.2)33.6 (33.2−34.1)32.8 (32.4−33.3)32.5 (32.1−32.9)0.017<0.001 Waist105 (105–106)106 (105−107)105 (104−106)104 (103−105)0.0710.001 Fasting glucose (mmol/L)5.9 (5.9–5.9)6.5 (6.4−6.6)6.2 (6.1−6.3)6.3 (6.2−6.4)<0.001<0.001 Glycohemoglobin (%)5.9 (5.9–5.9)6.1 (6.1−6.2)6.0 (6.0−6.0)6.0 (6.0−6.0)<0.0010.005 Glycohemoglobin (International Federation of Clinical Chemists)41.1 (40.9–41.3)43.4 (42.9−43.9)42.0 (41.5−42.5)42.4 (41.9−42.9)<0.0010.006 Fasting insulin (pmol/L)160 [158–164]178 [174-184]165 [160−169]161 [156−166]<0.001<0.001 Low-density lipoprotein cholesterol (mmol/L)3.23 (3.20–3.26)2.83 (2.79−2.88)2.81 (2.77−2.8)2.85 (2.81−2.89)0.240.96 High-density lipoprotein cholesterol (mmol/L)‡1.18 (1.17–1.19)1.27 (1.25−1.29)1.32 (1.3−1.34)1.30 (1.28−1.33)0.0030.007 Triglyceride (mmol/L)‡1.61 [1.58–1.64]1.45 [1.42-1.49]1.40 [1.37-1.44]1.35 [1.32-1.39]0.052<0.001 Systolic blood pressure124 (123–124)122 (122−123)122 (122−123)121 (120−122)0.570.006 Diastolic blood pressure78 (78–79)74 (73−74)74 (73−74)73 (73−74)0.770.047 Urine albumin/creatinine ratio (mg/mmol)0.67 [0.65–0.69]0.93 [0.88−0.98]0.90 [0.85−0.95]0.91 [0.86-0.96]0.410.61 Estimated glomerular filtration rate (mL·min–1·1.73 m–2)98.4 (97.8–99.0)89.6 (88.7−90.5)88.7 (87.8−89.7)88.7 (87.7−89.7)0.360.63Percent with condition at baseline and during follow-up Smoking, %0.0590.012 Never59606361 Past34323335 Current7854 Hypertension, %298082790.280.32 Hyperlipidemia, %699492910.090.03 Diabetes, %N/A6055530.010.001 Out-of-study metformin, %N/A432837<0.0010.002 Antihypertensive medications, %167473680.480.13 Statin therapy, %46259560.150.004
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 time point (n) is as follows: baseline, n=3234; year 5, n=2573; year 10, n=2356; year 15, n=2144; and year 20, n=1884.
During 21 years of median follow-up, 310 individuals experienced a first major cardiovascular event (Table 2, Figure 2). The incidence did not differ by treatment group; the metformin versus placebo hazard ratio was 1.03 (95% CI, 0.78–1.37; P=0.81) and the lifestyle versus placebo hazard ratio was 1.14 (95% CI, 0.87–1.50; P=0.34). Among the major cardiovascular event components, there were fewer nonfatal strokes in the metformin than in the placebo group, with no significant difference in rates, hazard ratio 0.57 (95% CI, 0.31–1.06; P=0.07), whereas the lifestyle group showed an opposite trend, hazard ratio 1.42 (95% CI, 0.87–2.30; P=0.16). Compared with placebo, the risk for cardiovascular death in both the metformin and lifestyle groups trended higher but was not different from the placebo group, hazard ratios 1.46 (95% CI, 0.90–2.39; P=0.13) and 1.40 (95% CI, 0.85–2.29; P=0.19), respectively. There were no significant associations between interventions and the incidence of the extended cardiovascular event outcome (Table 2, Figure 3, Table S2).
Table 2. Effect of Metformin and Lifestyle on First Major Adverse Cardiovascular Events and the First Occurrence of Individual Major Cardiovascular Components and Extended Cardiovascular Outcome Events
Cardiovascular eventsNumber of eventsEvent rate/1000 person-yearMetformin vs placeboLifestyle vs placeboPlaceboMetforminLifestylePlaceboMetforminLifestyleHazard ratio (95% CI)P valueHazard ratio (95% CI)P valueTotal major adverse cardiovascular events981011115.285.516.101.03 (0.78–1.37)0.811.14 (0.87–1.50)0.34Nonfatal myocardial infarction4346352.302.491.901.07 (0.71–1.63)0.730.82 (0.52–1.28)0.38Nonfatal stroke2816391.480.862.120.57 (0.31–1.06)0.071.42 (0.87–2.30)0.16Cardiovascular death2739371.422.071.991.46 (0.90–2.39)0.131.40 (0.85–2.29)0.19Extended cardiovascular events outcome1571571748.738.869.931.00 (0.80–1.25)0.991.12 (0.90–1.39)0.29
Figure 2. Cumulative incidence of total major adverse cardiovascular events (MACE) and individual cardiovascular event components by intervention groups. A, Effects of the interventions on the cumulative incidence (%) of first MACE. First occurrence of individual MACE shown are: nonfatal myocardial infarction (B), nonfatal stroke (C), and cardiovascular death (D). The metformin group is shown in red, the lifestyle group in green, and the placebo group in blue.
Figure 3. Effect of metformin and lifestyle interventions vs 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, the lifestyle group in green, and the placebo group in blue.
Prespecified subgroup analyses for intervention effects on major cardiovascular events (Figure 4, Table S3) showed no significant heterogeneity by age, sex, race/ethnicity, or diabetes development for either metformin or lifestyle.
Figure 4. Effect of metformin and lifestyle interventions vs placebo on the incidence of major adverse cardiovascular events (MACE) by age, sex, race or ethnicity, and diabetes status subgroups. A, Effect of metformin vs placebo groups on MACE. B, Effect of lifestyle vs placebo groups on MACE. Effects by subgroups are described as hazard ratio (95% CI). In prespecified age, sex, race or ethnicity, and diabetes status subgroups are shown as hazard ratios (95% CI). The heterogeneity P values reflect the interaction of subgroup × treatment group to assess the 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. HR indicates hazard ratio.
Study metformin use gradually fell, from 77% at the end of DPP to 41% at the most recent assessment, whereas out-of-study metformin use increased in all 3 original treatment groups (Table 1), primarily after diabetes diagnosis. We thus constructed adjusted models (Table S4) with time-dependent cardiovascular risk factors, diabetes status, and out-of-study metformin use which confirmed that assignment to metformin did not result in any benefit or harm in terms of major cardiovascular events.
Discussion
In this 21-year-long follow-up study of the effects of metformin and lifestyle interventions, each of which reduced the development of diabetes compared with placebo, on cardiovascular events in an ethnically diverse cohort with prediabetes, we found no overall beneficial or unfavorable effects associated with either intervention on time to first major cardiovascular event, or to the extended cardiovascular outcome. These metformin findings are consistent with a meta-analysis of clinical trials of metformin in type 2 diabetes35 that found no significant benefit for metformin on CVD, although there were favorable, nonsignificant, trends. However, the original UKPDS study performed in the prestatin era, and which was not included in the meta-analysis, found that metformin significantly reduced myocardial infarction by 39% and stroke by 41% in overweight subjects with newly diagnosed diabetes.11 In addition, metformin treatment was associated with a 53% reduction in stroke over a 4-year period in an observational Taiwanese database study.36 We found no significant difference in stroke events between the metformin and placebo groups.
Our earlier observation that coronary calcification, measured after 14 years of follow-up, was lower in men in the metformin than in the placebo group,25 raised the possibility that metformin would have beneficial effects on cardiovascular events. The absence of such an effect may be related to the fact that coronary calcification is a subclinical precursor of cardiovascular events, and more time may be needed to determine whether this beneficial effect of metformin on coronary calcification translates into a reduced number of events.
Overall rates for major cardiovascular events were slightly lower than national cross-sectional estimates for prediabetes and considerably lower than those for diagnosed diabetes.37 Our cohort with prediabetes is unique because of the selection criteria used for inclusion in the study and the semiannual fasting glucose and annual oral glucose tolerance testing protocol used to diagnose diabetes at the earliest time point. Furthermore, even after 21 years of follow-up, the degree of hyperglycemia in the cohort was mild, with mean glycohemoglobin values 6.0% to 6.1% despite the fact that 53% to 60% of participants had developed diabetes on the basis of fasting glucose and oral glucose tolerance testing in the 3 treatment groups. Furthermore, although only 16% and 4% of participants were taking antihypertensive and statin agents at randomization, between 68% to 74% and 53% to 62%, respectively, were receiving these medications from their physicians, and the mean blood pressure was 122/73 and low-density lipoprotein cholesterol was 2.8 mmol/L (108 mg/dL) in the 3 groups at 21 years of follow-up. Effective control of major cardiovascular risk factors in cohorts with diabetes has been shown to reduce the risk of CVD.38,39 This was therefore a relatively low-risk cohort from the standpoint of the prevention of CVD. It is thus possible that the accelerating effect of the duration of clinically diagnosed diabetes on cardiovascular risk40,41 has still not had enough time to manifest, making it more difficult to identify a beneficial effect of metformin.
The finding that lifestyle intervention had no beneficial effect on cardiovascular events, despite favorable influences on cardiovascular risk factors, may in part be because the lifestyle intervention was intensive only during DPP, after which group lifestyle was offered to all participants. Nevertheless, our findings are consistent with the lack of effect on cardiovascular events in 2 other studies of lifestyle change on diabetes prevention, namely the 10-year Finnish Diabetes Prevention Study14 and the 20-year follow-up of the Da Qing study.15 Lifestyle intervention also failed to show benefit despite favorable risk factor changes in the Look AHEAD trial (Action for Health in Diabetes) cohort with type 2 diabetes.42 However, a longer, 30-year follow-up of the Da Qing study did demonstrate a benefit with lifestyle for major cardiovascular events (hazard ratio 0.74 [95% CI, 0.59–0.92]).20 It should also be noted that the Da Qing cohort was a higher-risk population with a greater proportion of smokers, a higher prevalence of hypertension, and diabetes with more severe hyperglycemia and a higher overall CVD event rate.19 Thus, further follow-up of DPPOS may clarify our findings in terms of lifestyle intervention.
Unlike the studies just referred to, the current report raises the possibility of a sex difference in the effect of lifestyle on major cardiovascular events where there was borderline heterogeneity (P=0.053), with lifestyle being potentially harmful in women yet somewhat protective in men. We have also previously reported a less favorable effect of metformin in DPP on the development of the metabolic syndrome in women compared with men.23 These sex differences merit further investigation. Similarly, the finding of a reduced number of events in men aged <45 years compared with placebo that was not significant, given our earlier findings of a beneficial effect of metformin on coronary calcification in this group,25 should be further investigated to determine whether it too is simply the result of a play of chance.
A further limitation of these analyses is the possibility that the impact of our interventions was lessened by the reduced intensity of the lifestyle intervention after the DPP phase of the study as mentioned earlier, and by the gradual reduction in adherence to study metformin over time. Another limitation is the expanded use of out-of-study metformin that may have diluted the differences between study groups, especially in those with diabetes, although sensitivity analysis failed to show such an effect. Increased use of statin and antihypertensive treatment prescribed by participants’ primary care providers overall and significantly lower use of statins and nominally lower use of antihypertensive medications in the lifestyle group may also have influenced the results, although adjustment for medication use did not alter the results. It should also be recognized that these results cannot be generalized to all people with prediabetes because we selected a subgroup with both impaired glucose tolerance and an elevated fasting glucose >5.3 mmol/L (95 mg/dL) who were at particularly high risk for diabetes development. Last, there may also have been some underestimation of nonfatal events resulting from loss to follow-up.
These findings ultimately need to be evaluated in the context of the role of metformin and lifestyle intervention in diabetes prevention. Both interventions have demonstrated long-term reduction in diabetes development in DPP/DPPOS. Although it is reassuring that metformin was not associated with any overall unfavorable effects on CVD, it is surprising that neither intervention yielded benefit for CVD through their effect on diabetes prevention. It may be that a beneficial effect related to diabetes prevention was not apparent in our study because the development of diabetes in its very early stages may not, per se, have increased cardiovascular risk above the effect of known risk factors.
Article Information
Acknowledgments
The DPP Research Group gratefully acknowledges the commitment and dedication of the participants of the Diabetes Prevention Program (DPP) and DPPOS (Diabetes Prevention Program Outcomes Study), and the Outcomes Committee Members (Jill Crandall [Chairperson], Robert Ratner [prior Chair], Angela Brown, Richard Arakaki, Anna Bowers, Enrico Cagliero, Sharon Edelstein, David Ehrmann, Ronald Goldberg, Kieren Mather, Trevor Orchard, Hanna Sherif, Preethi Srikanthan, Marinella Temprosa, and Karol Watson). The sponsor of this study was represented on the Steering Committee and played a part in study design, how the study was done, and publication. All authors in the writing group had access to all data. The opinions expressed are those of the study group and do not necessarily reflect the views of the funding agencies. A complete list of investigators and staff can be found in the Supplemental Material.
Sources of Funding
Research reported in this publication was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (NIH) under award numbers U01 DK048489, U01 DK048339, U01 DK048377, U01 DK048349, U01 DK048381, U01 DK048468, U01 DK048434, U01 DK048485, U01 DK048375, U01 DK048514, U01 DK048437, U01 DK048413, U01 DK048411, U01 DK048406, U01 DK048380, U01 DK048397, U01 DK048412, U01 DK048404, U01 DK048387, U01 DK048407, U01 DK048443, and U01 DK048400, by providing funding during the Diabetes Prevention Program (DPP) and DPPOS (Diabetes Prevention Program Outcomes Study) 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. 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 National Cancer Institute, the Office of Research on Women’s Health, the National Institute on Minority Health and Health Disparities, the Centers for Disease Control and Prevention, and the American Diabetes Association. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. 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. Merck KGaA provided medication for DPPOS. DPP/DPPOS have also received donated materials, equipment, or medicines for concomitant conditions from Bristol-Myers Squibb, Parke-Davis, and LifeScan Inc., Health O Meter, Hoechst Marion Roussel Inc, Merck-Medco Managed Care Inc, Merck and Co., Nike Sports Marketing, Slim Fast Foods Co., and Quaker Oats Co. McKesson BioServices Corp., Matthews Media Group Inc, and the Henry M. Jackson Foundation provided support services under subcontract with the Coordinating Center. The sponsor of this study was represented on the Steering Committee and played a part in study design, how the study was done, and publication. All authors in the writing group had access to all data. The opinions expressed are those of the study group and do not necessarily reflect the views of the funding agencies. A complete list of investigators and staff can be found in the Supplemental Material.
Supplemental Material
Tables S1–S4
Figure S1
Nonstandard Abbreviations and Acronyms
CVD
cardiovascular disease
DPP
Diabetes Prevention Program
DPPOS
Diabetes Prevention Program Outcome Study
UKPDS
United Kingdome Prospective Diabetes Study
Disclosures Kishore M. Gadde received grant support from AstraZeneca and BioKer. The other authors report no conflicts.
Footnotes
*The authors listed in the byline are members of the Writing Group. A full list of the members of the Diabetes Prevention Program Research Group are listed in the Supplemental Material.
This manuscript was sent to Rury Holman, Guest Editor, for review by expert referees, editorial decision, and final disposition.
Supplemental Material, the podcast, and transcript are available with this article at https://www.ahajournals.org/doi/suppl/10.1161/CIRCULATIONAHA.121.056756.
Continuing medical education (CME) credit is available for this article. Go to http://cme.ahajournals.org to take the quiz.
For Sources of Funding and Disclosures, see page 1640.
Circulation is available at www.ahajournals.org/journal/circ
Correspondence to: DPP Research Group, Diabetes Prevention Program Coordinating Center, George Washington University Biostatistics Center, 6110 Executive Blvd, Rockville, MD 20852. Email [email protected]gwu.edu
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