Prevention of Type 2 Diabetes: Evidence and Strategies

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].

Xenical

Xenical is a gastrointestinal lipase inhibitor approved for use for weight reduction and maintenance. A possible diabetes prevention benefit of xenical was initially suggested by a retrospective analysis of xenical treatment effects on obese patients with IGT [68]. This finding was subsequently confirmed by a multicenter randomized placebo-controlled study, XENical in the prevention of Diabetes in Obese Subjects (XENDOS), where 3305 obese subjects, with normal glucose tolerance or IGT were randomly assigned to either xenical 120 mg 3 times a day or placebo, in addition to lifestyle changes for all participants [69]. In the group of patients with IGT (694 subjects), xenical treatment was associated with a 45% risk reduction of progression to diabetes at 4 years (18.8% versus 28.8% in placebo), whereas participants with baseline normal glucose tolerance had no significant change in incidence of diabetes. On the other hand, weight reduction at 4 years was significantly greater in all patients who received xenical (5.8 kg in intervention group vs 3 kg in control group). The beneficial effect of xenical in diabetes prevention seems to be additive to the benefit of weight loss. As in many weight reduction trials, this study was limited by the high discontinuation rate in both groups (48% in xenical group and 66% in control group), probably related to insufficient clinical response.

Fibric Acid Derivatives (Bezafibrate)

Bezafibrate, a nonselective ligand/activator for PPAR-α, was found to reduce not only triglycerides, but also FPG, fructosamine, and A1C levels significantly in T2DM patients with hyperlipidemia [70]. Different mechanisms of glucose lowering have been suggested with bezafibrate: nonselective activation of PPAR-γ, improving insulin sensitivity, and enhancing glucose disposal in adipose tissue and skeletal muscles [71]. Furthermore, bezafibrate treatment was associated with decreased incidence of diabetes in patients with IFG and in obese non-diabetic patients with normal glycemic levels [72,73]. In a posthoc analysis of the Bezafibrate Infarction Prevention study, 303 patients with IFG received either 400 mg of bezafibrate daily or placebo [73]. Over a mean follow-up of 6.2 years, development of diabetes was less prevalent (54.4% vs 42.3%, relative risk reduction of 22%) and delayed (mean 10 months) in the bezafibrate group compared to placebo. Multivariate analysis identified bezafibrate as an independent predictor of decreased risk of new diabetes development, regardless of BMI and lipid profile.