Prevention of Type 2 Diabetes: Evidence and Strategies

Nateglinide

Nateglinide is a short-acting insulin secretagogue that is mostly used in the treatment of postprandial hyperglycemia in diabetic patients. The protective effect of nateglinide in a prediabetic population was examined in the NAVIGATOR study (the NAteglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research), a large prospective multinational, randomized, double-blind, placebo-controlled trial. Nateglinide (30–60 mg 3 times daily) and valsartan (80–160 mg daily) versus placebo were used in a 2×2 factorial design in 9306 participants with IGT and increased risk of cardiovascular events [57]. At 5 years, nateglinide did not reduce the cumulative incidence of diabetes or cardiovascular outcomes, when compared to placebo, whereas risk of hypoglycemia was significantly increased in the intervention group.

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.

Similarly, in the NAVIGATOR trial that examined the effect of nateglinide and valsartan on the prevention of diabetes in 9306 participants with IGT and increased risk of cardiovascular events, valsartan significantly but slightly reduced the incidence of diabetes at 5 years, by 14%, when compared to placebo (33% versus 37%, respectively), with no significant reduction in cardiovascular outcome [66]. Unlike in the DREAM study, the patients enrolled in the NAVIGATOR trial had established cardiovascular disease or cardiovascular risk factors and assumable elevated RAS activation level. This baseline population difference might explain the more significant effect of RAS inhibition in the NAVIGATOR trial.

Given the positive glycemic effect of ACE inhibitors and ARBs, their use should be encouraged in prediabetic patients when indicated for treatment of high blood pressure or cardiovascular disease. Different mechanisms could explain this favorable glycemic impact: inhibition of the post-receptor insulin signaling abnormalities, increased blood flow to the skeletal muscle facilitating insulin action, enhanced differentiation of pre-adipocytes into mature adipocytes, and increased pancreatic islet blood perfusion leading to appropriate insulin release and possible partial PPAR-γ activity [67].