Long-term Sustainability of Diabetes Prevention Approaches: A Systematic Review and Meta-analysis of Randomized Clinical Trials

Abstract

Importance: Diabetes prevention is imperative to slow worldwide growth of diabetes-related morbidity and mortality. Yet the long-term efficacy of prevention strategies remains unknown.

Objective: To estimate aggregate long-term effects of different diabetes prevention strategies on diabetes incidence.

Data sources: Systematic searches of MEDLINE, EMBASE, Cochrane Library, and Web of Science databases. The initial search was conducted on January 14, 2014, and was updated on February 20, 2015. Search terms included prediabetes, primary prevention, and risk reduction.

Study selection: Eligible randomized clinical trials evaluated lifestyle modification (LSM) and medication interventions (>6 months) for diabetes prevention in adults (age ≥18 years) at risk for diabetes, reporting between-group differences in diabetes incidence, published between January 1, 1990, and January 1, 2015. Studies testing alternative therapies and bariatric surgery, as well as those involving participants with gestational diabetes, type 1 or 2 diabetes, and metabolic syndrome, were excluded.

Data extraction and synthesis: Reviewers extracted the number of diabetes cases at the end of active intervention in treatment and control groups. Random-effects meta-analyses were used to obtain pooled relative risks (RRs), and reported incidence rates were used to compute pooled risk differences (RDs).

Main outcomes and measures: The main outcome was aggregate RRs of diabetes in treatment vs control participants. Treatment subtypes (ie, LSM components, medication classes) were stratified. To estimate sustainability, post-washout and follow-up RRs for medications and LSM interventions, respectively, were examined.

Results: Forty-three studies were included and pooled in meta-analysis (49 029 participants; mean [SD] age, 57.3 [8.7] years; 48.0% [n = 23 549] men): 19 tested medications; 19 evaluated LSM, and 5 tested combined medications and LSM. At the end of the active intervention (range, 0.5-6.3 years), LSM was associated with an RR reduction of 39% (RR, 0.61; 95% CI, 0.54-0.68), and medications were associated with an RR reduction of 36% (RR, 0.64; 95% CI, 0.54-0.76). The observed RD for LSM and medication studies was 4.0 (95% CI, 1.8-6.3) cases per 100 person-years or a number-needed-to-treat of 25. At the end of the washout or follow-up periods, LSM studies (mean follow-up, 7.2 years; range, 5.7-9.4 years) achieved an RR reduction of 28% (RR, 0.72; 95% CI, 0.60-0.86); medication studies (mean follow-up, 17 weeks; range, 2-52 weeks) showed no sustained RR reduction (RR, 0.95; 95% CI, 0.79-1.14).

Conclusions and relevance: In adults at risk for diabetes, LSM and medications (weight loss and insulin-sensitizing agents) successfully reduced diabetes incidence. Medication effects were short lived. The LSM interventions were sustained for several years; however, their effects declined with time, suggesting that interventions to preserve effects are needed.

Figure 1.. Study Screening and Selection Flow

Overview of study screening and selection process according to PRISMA guidelines. RCT indicates randomized clinical trial.

Figure 2.. Relative Risks (RRs) and Diabetes Incidence Rates Among Lifestyle Modification Intervention Studies Stratified by Intervention Strategy at the End of the Active Intervention Period

Nineteen studies including 24 comparisons were analyzed. Active intervention mean (SD) duration was 2.6 (1.7) years (range, 0.5-6.0 years). Overall RR is the pooled effect for all studies; subgroup RR is the pooled effect for a subgroup of studies. DPP indicates Diabetes Prevention Program; DPS, Diabetes Prevention Study; EDIPS, European Diabetes Prevention Study; IDPP, Indian Diabetes Prevention Programme; and SLIM, Study on Lifestyle-Intervention and Impaired Glucose Tolerance Maastricht. ^aSecond arm of the same study. ^bThird arm of the same study.

Figure 3.. Relative Risks (RRs) and Diabetes Incidence Rates Among Medication Studies Stratified by Drug Class at the End of the Active Intervention Period

Twenty-one studies including 24 comparisons were analyzed. Active treatment mean (SD) duration was 3.1 (1.5) years (range, 1.0-6.3 years). Overall RR is the pooled effect for all studies; subgroup RR is the pooled effect for a subgroup of studies. ACE indicates angiotensin-converting enzyme; ACT NOW, Actos Now for Prevention of Diabetes; BIP, Bezafibrate Infarction Prevention Study; CANOE, Canadian Normoglycemia Outcomes Evaluation; DAISI, Dutch Acarbose Intervention Study in Persons With Impaired Glucose Tolerance; DIANA, Diabetes and Diffuse Coronary Narrowing; DPP, Diabetes Prevention Program; DREAM, Diabetes Reduction Assessment With Ramipril and Rosiglitazone Medication; ER, extended release; HERS, Heart and Estrogen/progestin Replacement Study; IDPP, Indian Diabetes Prevention Programme; NAVIGATOR, Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research; ORIGIN, Outcome Reduction With Initial Glargine Intervention; RAS, renin-angiotensin system; STOP-NIDDM, Study to Prevent Non–Insulin-Dependent Diabetes Mellitus; TRANSCEND, Telmisartan Randomised Assessment Study in ACE Intolerant Subjects With Cardiovascular Disease; and XENDOS, Xenical in the Prevention of Diabetes in Obese Subjects. ^aSecond arm of the same study.