Treatment of Hypertension in Obese Patients
Treatment of Hypertension in Obese Patients
Currently there are no specific guidelines for the treatment of obesity-related hypertension. No major trials have addressed this question specifically and choices must be made based on clinical experience, understanding of mechanisms of obesity-related hypertension, patient comorbidities, side effects, cost of medications, and frequency of dosing. Since a large proportion of hypertensive patients are either overweight or obese, the results of major hypertension trials, where the primary outcome measure is blood pressure response, are applicable to obese hypertensive patients as well.
Angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), direct renin inhibitors, and mineralocorticoid receptor antagonists (described below) are included in this category and are metabolically neutral. ACEIs as well as ARBs are effective in reducing blood pressure in obese patients, comparable to calcium channel blockers and diuretics. In addition, ACEIs and ARBs improve glucose tolerance, insulin levels, and visceral fat content, and reduce the risk of type 2 diabetes mellitus. Because of their favorable metabolic effects, ACEIs and ARBs (if ACEIs are not tolerated) are currently considered to be first-line agents for obesity-related hypertension. There is little difference in blood pressure lowering effect between ACEIs and ARBs. Direct renin inhibitors (e.g. aliskiren) have been available since 2007, and lower blood pressure to a degree comparable to other drugs used for monotherapy. However, this drug has not shown any benefit on primary cardiovascular or renal outcomes and is reportedly associated with a higher rate of adverse events (i.e. non-fatal stroke, hyperkalemia) and should not be combined with ACEIs or ARBs.
Volume expansion and sodium retention in obese hypertensive patients provide a rationale for the use of diuretics (thiazides, loop, and potassium sparing diuretics). They are generally inexpensive, well tolerated and effective. When used as monotherapy, they are at least as effective as ACEIs in most studies. However, thiazide diuretics increase insulin resistance, and dyslipidemia, and are associated with development of new-onset diabetes mellitus and increased activity of the sympathetic nervous system and renin–angiotensin system. In addition, thiazide diuretics (e.g. hydrochlorothiazide, chlorthalidone [a thiazide-like diuretic]) are also associated with hyponatremia, hypercalcemia, hyperuricemia, and hypokalemia, and careful monitoring of these laboratories is essential, at least at the beginning of therapy. Despite these adverse effects, most patients with obesity-related hypertension are volume expanded and require multi-drug therapy, and inclusion of a diuretic may be essential to achieve blood pressure control. Metabolic effects are minimized when these drugs are used in lower doses. Chlorthalidone has a longer half-life and is more effective in lowering systolic blood pressure than hydrochlorothiazide. Chlorthalidone is also more likely to be associated with adverse metabolic consequences than hydrochlorothiazide due to its increased potency. Even though chlorthalidone is associated with activation of sympathetic nervous system, chlorthalidone significantly reduces the risk of cardiovascular events and heart failure compared to hydrochlorothiazide. Based on these observations, some suggest that low to moderate dose chlorthalidone is the diuretic of choice. In the absence of overt congestive heart failure and renal insufficiency (creatinine clearance <30 ml/min), thiazide and thiazide-like diuretics are preferred over loop diuretics. Loop diuretics (e.g. torasemide, bumetanide, furosemide) are not recommended as first line agents for hypertension, as chronic use of loop diuretics is associated with distal tubular cell hypertrophy. If a loop diuretic is required for management of hypertension, torasemide may be preferable due to its long half-life and single daily dosing. Diuretic-induced hypokalemia may be attenuated by using diuretics in combination with other agents that increase potassium (ACEIs or ARBs) or by adding a potassium sparing diuretic to the regimen (e.g., amiloride, triamterene, or mineralocorticoid receptor antagonists such as spironolactone or eplerenone).
Mineralocorticoid receptor (MR) antagonists can be effective in the treatment of patients with drug-resistant hypertension, many of whom are obese, and their effects are additive to the use of ACEIs, ARBS, and other diuretics. Their efficacy is explained by the fact that there is generalized up-regulation of the renin–angiotensin–aldosterone system in obese patients. Several studies have shown efficacy of spironolactone in patients with multidrug resistant hypertension with average reduction of systolic and diastolic blood pressures in the range of 21–25 mmHg and 9–12 mmHg, respectively. While no such data exist for eplerenone, it may be an effective alternative in patients with adverse effects from spironolactone. One study showed that higher waist circumference is a predictor of blood pressure response to spironolactone. In addition, at daily doses of 25–50 mg daily of spironolactone, spironolactone had a greater anti-hypertensive effect than combined use of ACEIs and ARB.
Spironolactone is a non-specific MR antagonist having 30 % cross reactivity with the androgen receptor. This results in unwanted side effects in some men, such as gynecomastia, breast tenderness, and low libido. Eplerenone, a more specific aldosterone receptor antagonist, has fewer side effects and may be used in patients with spironolactone intolerance. Both of these drugs may lead to the development of hyperkalemia (especially in patients with renal impairment with or without diabetes mellitus); however, hyperkalemia is less frequent with eplerenone.
Calcium channel blockers consist of two sub-classes, dihydropyridine and non-dihydropyridine, and have a sharp distinction in their pharmacologic effects. Non-dihydropyridine agents are typically used in the cardiac dysrhythmia setting; however, they can reduce proteinuria in much the same way as ACEIs. The blood pressure lowering effect may be attenuated in obese, hypertensive subjects with these drugs, perhaps due to reduced peripheral resistance noted in obese subjects. The dihydropyridine (particularly first generation nifedipine) class of calcium channel blockers are associated with increases in albuminuria. While newer calcium channel blockers (e.g. amlodipine, felodipine) are considered preferable agents, their use as monotherapy should still be minimized secondary to risk of increased proteinuria.
These drugs (e.g. prazosin, doxazosin, and terazosin) are effective antihypertensive agents and improve insulin sensitivity, but there are concerns about their safety profile. In the ALLHAT trial, the alpha-blocker doxazosin arm was stopped prematurely because of an increased risk of cardiovascular events, particularly heart failure. Thus, an alpha blocker is no longer recommended for initial monotherapy; however, it can be used as a third- or fourth-tier agent if patients have contraindications to other drugs or have refractory hypertension.
These agents reduce cardiac output and heart rate, along with inhibiting renin secretion. They are more effective in lowering blood pressure in obese hypertensive patients than in lean. In patients with coronary artery disease, beta-blockers without sympathomimetic activity decrease the rates of sudden death, recurrent myocardial infarction, and hospitalization for congestive heart failure. In addition, beta-blockers are also given for rate control in patients with atrial fibrillation, control of angina, and a number of other conditions for symptom control. They also reduce morbidity and mortality in obese patients with a number of co-morbidities, including type 2 diabetes mellitus. However, they reduce energy expenditure, lipolysis, and insulin sensitivity. Their negative metabolic effect is associated with a small but significant weight gain (average 1.2 kg) and an increased risk of new onset diabetes. In addition, beta-blockers are not as effective in stroke prevention (particularly among smokers) compared with other antihypertensive regimens perhaps because central aortic pressure may not be lowered to the same extent as peripheral arterial pressure. Atenolol has also been associated with a slight increase in mortality particularly among those over the age of 60 years. Therefore, in the absence of specific indications mentioned above, beta blockers are not recommended as first line therapy in the treatment of hypertension, particularly in patients over the age of 60. Vasodilating beta-blockers with alpha-blocking activity (e.g. carvedilol, nebivolol, etc.) appear to be devoid of this negative metabolic profile, potentially related to their better peripheral glucose disposal effects permitted by vasodilatory component of these drugs. However, their effectiveness in improving cardiovascular outcomes in obesity-related hypertension has not been determined.
Although mechanistically attractive for the treatment of obesity-hypertension, in practice the effects of sympatholytic drugs such as clonidine or alpha-methyl dopa are disappointing because of adverse effects (such as sedation) and inferior outcomes. These side effects seem to be less prominent with newer imidazoline agonists approved in Europe for treatment of hypertension. Moxonidine and rilmenidine are prototype drugs of this class. Their efficacy is comparable to hydrochlorothiazide and ACEIs. Moxonidine was also noted to induce a 1- to 2-kg weight loss and to improve insulin sensitivity. These drugs lack the backing of clinical outcome trials, and moxonidine use in patients with heart failure has been associated with increased mortality due to worsening of heart failure.
Metformin, widely used for diabetes mellitus, reduces hyperinsulinemia. However, it has not been shown to reduce blood pressure significantly in meta-analyses of randomized controlled clinical trials as well as prospective studies, suggesting that metformin has no intrinsic effect on blood pressure. While thiazolidinediones have been shown to improve a number of cardiovascular risk factors and surrogate end-points, including endothelial function, vascular smooth muscle proliferation and progression of coronary atherosclerosis, effects on cardiovascular events have not been positive and concerns about fluid retention, heart failure, and myocardial infarction persist. Some early studies on troglitazone have shown modest reduction in blood pressure, but this has not been replicated with other members of the same class. Glucagon-like peptide (GLP)-1 agonists (e.g. Iiraglutide) when used in doses higher than the dose used for treatment of diabetes was associated with weight loss and statistically significant lowering of systolic blood pressure (−12.5 mmHg) at 2 years; however, it was also associated with a drop in heart rate (−3 bpm). Currently, it is not approved for treatment in doses used in the above study.
Despite a wide range of available drugs, blood pressure is uncontrolled in 50 % of hypertensive patients receiving antihypertensive treatment. With recognition of the roles of arterial stiffness, aldosterone production, and insulin resistance in the pathogenesis of hypertension in obesity, several new therapies have emerged; however, the path has not been easy, as evidenced by the fact that fewer than one in ten compounds selected for entering preclinical toxicological screening before testing in humans will reach the regulatory filing stage, yielding a failure rate of more than 90 %.Table 3 summarizes a few drugs currently in clinical trials that may be specifically useful for obesity hypertension.
The currently recommended target for blood pressure control is <140/90 mmHg. The blood pressure goal is <130/80 mmHg in high risk patients with the following disorders: diabetes mellitus, renal disease, coronary artery disease, coronary artery disease risk equivalents (carotid artery disease, peripheral arterial disease, abdominal aortic aneurysm), or a Framingham risk score ≥10 %. However, recent evidence suggests that overly aggressive targets for blood pressure control may not be advantageous in high risk patients. Among hypertensive patients with diabetes mellitus and coronary heart disease, "tight control" of systolic blood pressure (<130 mmHg) is not associated with improved cardiovascular outcomes. Caution should be exercised in lowering systolic blood pressure <130 mmHg in these patients.
Several strategies have been proposed which can serve as a blueprint; however, therapy should be highly individualized based on patient characteristics and co-morbidities ( Table 4 ). Most treatment regimens usually include a diuretic, an inhibitor of the renin–angiotensin system, and/or a calcium channel blocker. An MR antagonist can be added as a very effective fourth agent or at any stage as deemed appropriate. For patients with stage 2 hypertension (systolic blood pressure >160 mmHg or diastolic blood pressure >90 mmHg), it would be appropriate to simultaneously introduce two agents with complementary mechanisms of action. Most patients with obesity-related hypertension require multi-drug therapy. The capacity of thiazide diuretics to lower blood pressure in obese hypertensive patients is well established, although some consider ACEIs to be the most appropriate class of agents for these patients. The antihypertensive potencies of lisinopril and hydrochlorothiazide were reportedly similar in a study of 223 predominantly white, obese hypertensive patients. Several trials have documented the efficacy of the combination of hydrochlorothiazide with either an ACEI, and ARB, or the renin inhibitor aliskiren in obese hypertensive patients.
4 Drug Therapy for Obesity-Related Hypertension
Currently there are no specific guidelines for the treatment of obesity-related hypertension. No major trials have addressed this question specifically and choices must be made based on clinical experience, understanding of mechanisms of obesity-related hypertension, patient comorbidities, side effects, cost of medications, and frequency of dosing. Since a large proportion of hypertensive patients are either overweight or obese, the results of major hypertension trials, where the primary outcome measure is blood pressure response, are applicable to obese hypertensive patients as well.
4.1 Renin–Angiotensin–Aldosterone Blockers
Angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), direct renin inhibitors, and mineralocorticoid receptor antagonists (described below) are included in this category and are metabolically neutral. ACEIs as well as ARBs are effective in reducing blood pressure in obese patients, comparable to calcium channel blockers and diuretics. In addition, ACEIs and ARBs improve glucose tolerance, insulin levels, and visceral fat content, and reduce the risk of type 2 diabetes mellitus. Because of their favorable metabolic effects, ACEIs and ARBs (if ACEIs are not tolerated) are currently considered to be first-line agents for obesity-related hypertension. There is little difference in blood pressure lowering effect between ACEIs and ARBs. Direct renin inhibitors (e.g. aliskiren) have been available since 2007, and lower blood pressure to a degree comparable to other drugs used for monotherapy. However, this drug has not shown any benefit on primary cardiovascular or renal outcomes and is reportedly associated with a higher rate of adverse events (i.e. non-fatal stroke, hyperkalemia) and should not be combined with ACEIs or ARBs.
4.2 Diuretics
Volume expansion and sodium retention in obese hypertensive patients provide a rationale for the use of diuretics (thiazides, loop, and potassium sparing diuretics). They are generally inexpensive, well tolerated and effective. When used as monotherapy, they are at least as effective as ACEIs in most studies. However, thiazide diuretics increase insulin resistance, and dyslipidemia, and are associated with development of new-onset diabetes mellitus and increased activity of the sympathetic nervous system and renin–angiotensin system. In addition, thiazide diuretics (e.g. hydrochlorothiazide, chlorthalidone [a thiazide-like diuretic]) are also associated with hyponatremia, hypercalcemia, hyperuricemia, and hypokalemia, and careful monitoring of these laboratories is essential, at least at the beginning of therapy. Despite these adverse effects, most patients with obesity-related hypertension are volume expanded and require multi-drug therapy, and inclusion of a diuretic may be essential to achieve blood pressure control. Metabolic effects are minimized when these drugs are used in lower doses. Chlorthalidone has a longer half-life and is more effective in lowering systolic blood pressure than hydrochlorothiazide. Chlorthalidone is also more likely to be associated with adverse metabolic consequences than hydrochlorothiazide due to its increased potency. Even though chlorthalidone is associated with activation of sympathetic nervous system, chlorthalidone significantly reduces the risk of cardiovascular events and heart failure compared to hydrochlorothiazide. Based on these observations, some suggest that low to moderate dose chlorthalidone is the diuretic of choice. In the absence of overt congestive heart failure and renal insufficiency (creatinine clearance <30 ml/min), thiazide and thiazide-like diuretics are preferred over loop diuretics. Loop diuretics (e.g. torasemide, bumetanide, furosemide) are not recommended as first line agents for hypertension, as chronic use of loop diuretics is associated with distal tubular cell hypertrophy. If a loop diuretic is required for management of hypertension, torasemide may be preferable due to its long half-life and single daily dosing. Diuretic-induced hypokalemia may be attenuated by using diuretics in combination with other agents that increase potassium (ACEIs or ARBs) or by adding a potassium sparing diuretic to the regimen (e.g., amiloride, triamterene, or mineralocorticoid receptor antagonists such as spironolactone or eplerenone).
4.3 Mineralocorticoid Receptor Antagonists
Mineralocorticoid receptor (MR) antagonists can be effective in the treatment of patients with drug-resistant hypertension, many of whom are obese, and their effects are additive to the use of ACEIs, ARBS, and other diuretics. Their efficacy is explained by the fact that there is generalized up-regulation of the renin–angiotensin–aldosterone system in obese patients. Several studies have shown efficacy of spironolactone in patients with multidrug resistant hypertension with average reduction of systolic and diastolic blood pressures in the range of 21–25 mmHg and 9–12 mmHg, respectively. While no such data exist for eplerenone, it may be an effective alternative in patients with adverse effects from spironolactone. One study showed that higher waist circumference is a predictor of blood pressure response to spironolactone. In addition, at daily doses of 25–50 mg daily of spironolactone, spironolactone had a greater anti-hypertensive effect than combined use of ACEIs and ARB.
Spironolactone is a non-specific MR antagonist having 30 % cross reactivity with the androgen receptor. This results in unwanted side effects in some men, such as gynecomastia, breast tenderness, and low libido. Eplerenone, a more specific aldosterone receptor antagonist, has fewer side effects and may be used in patients with spironolactone intolerance. Both of these drugs may lead to the development of hyperkalemia (especially in patients with renal impairment with or without diabetes mellitus); however, hyperkalemia is less frequent with eplerenone.
4.4 Calcium Channel Blockers
Calcium channel blockers consist of two sub-classes, dihydropyridine and non-dihydropyridine, and have a sharp distinction in their pharmacologic effects. Non-dihydropyridine agents are typically used in the cardiac dysrhythmia setting; however, they can reduce proteinuria in much the same way as ACEIs. The blood pressure lowering effect may be attenuated in obese, hypertensive subjects with these drugs, perhaps due to reduced peripheral resistance noted in obese subjects. The dihydropyridine (particularly first generation nifedipine) class of calcium channel blockers are associated with increases in albuminuria. While newer calcium channel blockers (e.g. amlodipine, felodipine) are considered preferable agents, their use as monotherapy should still be minimized secondary to risk of increased proteinuria.
4.5 Alpha-Adrenergic Blockers
These drugs (e.g. prazosin, doxazosin, and terazosin) are effective antihypertensive agents and improve insulin sensitivity, but there are concerns about their safety profile. In the ALLHAT trial, the alpha-blocker doxazosin arm was stopped prematurely because of an increased risk of cardiovascular events, particularly heart failure. Thus, an alpha blocker is no longer recommended for initial monotherapy; however, it can be used as a third- or fourth-tier agent if patients have contraindications to other drugs or have refractory hypertension.
4.6 Beta-Blockers
These agents reduce cardiac output and heart rate, along with inhibiting renin secretion. They are more effective in lowering blood pressure in obese hypertensive patients than in lean. In patients with coronary artery disease, beta-blockers without sympathomimetic activity decrease the rates of sudden death, recurrent myocardial infarction, and hospitalization for congestive heart failure. In addition, beta-blockers are also given for rate control in patients with atrial fibrillation, control of angina, and a number of other conditions for symptom control. They also reduce morbidity and mortality in obese patients with a number of co-morbidities, including type 2 diabetes mellitus. However, they reduce energy expenditure, lipolysis, and insulin sensitivity. Their negative metabolic effect is associated with a small but significant weight gain (average 1.2 kg) and an increased risk of new onset diabetes. In addition, beta-blockers are not as effective in stroke prevention (particularly among smokers) compared with other antihypertensive regimens perhaps because central aortic pressure may not be lowered to the same extent as peripheral arterial pressure. Atenolol has also been associated with a slight increase in mortality particularly among those over the age of 60 years. Therefore, in the absence of specific indications mentioned above, beta blockers are not recommended as first line therapy in the treatment of hypertension, particularly in patients over the age of 60. Vasodilating beta-blockers with alpha-blocking activity (e.g. carvedilol, nebivolol, etc.) appear to be devoid of this negative metabolic profile, potentially related to their better peripheral glucose disposal effects permitted by vasodilatory component of these drugs. However, their effectiveness in improving cardiovascular outcomes in obesity-related hypertension has not been determined.
4.7 Central Sympathetic Blockade
Although mechanistically attractive for the treatment of obesity-hypertension, in practice the effects of sympatholytic drugs such as clonidine or alpha-methyl dopa are disappointing because of adverse effects (such as sedation) and inferior outcomes. These side effects seem to be less prominent with newer imidazoline agonists approved in Europe for treatment of hypertension. Moxonidine and rilmenidine are prototype drugs of this class. Their efficacy is comparable to hydrochlorothiazide and ACEIs. Moxonidine was also noted to induce a 1- to 2-kg weight loss and to improve insulin sensitivity. These drugs lack the backing of clinical outcome trials, and moxonidine use in patients with heart failure has been associated with increased mortality due to worsening of heart failure.
4.8 Drugs Reducing Insulin Resistance
Metformin, widely used for diabetes mellitus, reduces hyperinsulinemia. However, it has not been shown to reduce blood pressure significantly in meta-analyses of randomized controlled clinical trials as well as prospective studies, suggesting that metformin has no intrinsic effect on blood pressure. While thiazolidinediones have been shown to improve a number of cardiovascular risk factors and surrogate end-points, including endothelial function, vascular smooth muscle proliferation and progression of coronary atherosclerosis, effects on cardiovascular events have not been positive and concerns about fluid retention, heart failure, and myocardial infarction persist. Some early studies on troglitazone have shown modest reduction in blood pressure, but this has not been replicated with other members of the same class. Glucagon-like peptide (GLP)-1 agonists (e.g. Iiraglutide) when used in doses higher than the dose used for treatment of diabetes was associated with weight loss and statistically significant lowering of systolic blood pressure (−12.5 mmHg) at 2 years; however, it was also associated with a drop in heart rate (−3 bpm). Currently, it is not approved for treatment in doses used in the above study.
4.9 Novel Therapies
Despite a wide range of available drugs, blood pressure is uncontrolled in 50 % of hypertensive patients receiving antihypertensive treatment. With recognition of the roles of arterial stiffness, aldosterone production, and insulin resistance in the pathogenesis of hypertension in obesity, several new therapies have emerged; however, the path has not been easy, as evidenced by the fact that fewer than one in ten compounds selected for entering preclinical toxicological screening before testing in humans will reach the regulatory filing stage, yielding a failure rate of more than 90 %.Table 3 summarizes a few drugs currently in clinical trials that may be specifically useful for obesity hypertension.
4.10 Strategies for Drug Treatment of Obesity-Related Hypertension
The currently recommended target for blood pressure control is <140/90 mmHg. The blood pressure goal is <130/80 mmHg in high risk patients with the following disorders: diabetes mellitus, renal disease, coronary artery disease, coronary artery disease risk equivalents (carotid artery disease, peripheral arterial disease, abdominal aortic aneurysm), or a Framingham risk score ≥10 %. However, recent evidence suggests that overly aggressive targets for blood pressure control may not be advantageous in high risk patients. Among hypertensive patients with diabetes mellitus and coronary heart disease, "tight control" of systolic blood pressure (<130 mmHg) is not associated with improved cardiovascular outcomes. Caution should be exercised in lowering systolic blood pressure <130 mmHg in these patients.
Several strategies have been proposed which can serve as a blueprint; however, therapy should be highly individualized based on patient characteristics and co-morbidities ( Table 4 ). Most treatment regimens usually include a diuretic, an inhibitor of the renin–angiotensin system, and/or a calcium channel blocker. An MR antagonist can be added as a very effective fourth agent or at any stage as deemed appropriate. For patients with stage 2 hypertension (systolic blood pressure >160 mmHg or diastolic blood pressure >90 mmHg), it would be appropriate to simultaneously introduce two agents with complementary mechanisms of action. Most patients with obesity-related hypertension require multi-drug therapy. The capacity of thiazide diuretics to lower blood pressure in obese hypertensive patients is well established, although some consider ACEIs to be the most appropriate class of agents for these patients. The antihypertensive potencies of lisinopril and hydrochlorothiazide were reportedly similar in a study of 223 predominantly white, obese hypertensive patients. Several trials have documented the efficacy of the combination of hydrochlorothiazide with either an ACEI, and ARB, or the renin inhibitor aliskiren in obese hypertensive patients.
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