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Evidence summaries

Prevention of Type 2 Diabetes in Persons at Increased Risk for the Development of T2d

Both intensive diet and exercise or metformin alone are effective in prevention of type 2 diabetes in persons at increased risk (including women with prior gestational diabetes) compared to placebo or no intervention. The reduction in incidence is up to 50 percent. Level of evidence: "A"

Exercise and intensive diet are recommended over metformin for all persons at increased risk of type 2 diabetes.

The recommendation attaches a relatively high value on the many beneficial effects of the diet used in the studies as well as exercise on other outcomes in addition to diabetes prevention, and the lack of significant adverse effects of these interventions, and on avoiding pharmacological treatment when an equally effective and safe lifestyle intervention is available.

Summary

The Diabetes Prevention Program Outcomes (DPPO) study 2 examined the effect of lifestyle intervention and metformin on preventing or delaying diabetes among women with and without gestational diabetes (GDM). A lifestyle-modification program (goals: at least a 7% weight loss and at least 150 minutes of physical activity per week) was compared with metformin (850 mg twice daily) and with placebo. The incidence of diabetes was 11.0, 7.8, and 4.8 cases per 100 person-years in the placebo, metformin, and lifestyle groups, respectively. The lifestyle intervention reduced the incidence by 58% (95% CI, 48 to 66%) and metformin by 31% (95% CI, 17 to 43%), as compared with placebo; the lifestyle intervention was significantly more effective than metformin. To prevent one case of diabetes during a period of three years, 6.9 persons would have to participate in the lifestyle-intervention program, and 13.9 would have to receive metformin. All 3 groups were offered group-implemented lifestyle intervention. Metformin treatment was continued in the original metformin group. During the 10-year follow-up, the original lifestyle group lost, then partly regained weight. The modest weight loss with metformin was maintained. Diabetes incidence rates in this follow-up study were similar between treatment groups: 5.9 per 100 person-years (5.1-6.8) for lifestyle, 4.9 (4.2-5.7) for metformin, and 5.6 (4.8-6.5) for placebo. Diabetes incidence in the 10 years since randomisation was reduced by 34% (24-42) in the lifestyle group and 18% (7-28) in the metformin group compared with placebo.

A Cochrane review [Abstract] 1 included 20 studies with a total of 6774 subjects. The DPPO study contributed 48% of all participants. Comparing metformin with diet and exercise with or without placebo, incidence of type 2 diabetes (T2D) was significantly lower (RR 0.50, 95% CI 0.38 to 0.65; P < 0.001; 12 trials, n=3632). Comparing metformin with intensive diet and exercise, incidence of T2D was similar (RR 0.80, 95% CI 0.47 to 1.37; P = 0.42; 7 trials, n=2960), though there was a trend favouring metformin. In 3 RCTs comparing metformin plus intensive diet and exercise with identical intensive diet and exercise incidence of T2D was similar (RR 0.55, 95% CI 0.10 to 2.92; P = 0.49; n=332). There were no differences in all-cause or cardiovascular mortality, non-fatal myocardial infarction or stroke, probably the follow-up was too short. Serious adverse events were poorly reported.

In part of the Diabetes Prevention Program (DPP) 4 women with impaired glucose tolerance (350 with prior GDM and 1416 without GDM) were randomized to either standard lifestyle and placebo (n=122, placebo group) or standard lifestyle and metformn 850mg bid. (n=111, metformin group), or to an intensive lifestyle intervention (n=117, ILS group). Whereas entering the study with similar glucose levels, women with a history of GDM randomized to placebo had a crude incidence rate of diabetes 71% higher than that of women without such a history. Among women reporting a history of GDM, both intensive lifestyle and metformin therapy reduced the incidence of diabetes by approximately 50% compared with the placebo group.

In 15-year follow-up of DPP-study 3 the subgroups that benefited most were assessed. During the DPP adults at high risk were randomly assigned to masked placebo (n=1082) or metformin 850 mg twice daily (n=1073). Participants originally assigned to metformin continued to receive metformin unmasked. Metformin reduced the incidence (by hazard ratio [HR]) of diabetes compared to placebo by 17% or 36% based on glucose tolerance test or HbA1c levels, respectively. Metformin's effect was greater for women with a history of prior GDM (HR 0.59, rate differences -4.57 cases/100 person-years) compared with parous women without GDM (HR 0.94, rate difference -0.38 cases/100 person-years [interaction P = 0.03 for HR, P = 0.01 for rate difference]). Metformin also had greater effects at higher baseline fasting glucose levels.

A study 5 evaluating the efficacy of a lifestyle intervention for the prevention of glucose disorders (impaired fasting glucose, impaired glucose tolerance or T2D) included 260 women with prior GDM.Women were randomised to a Mediterranean lifestyle intervention group (an educational program on nutrition and a monitored physical activity program) and a control group with a conventional follow-up. Less women in the intervention group (42.8%) developed glucose disorders at the end of the 3-year follow-up compared with the control group (56.75%). Glucose disorders were reduced especially with a BMI of less than 27 kg/m² (OR 0.28, 95% CI 0.12 to 0.65) and low fat intake pattern (OR 0.30, 95% CI 0.13 to 0.70).

Clinical comments

Note

Date of latest search: 2020-03-14

    References

    • Madsen KS, Chi Y, Metzendorf MI et al. Metformin for prevention or delay of type 2 diabetes mellitus and its associated complications in persons at increased risk for the development of type 2 diabetes mellitus. Cochrane Database Syst Rev 2019;(12):CD008558. [PubMed]
    • Aroda VR, Christophi CA, Edelstein SL et al. 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 2015;100(4):1646-53. [PubMed]
    • Diabetes Prevention Program Research Group.. Long-term Effects of Metformin on Diabetes Prevention: Identification of Subgroups That Benefited Most in the Diabetes Prevention Program and Diabetes Prevention Program Outcomes Study. Diabetes Care 2019;42(4):601-608. [PubMed]
    • Ratner RE, Christophi CA, Metzger BE et al. Prevention of diabetes in women with a history of gestational diabetes: effects of metformin and lifestyle interventions. J Clin Endocrinol Metab 2008;93(12):4774-9. [PubMed]
    • Pérez-Ferre N, Del Valle L, Torrejón MJ et al. Diabetes mellitus and abnormal glucose tolerance development after gestational diabetes: A three-year, prospective, randomized, clinical-based, Mediterranean lifestyle interventional study with parallel groups. Clin Nutr 2015;34(4):579-85. [PubMed]

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