Use of carvedilol in hypertension: an update

Abstract

β-blockers are effective antihypertensive agents and, together with diuretics, have been the cornerstone of pioneering studies showing their benefits on cardiovascular morbidity and mortality as a consequence of blood pressure reduction in patients with hypertension. However, evidence from recent meta-analyses have demonstrated no benefit afforded by atenolol compared with placebo in risk of mortality, myocardial infarction, or stroke, and a higher risk of mortality and stroke with atenolol/propranolol compared with other antihypertensive drug classes. Thus, the effect of these agents on cardiovascular morbidity and mortality in hypertensive patients, especially their use in uncomplicated hypertension, has remained largely controversial. However, it is recognized that the clinical studies used in these meta-analyses were mainly based on the older second-generation β-blockers, such as atenolol and metoprolol. Actually, considerable heterogeneity in, eg, pharmacokinetic, pharmacological, and physicochemical properties exists across the different classes of β-blockers, particularly between the second-generation and newer third-generation agents. Carvedilol is a vasodilating noncardioselective third-generation β-blocker, without the negative hemodynamic and metabolic effects of traditional β-blockers, which can be used as a cardioprotective agent. Compared with conventional β-blockers, carvedilol maintains cardiac output, has a reduced prolonged effect on heart rate, and reduces blood pressure by decreasing vascular resistance. Studies have also shown that carvedilol exhibits favorable effects on metabolic parameters, eg, glycemic control, insulin sensitivity, and lipid metabolism, suggesting that it could be considered in the treatment of patients with metabolic syndrome or diabetes. The present report provides an overview of the main clinical studies concerning carvedilol administered as either monotherapy or in combination with another antihypertensive or more frequently a diuretic agent, with particular focus on the additional benefits beyond blood pressure reduction.

Keywords: atherosclerosis; carvedilol; diabetes; hypertension; β-blocker.

Figure 1

Chemical structure of carvedilol.

Figure 2

Antihypertensive effect of carvedilol compared with captopril, slow-release nifedipine, hydrochlorothiazide, and nebivolol. (A) Carvedilol was administered at 25–50 mg once daily. Captopril was administered at 25–50 mg twice daily. Slow-release nifedipine was administered at 20–40 mg twice daily and hydrochlorothiazide was administered at 25–50 mg once daily. Reprinted by permission from Macmillan Publishers Ltd: American Journal of Hypertension. Moser M, Frishman W. Results of therapy with carvedilol, a beta-blocker vasodilator with antioxidant properties, in hypertensive patients. Am J Hypertens. 1998;11(1 Pt 2):15S–22S. Copyright 1998. (B) Antihypertensive effect of carvedilol 5 mg/day versus nebivolol 5 mg/day. Copyright (c) 2011, Aves Yayincilik. Adapted with permission from Erdoğan O, Ertem B, Altun A. Comparison of antihypertensive efficacy of carvedilol and nebivolol in mild-to-moderate primary hypertension: a randomized trial. Anadolu Kardiyol Derg. 2011;11(4):310–313. Turkish. Notes: P values represent significant differences compared with placebo (for either carvedilol or nebivolol) for mean systolic and diastolic blood pressure. Filled bars represent systolic blood pressure and open bars represent diastolic blood pressure. Abbreviations: SR-Nifedip, slow-release nifedipine; Carved, carvedilol; HCTZ, hydrochlorothiazide.

Figure 3

Comparison of the effects of carvedilol and atenolol on lipid parameters in patients with hypertension. P values represent significant differences in HDL cholesterol (B) and triglycerides (C) between carvedilol and atenolol treatment; the difference for total cholesterol was not significant (A). Open bars represent baseline and filled bars represent the 6-month time point. Notes: Data values are also presented. Carvedilol was administered at 25 mg once daily (n = 23) and atenolol was administered at 50 mg once daily (n = 22). Copyright (c) 1997, American College of Physicians–American Society of Internal Medicine. Adapted with permission from Giugliano D, Acampora R, Marfella R, et al. Metabolic and cardiovascular effects of carvedilol and atenolol in non-insulin-dependent diabetes mellitus and hypertension. A randomized, controlled trial. Ann Intern Med. 1997:126(12):955–959. Abbreviation: HDL, high-density lipoprotein.

Figure 4

Comparison of the effects of carvedilol and atenolol on metabolic parameters in patients with hypertension. P values represent significant differences in metabolic parameters (A–C) between carvedilol and atenolol treatment. Open bars represent baseline and filled bars represent the 6-month time point. Notes: Data values are also presented. Carvedilol was administered at 25 mg once daily (n = 23) and atenolol was administered at 50 mg once daily (n = 22). Copyright (c) 1997, American College of Physicians–American Society of Internal Medicine. Adapted with permission from Giugliano D, Acampora R, Marfella R, et al. Metabolic and cardiovascular effects of carvedilol and atenolol in non-insulin-dependent diabetes mellitus and hypertension. A randomized, controlled trial. Ann Intern Med. 1997:126(12):955–959. Abbreviation: HbA_1c, glycosylated hemoglobin.

Figure 5

Effects of different antihypertensive drugs on metabolic parameters in patients with metabolic syndrome. Note: *Significant difference (P < 0.05) versus baseline values. Copyright (c) 2006, International Heart Journal Association. Adapted with permission from Uzunlulu M, Oguz A, Yorulmaz E. The effect of carvedilol on metabolic parameters in patients with metabolic syndrome. Int Heart J. 2006;47(3):421–430. Abbreviations: SBP, systolic blood pressure; DBP, diastolic blood pressure; waist circ, waist circumference; BMI, body mass index; FBG, fasting blood glucose; HbA_1c, glycosylated hemoglobin.

Figure 6

Effect of carvedilol on left ventricular hypertrophy in hypertensive patients. Notes: Carvedilol was administered at 25 mg once daily (n = 22). Data are presented as the mean ± standard deviation. Reprinted from Archives of Gerontology and Geriatrics, 22 Suppl 1, Verza M, Ammendola S, Cambardella A, et al, Regression of left ventricular hypertrophy in hypertensive elderly patients with carvedilol, 143–147, Copyright 1996, with permission from Elsevier. Abbreviations: SBP, systolic blood pressure; DBP, diastolic blood pressure; LVM, left ventricular mass; LVMI, left ventricular mass index.

Figure 7

Effect of carvedilol, metoprolol, and nebivolol on coronary flow reserve. (A) Carvedilol was administered at 10 mg twice daily (n = 28) and metoprolol was administered at 50 mg twice daily (n = 29). P values denote statistically significant differences between duration and type of treatment. Adapted from Xiaozhen et al. (B) Carvedilol was administered at 20–50 mg daily and (C) nebivolol was administered at 5 mg daily. Copyright (c) 2008, ADIS Press. Adapted with permission from Galderisi M, D’Errico A. Beta-blockers and coronary flow reserve: the importance of a vasodilatory action. Drugs. 2008;68(5):579–590. Notes: Open bars represent baseline and filled bars represent the treatment time points. Significant differences from baseline are shown. Data are presented as the mean ± standard deviation.

Figure 8

Control of morning blood pressure in newly diagnosed hypertensive patients. The effects of carvedilol 12.5–20 mg and metoprolol 10–20 mg on both systolic (filled dots) and diastolic blood pressure (open dots) were compared over a 24-hour period. Reprinted by permission from Macmillan Publishers Ltd: American Journal of Hypertension. Marfella R, Siniscalchi M, Nappo F, et al. Regression of carotid atherosclerosis by control of morning blood pressure peak in newly diagnosed hypertensive patients. Am J Hypertens. 2005;18(3):308–318. Copyright 2005. Notes: Data are presented as the mean ± standard deviation. P values represent statistically significant differences between carvedilol and metoprolol groups. Abbreviations: Carv, carvedilol; Metop, metoprolol.