Prevention of Type 2 Diabetes: Evidence and Strategies

Liraglutide

Liraglutide is an injectable glucagon-like peptide-1 (GLP-1) receptor agonist used to treat T2DM, and recently approved as a weight-reducing agent at the dose of 3 mg injected subcutaneously. GLP-1 receptor agonists work by stimulating insulin secretion in a glucose-dependent manner, suppressing glucagon secretion, inducing satiety, and slowing gastric emptying. In the international double-blind SCALE (Satiety and Clinical Adiposity-Liraglutide Evidence) trial, 3731 nondiabetic patients, among whom 61.2% had prediabetes, were randomly assigned to liraglutide 3 mg subcutaneous injection daily or placebo, in addition to diet and exercise [58]. Liraglutide was associated with lower glucose levels on OGTT and lower A1C values at the end of the study (56 weeks), with this decrease especially prominent in prediabetic patients. Significantly fewer participants in the liraglutide group (4/2219) compared to the placebo group (14/1225) developed diabetes at 56 weeks, nearly all of whom (except for 1 in the placebo group) had prediabetes at the beginning of the study. Of note, the liraglutide group had a mean 8.4-kg weight reduction by week 56, compared to 2.8 kg in the placebo group.

Insulin

Insulin has also been investigated as a possible diabetes prevention agent, given the assumed protective effect insulin could exert on beta cell reserve. In the landmark international Outcome Reduction with Initial Glargine Intervention (ORIGIN) trial, 12,537 participants (mean age 63.5 years) with cardiovascular risk factors plus IFG, IGT, or type 2 diabetes were randomly assigned to receive insulin glargine (with a target FBG ≤ 95 mg/dL) or standard care and were monitored for cardiovascular outcomes and other secondary endpoints including incidence of diabetes [59]. After a median follow-up of 6.2 years, and 3 months after discontinuation of therapy, among the 1456 participants without baseline diabetes, new diabetes was diagnosed in 30% of participants receiving glargine versus 35% of those receiving standard therapy. However, rates of severe hypoglycemia and modest weight gain were higher in the insulin group, calling in to question the benefit/risk balance with the use of basal insulin for diabetes prevention.

ACE Inhibitors and ARBs

A possible diabetes preventive effect was observed with renin-angiotensin system (RAS) blockade agents in secondary analysis of several hypertension trials, such as with ramipril in the Heart Outcomes Prevention Evaluation study, captopril (compared to diuretics and beta blockers) in the CAptopril Prevention Project, lisinopril (compared to amlodipine and chlorthalidone) in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial, losartan (compared to atenolol) in the Losartan Intervention For Endpoint reduction in hypertension study), and multiple other randomized controlled trials [60–64]. Therefore, 2 major trials were designed to examine, as a primary outcome, the effect of RAS inhibition on diabetes prevention in a population at risk. The DREAM trial randomly assigned, in a 2 × 2 factorial design, 5269 relatively healthy participants with IGT and/or IFG to rosiglitazone, ramipril, or placebo [65]. Although the use of ramipril at a dose of 15 mg daily for 3.5 years did not prevent diabetes significantly, it was associated with a 9%, nonsignificant decrease in new-onset of diabetes and a 16%, significant increase in regression of IFG and IGT to normoglycemia, as well as a significant decrease in OGTT 2-hour glucose level (135.1 vs 140.5 mg/dL) with no improvement in FBG.