No abstract

Dipeptidyl peptidase-IV inhibitors improve glucose homeostasis in type 2 diabetics by inhibiting degradation of the incretin hormones. Dipeptidyl peptidase-IV inhibition also prevents the breakdown of the vasoconstrictor neuropeptide Y and, when angiotensin-converting enzyme (ACE) is inhibited, substance P. This study tested the hypothesis that dipeptidyl peptidase-IV inhibition would enhance the blood pressure response to acute ACE inhibition. Subjects with the metabolic syndrome were treated with 0 mg of enalapril (n = 9), 5 mg of enalapril (n = 8), or 10 mg enalapril (n = 7) after treatment with sitagliptin (100 mg/day for 5 days and matching placebo for 5 days) in a randomized, cross-over fashion. Sitagliptin decreased serum dipeptidyl peptidase-IV activity (13.08 ± 1.45 versus 30.28 ± 1.76 nmol/mL/min during placebo; P≤0.001) and fasting blood glucose. Enalapril decreased ACE activity in a dose-dependent manner (P<0.001). Sitagliptin lowered blood pressure during enalapril (0 mg; P=0.02) and augmented the hypotensive response to 5 mg of enalapril (P=0.05). In contrast, sitagliptin attenuated the hypotensive response to 10 mg of enalapril (P=0.02). During sitagliptin, but not during placebo, 10 mg of enalapril significantly increased heart rate and plasma norepinephrine concentrations. There was no effect of 0 or 5 mg of enalapril on heart rate or norepinephrine after treatment with either sitagliptin or placebo. Sitagliptin enhanced the dose-dependent effect of enalapril on renal blood flow. In summary, sitagliptin lowers blood pressure during placebo or submaximal ACE inhibition; sitagliptin activates the sympathetic nervous system to diminish hypotension when ACE is maximally inhibited. This study provides the first evidence for an interactive hemodynamic effect of dipeptidyl peptidase-IV and ACE inhibition in humans.

Early generation β-blockers lower blood pressure and reduce cardiovascular morality in coronary artery disease and congestive heart failure, but worsen glucose homeostasis and fibrinolytic balance. Nebivolol is a third-generation β-blocker which increases the bioavailability of nitric oxide. We compared the effect of nebivolol (5mg/d) and the β1-selective antagonist metoprolol (100mg/d) on glucose homeostasis and markers of fibrinolysis in 46 subjects with metabolic syndrome. Subjects underwent a frequently sampled intravenous glucose tolerance test after 3-week washout and placebo treatment, and following randomized treatment with study drug. After 12-week treatment, nebivolol and metoprolol equivalently decreased systolic blood pressure, diastolic blood pressure, and heart rate. Neither drug affected beta cell function, disposition index, or acute insulin response to glucose. Metoprolol significantly decreased the insulin sensitivity index. In contrast, nebivolol did not affect insulin sensitivity, and the decrease in sensitivity was significantly greater following metoprolol than nebivolol (-1.5±2.5 × 10-4 × min-1 per mU/L versus 0.04±2.19 × 10-4 × min-1 per mU/L after nebivolol, P=0.03). Circulating plasminogen activator inhibitor also increased following treatment with metoprolol (from 9.8±6.8 to 12.3±7.8 ng/mL), but not nebivolol (from 10.8±7.8 to 10.5±6.2 ng/mL, P=0.05 versus metoprolol). Metoprolol, but not nebivolol, increased F2-isoprostane concentrations. In summary, treatment with metoprolol decreased insulin sensitivity and increased oxidative stress and the antifibrinolytic plasminogen activator inhibitor-1in patients with metabolic syndrome, whereas nebivolol lacked detrimental metabolic effects. Large clinical trials are needed to compare effects of nebivolol and the β1 receptor antagonist metoprolol on clinical outcomes in patients with hypertension and the metabolic syndrome.

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