Related information on this website: In the Slide Library section: ALLHAT-LLT: All-Cause Mortality ALLHAT-LLT: Comparison to Other Large, Long-Term Statin Trials ASCOT-LLA: Primary End Point ASCOT-LLA: Primary End Point in Subgroups ATP III: Risk Categories, LDL-C Goals In the Current Literature section: Major Outcomes in Moderately Hypercholesterolemic, Hypertensive Patients Randomized to Pravastatin vs Usual Care: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT) Furberg CD, Wright JT, Davis BR, et al, for the ALLHAT Collaborative Research Group. JAMA. 2002;288:2998-3007. Prevention of Coronary and Stroke Events With Atorvastatin in Hypertensive Patients Who Have Lower-Than-Average Cholesterol Concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA): A Multicentre Randomised Controlled Trial Sever PS, Dahlöf B, Poulter NR, et al, for the ASCOT Investigators. Lancet. 2003;361:1149-1158. Should Diastolic and Systolic Blood Pressure Be Considered for Cardiovascular Risk Evaluation: A Study in Middle-Aged Men and Women Benetos A, Thomas F, Safar ME, Bean KE, Guize L. J Am Coll Cardiol. 2001;37:163-168.

Hypertension and hypercholesterolemia are independent risk factors for the development of coronary heart disease (CHD).¹ Although it is not yet known whether the frequent coexistence of these two conditions in epidemiologic studies represents a statistical association or pathophysiologic link,² several recent clinical trials suggest that treatment of hypercholesterolemia with HMG-CoA reductase inhibitors (statins) not only improves lipid profiles in patients with hypertension, but also enhances blood pressure (BP) control.³

What, then, is the optimal therapeutic approach, based on current research findings, for managing coexisting hypertension and hypercholesterolemia in patients? Might lipid-lowering be an additional method of correcting hypertension in this high-risk population? What effect, if any, does lipid-lowering have on the incidence of CHD-related events in these patients? Finally, do any antihypertensive medications have long-term adverse effects on lipid profiles or interact adversely with statins?

Association Between Hypertension and Hypercholesterolemia
Up to 40% of hypertensive patients have hypercholesterolemia,⁴ and 40% of hypercholesterolemic patients have hypertension.⁵ In the Multiple Risk Factor Intervention Trial (MRFIT) of 316,099 white men aged 35 to
57 years, graded increases in cholesterol and systolic or diastolic BP levels were related to corresponding increases in CHD death rates. Moreover, the CHD death rate associated with these combined risk factors exceeded that associated with each risk factor individually.⁶ Certain populations are particularly vulnerable to both conditions (see “Populations at Risk…,” below). It is likely that common pathogenetic features—such as insulin resistance and endothelial dysfunction—contribute to the coexistence of these conditions.¹

   One team of researchers had surmised that factors affecting the endothelium (ie, lipoproteins) might play a role in the development of hypertension. They found that, among 73 patients with recently discovered and never-treated arterial hypertension, those in the highest tertile of serum TC level experienced significant increases in BP during isometric exercise.² Investigators who examined 803 asymptomatic individuals aged 40 or older in the Rochester Family Heart Study found that hypertensive men, as compared with their normotensive counterparts, had a significantly lower level of HDL-C and a significantly higher prevalence and amount of coronary artery calcification.⁷ Palmiero et al, who studied 200 postmenopausal women with previously untreated hypertension, found that those who also had diastolic dysfunction had significantly higher levels of TC and LDL-C and significantly lower levels of HDL-C.⁵ The research of Sander and Giles has elucidated one of the biochemical mechanisms that may connect hypertension and dyslipidemia: LDL-C has been shown to upregulate the angiotensin (AT)-I receptor, resulting in an increase in BP.⁸

Effects of Statins on BP Control
Three reviews suggest that statins—either alone or in combination with certain antihypertensive agents—may lower BP in patients with coexisting hypertension and hypercholesterolemia.^1,3,4 All of these reviews cited a variety of studies demonstrating the BP-lowering effect of statins in patients with untreated hypertension, including some with type 2 diabetes. In some of these studies, reductions in diastolic and systolic BP were found to be independent of plasma TC reductions. Borghi also described studies in which retrospective analyses found that statins enhanced the antihypertensive effect of angiotensin-converting enzyme (ACE) inhibitors and calcium channel blockers (CCB), but not that of ß-blockers or diuretics.³ The mechanism responsible for the statins’ BP-lowering effect appears to be largely independent of their effect on plasma TC levels, and may be due to their effects on endothelial function and AT-II receptors.⁴ In addition, statins may enhance the ability of ACE inhibitors and CCBs to reduce peripheral vascular tone and improve peripheral vasodilator capacity.³

Effect of Statins on Arterial Stiffness
A recent double-blind crossover study showed that atorvastatin reduced BP and large artery stiffness in 22 normolipidemic patients with isolated systolic hypertension.⁹ Patients received a 3-month course of atorvastatin 80 mg daily or placebo. Along with its favorable effect on lipid profiles (even in a normolipidemic population), atorvastatin, when compared with placebo, increased systemic arterial compliance, as measured by carotid applanation tonometry and Doppler velocimetry of the ascending aorta. It also significantly reduced brachial systolic BP by an average of 6 mm Hg (P=0.03) and diastolic BP by an average of 2 mm Hg (P=0.04).

Effects of Statins on Mortality/CHD in Hypertensive Patients
Substudies of two large trials have assessed the effects of statins in patients with hypertension. (See “Two Major Clinical Trials…,” below, for a description of the main elements of the trials.)

Two Major Clinical Trials Exploring the Lipid/Blood Pressure Connection ASCOT-LLA1: Substudy: lipid-lowering arm of the ongoing Anglo-Scandinavian Cardiac Outcomes Trial Participants: 10,305 aged 40–79 years with BP >160 mm Hg systolic and/or >100 mm Hg diastolic (untreated) or >140 mm Hg systolic and/or >90 mm Hg diastolic (treated); TC <250 mg/dL and TG <400 mg/dL; >3 risk factors for CVD Randomization: atorvastatin 10 mg (5,168) or placebo (5,137) Primary end-point outcomes: 36% reduction in atorvastatin group vs placebo in nonfatal MI (including silent MI) and fatal CHD (significant; P=0.0005) Significant secondary end-point outcomes: (in atorvastatin group vs placebo for all) 27% reduction, fatal and nonfatal stroke (P=0.0236); 21% reduction, total CV events including revascularization (P=0.0005); 29% reduction, total coronary events (P=0.0005); 38% reduction, primary end point excluding silent MI (P=0.0005) Lipid reductions: (in atorvastatin vs placebo) 19% TC; 29% LDL-C; 14% TG Length: LLA terminated after 3.3 years (5-year planned length) due to early positive results ALLHAT-LLT2: Substudy: lipid-lowering trial component of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial Participants: 10,355 ALLHAT participants (age =55 years, stage 1 or 2 hypertension with at least 1 additional CHD risk factor); LDL-C: 120–189 mg/dL (100–129 mg/dL if known CHD) and TG <350 mg/dL Randomization: open-label pravastatin 40 mg (5,170) or usual care (5,185); Note: during trial, 32% of usual-care participants with, and 29% without, CHD started on a lipid-lowering drug Primary end-point outcomes: 6-year all-cause mortality rates: 14.9% for pravastatin vs 15.3% for usual care (P=0.88) Secondary end-point outcomes: 6-year CHD event (nonfatal MI or fatal CHD combined) rates: 9.3% for pravastatin vs 10.4% for usual case (not significantly different; P=0.16) Lipid reductions: (in pravastatin vs usual care at 4 years) 9.6% TC; 16.7% LDL-C Length: LLT follow-up was 6 years REFERENCES 1. Sever PS, Dahlof B, Poulter NR, et al, for the ASCOT Investigators. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the ASCOT —Lipid Lowering Arm: a multicenter randomized controlled trial. Lancet. 2003;361:1149-1158. 2. The ALLHAT Collaborative Research Group. Major outcomes in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin vs usual care. JAMA. 2002;288:2998-3007.

    ASCOT-LLA. Results of the Lipid-Lowering Arm (LLA)¹⁰ of the ongoing Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT)¹¹ were dramatic enough to warrant the substudy’s premature termination. The study was designed to assess benefits of cholesterol lowering in the primary prevention of CHD in hypertensives not considered dyslipidemic. A total of 10,305 ASCOT participants (TC <250 mg/dL) were randomized to receive atorvastatin 10 mg daily or placebo. These subjects did not have preexisting CHD, although they had >3 CVD risk factors. After 3 years, atorvastatin recipients, relative to placebo recipients, had a significantly lower incidence of MI and stroke.
    ALLHAT-LLT. Results of the Lipid-Lowering Trial (LLT)¹² of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)¹³ were modest. The goal of the LLT was to assess the impact of reductions in TC and LDL-C on all-cause mortality in a hypertensive cohort with at least one additional CHD risk factor and to assess CHD reduction (fatal CHD or nonfatal MI) in populations excluded from or underrepresented in previous trials.¹² A total of 10,355 patients who were enrolled in ALLHAT and who had moderate hypercholesterolemia were randomized to receive open-label pravastatin 40 mg daily or usual care provided by their primary care physician. After 6 years of follow-up, the mean differences in TC and LDL-C levels (pravastatin vs usual care) were 18.9 mg/dL and 17.2 mg/dL, respectively. All-cause mortality, the primary outcome measure, did not differ significantly between groups, and rates of CHD and stroke were only slightly and nonsignificantly lower in pravastatin recipients.
    One of the main reasons that the pravastatin group did not have a significant reduction in risk compared with the usual-care group is that almost one third of the latter received a statin. At the same time, a sizable proportion of pravastatin recipients did not adhere to their regimen. As a result, the differential in cholesterol lowering between the two groups was insufficient to produce the degree of risk reduction seen in the major placebo-controlled statin trials, in which the placebo subjects experienced little or no cholesterol lowering.

Effects of Antihypertensive Drugs on Lipid Profiles
Do any antihypertensive drug classes have adverse effects on lipid profiles or interact adversely with statins, possibly canceling the potential benefits of the lipid-lowering agents?
     Thiazide diuretics and loop diuretics may raise levels of TC, TG, and LDL-C,¹⁴ although these values appear to revert to pretreatment levels with long-term thiazide therapy. One study showed that only hydrochlorothiazide nonresponders—not responders—experienced adverse changes in lipid profiles.¹⁵ Similarly, ß-blockers may increase levels of TC, TG, LDL-C, and VLDL-C, and they may slightly decrease levels of HDL-C,¹⁴ but one study of atenolol found that these changes were not significant after 1 year of therapy.¹⁵ Other studies suggest that pindolol does not significantly alter lipid profiles, that acebutolol lowers TC and LDL-C, and that carvedilol and bisoprolol have no significant effect on TC and TG.¹⁴ Alpha 1-blockers have favorable effects on lipids and may reverse the deleterious lipid effects of diuretics and ß-blockers.¹⁶ CCBs, ACE inhibitors, and AT-II receptor blockers are not known to have adverse effects on lipid profiles or to interact with statins. In fact, ACE inhibitors may improve lipid metabolism in patients with hypertension.¹⁷

Conclusion
The chance of developing CHD frequently depends on the presence of two or more risk factors, each of which may be mild in degree.² In many patients with both hypertension and hypercholesterolemia, a multidrug regimen is needed to address these individual risk factors. However, it may be possible to derive dual benefits from statins: Although further study is needed to confirm early findings, it appears that statins, through their lipid-lowering effect and/or another mecha-nism, may help lower BP as well. At the very least, large trials have shown that these medications are effective in improving lipid profiles in this high-risk population. They may also improve BP control in patients taking antihypertensive medication.