Differential effects of nebivolol and metoprolol on insulin sensitivity and plasminogen activator inhibitor in the metabolic syndrome

Abstract

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 that increases the bioavailability of nitric oxide. We compared the effect of nebivolol (5 mg/d) and the β(1)-selective antagonist metoprolol (100 mg/d) on glucose homeostasis and markers of fibrinolysis in 46 subjects with metabolic syndrome. Subjects underwent a frequently sampled IV glucose tolerance test after 3-week washout and placebo treatment and after 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 β-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 after metoprolol than after nebivolol (-1.5±2.5×10(-4)×min(-1) per milliunit per liter versus 0.04±2.19×10(-4)×min(-1) per milliunit per liter after nebivolol; P=0.03). Circulating plasminogen activator inhibitor also increased after 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 F(2)-isoprostane concentrations. In summary, treatment with metoprolol decreased insulin sensitivity and increased oxidative stress and the antifibrinolytic plasminogen activator inhibitor 1 in patients with metabolic syndrome, whereas nebivolol lacked detrimental metabolic effects. Large clinical trials are needed to compare effects of nebivolol and the β(1) receptor antagonist metoprolol on clinical outcomes in patients with hypertension and the metabolic syndrome.

Trial registration: ClinicalTrials.gov NCT00775671.

Figure 1

Study Protocol. Upper figure shows overall study protocol. Lower protocol shows protocol for frequently sampled intravenous glucose tolerance test performed on each study day.

Figure 2

Effect of metoprolol and nebivolol on systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR). Changes are shown as both absolute change (Δ) and percent change (%Δ) compared to baseline.

Figure 3

Effect of metoprolol and nebivolol on plasminogen activator inhibitor-1 (PAI-1) and tissue plasminogen activator (t-PA). *P<0.05 versus pretreatment, †P=0.05 versus the metoprolol treatment group, after controlling for race and baseline PAI-1 antigen.