Emerging Mechanisms in Glucose Metabolism

LIFE: Total mortality by treatment in cohort with diabetes The Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) study compared the ARB losartan with the beta-blocker atenolol in 9193 patients with HTN (BP 160-200/95-115 mm Hg). Patients were randomly allocated to losartan 50-100 mg or atenolol 50-100 mg, and were treated for at least 4 years; hydrochlorothiazide and additional antihypertensive drugs were added as required to reach the target BP. In the 1195 subjects with diabetes, HTN, and left ventricular hypertrophy (LVH) at baseline, losartan was associated with an adjusted 39% relative reduction in risk of all-cause mortality.

Comparative effect of telmisartan and losartan on metabolic parameters This study found that compared with once-daily losartan 50 mg, once-daily telmisartan 80 mg improved metabolic parameters in patients with metabolic syndrome, including glucose tolerance and insulin sensitivity. Telmisartan reduced fasting plasma glucose by 8%, fasting plasma insulin by 10%, homeostasis model assessment (HOMA)-insulin resistance by 26%, and hemoglobin A1C by 9%. Losartan did not have a significant effect on these parameters. The insulin-sensitizing activity displayed by telmisartan (but not by losartan) may be explained by its partial PPAR-gamma activity.

Effect of ACEIs and ARBs on new-onset diabetes Abuissa et al conducted a meta-analysis of 12 randomized trials (N = 116,220) of ACEIs (5 trials) and ARBs (7 trials), that reported the incidence of new-onset T2DM. There were 72,333 patients without T2DM at baseline. ACEIs were associated with a 27% relative risk reduction in new onset of T2DM; ARBs were associated with a 23% relative risk reduction. Only 2 of these trials included new-onset diabetes as a prespecified endpoint.

RAAS, ACEIs, and ARBs: Summary Reduction of CVD risk by the RAAS blockade is caused by BP lowering, but it also involves additional antiatherosclerotic effects mediated by anti-inflammatory, antiproliferative, and oxidative stress-lowering properties. The ARBs and ACEIs are the best proven interventions to reduce target organ damage in hypertension, atherosclerosis, and diabetes. Clinical trials have shown that ACEIs or ARBs reduce the frequency of new-onset T2DM (as opposed to beta-blockers and diuretics). Mechanistically, these drugs differ in the RAAS blockade: ACEIs do not prevent angiotensin II formation by non-ACE pathways, which can lead to “angiotensin II escape” during chronic therapy, whereas ARBs antagonize all AT1 receptor effects. Whereas ACEIs block AT1 and AT2 receptors equally, ARBs selectively inhibit AT1 receptors and stimulate the AT2 receptors.