1 Review 667 Choice of drug treatment for obesity-related hypertension: where is the evidence? Arya M. Sharma a, Tobias Pischon a, Stefan Engeli a and Juergen Scholze b Hypertension and obesity are common medical conditions independently associated with increased cardiovascular risk. Many large epidemiological studies have demonstrated associations between body mass index and blood pressure, and there is evidence to suggest that obesity is a causal factor in the development of hypertension in obese individuals. Consequently, all hypertension management guidelines consider weight reduction as a rst step in the management of increased blood pressure in obese individuals. Weight reduction may be achieved by behaviour modi cation, diet and exercise, or by the use of anti-obesity medications. However, the long-term outcomes of weight management programmes for obesity are generally poor, and most hypertensive patients will require antihypertensive drug treatment. Some classes of antihypertensive agents may have potentially unwanted effects on some of the metabolic and haemodynamic abnormalities that link obesity and hypertension, yet most hypertension guidelines fail to provide speci c advice on the pharmacological management of obese patients. This may be because there are currently no studies examining the ef cacy of speci c antihypertensive agents in reducing mortality in obese hypertensive patients. This paper reviews the theoretical reasons for the differential use of the major classes of antihypertensive agents in the pharmacological management of obesity-related hypertension and also considers the potential role of anti-obesity agents. J Hypertens 19:667±674 & 2001 Lippincott Williams & Wilkins. Journal of Hypertension 2001, 19:667±674 Keywords: obesity, body weight, weight gain, hypertension, therapy, treatment a Franz-Volhard Klinik, ChariteÂ Campus-Buch and Max-DelbruÈ ck Centre for Molecular Medicine, and b ChariteÂ Campus-Mitte, Berlin, Germany. Correspondence and requests for reprints to Professor Arya M. Sharma, Franz- Volhard Klinik am MDC, ChariteÂ Campus Buch, Wiltbergstr. 50, Berlin, Federal Republic of Germany. Tel: ; fax: ; Received 22 September 2000 Revised 21 November 2000 Accepted 21 November 2000 Introduction Hypertension and obesity are common medical conditions [1,2] independently associated with increased cardiovascular risk [3±5]. Epidemiological studies have consistently shown a tight correlation between body weight and blood pressure, with 70% of hypertension in men and 60% in women being directly attributable to excess adiposity [6,7]. Furthermore, there is substantial evidence to suggest that obesity per se is a prime cause of hypertension in obese individuals [8,9]. Current guidelines for the management of hypertension provide speci c recommendations for a variety of special populations, including patients with diabetes mellitus, coronary artery disease or renal dysfunction, or the elderly [3,4]. Surprisingly, however, these guidelines do not provide speci c recommendations for the management of the obese hypertensive patient that go beyond the rather general recommendation to reduce body weight: for example, the Sixth Report of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure guidelines  include only a single paragraph on the speci c management of hypertension in obese patients, with a focus on non-pharmacological weight reduction. Similarly, in the 1999 World Health Organization± International Society of Hypertension (WHO±ISH) guidelines , obesity is listed as a risk factor adversely in uencing prognosis, and weight reduction is recommended, but no speci c recommendations are made for the pharmacological management of the obese patient. This surprising lack of speci c recommendations for the obese hypertensive patient may re ect the paucity of `hard data' from prospective intervention studies for this important `special' population. Thus, although recent years have seen a number of prospective trials focusing on outcomes among the elderly , patients with diabetes  or high-risk patients , prospective outcome studies on the management of the obese hypertensive patient remain to be undertaken. Unfortunately, even retrospective analysis of the outcome in obese patients from existing trials is hampered by the fact that frankly obese individuals (those with a body mass index (BMI) greater than 30 kg/m 2 ) are often excluded from intervention trials, because of either excess body weight or the presence of co-morbid conditions such as congestive heart failure, diabetes or atrial brillation. Surprisingly, even recently published prospective intervention studies (e.g. ), despite the inclusion of large numbers of overweight and obese & 2001 Lippincott Williams & Wilkins
2 668 Journal of Hypertension 2001, Vol 19 No 4 patients, fail to present subanalyses for this important patient population. The lack of speci c recommendations for the obese hypertensive patient is far from trivial. Not only is it clear that obese hypertensive patients often have metabolic abnormalities known to be exacerbated by commonly used antihypertensive agents [13,14], but also, obesity per se is often associated with end-organ damage, including eccentric left-ventricular hypertrophy , glomerular hyper ltration and microalbumiuria , congestive heart failure  or sudden cardiac death [18,19]. Furthermore, an increase in adipose mass may be important as a potential determinant of response to treatment, possibly reducing the effectiveness of antihypertensive therapy. Thus patient surveys clearly show that overweight hypertensive individuals are less likely to achieve normal blood pressure in response to treatment [7,20]. This may not be surprising, as the pathophysiology and haemodynamic alterations found in obese patients may substantially differ from those found in non-obese patients; for example, studies in obese patients have revealed volume expansion, increased cardiac output, and lower total peripheral resistance compared with lean patients [15,21]. Furthermore, hypertension in obese patients appears to be related to increased activity of both the sympathetic nervous [22,23] and renin±angiotensin  systems. As antihypertensive agents have variable effects on these systems, it can reasonably be argued that these agents will differ in their blood pressure-decreasing ef cacy in obese patients compared with that in non-obese patients. The aim of this paper is therefore to discuss the role of speci c groups of antihypertensive agents in the pharmacological management of obesity-related hypertension. In addition, the use of anti-obesity agents is considered. Pharmacological management Pharmacokinetic aspects in the obese patient A potentially important aspect of choosing the correct antihypertensive agent in obese individuals may relate to the effect of increased fat mass on pharmacokinetics. Few studies have considered this issue with respect to antihypertensive drugs. In a study comparing the water-soluble â-blocker, atenolol, and the lipophilic agent, metoprolol, in lean and obese patients, there were profound differences in the pharmacokinetics of metoprolol, but not of atenolol . Surprisingly, however, pharmacodynamics ± the blood pressure-decreasing effects of the two compounds ± were comparable. Similarly, in obese patients, distribution volume and elimination half-life after intravenous administration of the calcium-channel blocker, verapamil, were markedly greater than those in non-obese patients . For a similar effect on blood pressure, prolongation of the P± R interval and re ex increase in heart rate were less in the obese patients, suggesting that adipose mass may also in uence the pharmacodynamic effect of intravenous verapamil. Fat mass, therefore, may signi cantly affect the pharmacokinetics of lipophilic drugs; this is an issue that has yet to be widely studied for other antihypertensive agents. Diuretics Diuretics achieve their blood pressure-decreasing effects primarily by reducing intravascular volume and cardiac output  and should thus be bene cial in the treatment of obesity-associated hypertension. However, these drugs stimulate both sympathetic nerve activity and the renin±angiotensin system , and long-term administration of the thiazide diuretic, hydrochlorothiazide, has been associated with increased insulin resistance and dyslipidaemia [27,28]. In a trial in 232 obese hypertensive patients, hydrochlorothiazide was as effective as the angiotensin converting enzyme (ACE) inhibitor, lisinopril, in decreasing blood pressure, but monotherapy with the diuretic showed a lower ef cacy at lower doses and had a slower rate of response than was achieved with the ACE inhibitor . Although neither drug had a signi cant effect on insulin and lipid pro les, the plasma glucose concentration was greater after 12 weeks treatment with the diuretic. Nevertheless, in the prospective Atherosclerosis Risk in Communities (ARIC) study , the use of thiazide diuretics was not associated with an excess risk of subsequent diabetes compared with the risk in patients who were not receiving antihypertensive therapy [relative hazard 0.91; 95% con dence interval (CI) 0.73±1.13]. Interestingly, in the Trial of Antihypertensive Interventions and Management , mildly hypertensive obese patients were noted to lose more weight when receiving chlorthalidone than when receiving placebo or atenolol. Weight loss was most pronounced at 6 months, but persisted at 24 months. The authors speculated that the difference between the drugs may be due to their intrinsic effects on the sympathetic nervous system and related metabolic changes. Thus it appears that diuretics, particularly in lower doses and in combination with other agents (such as ACE inhibitors and angiotensin receptor blockers), should perhaps play a central role in the management of obese hypertensive patients. â-blockers â-blockers act by reducing cardiac output and renin activity, and have been shown to reduce cardiovascular morbidity and mortality in patients with essential hypertension , including patients with diabetes .
3 Choice of drug treatment for obesity-related hypertension Sharma et al. 669 From a pathophysiological viewpoint, arguments have been put forward for their use in overweight and obese hypertensive patients. Obese patients commonly have increased sympathetic nerve activity [22,23] resulting in increased cardiac output and hypercirculation . These effects may be antagonized by the use of â- blockers. Thus, for example, metoprolol was shown to be more effective in decreasing blood pressure in obese than in lean hypertensive patients . Obesity is also associated with an increased risk for arrhythmias, potentially explaining the increased incidence of sudden death in obese individuals [18,19]. Furthermore, obesity is commonly associated with cardiac dysfunction and is an important risk factor for the development of eccentric left-ventricular hypertrophy and congestive heart failure [15,34]. Thus a fair case can be made for the use of â-blockers in these patients, as this class of drug has been shown not only to prevent sudden cardiac death, but also to improve prognosis in patients with congestive heart failure . Conversely, certain features of â-blockers may limit their use in the treatment of hypertension in the young obese patient with uncomplicated hypertension. First, â-blockers can cause weight gain [36,37], a fact that was also con rmed in diabetic patients in the United Kingdom Prospective Diabetes Study . Weight reduction, or even control of body weight ± an important aspect of hypertension management ± may thus be hampered by the use of a â-blocker. Second, â-blockers can interfere with carbohydrate and lipid metabolism, leading to disturbed glucose tolerance [38,39], increased triglycerides and reduced high-density lipoprotein cholesterol concentrations . The Gothenburg study found that propranolol was associated with a six-fold risk of developing diabetes . In the prospective ARIC study, the use of â-blockers was associated with a 28% greater risk of subsequent diabetes compared with the risk in those taking no medication (relative hazard 1.28; 95% CI 1.04±1.57) . Whether this also applies to newer atypical â-blockers such as carvedilol or nebivolol remains to be determined. Thus, given that obesity is the major risk factor for non-insulin-dependent diabetes and hypertension and is often accompanied by insulin resistance, the rationale for the use of â-blockers as rst-line agents in obesityrelated hypertension may be questioned. There should be no hesitation to use â-blockers in patients with ischaemic heart disease or heart failure, but alternatives should perhaps be preferred as rst-line therapy in young obese patients with uncomplicated hypertension. Calcium-channel blockers Calcium-channel blockers act by inhibiting the intracellular migration of calcium ions into smooth muscle and myocardial cells, leading to a reduction in arterial pressure through a decrease in peripheral vascular resistance . In addition, dihydropyridine calciumchannel blockers promote natriuresis  and may therefore work well in obese patients who have an increased intravascular volume . Conversely, peripheral vascular resistance is often lower in obese than in non-obese hypertensive patients [15,21], potentially attenuating the therapeutic effect of calcium-channel blockers in obese patients. It may therefore not be surprising that isradipine was found to be less effective than metoprolol in decreasing blood pressure in obese hypertensive individuals, whereas the calcium-channel blocker was more effective in lean individuals . Similarly, the blood pressure response to ni depine was negatively correlated to body fat . Calcium-channel blockers are believed not to have adverse metabolic effects  and, in the recent prospective ARIC study , the use of a calciumchannel blocker was not associated with excess risk for developing diabetes. A special case can perhaps be made in favour of the use of the non-dihydropyridine calcium-channel blocker, verapamil, in obese patients. This drug has been shown to decrease heart rate ± a potentially bene cial effect in obese individuals when one wishes to avoid the use of a â-blocker . Furthermore, in contrast to dihydropyridine calcium-channel blockers, verapamil does not produce re ex activation  or may even inhibit sympathetic activity [47,49]. In addition, verapamil may reverse the hyper ltration and microalbuminuria  that are often seen in patients with the metabolic syndrome . ACE inhibitors ACE inhibitors are safe and effective agents for decreasing blood pressure, being particularly effective in reducing morbidity and mortality in patients with heart failure . They are probably the most appropriate form of antihypertensive agent for obese hypertensive patients, as they exert a range of hypotensive effects [14, 29]. They are effective agents for decreasing arterial pressure (and thus total peripheral resistance), which is achieved by blockade of the renin±angiotensin system and by inhibition of the sympathetic nervous system. They also have bene cial effects on metabolic abnormalities, improving insulin sensitivity with no adverse effects on lipid pro les [27,52]. In the ARIC study , the use of an ACE inhibitor was not associated with an excess risk of subsequent noninsulin-dependent diabetes, and indeed both the Heart Outcomes Prevention Evaluation  and Captopril Prevention Project  trials, reported a reduced risk for the development of non-insulin-dependent diabetes with ACE inhibition.
4 670 Journal of Hypertension 2001, Vol 19 No 4 ACE inhibitors may also be the drugs of choice for the obese hypertensive patient because of the frequent association of obesity with left-ventricular hypertrophy, congestive heart failure , renal hyper ltration and microalbumuria  ± conditions known to be positively in uenced by ACE inhibition [52,54]. Interestingly, recent studies demonstrate that adipose tissue expresses several components of the renin± angiotensin system and that adipose-tissue-derived angiotensinogen, the single precursor of angiotensin II, may contribute to obesity-related hypertension . Blockade of the renin±angiotensin system may thus be of particular bene t in the management of obesityrelated hypertension. Angiotensin receptor blockers Angiotensin II receptor antagonists have many features in common with ACE inhibitors, as they directly antagonize the effect of angiotensin II by blocking the angiotensin II type 1 receptor. They are now recognized as effective and well-tolerated antihypertensive agents . Although there is currently no evidence from studies with hard endpoints regarding the effect of angiotensin receptor blockers on mortality in patients with hypertension, extensive trials are under way, including trials in patients with diabetes. The ndings of one small study in patients with severe hypertension suggest that the angiotensin II receptor antagonist, losartan, is associated with an improvement in insulin sensitivity . The authors postulate that a decrease in plasma noradrenaline during treatment suggests a sympatholytic effect, which, together with vasodilatation, may explain the decrease in blood pressure and the improvement in insulin sensitivity. Other studies have also suggested increased insulin sensitivity with angiotensin II receptor antagonists (reviewed in ), although a randomized trial in overweight patients with mild-to-moderate hypertension found that losartan, in contrast to perindopril, had no positive in uence on insulin sensitivity . In a recent study, irbesartan resulted in a decrease in brinogen and plasminogen activating inhibiting factor 1 , which are thrombogenic factors known to be increased in obese individuals [60,61]. Clearly, angiotensin II receptor antagonists provide an important alternative to the use of ACE inhibitors in patients with obesityrelated hypertension. á-blockers Current guidelines suggest that á-blockers are safe and effective agents for decreasing blood pressure, with particular advantages in individuals with dyslipidaemia or glucose intolerance . In general, á-blockers have been considered useful for the treatment of hypertensive patients with diabetes, because of their lack of adverse metabolic effects. Both prazosin  and doxazosin  have been associated with reduced glucose concentrations and improved insulin sensitivity. Although there is limited information on the use of á-blockers in obese patients, one small study showed bene cial effects on insulin resistance . It should be noted, however, that there are some concerns about the use of doxazosin in hypertensive patients, after discontinuation of the doxazosin arm of the patient Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial (ALL- HAT) . Compared with those allocated randomly to receive chlorthalidone, patients treated with doxazosin had a 25% increase in risk of cardiovascular disease events, including a doubling in risk of congestive heart failure. In the Framingham study, 90% of cases of heart failure were preceded by hypertension; furthermore, left ventricular hypertrophy is a common precursor of heart failure in hypertensive patients . As both leftventricular hypertrophy and reduced left-ventricular ejection fraction are commonly present in obesityassociated hypertension , the ndings of ALLHAT cast some doubt on the value of doxazosin in obese patients. Centrally acting agents As the sympathetic nervous system is implicated in obesity-related hypertension, centrally acting agents such as clonidine, moxonidine or methyldopa may potentially be useful. Clonidine has been shown to be effective in diabetic hypertensive patients , although its use is limited by side effects such as sedation and dry mouth. Use of this drug has been associated with reduced blood volume and reduced total body sodium . However, inhibition of sympathetic activity with clonidine can result in a marked reduction of both resting metabolic rate  and the thermic response to food  ± effects that may contribute to net positive energy balance, and thus weight gain, in obese patients. Speci c studies on the metabolic effects of centrally acting agents in obese hypertensive patients have yet to be undertaken. Weight management Most management guidelines recognize weight loss as one of the most effective strategies for decreasing blood pressure [3,4]. The WHO±ISH guidelines , for example, recommend weight reduction of at least 5 kg in the rst instance, as this is associated with reduced blood pressure and bene cial effects on associated risk factors.
5 Choice of drug treatment for obesity-related hypertension Sharma et al. 671 Dietary treatment consisting of a moderate restriction of energy, salt and alcohol intake, backed by exercise, promotes a reduction in blood pressure . In addition, exercise, moderate weight reduction and a low-fat, high-carbohydrate, high- bre diet can markedly improve insulin sensitivity and correct dyslipidaemia . It is important to note, however, that the bene ts of weight loss on hypertension have largely been observed in trials. In general practice, the achievement of longterm weight loss through behaviour modi cation, diet and exercise alone is unrealistic [72±74]. Thus a large proportion of patients may also require a pharmacological approach to achieving and maintaining weight loss in the long term. Pharmacological weight loss In contrast to the rather disappointing long-term success of non-pharmacological weight loss programmes, there are now good data showing that the use of newer pharmacological agents such as orlistat or sibutramine can result in 5±10% weight loss which is largely maintained for up to 2 years. Orlistat Orlistat is a gastrointestinal lipase inhibitor that restricts the absorption of dietary fat by about 30% . In a meta-analysis of trial data, obese patients (33% of whom were hypertensive) treated with orlistat and who lost more than 5% of their initial body weight after 1 year of treatment had mean reductions in systolic and diastolic blood pressure of 7.1 and 5.4 mmhg, respectively, similar to the decreases expected with many antihypertensive therapies when used as monotherapy . Substantial improvement in cardiovascular risk factors has also been observed in long-term studies lasting at least 2 years [77,78]. Furthermore, the use of orlistat was associated with a signi cant improvement in metabolic parameters, both in diabetic  and in non-diabetic patients . Because of its lack of speci c cardiovascular side effects, it may be well suited for managing the obese hypertensive patient. Its use can, however, be limited by gastrointestinal effects, which may result in discontinuation of medication in some patients. Sibutramine Sibutramine is a centrally acting inhibitor of serotonin and noradrenaline reuptake that enhances satiety and increases energy expenditure . Recent data from the Sibutramine Trial in Obesity Reduction and Management suggest that sibutramine in combination with an obesity management programme can result in weight loss accompanied by relevant improvements in metabolic parameters . Mean weight loss with sibutramine was 11.3 kg at 6 months, with recent data demonstrating signi cant maintenance of weight loss after 2 years. In terms of response, 93% of patients achieved a weight loss of more than 5% body weight, whereas 54% achieved a weight loss of more than 10%. However, treatment with sibutramine is associated with small increases in blood pressure in some patients, and an increase in heart rate in most . Nevertheless, after 2 years, weight maintainers had negligible blood pressure and heart-rate changes compared with baseline. Interestingly, results from a recent 6-month study of about 180 obese patients (BMI. 30 kg/m 3 ) demonstrated that weight loss with sibutramine was associated with reductions in left ventricular mass, with no effect on heart valves . Sibutramine possesses a thermogenic effect that appears to prevent the decline in energy expenditure that follows weight loss . Together with the increase in sympathetic nervous activity, this thermogenic effect may also contribute directly to the mild increase in heart rate. Nevertheless, the associated bene t from sibutramine with respect to metabolic risk factors may well outweigh the potential risk of sympathetic activation or increase in heart rate. Thus, although sibutramine can apparently be used for weight reduction and maintenance in obese hypertensive patients, blood pressure must be carefully controlled and monitored throughout treatment . Sibutramine is currently not indicated for patients with ischaemic heart disease or congestive heart failure. Outlook On the basis of our current understanding of the pathophysiology of obesity-related hypertension, it will be of interest to examine the ef cacy of some newer antihypertensive agents for these patients. For example, obese patients, perhaps as a result of increased expression of the atrial natriuretic peptide (ANP) clearing receptor in adipose tissue , have lower plasma ANP concentrations than would be expected given the degree of volume expansion . They may thus speci cally bene t from the use of vasoendopeptidase inhibitors such as omapatrilat , which can increase the availability of ANP and thus promote natriuresis and vasodilatation in these patients. In addition, given the recent nding that obesity is associated with increased concentrations of endothelin-1 [89,90], exploring the use of endothelin antagonists  in obese patients may appear promising. Whether or not newer developments, such as choosing the ideal antihypertensive agent for the obese patient on the basis of pharmacogenomic pro les , will help in the future treatment of obesity-associated hypertension also remains to be determined. Conclusion Weight reduction and maintenance are essential rst
6 672 Journal of Hypertension 2001, Vol 19 No 4 Table 1 Possible considerations in selecting pharmacological agents for treating obesity-related hypertension Agent Potential bene ts Potential drawbacks Diuretics (low dose) â-blockers Decrease in intravascular volume and cardiac output May antagonize enhanced SNS activity of obesity-related hypertension Increase in SNS and RAS activity Possible dose-related worsening of insulin resistance and dyslipidaemia Increased risk of both weight gain and diabetes Possible interference with carbohydrate and lipid metabolism Calcium-channel blockers Potential for decrease in peripheral resistance Neuroendocrine activation and intravascular volume No excess risk of diabetes Verapamil decreases heart rate ACE inhibitors Decrease in peripheral resistance None No excess risk of diabetes No dyslipidaemic effects Regression of LVH Angiotensin receptor blockers Effects similar to those of ACE inhibitors None Possible improvement in insulin sensitivity á-blockers Improvement in metabolic pro le Excess risk of cardiovascular events, particularly CHF? Centrally acting agents Decrease in SNS activity Possible impairment of glucose tolerance, weight gain SNS, sympathetic nervous system; RAS, renin±angiotensin system; ACE, angiotensin converting enzyme; LVH, left-ventricular hypertrophy; CHF, congestive heart failure. steps in the treatment of obesity-associated hypertension. Where weight loss is not possible or achievable, weight stabilization should be the aim. Because of the high rate of recidivism with diet, exercise and behavioural changes alone , pharmacological approaches are appropriate. When antihypertensive therapy is necessary, the aim should be to use agents that have bene ts beyond decreasing blood pressure and to improve the conditions most commonly linked with obesity-associated hypertension, such as hyperlipidaemia, non-insulin-dependent diabetes, left ventricular hypertrophy, coronary artery disease or congestive heart failure. Table 1 summarizes some of the potential bene ts and drawbacks of the main classes of antihypertensive agents in obese hypertensive patients. On the basis of their favourable metabolic pro les, it would appear that ACE inhibitors, angiotensin receptor blockers, calcium-channel blockers and á-blockers can decrease blood pressure without worsening the metabolic abnormalities that accompany hypertension in obese patients. ACE inhibitors, low-dose diuretics and non-dihydropyridine calcium-channel blockers are probably the drugs of rst choice in this setting. However, given that control of hypertension in the majority of hypertensive patients is unlikely to be achieved with any single drug alone , the discussion on choice of drug class may be moot. It is important, however, to note that, despite the potentially adverse effects of â-blockers and diuretics on metabolic factors, recent trials have so far failed to demonstrate the superiority of newer antihypertensive agents [53,94,95]. The discontinuation of the doxazosin arm of the ALLHAT trial tells a similar story . Hence, one must be cautious in trying to forsee the clinical effects of different antihypertensive drugs on the basis of theoretical advantages alone. Clearly, we must await reports on `hard endpoints' from prospective studies in obese patients before deciding on the best antiyhpertensive treatment for these patients. Novel therapeutic approaches that may prove useful in preventing the development of obesity-associated hypertension should also be studied in greater depth. These approaches may include treatment of obesity per se, using newer anti-obesity drugs to encourage longterm weight reduction and maintenance. There is also clearly a need for further work in elucidating the complex mechanisms involved in the development of obesity-associated hypertension, in addition to extension of the evidence base into the pharmacodynamic and pharmacokinetic considerations of treating obesity-associated hypertension. As a rst step, investigators of large intervention trials should be encouraged to provide subanalyses regarding outcomes in obese participants. Future studies should speci cally examine this issue in a prospective setting. References 1 Burt VL, Whelton P, Roccella EJ, Brown C, Cutler JA, Higgins M, et al. Prevalence of hypertension in the US adult population: results from the Third National Health and Nutrition Examination Survey, 1988±1991. Hypertension 1995; 25:305± Seidell JC, Flegal KM. Assessing obesity: classi cation and epidemiology. Br Med Bull 1997; 53:238±252.
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