Choice of drug treatment for obesity-related hypertension: where is the evidence?

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 first step in the management of increased blood pressure in obese individuals. Weight reduction may be achieved by behaviour modification, 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 specific advice on the pharmacological management of obese patients. This may be because there are currently no studies examining the efficacy of specific 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.     

Diagnosis and management of hypertension in obesity

Cardiovascular risk in a patient with obesity hypertension increases with the extent of risk factor clustering. It is therefore important to determine the global risk of a patient with hypertension rather than to focus solely on blood pressure. Every hypertensive should be screened for other than blood pressure risk factors, target organ damage and concomitant diseases or accompanying clinical conditions. Assessment of blood pressure and target organ damage might be more difficult in obese hypertensives than in normal-weight patients. Intensive lifestyle interventions can reduce weight, and decrease blood pressure and cardiovascular risk in obese hypertensive patients. Current guidelines do not provide specific recommendation for pharmacological management of the hypertensive patients with obesity. Recent trials have consistently shown that therapy involving beta-blockers and diuretics may induce more new-onset diabetes compared with other combination therapies. Several lines of evidence suggest that anti-hypertensive agents that block the renin-angiotensin system may be especially beneficial in treating obese hypertensive patients. Hypertension management in obese individuals is complicated by poorer response to treatment, and the increased need for multiple medications. It is important to consider obstructive sleep apnoea in the differential diagnosis of hypertensive patients who respond poorly to combination therapy with anti-hypertensive medications.     

Therapeutic considerations in the treatment of obesity hypertension

Obesity, now recognized as an independent risk factor for cardiovascular disease, is closely associated with hypertension. Complex mechanisms link increasing body weight with increasing blood pressure. Treatment of the obese patient with hypertension requires consideration of physiologic changes related to obesity hypertension. Lifestyle modification, including weight reduction and increased physical activity, can directly influence blood pressure levels and improve blood pressure control in obese, hypertensive patients. Clinical trials are needed to determine the most effective antihypertensive drugs for the obese, hypertensive patient. Antiobesity drugs offer viable adjunctive pharmacotherapy for obesity hypertension, but additional long-term studies are needed to support their safety and efficacy.     

Therapeutic Considerations in the Treatment of Obesity Hypertension

Obesity, now recognized as an independent risk factor for cardiovascular disease, is closely associated with hypertension. Complex mechanisms link increasing body weight with increasing blood pressure. Treatment of the obese patient with hypertension requires consideration of physiologic changes related to obesity hypertension. Lifestyle modification, including weight reduction and increased physical activity, can directly influence blood pressure levels and improve blood pressure control in obese, hypertensive patients. Clinical trials are needed to determine the most effective antihypertensive drugs for the obese, hypertensive patient. Antiobesity drugs offer viable adjunctive pharmacotherapy for obesity hypertension, but additional long-term studies are needed to support their safety and efficacy.     

Behandlung der Hypertonie bei Adipositas

BACKGROUND: 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 subjects. Weight Reduction and maintenance is an essential first step in the treatment of obesity-associated hypertension. Weight reduction may be achieved by behavior modification, diet, and exercise or by the use of anti-obesity medication. However, the long-term outcomes of weight management programs for obesity are generally poor, and most hypertensive patients will require antihypertensive drug therapy. PATHOPHYSIOLOGY: Obese hypertensive patients often have metabolic abnormalities known to be exacerbated by commonly used antihypertensive agents but also obesity per se is often associated with endorgan damage including left ventricular hypertrophy, glomerular hyperfiltration and microalbuminuria, congestive heart failure or sudden cardiac death. Furthermore they have revealed volume expansion, increased cardiac output, and lower total peripheral resistance than lean patients. Hypertension in obese patients appears to be related to both increased sympathetic nervous system activity and activation of the renin-angiotensin system. Where antihypertensive therapy is necessary, the aim should be to use agents based on the hemodynamic and metabolic background and that have benefits beyond blood pressure lowering and improve the conditions most commonly linked with obesity-associated hypertension, such as hyperlipidaemia, Type II diabetes, left ventricular hypertrophy, coronary artery disease, or congestive heart failure. PHARMACOTHERAPY: Based on their favorable metabolic profiles, it would appear that ACE inhibitors, angiotensin receptor blockers, calcium channel blockers, moxonidine and alpha-blockers can lower blood pressure without worsening the metabolic abnormalities, that is just one aspect of the problem. Yet, most guidelines fail to provide specific advice on the pharmacological management of hypertension in obese patients. This may be due to the fact that there are currently no studies that have addressed the efficacy of specific 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.     

Management of hypertension in overweight and obese patients: A practical guide for clinicians

The association between obesity and cardiovascular disease is well established, and up to 60% of overweight or obese patients have hypertension. Dietary interventions associated with modest weight loss are effective in controlling blood pressure and in reducing use of antihypertensive drug therapy in overweight and obese patients. However, long-term maintenance of weight loss is achieved only in a small proportion of patients. Orlistat and sibutramine may help to achieve and maintain weight loss but may not be sufficient to control blood pressure in overweight and obese hypertensive patients. Consequently, antihypertensive drug therapy is often necessary in addition to weight loss interventions. Few studies have investigated different antihypertensive drugs, specifically in overweight and obese patients with hypertension. Based on studies involving obese and nonobese patients, first-line treatment options include a diuretic alone or an angiotensin-converting enzyme (ACE) inhibitor alone. If monotherapy is inadequate for blood pressure control, combination therapy with diuretic and ACE inhibitor and/or combining either of these drugs with a calcium channel blocker are reasonable treatment options. Additional studies to further clarify the management of these patients are warranted.     

Novel Metabolic Drugs and Blood Pressure: Implications for the Treatment of Obese Hypertensive Patients?

Hypertension and obesity often coexist, exposing patients to cardiovascular and metabolic risks, particularly type 2 diabetes mellitus. Moreover, obesity may render hypertensive patients treatment resistant. We review how drugs recently approved for obesity or type 2 diabetes mellitus treatment affect blood pressure. The weight-reducing drug lorcaserin induces modest reductions in body weight while slightly improving blood pressure. The fixed low-dose topiramate/phentermine combinations elicit larger reductions in body weight and blood pressure. Concomitant improvements in glucose metabolism, adiposity, and blood pressure differentiate the first clinically available SGLT2 inhibitor dapagliflozin from other oral antidiabetic drugs. Yet, the mechanisms through which metabolic drugs affect blood pressure and their interaction with antihypertensive drugs are poorly understood. Blood pressure-lowering effects of metabolic drugs could be exploited in the clinical management of obese hypertensive patients with and without type 2 diabetes mellitus, particularly in patients with difficult to control arterial hypertension.     

Obesity and hypertension: epidemiological aspects of the relationship

A large proportion of hypertensive men and women in Europe and North America are overweight. In obesity, the expanded blood volume increases cardiopulmonary volume, cardiac filling, left ventricular preload, stroke volume and, thereby, left ventricular work. Given enough exposure time, it is probable that all obese persons in the Western hemisphere would become hypertensive unless they succumb to competing causes of death. A postulated causal role of obesity in hypertension is based on epidemiological observations. In prospective studies weight gainers in adolescence are more often hypertensive than weight stable individuals. In the lower socio-economic strata of industrialized countries there is a higher prevalence of obesity and hypertension. Persons with high body weight show the greatest rise of BP with age. More relevant demonstration of a causal relationship is weight reduction in hypertensive patients. The evidence from a variety of sources, a) risk factor reduction and enhanced BP reduction in the Hypertension Detection and Follow-up Program patients on antihypertensive medication who experienced modest weight loss, b) clinical observations of formerly obese hypertensives who can forego BP lowering drugs, and c) the reversibility of haemodynamic change found in many overweight hypertensive patients after losing 10 kg, strongly suggests that the impact of obesity on hypertension is considerable.     

Sympathetic nervous system in obesity-related hypertension: mechanisms and clinical implications

Obesity markedly increases the risk of hypertension and cardiovascular disease, which may be related to activation of the sympathetic nervous system (SNS). Sympathetic overactivity directly and indirectly contributes to blood pressure (BP) elevation in obesity, including stimulation of the renin-angiotensin-aldosterone system (RAAS). The adipocyte-derived peptide leptin suppresses appetite, increases thermogenesis, but also raises SNS activity and BP. Obese individuals exhibit hyperleptinemia but are resistant to its appetite-suppressing actions. Interestingly, animal models of obesity exhibit preserved sympathoexcitatory and pressor actions of leptin, despite resistance to its anorexic and metabolic actions, suggesting selective leptin resistance. Disturbance of intracellular signaling at specific hypothalamic neural networks appears to underlie selective leptin resistance. Delineation of these pathways should lead to novel approaches to treatment. In the meantime, treatment of obesity-hypertension has relied on antihypertensive drugs. Although sympathetic blockade is mechanistically attractive in obesity-hypertension, in practice its effects are disappointing because of adverse metabolic effects and inferior outcomes. On the basis of subgroup analyses of obese patients in large randomized clinical trials, drugs such as diuretics and RAAS blockers appear superior in preventing cardiovascular events in obesity--hypertension. An underused alternative approach to obesity-hypertension is induction of weight loss, which reduces circulating leptin and insulin, partially reverses resistance to these hormones, decreases sympathetic activation and improves BP and other risk factors. Though weight loss induced by lifestyle is often modest and transient, carefully selected pharmacological weight loss therapies can produce substantial and sustained antihypertensive effects additive to lifestyle interventions.     

Insulin resistance in hypertension and cardiovascular disease

Insulin resistance is not simply a problem of decreased glucose uptake in response to insulin, but a multifaceted syndrome that significantly increases the risk for cardiovascular disease. Insulin resistance is strongly associated with arterial hypertension and a pathogenetic role in the development of arterial hypertension has been suggested. One question that remains open concerns the clinical approach to insulin-resistant patients. Observational and clinical trial data suggest that lifestyle changes including weight reduction and regular physical activity can improve insulin sensitivity and reduce the incidence and mortality of cardiovascular disease. Daily physical activity of moderate intensity for 30 min has a cardioprotective effect and reduces insulin resistance, independent of the effect on body weight. A pharmacological therapy for insulin resistance reducing cardiovascular disease remains to be defined. Concerning the antihypertensive therapy of insulin-resistant hypertensive patients, most hypertensive guidelines fail to provide specific advice.     

Obesity and hypertension

Substantial evidence from epidemiological data supports a link between obesity and hypertension. However, the relationship between the two disorders is not straightforward and most likely represents an interaction of demographic, genetic, hormonal, renal, and hemodynamic factors. Age, race, and sex also modulate the strength of the association between obesity and hypertension. Hyperinsulinemia, which is characteristic of obesity, can contribute to the probability of developing hypertension by activating the sympathetic nervous system (SNS) and by causing sodium retention. The pressor effect of insulin in obesity may be further enhanced by the observation that its vasodilator action can be blunted in obese subjects. Preliminary data have shown that leptin, whose levels are increased in most obese individuals, can contribute to hypertension in obesity through its effects on insulin, SNS, and sodium excretion. The kidney may also have a role in the pathophysiology of hypertension in obesity. Abnormal renal sodium handling coupled with structural changes in the kidney of an obese patient can raise blood pressure. In addition, obesity is associated with distinct cardiovascular hemodynamic alterations and development of eccentric myocardial hypertrophy. Most of these obesity-associated abnormalities, as well as hypertension itself, can be reversed by weight loss. Furthermore, weight loss can prevent, or at least delay, the development of hypertension in patients with high-normal blood pressure. Weight reduction should be the first-line treatment in every obese hypertensive patient. However, the majority of patients will need pharmacologic intervention in conjunction with weight loss. Selection of antihypertensive agents in the overweight patient should take into account the mechanisms leading to hypertension and the metabolic abnormalities that characterize the obese patient.     

Cardiovascular prevention (VI). Use of drugs in the primary prevention of arterial hypertension and dyslipidemia

Arterial hypertension and dyslipidemia are two of the main risk factors for cardiovascular and renal disease in Spain. Lifestyle modification and drug therapy are the mainstays of risk reduction. Both the goals of therapy and the choice of drug treatment, in particular of antihypertensive treatment, are determined by the patient's demographic characteristics, the presence of other cardiovascular risk factors and the coexistence of asymptomatic vascular and kidney disease; that is, by the determinants of overall cardiovascular risk. Although some clinical guidelines exclude beta-blockers from first-line treatment of hypertension because they may have little effect, we believe that the five main classes of antihypertensive drugs currently available could provide first-line therapy since the majority of the hypertensive patients require combination therapy to achieve their blood pressure targets. Statins are fundamental to the pharmacologic treatment of dyslipidemia. Their primary effect is to reduce the plasma low-density lipoprotein level, which has been shown to be closely related to the reduction in cardiovascular risk. Other therapeutic agents include selective cholesterol absorption inhibitors (e.g., ezetimibe), which must be used in combination with statins, and fibrates, whose use is more restricted but which are helpful in patients with hypertriglyceridemia.     

Left ventricular hypertrophy and QT interval in obesity and in hypertension: effects of weight loss and of normalisation of blood pressure

BACKGROUND: Left ventricular hypertrophy (LVH) and prolonged QT interval at ECG (QTc) are common in both obesity and arterial hypertension (AH), and are risk factors for cardiovascular disease and sudden death. METHODS: We compared the frequencies of LVH (ECG criteria) and QTc in obese-AH (n=41), in normotensive obese (n=75), in lean-AH (n=30), and in lean controls (n=68) comparable for age and sex; in obese patients, LVH and QTc were evaluated under basal conditions and 1 y later, that is, after a significant weight loss induced by bariatric surgery. RESULTS: LVH was more frequent, and QTc was longer, in obese-AH, in normotensive obese, and in lean-AH than in lean controls; after weight loss, frequency of LVH decreased in obese subjects becoming normotensive (n=87), not in obese subjects remaining hypertensive (n=29), while QTc decreased in all obese subjects. CONCLUSION: Weight loss can effectively reduce QTc; when concomitant AH disappears, weight loss can also reduce the prevalence of LVH. In obese patients remaining hypertensive, aggressive pharmacological treatment is therefore indicated to correct LVH.     

Hypertension in obesity

AIM: To review various topics regarding the relationship between obesity and hypertension. DATA SUMMARY: Obesity is a widespread and increasingly prevalent condition associated with a large number of comorbid diseases, one of the most important of which is obesity-induced hypertension (HTN). The association between obesity and HTN has been well documented in most racial, ethnic and socio-economic groups, although the relationship between body mass index (BMI) and blood pressure values depends on age, gender, type of obesity and race differences. Obesity-induced HTN has some unique characteristics that differ from those observed in lean hypertensive patients. The hemodynamic profile of obese subjects is characterised by high cardiac output, high plasma and total blood volume, and inappropriately normal to total peripheral resistance. Clinically, hypertensive obese subjects are more likely to develop left ventricular hypertrophy and kidney damage than their lean counterparts. Various common factors are involved in establishing sodium retention and vascular resistance and may be critically influenced by the neurobiological/genetic mechanisms leading to obesity, in which insulin, leptin and the adrenergic system play major roles. Obesity is one of the main causes of therapeutic failure, and a number of studies have demonstrated that obese subjects need more antihypertensive drugs than sex and age-matched lean hypertensives. Long-term dietary treatment, consisting of a moderate restriction of energy and salt intake, is the most effective and safe treatment for obesity-associated HTN. The use of treatments other than calorie restriction should be considered with caution. Drugs that increase energy expenditure or reduce appetite may variably increase blood pressure (BP) and are unsuitable for hypertensive subjects. There do not seem to be any clear differences in the efficacy of the various antihypertensive drug classes. The clustering of cardiovascular risk factors other than HTN needs to be taken into account when choosing antihypertensive treatment for obese subjects. CONCLUSIONS: Obesity is a highly prevalent condition that causes or exacerbates many health problems including HTN. Combined interventions at different levels can help in losing weight and therefore reduce the cardiovascular risk, morbidity and mortality associated with obesity.     

Exercise in patients with hypertension

A progressive increase in arterial stiffness with aging contributes to systolic hypertension that results in left ventricular hypertrophy and concentric remodeling in the elderly. Lowering of blood pressure in older adults reduces cardiovascular risks. Endurance exercise training can lower blood pressure in older adults with mild (grade I) hypertension. However, the blood pressure-lowering effect of exercise training, compared with antihypertensive medications, is generally modest for both systolic and diastolic blood pressure. Exercise training alone is likely to be ineffective in lowering blood pressure sufficiently in older adults with moderate to severe (grade II and higher) hypertension. However, exercise and weight loss may potentiate the effects of antihypertensive medications in these subjects. Low-intensity endurance exercise training appears to be most effective in reducing blood pressure in older hypertensive adults. Metabolic adaptations to exercise training can significantly reduce other risk factors for coronary artery disease and atherosclerosis, in addition to reducing blood pressure. Endurance exercise training improves exercise capacity and quality of life, and can induce a modest but significant regression of left ventricular hypertrophy and remodeling in older adults with hypertension.     

Management of arterial hypertension in obese patients

Obesity prevalence is increasing. Obesity frequently coexists with—and can cause or worsen—arterial hypertension. However, no current guidelines provide specific recommendations. Antihypertensive drug treatment is indicated in most obese hypertensive patients, leading to the obvious question: what is the best drug treatment for this population? Some antihypertensive agents may have unwanted effects on the metabolic and hemodynamic abnormalities linking obesity and hypertension. Without adequate studies, recommendations for or against each class of antihypertensive agents are based on subjective criteria and pathophysiologic assumptions. Diuretics and β-blockers have unwanted effects, whereas calcium antagonists are metabolically neutral, and angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers may increase insulin sensitivity. The renin-angiotensin system in adipose tissue has been implicated in arterial hypertension, and sodium retention is central to obesity-related hypertension. Therefore, an ACE inhibitor or diuretic should be considered as first-line antihypertensive drug therapy in obesity-hypertension.     

Differential therapeutic topics in antihypertensive therapy. What can angiotensin-converting enzyme inhibitors accomplish?

The results of large epidemiological studies dealing with the prognosis and unfavourable outcome of essential hypertension, clearly show that the pharmacological reduction of the elevated blood pressure of hypertensive patients significantly reduces the risk of at least some major cardiovascular complications. Satisfactory antihypertensive efficacy reflects, nevertheless, merely a minimal requirement for a modern antihypertensive drug. Additional pharmacological properties, which counteract the typical concomitant diseases like CHD, heart failure and other cardiovascular complications would be desirable. In this respect, the oral CE-inhibitors captopril and enalapril offer an exciting new approach to the treatment of arterial hypertension. As the most predictive international studies on prevention of hypertension were conducted before CE-inhibitors were available, the present review evaluates the pharmacological profile of this new class of antihypertensive compounds in the light of previously available baseline drugs, including the calcium channel antagonists. Until now, captopril and enalapril have been the best investigated and documented representatives. Besides new experimental results concerning the molecular mechanism of these drugs, clinical and experimental approaches to verify protective effects on the cardiovascular and the renal system are addressed. These offer a rational basis for the preferential treatment of hypertensive patients with reduced renal function, diabetes and chronic heart failure. In addition, some distinct advantages of enalapril over captopril, resulting mainly from the long-term reduction of high blood pressure, are discussed.     

The heart,kidney, and brain as target organs in hypertension

The heart, kidney, brain, and arterial blood vessels are prime targets of hypertensive damage. Uncontrolled hypertension accelerates the damage to these organs and results in eventual organ failure and cardiovascular death and disability. Current guidelines for the appropriate treatment and control of hypertension requires an assessment of the presence of target organ damage. When present, evidence of target organ damage determines the urgency and intensity of drug treatment and may also dictate the choice of initial antihypertensive drug class. Thus, evaluation of persons with suspected or established hypertension must include a meticulous search for evidence of target organ damage. Fortunately, treatment with all antihypertensive medications that results in significant BP reductions also reduces fatal and nonfatal hypertensive complications and significantly slows down the progression to organ failure. Because of the important role that adverse activation of the renin-angiotensin-aldosterone system plays in target organ damage, drugs that antagonize this system have provided consistent and compelling proof of organ protection in both primary and secondary prevention of adverse outcomes. The challenge now is to use these and all other antihypertensive agents effectively to control BP to target levels in patients with hypertension. Continued emphasis on the adoption of lifestyle changes for prevention of hypertension in the first place or as adjunctive therapy in hypertensive patients is essential.     

The heart,kidney, and brain as target organs in hypertension

The heart, kidney, brain, and arterial blood vessels are prime targets of hypertensive damage. Uncontrolled hypertension accelerates the damage to these organs and results in eventual organ failure and cardiovascular death and disability. Current guidelines for the appropriate treatment and control of hypertension requires an assessment of the presence of target organ damage. When present, evidence of target organ damage determines the urgency and intensity of drug treatment and may also dictate the choice of initial antihypertensive drug class. Thus, evaluation of persons with suspected or established hypertension must include a meticulous search for evidence of target organ damage. Fortunately, treatment with all antihypertensive medications that results in significant BP reductions also reduces fatal and nonfatal hypertensive complications and significantly slows down the progression to organ failure. Because of the important role that adverse activation of the renin-angiotensin-aldosterone system plays in target organ damage, drugs that antagonize this system have provided consistent and compelling proof of organ protection in both primary and secondary prevention of adverse outcomes. The challenge now is to use these and all other antihypertensive agents effectively to control BP to target levels in patients with hypertension. Continued emphasis on the adoption of lifestyle changes for prevention of hypertension in the first place or as adjunctive therapy in hypertensive patients is essential.     

Arterial hypertension and obesity--a dangerous combination

The combination of obesity with arterial hypertension is frequent finding in clinical practice. In 70% of the males and 61% of the females the high blood pressure is directly connected with obesity. The assumed mechanisms by which obesity leads to arterial hypertension are: insuline resistance; genetic factors (hypothesis for the sparing gene); correlations leptin-neuropeptide Y; fatty tissue as origin of local pressor and depressor humoral factors. The arterial hypertension in obesity is salt-sensible, associated with increased intraglomerular pressure, microalbuminuria and increased risk for cardiovascular complications. The reduction of the body weight is the principal nonmedical mean for treatment of the arterial hypertension. Of the antihypertensive drugs those which are neutral with respect to the carbohydrat and fat metabolism are preferred inhibitors of the converting enzyme, calcium antagonists, selective alpha-1 blockers, central alpha-2 agonist.