The widespread obesity epidemic is linked to an increased prevalence of type 2 diabetes mellitus and hypertension, resulting in higher cardiovascular risk.¹ Recommendations for the treatment of obese hypertensive patients are not included in existing guidelines for hypertensive patients. Although nonpharmacologic approaches, such as lifestyle changes, should be attempted before prescribing medication, lifestyle modification often requires a combination regimen with antihypertensive and antiobesity medication.²

A well-accepted pharmacologic therapy for weight reduction is the selective serotonin and norepinephrine reuptake inhibitor, sibutramine (Meridia), which has been shown to be effective for weight loss by increasing satiety and augmenting energy expenditure.³ A potential side effect of sibutramine is increased blood pressure, resulting from the drug's effects as a monoamine reuptake inhibitor.⁴ The goal of our study was to determine the best course of treatment regimen and to evaluate interactions between sibutramine and 3 antihypertensive drug regimens in an investigator-initiated, 16-week, prospective, double-blind, randomized, placebo-controlled, multicenter study of obese hypertensive subjects.

Subjects and methods

Overweight and obese hypertensive subjects (systolic blood pressure [SBP], 140-160 mm Hg; diastolic blood pressure [DBP], 90-100 mm Hg receiving pretreatment with prespecified antihypertensive combination therapy), aged 20 to 65 years were included in the study. Subjects were divided into 3 groups based on their antihypertensive drug regimen: metoprolol succinate (Lopressor; Toprol XL) 95 mg/hydrochlorothiazide (Hydrodiuril; Microzide; Oretic) 12.5 mg (n = 59; 34.3%); slow-release verapamil (Calan SR; Isoptin SR) 180 mg/trandolapril (Mavik) 2 mg (n= 55; 32.3%); or felodipine (Plendil) 5 mg/ramipril (Altace) 5 mg (n = 57; 33.3%). Subjects were randomly assigned to receive placebo or 10 mg of sibutramine. After 8 weeks, the sibutramine dose was increased to 15 mg.

For statistical analysis, body weight, body mass index, waist circumference, heart rate, and blood pressure were documented on the day of randomization and at the end of the study. Data regarding the degree of general physical activity was assessed through administration of a questionnaire. The results of ambulatory 24-hour blood pressure monitoring and an oral glucose tolerance test were documented, as well as fasting concentrations of total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, glycosylated hemoglobin (A1C), and glucose.

Results

Compared with the placebo group, subjects in the sibutramine-treated group lost significantly more weight (–5.7 ± 0.5 kg in the sibutramine group vs –1.5 ± 0.5 kg in the placebo group; P < .01), had a decreased body mass index (–2 ± 0.2 kg/m² in the sibutramine group vs -0.5 ± 0.2 kg/m² in the placebo group), and had a significantly decreased waist circumference (–5.0 ± 0.6 cm in the sibutramine group vs –0.8 ± 0.6 cm in the placebo group; P < .001). A body weight reduction of more than 5% occurred in 54.7% of the sibutramine-treated subjects, whereas only 14.5% of subjects in the placebo group had the same body weight reduction.

Although subjects on all treatment regimens experienced weight reduction from sibutramine, the metoprolol/hydrochlorothiazide group had significantly less weight loss (–3.9 ± 0.8 kg) compared with the verapamil/trandolapril (–6.1 ± 0.7 kg; pairwise comparison, P = 05) and the felodipine/ramipril (–7.2 ± 0.8 kg; pairwise comparison, P = .004) groups (Figure 1).

Figure 1. Effect of different antihypertensive combination therapies on the weight loss effect of sibutramine. HCT indicates hydrochlorothiazide.

The same significant results were shown for the decrease of body mass index, which was less in the metoprolol/hydrochlorothiazide group (global comparison, P = .016). Even more interesting was the fact that in contrast to the angiotensin-converting enzyme (ACE) inhibitor/calcium antagonist subgroup, the sibutramine-mediated reduction in the waist circumference was not significantly discriminated from placebo in subjects treated with the metoprolol/hydrochlorothiazide regimen, therefore indicating the loss of sibutramine's beneficial actions on visceral obesity. The grade of physical mobility increased significantly in the sibutramine group (11.9 ± 1.8) compared with the placebo group (5.0 ± 1.9; P = .096), and there were no significant differences among the 3 antihypertensive groups.

The baseline measurement of blood pressure was similar between the sibutramine and placebo groups, and there were no significant changes in blood pressure responses between the 2 groups (SBP, –5.9 vs –4.8 mm Hg; DBP, –0.7 vs –2.3 mm Hg, respectively) and among the 3 antihypertensive groups at the end of the study, although the heart rate did increase in the sibutramine group (+4.5 ± 1 beats/min in the sibutramine group vs –1.4 ± 1.0 beats/min in the placebo group; P < .001). This difference in heart rate was not specific for any antihypertensive treatment.

Fasting glucose levels were unchanged in the placebo group, whereas they were significantly decreased from baseline in the sibutramine group (5.7 ± 0.3 mmol/L before treatment vs 5.4 ± 0.2 mmol/L after treatment; P = .04). Results of the glucose tolerance test at 60 min were also improved among subjects taking sibutramine (–1.1 ± 0.3 mol/L; P = .001). As shown in Figure 2, compared with the felodipine/ramipril (–2.1 ± 0.6 mmol/L; pairwise comparison P = 0.1) and verapamil/trandolapril (–1.3 ± 0.5 mmol/L; pairwise comparison P = .08) groups, the effect on the glucose tolerance test was abrogated (–0.1 ± 0.5 mmol/L) in the group treated with metoprolol/hydrochlorothiazide (–0.1 ± 0.5 mmol/L).

Figure 2. Effect of different antihypertensive combination therapies on glucose tolerance measured by oral glucose tolerance test (oGTT).

Triglyceride levels were significantly decreased with sibutramine (–0.4 ± 0.1 mmol/L), which was most evident in the felodipine/ramipril group (–0.6 ± 0.2 mmol/L). Levels of total cholesterol, LDL cholesterol, and A1C were decreased, and the HDL cholesterol level was increased in the sibutramine group. There were no differences, however, among the various antihypertensive treatment groups.

Discussion

This study shows for the first time that the antihypertensive combination therapy of metoprolol/hydrochlorothiazide is less effective in supporting the weight reduction and metabolic changes induced by sibutramine than combination therapy with ACE inhibitors and calcium channel blockers. ß blocker/diuretic therapy assuaged the decrease in visceral obesity by sibutramine and eliminated the sibutramine-mediated improvement of glucose tolerance and the reduction of triglyceride levels. Under weight reduction management with sibutramine, the mean blood pressure decrease that occurred in hypertensive subjects did not occur in normotensive patients, which was first shown in a postmarketing surveillance study.⁵ A possible mechanism for this apparently paradoxical action of sibutramine could be the result of a different action on central and peripheral autonomic cardiovascular regulation.⁴ The effect of sibutramine on blood pressure regulation was similar among the antihypertensive treatment groups.

Visceral obesity is a key factor in the metabolic syndrome, and the pathophysiologic connection between abdominal fat and metabolic disorders such as dyslipidemia, glucose intolerance, and insulin resistance has been previously established.⁶ Furthermore, visceral obesity is increasingly acknowledged as a significant risk factor for cardiovascular morbidity and mortality, and a decrease in visceral obesity is linked to a reduction in cardiovascular risk.⁷ One method of quantifying visceral obesity is to measure the waist circumference, which can be successfully decreased with the use of sibutramine. Results from our study show that the ß blocker/diuretic combination not only decreased the weight-reducing effects of sibutramine, but also neutralized the drug's effect on visceral obesity. As a result, improvement in glucose tolerance was decreased. One possible explanation for this effect is the well-known weight gain triggered by ß blockers, which possibly opposes the effects of sibutramine on body weight.⁸ This weight gain is caused by a decrease in the basal metabolic rate and energy expenditure by ß blockade.⁹ The analysis of the degree of physical activity of our subjects showed no differences among the 3 antihypertensive groups, so that the ß blockade did not have a powerful effect on physical activity.

A second possibility to account for the study results is the prodiabetic effect of ß blockers through an impairment of glucose tolerance. Different ß blockers and different ß-1 and ß-2 selectivity can result in differences in the drugs' metabolic profiles, which need to be examined in future studies. Thiazide diuretics also impede insulin and glucose metabolism¹⁰; therefore, the combination possibly has even amplified the disadvantageous effects.

Conclusions

In light of the critical use of ß blockers in patients with primary hypertension without coronary heart disease or heart insufficiency¹¹ and a new positioning on the 4e level in the British Hypertension Guidelines,¹² the data from our prospective study show an advantage of the combination of ACE inhibitors and calcium channel blockers over the ß blocker/diuretic antihypertensive regimen in weight reduction, a decrease in visceral obesity, and metabolic regulation.

References

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A more detailed discussion of this topic can be found in Scholze J, Grimm E, Herrmann D, et al. Optimal treatment of obesity-related hypertension: the Hypertension-Obesity-Sibutramine (HOS) study. Circulation. 2007;115(15):1991-1998.