Comparison of nebivolol and atenolol on blood pressure, blood sugar, and lipid profile in patients of essential hypertension.

BACKGROUND: Nebivolol is a third-generation β-blocker, with highest β(1) selectivity and nitric-oxide-derived vasodilatation. It also exhibits antiproliferative and antioxidant property that has beneficial metabolic profile compared to second-generation β blockers like atenolol. This study was planned to study the comparative effects of nebivolol and atenolol on metabolic parameters in patients with essential hypertension.
MATERIALS AND METHODS: A prospective, randomized, parallel, open-label clinical study was carried out on patients with essential hypertension. The patients were randomly assigned to receive tablet atenolol (Group A) and nebivolol (Group B) for a period of 24 weeks. Investigations were carried out at baseline and at the end of study period, that is, 24 weeks. Out of 69 patients, 60 completed the study and the data was analyzed using student's t-test. P < 0.05 was considered statistically significant.
RESULTS: Atenolol and nebivolol both showed significant (P < 0.001) antihypertensive action after 24 weeks. Mean blood sugar and lipid profile were found to be significantly (P < 0.001) elevated after 24 weeks of treatment with atenolol but not with nebivolol. Heart rate was significantly (P < 0.001) decreased in both groups at 24 weeks.
CONCLUSION: In view of metabolic adverse effects of atenolol, nebivolol is the better choice whenever β-blockers have to be used in essential hypertension.

RCT Entities:   Population Interventions Outcomes

Introduction

Essential hypertension is a common cardiovascular disorder with sustained increase in blood pressure ≥140/90 mmHg. The elevated arterial pressure causes pathological changes in the vasculature and hypertrophy of the left ventricle. Hypertension is the principle cause of stroke that is a major risk factor for coronary artery disease (CAD) and its attendant complications like myocardial infarction and sudden cardiac death. It is also a major contributor to cardiac failure, renal insufficiency, and dissecting aneurysm of aorta.[1]

Beta blockers have been used in the treatment of hypertension, since last four decades. Apart from lowering BP, they have antianginal and antiarrythmic actions which effectively reduce CAD and death.[2] Nebivolol, a third-generation β-blocker has highest β1 selectivity and is devoid of intrinsic sympathomimetic activity.[3] Along with peripheral vasodilatation and nitric oxide (NO)-induced benefits such as antioxidant activity and reversal of endothelial dysfunction nebivolol facilitates better protection from cardiovascular events. It has also shown an improved tolerability profile, with respect to adverse events commonly associated with nonselective β-blockers such as bronchospasm, bradycardia, loss of libido, fatigue, insomnia, negative effect on lipid profile, and blood sugar.[4-7] Hence, the study was planned to study the comparative effects of atenolol and nebivolol on metabolic parameters with patients of essential hypertension.

Materials and Methods

A prospective, randomized, parallel, open clinical trial was conducted between Sep.2006 to Oct.2007 on 69 patients at medicine outpatient department (OPD) of Indira Gandhi Government Medical College and Hospital, Nagpur, after getting approval from the Institutional Ethics Committee.

The patients meeting the inclusion criteria were explained in detail about the nature of the trial, its purpose, procedures, and follow-up. They were provided with detailed trial information sheet. Written informed consent was obtained from those who volunteered to participate in the trial. Patients of either gender in the age group of 18-60 years with blood pressure ≥140/90 mmHg either newly diagnosed or taking any antihypertensive medicine for less than last 6 months were included in the study.The patients with blood pressure ≥180/110 mmHg, secondary hypertension, diabetic mellitus, bronchial asthma, chronic obstructive pulmonary disease, hepatic or renal diseases, sinus bradycardia, sick sinus syndrome, prinzmetal's angina, heart block, chronic heart failure, myocardial infarction, and peripheral vascular disease were excluded. Pregnant and lactating women and patients with history of hypersensitivity or allergy to atenolol/ nebivolol were also excluded.

The patients were examined by the consultant physician to rule out secondary hypertension. Systolic and diastolic blood pressure was measured in right arm, sitting posture by auscultatory method using standard mercury sphygmomanometer. Two recordings of blood pressure were taken at an interval of 15 min by the same physician.

After initial screening, the demographic data, past medical history, family history, findings of physical examination, and clinical examination were recorded in the case report form. Diagnosed cases of essential hypertension were randomly allocated using random number table to either Group A (to receive tablet atenolol 50 mg) or Group B (to receive tablet nebivolol 5 mg) after washout of 7 days. All patients were instructed to take the tablet orally once a day with glass of water in the morning.

After allocating the patients to respective group, blood samples were drawn by taking all aseptic precaution in fasting state. Baseline fasting blood sugar, serum cholesterol, serum triglyceride, serum very low-density lipoproteins (VLDL), serum low-density lipoproteins (LDL), serum high-density lipoproteins (HDL), and electrocardiography (ECG) were done. Estimation of fasting blood sugar and serum lipids were done by using calibrated semiauto analyzer, Erba (Diagnostic Mannheim, Germany) Transania Bio-medicals Ltd., (Chandigarh) by using glucose oxidase/peroxidase (GOD/POD) method for the estimation of fasting blood sugar, cholesterol oxidase peroxidase method for serum cholesterol, precipitation method for HDL, glycerol phosphate oxidase method for TG, Friedewald's formula for calculation of VLDL and LDL. Heart rate was calculated from ECG. The patients were recalled for review with filled and empty blisters of the tablets after 12 weeks and 24 weeks for evaluation by the physician and repeat investigations. Compliance to study medicines was measured by pill count during each follow up.

Results

Out of 69 patients enrolled, 60 completed the study and nine lost to follow up (5 from the atenolol group and 4 from the nebivolol group). Patient's age for both groups ranged between 34 to 60, with mean age being 50.7± 1.3 years in the atenolol group and 48.9±1.2 years in the nebivolol group. There were more men (n=26) in both groups as compared to women (n=4). Both the groups were comparable.

There was significant (P < 0.001) reduction in systolic BP, diastolic BP, and heart rate in both the groups as compared to baseline data [Table 1]. However, no change was observed in fasting blood sugar, serum total cholesterol, triglyceride, VLDL, HDL, and LDL in patients at 24 weeks of treatment with nebivolol [Table 1]. On the other hand, there was significant (P < 0.001) increase in fasting blood sugar, total cholesterol, triglyceride, VLDL and LDL at 24 weeks of treatment with atenolol. It was also observed that HDL decreased significantly (P < 0.001) at 24 week of treatment with atenolol.

Table 1

Comparison of effect of atenolol and nebivolol on cardiovascular and metabolic parameters in patients of essential hypertension

The mean changes in the heart rate, blood sugar, serum total cholesterol, triglyceride, VLDL, HDL, and LDL from base line to 24 weeks was statistically significant (P < 0.001) in atenolol group as compared to the nebivolol group [Table 2]. Both the drugs were well tolerated and common adverse effects were seen, with both groups facing headache and fatigue.

Table 2

Comparison of mean differences in cardiovascular and metabolic parameters at 24 weeks in patients treated with atenolol and nebivolol

Statistical analysis was done using Paired “t” test [Table 1] and unpaired “t” test [Table 2] with confidence interval of 95%. P < 0.05 was considered to be statistically significant.

Discussion

Beta blockers are considered safe and effective as first line medicines in the management of hypertension. The newer hypertension treatment guidelines from National Institute for Health and Clinical Excellence (NICE) and the British Hypertension Society (BHS) recommend that “β blockers should no longer be used as first-line drugs for the treatment of uncomplicated hypertension.” This recommendation is based on the evidence of various studies of atenolol alone or in addition diuretics increases the risk of new onset diabetes mellitus than other medicines such as ACE inhibitors, angiotensin receptor blockers and calcium channel blockers, due to its adverse effect on carbohydrate and lipid metabolism. Hence, β-blockers are now reserved as third- or fourth-line medicines unless there are compelling indications otherwise.[8] Patients treated with atenolol (±diuretics) have 30% higher chances of new onset diabetes compared to those receiving calcium channel blockers (±ACE inhibitors).[9]

This study observed that atenolol and nebivolol were equally effective in reducing arterial blood pressure. However, the decrease in the heart rate at 24 weeks was more with atenolol as compared to nebivolol as observed in other studies.[10-13] Being sympatholytic, nebivolol decreases sympathetic activity and the vasodilator property may refluxly accelerate the parasympathetic activity. It has been observed that nebivolol attenuates the sympathetic tone, but does not promote vagal activity more than atenolol. Hence, fall in the heart rate with nebivolol is less as compared to atenolol.[14]

The metabolic parameters were not altered in nebivolol group as reported by various studies recommending nebivolol based on the safety profile.[1015-17] The β receptors mediate activation of hormone sensitive lipase in fat cells, leading to release of free fatty acids into the circulation. Beta receptor antagonists modify the metabolism of carbohydrates and lipids by attenuating the release of free fatty acids from adipose tissue. Nonselective β receptor antagonists consistently reduce HDL cholesterol, increase LDL cholesterol, and increase triglycerides. In contrast, β1 selective antagonists, including celiprolol, carteolol, nebivolol, carvedilol, and bevantolol, improve the serum lipid profile of dyslipidemic patients.[18]

The vasodilator β-blockers increase insulin sensitivity in patients with insulin resistance as compared to classical β-blockers which decrease insulin sensitivity. Improvement in insulin sensitivity and cardioprotective effect of vasodilator β-blockers may partially counterbalance the hazard from worsened lipid abnormalities associated with diabetes. Hence, if β blocker has to be used, β1 selective or vasodilator β receptor antagonists should be preferred.[1920] Various hypotheses have been put forward to link the association between favorable metabolic profiles of vasodilator β1 blockers. Antioxidant property of nebivolol and increase in NO by reducing its oxidative inactivation may be responsible for beneficial lipid and carbohydrate metabolic profile.[2122] Nebivolol causes vasodilatation by directly secreting NO from endothelial cells by various mechanisms. It has been hypothesized that nebivolol and its metabolites increase the activity of NO synthase enzyme III (NOS III) which increases the synthesis of NO. Nebivolol is also supposed to inhibit degradation of NO due to reactive oxygen species such as super oxides and oxidative stress by its antioxidant property. The improved secretion of NO and antioxidant property of nebivolol helps in the maintenance of normal endothelial functions, prevention of vascular smooth muscle cell hypertrophy, decrease in LDL oxidation, decrease in platelet aggregation and adhesion, prevention of atherosclerotic plaque deposition, and apoptosis. Thus NO has important therapeutic implications in protecting the cardiovascular system from atherosclerotic complications.

The result of the study showed that nebivolol 5 mg and atenolol 50 mg had similar antihypertensive effect. But decrease in the heart rate, alteration in fasting blood sugar and lipid profile was greater in patients receiving atenolol, which on long-term use may cause diabetes mellitus and metabolic syndrome. Nebivolol is a unique, highly selective β-blocker that improves NO availability causing vasodilatation; thus, it prevents/improves endothelial dysfunction which predisposes to essential hypertension. Thus, nebivolol may be a better therapeutic option for the patients requiring β-blocker due to its favorable metabolic properties.