CLINICAL UPDATES

It has taken almost 50 years for the medical community to recognize that hypertension, that is, “benign essential hypertension,� is neither benign nor essential. As is now well known, the association between elevated blood pressure (BP) and cardiovascular disease (CVD) is strong, predictive, and etiologically significant,1 as is the relationship between elevated levels of serum total and low-density lipoprotein cholesterol (LDL-C) and CVD.2,3

Recognition is also growing that hypertension and dyslipidemia often do not exist in isolation. Moreover, concomitant hypertension and dyslipidemia have been shown to accelerate the course of atherosclerosis and the progression to cardiovascular (CV) morbidity and mortality.4 As a result, treatment recommendations should take into account a person's overall CV risk, which is determined not only by BP levels and lipid profiles, but also by the presence or absence of other CV risk factors, such as diabetes mellitus, smoking, past CV events, physical inactivity, obesity, and a family history of premature CVD.2 Markers of inflammation, such as high-sensitivity C-reactive protein, have been identified as useful adjuncts to the major risk factors to further assess the absolute risk of CVD in primary prevention.5 Patients with concomitant hypertension and dyslipidemia, or other combinations of CV risk factors, often fall into the highest risk category, that is, they have a greater than 20% chance of developing coronary heart disease (CHD) within 10 years.2 Therefore, optimal management of CVD, including therapeutic considerations, takes all CV risk factors into account.

Evidence suggesting that concomitant hypertension and dyslipidemia are compelling candidates for a unified approach to treating CV risk is reviewed in this article, together with important new findings documenting the need for, and benefits of, a more integrated approach to treating hypertension and dys-lipidemia.

Prevalence

The prevalence of hypertension has been estimated to be 28% in the United States and to range from 38% to 55.3% in Europe.6 In developed countries, dyslipidemia is more common than hypertension. A recent analysis of the National Health and Nutrition Examination Survey (NHANES) 1999-2000 data indicated a prevalence of dyslipidemia of 56% in men and 54% in women.7 Hypertension tends to occur in association with other atherogenic risk factors. Approximately 80% of Framingham Study subjects (78% of men and 82% of women) with elevated BP had CV risk factors in addition to hypertension8 (figure 1). A study conducted in 193,784 French adults younger than 55 years of age demonstrated that more than 50% of patients with hypertension also had dyslipidemia.9 A recent examination of ethnic and gender differences among hypertensive subjects in the United States revealed that the prevalence of dyslipidemia was significantly greater among white than black subjects (women, 65% vs 50%; men, 79% vs 57%; P<.001 for both).10

Additional CV risk factors frequently co-occur in patients with concomitant hypertension and dyslipidemia. Concomitant hypertension, dyslipidemia, hyperinsulinemia or insulin resistance, and obesity have been variously termed syndrome X, the deadly quartet, the insulin-resistance syndrome, and, most recently, the metabolic syndrome. The National Cholesterol Education Program (NCEP) now recognizes this constellation of risk factors as a secondary target after reducing LDL-C.2

Associated factors

Weight gain increases the tendency for CV risk factors to cluster in persons with hypertension.8 Brown and associates11 investigated the prevalence of hypertension and dyslipidemia in relation to body mass index using data from NHANES III. In individuals under 60 years of age, the prevalence of high BP increased with body mass index. Similarly, the prevalence of dyslipidemia rose with body mass index in both sexes and within all racial or ethnic groups.11 These are particularly pertinent observations because a growing number (122 million American adults) are currently overweight or obese,1 suggesting that concomitant hypertension and dyslipidemia will become even more common, and thus an even greater healthcare problem.

Cumulative impact on atherosclerosis and cardiovascular disease

The co-occurrence of hypertension and dyslipidemia markedly increases the likelihood that patients will die of CHD compared with patients with hypertension or dyslipidemia alone.8 In the Framingham Study, 86% of coronary events in men and 95% of coronary events in women occurred in patients with CV risk factors in addition to hypertension.8

Recent insight into the pathogenesis of atherosclerosis has suggested that vascular disease is a multifactorial process, with hypertension and dyslipidemia contributing to endothelial dysfunction.12 The endothelial changes that occur early on in both hypertension and dyslipidemia impair endothelium-dependent arterial relaxation, promote plaque formation, and may open a path to clinical atherosclerotic disease that ultimately results in clinical sequelae such as myocardial infarction (MI) or stroke. However, both hypertension and dyslipidemia can be effectively treated through lifestyle changes and with therapeutic interventions.

Therapeutic considerations

The immense potential for reducing CVD by targeting hypertension and dyslipidemia has been quantified using Framingham algorithms and data from NHANES III for patients with metabolic syndrome.13 Controlling BP, high-density lipoprotein cholesterol, and LDL-C to normal levels could prevent 51% of CHD events for men and 43% for women with metabolic syndrome. Moreover, the investigators calculated that control to optimal levels would prevent 81% and 82% of CHD events for men and women, respectively.

Importance of nonpharmacologic measures

Lifestyle modifications can lower BP, enhance antihypertensive drug efficacy, and blunt the effects of other CV risk factors.1 Weight control, exercise, and a prudent diet early in life may prevent the onset of clinical manifestations of CVD.2 Furthermore, members of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) recommend that public health approaches, such as the adaptation of healthier lifestyles, may be able to contribute to reducing the costs of managing hypertension and its complications.1

Therapeutic considerations in selecting an antihypertensive agent

Clinical trials have provided compelling evidence supporting the benefits of antihypertensive therapy for CVD. For example, antihypertensive therapy has been associated with reductions in the incidence of stroke averaging 30% to 40% and major CV events by 21% to 28%.14 A wide variety of antihypertensive agents are available, and the choice of agent is in part dependent on the exact indication and the degree of hypertension. As demonstrated in recent clinical trials,14–16 prompt and effective BP control is vital to maximize treatment benefits, regardless of the type of agent used. For patients with hypertension, the JNC 7 therapeutic guidelines recommend a target BP of 140/90 mm Hg (<130/80 mm Hg for patients with diabetes or chronic kidney disease) (table 1).

Therapeutic considerations in selecting a lipid-lowering agent

Clinical trials have demonstrated that lipid-lowering therapies can reduce major coronary events and, for some classes of medication, total mortality (table 2). On the basis of these observations, the NCEP has provided recommendations on when lifestyle changes and lipid-lowering medications should be considered, together with LDL-C goals (tables 3 and 4). Statins are generally recommended as first-line LDL-C-lowering agents, although alternatives include bile acid sequestrants, nicotinic acid, and ezetimibe. The patient's response should be evaluated approximately 6 weeks after drug therapy was initiated. If the LDL-C goal has been achieved, the current dose should be maintained. However, if the goal has not been achieved, lipid-lowering therapy can be intensified, either by increasing the statin dose or by combining a statin with a bile acid sequestrant, nicotinic acid, or ezetimibe. Combination lipid-lowering therapy may provide further increases in benefit to patients' lipid profiles.

The focus on multiple CV risk factors, in addition to LDL-C, is an important new feature of the NCEP Adult Treatment Panel III guidelines. These risk determinants, such as hypertension, smoking, family history of CHD, and diabetes, have an impact on goals for LDL-C. Recently, there has been a call for even more aggressive goals for LDL-C for patients at very high risk for CVD (tables 3 and 4).

In patients with concomitant hypertension and dyslipidemia, the selected lipid-lowering agent should not have any potential drug-drug interactions with antihypertensive therapies.

An integrated approach to treatment

Many of the landmark antihypertensive and statin trials have contained a high proportion of patients with concomitant hypertension and dyslipidemia. For example, in the Heart Protection Study (HPS), substantial reductions in total cholesterol levels and CHD events were observed in statin-treated patients, 41% of whom had a history of hypertension.17 Similarly, in the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial, which showed reductions in major cardiovascular outcomes in patients treated with either valsartan or amlodipine, 46% of patients were taking concomitant statin therapy.15,18

A number of clinical trials simultaneously targeting both BP and cholesterol levels have recently been completed or are under way. In the lipid-lowering arm of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT),16 more than 10,000 dyslipidemic patients treated for hypertension were randomly assigned to statin therapy or “usual care.� Although reductions in all-cause mortality in the statin group did not reach statistical significance compared with usual care, an unexpectedly large proportion of the usual care patients received statin therapy (26% by year 6), reducing the differential between the two groups. Indeed, reductions in all-cause mortality and CHD deaths in the statin group were consistent with those expected based on the degree of cholesterol reduction achieved.

The lipid-lowering arm of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) randomly assigned hypertensive patients with normal or slightly elevated nonfasting total cholesterol levels (≤6.5 mmol/L [251 mg/dL]) to either a statin or placebo.19 The statin arm of ASCOT was terminated in October 2002, earlier than the planned follow-up period, on account of a clear benefit of statin therapy in reducing the risk of nonfatal MI and stroke. This landmark study demonstrated that in patients with hypertension, low-dose statin therapy is of benefit, even in patients with normal or slightly elevated cholesterol levels, because there was a 36% relative risk reduction in the primary end point of nonfatal MI plus fatal CHD (P = .0005). In addition, patients treated with statin experienced a 21% reduction in CV events and procedures and a 27% decrease in stroke.19 These results were observed in patients who had their BP controlled throughout the trial, with mean BP values similar in atorvastatin- and placebo-treated patients, (138.3/80.4 mm Hg and 138.4/80.4 mm Hg, respectively), at study end.

Undertreatment of hypertension and dyslipidemia

Despite clear evidence demonstrating the clinical benefits of treating both hypertension and dyslipidemia, and the accumulating support for an integrated approach to the treatment of these conditions, many patients are still not being diagnosed or treated. Even patients at high risk for CV events, such as survivors of MI, are frequently not receiving aggressive antihypertensive therapy.

Furthermore, even among those that have been diagnosed and treated, few are achieving their BP or lipid goals. For example, data from NHANES showed that in 1999-2000, 31% of persons with hypertension were unaware that they had this condition, 42% were not receiving antihypertensive treatment, and 69% of patients were not at BP goal.20 Potential explanations for low goal attainment include poor patient adherence and persistence with treatment regimens and a poor clinician awareness of current guidelines.

One of the factors demonstrated to increase compliance with antihypertensive therapy is the use of a single-pill combination therapy versus concurrent two-pill therapy.21 This approach may also prove to be useful in treating multiple CV risk factors. Indeed, it has recently been suggested that the treatment of four CV risk factors (LDL-C, BP, serum homocysteine, and platelet dysfunction) with a “polypill� could result in dramatic reductions in morbidity and mortality caused by CVD.22

Data from NHANES 1999-2000 indicated that among participants who had high cholesterol levels at baseline (≥200 mg/dL) or used cholesterol-lowering treatments, 30% reported having unchecked cholesterol, 65% were unaware they had hypercholesterolemia, just 12% were being treated for this condition, and only 5% achieved a total cholesterol level of <200 mg/dL.7

A recent study has estimated that less than 10% of US patients with concomitant hypertension and dyslipidemia are at both their BP and LDL-C goals.23 This poor attainment of therapeutic targets is likely due to poor persistence with antihypertensive and lipid-lowering medications. Indeed, a retrospective cohort study that evaluated 10,526 enrollees in a US managed care plan demonstrated that the percentage of patients adherent to concomitant antihypertensive and lipid-lowering therapy declined sharply following treatment initiation, with only 34% of patients adherent to both classes of medication at 6 months.24 An additional 27% to 32% of patients were adherent to either their antihypertensive or lipid-lowering therapy, but not both. This study also demonstrated that patients were more likely to be adherent to concomitant therapy if they initiated antihypertensive and lipid-lowering therapies together and were administered few other medications. These findings have important implications for the treatment of patients with concomitant hypertension and dyslipidemia.

All of these studies suggest that there is a need for renewed commitment to the control of CV risk factors. This is particularly important in patients with concomitant hypertension and dyslipidemia, because this group is at a high risk for CVD, and in order to substantially reduce this risk, both BP and LDL-C goals must be achieved.

Conclusions

If one clinical axiom can be drawn from the available data, it is that the management of CV risk factors in isolation will not adequately reduce the risk of CV events. Effective management is evolving to address the implications of multiple CV risk factors, and an awareness of overall CV risk must be incorporated into everyday medical practice if further significant reductions in the still-high rates of CVD are to be made. Moreover, the results of recent clinical trials such as ASCOT contribute to our knowledge concerning the optimal management of concomitant hypertension and dyslipidemia. Future trials using concurrent antihypertensive and lipid-lowering therapies may find that this approach will accomplish better results and improve the management of CVD rather than focusing on the treatment of hypertension or dyslipidemia in isolation. Meanwhile, stratifying patients according to their level of CV risk and managing them by following readily accessible treatment guidelines have been demonstrated to reduce CV events.

Dr Nash has received research support from Merck & Co, Inc, and Pfizer Inc, and has been a consultant for Eli Lilly and Company and Pfizer. He discloses no unlabeled uses of any product mentioned in this article. Dr Nash is clinical professor of medicine, State University of New York at Syracuse—Upstate Medical Center, and is active at the Syracuse Preventive Cardiology Practice.

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