The observed relationship linking obesity, severity of hypertension, and increase in cardiovascular risk was traditionally thought to emanate from the increase in circulatory volume, persistently increased systemic resistance from obesity, and clustering of major cardiovascular risk factors (eg, hypercholesterolemia and diabetes mellitus) among obese patients.
The observed relationship linking obesity, severity of hypertension, and increase in cardiovascular risk was traditionally thought to emanate from the increase in circulatory volume, persistently increased systemic resistance from obesity, and clustering of major cardiovascular risk factors (eg, hypercholesterolemia and diabetes mellitus) among obese patients. Using data from the Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) study, de Simone and Lyle investigated whether body mass index (BMI) was independently associated with higher cardiovascular risk in patients with established hypertension and left ventricular hypertrophy (LVH).
Patients enrolled in the LIFE study had LVH documented by electrocardiographic criteria and a blood pressure of 160-200/90-115 mm Hg after a 2-week placebo run-in period. They were randomly assigned to receive the angiotensin-receptor blocker (ARB) losartan (Cozar) or the beta blocker atenolol (Tenormin). Other antihypertensive medications, with the exception of angiotensin-converting enzyme inhibitors, ARBs, and beta blockers, were added to reach the goal blood pressure of < 140/90 mm Hg. For obese patients, BMI was classified into 3 groups: class I (30-34.9 kg/m2), class II (35-39.9 kg/m2), and class III (≥40 kg/m2), according to 1998 National Institutes of Health guidelines. The effect of BMI on the primary composite end point of cardiovascular death, stroke, and myocardial infarction (MI) was analyzed.
Mean systolic blood pressure was comparable among strata, but diastolic blood pressure was higher with obesity. The prevalence of ischemic heart disease was lowest in patients with class III obesity. The prevalence of diabetes mellitus at baseline increased with the severity of obesity, from 15% in class I to 34% in class III. The urinary albumin-to-creatinine ratio was markedly higher with class III obesity. The lowest creatinine clearance was found in the most obese patients. The rates for the primary composite end point of cardiovascular death, stroke, and MI were similar among the strata, with 12% in the normal weight group vs 10% to 12% in the class I to III obesity groups in these patients with preestablished LVH. After controlling for covariates, it was noted that the group of overweight patients had a 17% higher risk of the primary composite end point than normal weight individuals. The pooled risk for class II and III patients was even higher, at 35%. New-onset diabetes mellitus was more prevalent with increasing obesity, with an occurrence rate of 1% in normal weight patients, 12% in class I patients, 15% in class II patients, and 23% in class III patients. This relationship was multifaceted, and we will intentionally focus our discussion on uric acid, which may be the pivotal link joining obesity and diabetes with hypertension and the increase in cardiovascular risk.
The association between hyperuricemia and hypertension has been well known for more than 50 years. This association had long been viewed as just that—an association—but the latest evidence indicates that this is causally linked.1
Central obesity, and more specifically, visceral fat accumulation worsen insulin resistance.2 This, in part, is due to tumor necrosis factor-α (TNF-α), which is overexpressed in obesity and inhibits insulin receptor substrate-1 and tyrosine kinase activity, leading directly to insulin resistance.3 In addition, plasma adiponectin normally blocks TNF-α signals and protects against insulin resistance, but this is reduced with an increase in visceral adipose tissue.3 Insulin resistance also reduces the urinary fractional excretion or renal elimination of uric acid by 30% and directly leads to hyperuricemia.4 The ensuing hyperuricemia, through proinflammatory and proliferative effects on vascular smooth muscle cells, may induce endothelial cell dysfunction and lead to anatomical arterial changes (eg, arteriosclerosis) and reduction in nitric oxide release leading to hypertension and cardiovascular disease.5-7 Johnson and Kang’s laboratory has elegantly shown that the simple attenuation of hyperuricemia with allopurinol (Zyloprim) ameliorates these arteriosclerotic changes in rats.8 With the renewed interest in the cardiovascular effect of uric acid, its biochemical cascade may soon be clarified.
Greater evidence now supports the benefit of reducing serum uric acid levels. Losartan is the only ARB that reduces serum uric acid levels by competing with the anion exchanger to increase urinary excretion of uric acid. The reduction in serum uric acid by losartan may contribute to the 25% risk reduction in stroke and achieve the same efficacy as a beta blocker in reducing cardiovascular events and MI.1,9 Although other ARBs also reduce stroke risk directly through their antihypertensive effects and likely through their angiotensin II type 1 (AT1) receptor antagonism and AT2 receptor upregulation, nearly one third of the benefit observed with losartan is thought to be attributable to its uricosuric properties.1
Fenofibrate (TriCor) also enhances the renal elimination of uric acid and lowers serum uric acid levels. It is known to reduce several markers of chronic vessel wall inflammation and to reduce the level of insulin resistance.10,11 In the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study, fenofibrate de­creased the number of nonfatal MIs and revascularizations but resulted in only a nonsignificant reduction in deaths due to coronary artery disease in patients with diabetes.12 Serum uric acid levels in the FIELD study were not determined and should be addressed in future studies.
Atorvastatin (Lipitor) may provide cardioprotection with its unique ability to lower serum uric acid by increasing urinary excretion of uric acid. This may contribute to the improvement in endothelial cell function and the anti-inflammatory effect.6,11 It is interesting to postulate that fenofibrate and atorvastatin improve endothelium-dependent vascular reactivity by their ability to reduce serum uric acid levels.10 This benefit could not be explained by changes in the lipid profile.10
Allopurinol can also provide cardiorenal protection by possibly lowering serum uric acid.13,14 Such an ap­proach may not be advisable because of potentially serious complications associated with allopurinol, including severe patient hypersensitivity to the drug, acute renal failure, and death. Other interventions, such as losartan, atorvastatin, fenofibrate, a low-purine diet, and insulin sensitizers, may be viable options. The combined use of fenofibrate and losartan leads to a greater urate-lowering effect than either medication alone,15 and concomitant use of fenofibrate and atorvastatin may be safer than previously thought.12,16 Newer medications, including febuxostat and uricase (Elitek), may provide additional options in treatment along with strategies to improve insulin resistance in the treatment of hyperuricemia.17
Improvement in insulin resistance by either weight loss or with an insulin sensitizer similar to troglitazone may reduce the uric acid level in obese hypertensive patients.18 Even in children younger than 14 years of age, obesity is correlated with higher serum uric acid, low-density lipoprotein cholesterol, and triglyceride levels, and lower adiponectin levels.3 As obesity becomes more prevalent among the pediatric population, greater effort will be needed to halt the growing endemic of metabolic syndrome and its lifelong complications.