Journal of the American Society of Hypertension
Volume 2, Issue 4, Supplement , Pages S23-S29, July 2008

Does it matter how blood pressure is lowered in patients with metabolic risk factors?

Based on material presented at a Boehringer Ingelheim- Sponsored Meeting held in Madrid, Spain, May 4–5, 2007.

  • Arya M. Sharma, MD, FRCP(C)

      Affiliations

    • Corresponding Author InformationCorresponding author: Arya M. Sharma, MD, FRCP(C), Chair for Obesity Research and Management, University of Alberta, Royal Alexandra Hospital, 10240 Kingsway Avenue, Edmonton AB T5H 3V9, Canada. Tel: 780-735-5859; fax: 780-735-5861.

University of Alberta, Royal Alexandra Hospital, Edmonton, Canada

Article Outline

Abstract 

Abdominal obesity is an important cardiovascular risk factor. It is a primary driver of the metabolic syndrome, the cluster of metabolic risk factors that includes insulin resistance and dyslipidemia, and often occurs in association with hypertension. The aim of antihypertensive therapy in patients with metabolic risk factors is to reduce cardiovascular risk, but some antihypertensive agents can exert adverse metabolic effects. For example, beta-blockers produce significant weight gain, and are associated with an increased incidence of diabetes. By contrast, agents that inhibit the renin-angiotensin system (RAS), such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs), have been shown to be associated with a decreased risk of new-onset diabetes. This reflects the finding that increased activation of the RAS in obese individuals can contribute to the development of the metabolic syndrome. The ARB telmisartan has been shown to act as a selective peroxisome proliferator-activated receptor (PPAR)-γ modulator. It is known that PPAR-γ plays a role in the regulation of multiple genes affecting carbohydrate and lipid metabolism; however, the clinical significance of this remains to be established. The potential metabolic effects of RAS blockade should be considered in the choice of antihypertensive therapy for patients with metabolic risk factors, including obesity.

Keywords: Abdominal obesity, antihypertensive therapy, RAS, telmisartan

 

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Introduction 

It is estimated that the prevalence of obesity in developed countries ranges from 40% to 60%.1 Obesity is a recognized risk factor for stroke, renal dysfunction, gallbladder disease, sleep apnea, osteoarthritis, and certain forms of cancer, and can markedly impair quality of life.1 In addition, hypertension is common among obese or overweight individuals,2, 3, 4 and even moderate weight loss can significantly lower blood pressure (BP).5, 6 Hypertension is a key component of the metabolic syndrome, a cluster of risk factors that includes abdominal obesity, impaired glucose tolerance, insulin resistance, and dyslipidemia, and is associated with a high risk of cardiovascular morbidity.1, 7 There is, thus, a strong rationale for antihypertensive therapy to reduce cardiovascular risk in patients with the metabolic syndrome.

This raises the question of how BP should be lowered in patients with metabolic risk factors including obesity. Ideally, an antihypertensive agent should satisfy a number of criteria.8 It should provide effective BP control over 24 hours, without the development of tolerance during continued treatment or rebound effects following temporary discontinuation of treatment. It should be well tolerated, and lack any propensity for reflex sympathetic activation or precipitous falls in BP. Finally, it should reduce cardiovascular risk, offer protection against target-organ damage, and be devoid of deleterious metabolic effects. In practice, however, available antihypertensive therapies differ markedly in their clinical profiles, and hence care is necessary in selecting an appropriate agent for a patient with metabolic risk factors.

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Obesity as a Cardiovascular Risk Factor 

The impact of obesity on cardiovascular risk has been highlighted in a case-control study of acute myocardial infarction that involved approximately 30,000 participants from 52 countries (INTERHEART).9 This study identified nine factors (abnormal lipids [apolipoproteins B and A1], smoking, hypertension, diabetes, abdominal obesity, consumption of fruit, vegetables, and alcohol, and regular physical activity) that were significantly (positively or negatively) related to myocardial infarction. In particular, the odds ratio (OR) for the risk of myocardial infarction associated with abdominal obesity was 2.24 after adjustment for age, gender, and smoking (99% confidence interval [CI], 2.06 to 2.45); the population attributable risk of myocardial infarction associated with obesity was 33.7% (99% CI, 30.2% to 37.4%).9

The INTERHEART Study also highlighted the importance of visceral fat deposition as a cardiovascular risk factor. Traditionally, obesity has been expressed in terms of the body mass index (BMI), which is calculated as the weight in kilograms divided by the square of the height in meters; a BMI of 25.0 to 29.9 kg/m2 indicates overweight, while BMIs of 30 kg/m2 or above denote obesity.10 The BMI shows strong correlations with measures of body fat,10 but gives no information about the distribution of fat deposition. In the INTERHEART Study, in which abdominal obesity was expressed in terms of the waist-to-hip ratio, there were significant associations between this measure and the risk of myocardial infarction at all levels of BMI (Figure 1).11 The ORs for each successive quintile of BMI were significantly greater than that of the preceding quintile, and this association persisted after adjustment for other risk factors (OR for highest vs. lowest quintile, 1.75; 95% CI, 1.57 to 1.95; P < .0001). By contrast, BMI ceased to be an independent predictor of myocardial infarction risk after adjustment for other risk factors (OR, 0.98; 95% CI, 0.88 to 1.09). Thus, in this study waist-to-hip ratio was a stronger predictor of myocardial infarction risk than BMI. This shows that it is abdominal, rather than subcutaneous, fat deposition that is paramount in terms of cardiovascular risk.

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  • Figure 1. 

    Association between waist-to-hip ratio and risk of myocardial infarction according to BMI in a study of risk factors for first myocardial infarction in 52 countries and over 27,000 subjects (INTERHEART). Vertical bars indicate 95% CIs. BMI, body mass index; CI, confidence intervals; OR, odds ratio. Reprinted with permission from Yusuf S, Hawken S, Ounpuu S, Bautista L, Franzosi MG, Commerford P, et al. Obesity and the risk of myocardial infarction in 27,000 participants from 52 countries: a case-control study. Lancet 2005;366:1640–49.11

Visceral (abdominal) fat deposition is a primary driver of the metabolic syndrome. There are significant associations between visceral adiposity and hypertension, endothelial dysfunction, lipid abnormalities, increased inflammatory responses, and increases in prothrombotic factors (Figure 2), all of which may contribute to an increased cardiovascular risk.12

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  • Figure 2. 

    Factors contributing to cardiovascular risk in patients with visceral adiposity. Apo-B, apolipoprotein B; C, cholesterol; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; PAI-1, plasminogen activator inhibitor-1. Reproduced with permission from Sharma AM. Adipose tissue: a mediator of cardiovascular risk. Int J Obes 2002;26:S5–7.12

In view of the importance of abdominal obesity as a cardiovascular risk factor, current guidelines recommend that waist circumference should be measured routinely in order to assess obesity-related health risks.13 The waist circumference should be measured at a level midway between the lower costal margin and the iliac crest, with the patient standing with their feet about 25 to 30 cm apart.10

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Antihypertensive Therapy in Obese Patients 

Recent studies have highlighted the marked differences that exist between the available classes of antihypertensive agents, in terms of their effects on metabolic risk factors. For example, the recent Hypertension-Obesity-Sibutramine (HOS) Study investigated the efficacy of the antiobesity drug sibutramine in 171 obese hypertensive patients who also received 1 of 3 antihypertensive regimens: the dihydropyridine calcium antagonist felodipine plus the angiotensin-converting enzyme (ACE) inhibitor ramipril; the nondihydropyridine calcium antagonist verapamil plus the ACE inhibitor trandolapril; or the beta-blocker metoprolol plus hydrochlorothiazide.14 BP was decreased to similar extents by each of these regimens. However, sibutramine-induced weight loss was significantly (P = .0124) lower in patients receiving metoprolol/hydrochlorothiazide (mean loss, −3.9 ± 0.8 kg), compared with those receiving felodipine/ramipril (mean loss, −7.2 ± 0.8 kg) or verapamil/trandolapril (mean loss, −6.1 ± 0.7 kg). Similarly, BMI decreased to a significantly (P = .0156) lesser extent in sibutramine-treated patients receiving the beta-blocker/thiazide combination (mean decrease, −1.4 ± 0.3 kg/m2) than in those receiving felodipine/ramipril (mean decrease, −2.4 ± 0.3 kg/m2) or verapamil/trandolapril (mean decrease, −2.2 ± 0.3 kg/m2). In patients receiving the latter two combinations, sibutramine produced a significant reduction in waist circumference, compared with placebo; by contrast, in patients receiving metoprolol/hydrochlorothiazide, sibutramine had no significant effect on waist circumference. Since sibutramine exerts its effects by inhibiting catecholamine reuptake and beta-blockers may also partly inhibit catecholamine reuptake, this could explain the lack of additional efficacy when the two are used in combination.

However, a number of other studies have also shown that beta-blocker therapy is associated with significant weight gain in hypertensive patients. In the United Kingdom Prospective Diabetes Study (UKPDS), for example, tight BP control using atenolol-based regimens resulted in significantly more weight gain in hypertensive patients with type 2 diabetes than regimens based on an ACE inhibitor (mean gain 3.4 kg vs. 1.6 kg, respectively; P = .02).15 Similarly, in a systematic analysis16 of 8 prospective randomized trials involving a total of 7,048 patients, the median difference in weight between patients receiving beta-blockers and those receiving other antihypertensive therapies was 1.2 kg (range, −0.4 to 3.5 kg). This weight gain during beta-blocker therapy is largely attributable to reduced energy expenditure.16 In obese hypertensive patients, beta-blockade has been shown to reduce the basal metabolic rate by 12%, compared with other antihypertensive therapies.17 Total energy expenditure is also reduced during beta-blocker treatment,18, 19, 20 as is the thermogenic effect of food.21 In addition, beta-blockers may reduce energy expenditure indirectly by increasing fatigue and reducing anxiety, thereby decreasing fidgeting movements and hence non-exercise-associated thermogenesis.16 Beta-blockers have also been shown to inhibit lipolysis in response to adrenergic stimulation,22 an effect that could render it more difficult for patients to lose weight during treatment with these agents.16

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Antihypertensive Therapy and Diabetes Risk 

Certain antihypertensive agents are associated with adverse metabolic effects that can lead to the development of diabetes during long-term treatment. For example, in the Atherosclerosis Risk in Communities (ARIC) Study, a prospective study involving 12,550 nondiabetic participants aged 45 to 64 years, the hazard ratio for the development of diabetes among hypertensive participants (n = 3,804) treated with beta-blockers, compared with those receiving no antihypertensive therapy, was 1.26 (95% CI, 1.03 to 1.52; P < .05); by contrast, the risk of diabetes among participants treated with ACE inhibitors, calcium antagonists, or thiazide diuretics was not significantly different from that in untreated individuals.23 In a post-hoc analysis of the Antihypertensive and Lipid-Lowering treatment to prevent Heart ATtack (ALLHAT) Study, chlorthalidone produced a greater increase in fasting blood glucose over 4 years than amlodipine or lisinopril, and this was associated with a significantly (P < .01) higher risk of diabetes.24

There is evidence that blockade of the renin-angiotensin system (RAS) with ACE inhibitors or angiotensin receptor blockers (ARBs) results in a decreased risk of diabetes in hypertensive patients. In a meta-analysis of seven studies,25 involving approximately 70,000 participants, the incidence of new-onset diabetes was reduced by approximately 22% in those receiving ACE inhibitors or ARBs (OR, 0.78; 95% CI, 0.75 to 0.82; P < .0001). The number-needed-to-treat to prevent one new case of diabetes over about 5 years was approximately 45. In the Losartan Intervention For Endpoint (LIFE) Study, which enrolled 9,193 patients to treatment with atenolol or losartan, the proportion of patients with a first event (new-onset diabetes) was significantly reduced with losartan (an ARB) than atenolol (hazard ratio, 0.75; P = .001).26

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The RAS in Obesity 

Recent data suggest that blockade of the RAS is associated with a decreased incidence of diabetes. In one study, markers of RAS activation were measured in plasma samples and adipose tissue biopsies from 19 obese and 19 nonobese women.27 The obese women showed significantly higher circulating concentrations of angiotensinogen, renin, aldosterone, ACE activity, and angiotensin II than the nonobese women, and decreased expression of the angiotensinogen gene in adipose tissue. In 17 obese women who successfully participated in a weight reduction program, an average 5% reduction in body weight was associated with significant (P < .05) decreases of 12% to 43% in RAS components (Figure 3). There was a significant correlation between the reduction in plasma angiotensinogen and the decrease in waist circumference (r = 0.74; P < .001).

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  • Figure 3. 

    Effect of weight loss on circulating components of the RAS in 17 obese women. Results are presented as means ± standard deviation. *P < .05. Note: the glucose curves before and after amlodipine treatment were exactly similar and overlapped. ACE, angiotensin-converting enzyme; AGT, angiotensinogen; Ang II, angiotensin II; RAS, renin-angiotensin system. Reproduced with permission from Engeli S, Böhnke J, Gorzelniak K, Janke J, Schling P, Bader M, et al. Weight loss and the renin-angiotensin-aldosterone system. Hypertension 2005;45:356–62.27

Such findings show that weight loss in obese individuals is associated with inhibition of the RAS. While this may be partly due to reduced sympathetic nervous activity, resulting in decreased renin release, it seems likely that changes in adipocyte function also contribute. It is now recognized that adipose tissue, rather than being an inert storage depot, is a metabolically active tissue and that visceral adipose tissue is more active than subcutaneous adipose tissue.28, 29 Visceral adipose tissue secretes a variety of metabolically active factors, collectively termed adipokines, that include angiotensinogen and angiotensin II.29 The latter are known to play a local role in adipocyte differentiation and metabolism,12, 29, 30 and, hence, inhibition of the RAS may result in a shift in adipocyte distribution from visceral to subcutaneous depots. Furthermore, there is a correlation between 24-hour BP and the expression of genes related to the RAS in adipocytes.12, 31 Expression of the RAS, therefore, plays an important role in the development of many of the manifestations of metabolic syndrome.

One mechanism by which angiotensin II may contribute to the development of the metabolic syndrome is stimulation of nicotinamide dinucleotide phosphate hydrogen (NADPH) oxidation, thereby increasing oxidative stress, which leads to increased insulin resistance and the development of atherosclerosis. Fat accumulation is associated with increased oxidative stress, with production of radical oxygen species (ROS), activation of NADPH oxidase, and decreased expression of antioxidative enzymes.32 It has been suggested that angiotensin II increases ROS production in human preadipocytes, and that this effect can be inhibited by ARBs; telmisartan was more effective in this respect than irbesartan or eprosartan. Telmisartan was also found to restore the secretion of adiponectin, an adipokine that acts as an endogenous insulin sensitizer, in preadipocytes subjected to oxidative stress.

Recent data suggest that telmisartan might exert beneficial metabolic effects via selective peroxisome proliferator-activated receptor (PPAR)-γ modulation. PPAR-γ is a nuclear receptor that plays an important role in the regulation of multiple genes affecting carbohydrate and lipid metabolism, and telmisartan has been shown to act as a partial agonist at this receptor in vitro.33 The potential clinical significance of this activity has recently been studied in a prospective randomized study involving 54 Japanese patients with metabolic syndrome and abdominal obesity (defined in Japan as a waist circumference ≥ 85 cm in men or ≥ 90 cm in women).34 Patients were randomized to receive either telmisartan, 20 to 40 mg, or amlodipine, 2.5 to 5 mg, and the effects of treatment on visceral fat content (measured by computed tomography) and oral glucose tolerance were assessed after 24 weeks. Both treatments reduced BP to comparable extents. However, telmisartan was associated with significant reductions in plasma glucose and insulin following an oral glucose tolerance test, whereas amlodipine had no effect (Figure 4). In addition, patients treated with telmisartan showed a significant reduction in visceral fat, whereas no such change was seen in amlodipine-treated patients (Figure 5). Although these changes may be attributable to effects of telmisartan on PPAR-γ, it should be noted that the clinical significance of such effects remains to be definitively established. However, coupled with its proven clinical efficacy in obese patients with type 2 diabetes and hypertension, telmisartan could play a useful role in the treatment of obese patients. In the Study of Micardis (telmisartan) in Overweight/Obese patients with Type 2 diabetes and Hypertension (SMOOTH), which enrolled 840 patients to telmisartan 80 mg or valsartan 160 mg with add-on hydrochlorothiazide 12.5 mg, telmisartan plus hydrochlorothiazide provided significantly greater reductions during the last 6 hours of the 24-hour dosing period compared with valsartan plus hydrochlorothiazide.35

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  • Figure 4. 

    Changes in glucose tolerance following a 75-g oral glucose load in Japanese patients with metabolic syndrome and abdominal obesity treated with telmisartan, 20 to 40 mg, or amlodipine, 2.5 to 5 mg, for 6 months. Results are presented as means ± standard deviation. Reproduced with permission from Shimabukuro M, Tanaka H, Shimabukuro T. Effects of telmisartan on fat distribution in individuals with the metabolic syndrome. J Hypertens 2007;25:841–48.34

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  • Figure 5. 

    VFA in Japanese patients with metabolic syndrome and abdominal obesity treated with telmisartan, 20 to 40 mg, or amlodipine, 2.5 to 5 mg, for 6 months. VFA, visceral fat area. Reproduced with permission from Shimabukuro M, Tanaka H, Shimabukuro T. Effects of telmisartan on fat distribution in individuals with the metabolic syndrome. J Hypertens 2007;25:841–48.34

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Conclusion 

The choice of antihypertensive therapy in obese patients will depend on a variety of factors. However, the ultimate aim of antihypertensive therapy is to reduce cardiovascular risk, and visceral adiposity is an important determinant of this risk. Antihypertensive drugs vary markedly in their effects on visceral obesity and metabolic risk factors: for example, beta-blockers induce weight gain whereas ACE inhibitors and ARBs appear to be protective against the development of diabetes. Clearly, the beneficial effects of BP reduction on cardiovascular risk should not be reversed by adverse metabolic effects of antihypertensive therapy. There is, thus, a case for considering the potential metabolic effects of RAS blockade when choosing an antihypertensive agent in an obese patient.

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References 

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 Conflict of interest: none.

PII: S1933-1711(08)00043-0

doi:10.1016/j.jash.2008.03.006

Journal of the American Society of Hypertension
Volume 2, Issue 4, Supplement , Pages S23-S29, July 2008

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