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Antihypertensive therapy and lipids: Paradoxical influences on cardiovascular disease risk
Antihypertensive Therapy and Lipids ParadoxicalInfluenceson CardiovascularDisease Risk
MYRON H. WEINBERGER, M.D. Indianapolis,
It is generally acknowledged that hypertension is associated with an increased risk of cardiovascular morbidlty and mortality, and that lowering elevated blood pressure is effective in reducing that risk. However, hypertension is more likely to cause cardiovascular disease in those with additional risk factors, such as cigarette smoking, hyperlipldemia, diabetes mellitus, hypokalemia, left ventricular hypertrophy, or electrocardiographic abnormalities. The evidence to date indicates that not all patients wlth mild hypertension need to bs treated with drugs; not all of those receiving drug therapy should be treated with the same drugs; and the benefit of the same degree of reduction in blood pressure may not be equivalent for different drugs. The use of traditional step 1 diuretic therapy is not uniformly appropriate. As an alternative, the vasodilator prazosin can be effective as monotherapy in the treatment of mild hypertension, and its addition to diuretic or beta blocker therapy appears to blunt or prevent the adverse effects of those agents on lipid levels. Since prazosin therapy is least likely to worsen existing risk factors or precipitate their occurrence, it should enhance the benefit of blood pressure reduction In delaying or preventing cardiovascular disease.
Indiana
From the Hypertension Research Center, Indiana University School of Medicine, Indianapolis, Indiana. Requests for reprints should be addressed to Dr. Myron H. Weinberger, Hypertension Research Center, 541 Clinical Drive, Indianapolis, Indiana 46223.
64
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Morbidity and mortality from cardiovascular disease have been the scourge of modern industrialized society [l]. The progression of medical practice has closely paralleled both a clearer understanding of the causes of this disease and an improvement in treatment technology. Increased knowledge concerning the disease’s manifestations has led to prompt detection of the disorder and to earlier treatment of symptomatic patients. Since many individuals did not survive their initial cardiovascular episode, attention during the first 50 years of the 20th century was directed primarily toward the diagnosis of coronary artery disease and the treatment of angina. With improvement in physical facilities and emergency therapeutic approaches, it is now possible to save many of the patients who have acute myocardial infarction and who would have died otherwise. Wellequipped ambulances and coronary care units and well-trained personnel to staff these facilities have improved immediate survival rates. Although surgical intervention to treat coronary artery lesions can limit the symptoms of this disease, its ability to extend life span is not well established. These aooroaches have not imoacted on the develooment of cor. . onary artery disease since they were directed toward intervention in those with established symptomatic disease. One of the most important advances in controlling cardiovascular disease in general, and coronary artery disease in particular, has been the
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precise definition of risk factors, since such identification helps to prevent disease or limit the progression of existing disease. The Framingham Study was a landmark study in this regard [2]. It not only delineated the isolated risks of elevated blood pressure, elevated cholesterol, obesity, diabetes mellitus, cigarette smoking, and age, but it also emphasized the synergistic interactions of these factors. During the past 20 years, much emphasis has been placed on the detection and treatment of hypertension as a major risk factor for cardiovascular disease-a factor that is eminently treatable. Recently, several large-scale trials have been conducted, each seeking to demonstrate, in a slightly different manner or population, the benefits to be gained from an aggressive treatment approach to hypertension and blood pressure reduction at different levels of risk. As a whole, these studies have indeed confirmed the long-acknowledged advantage of reducing elevated blood pressure, namely, a decrease in cardiovascular morbidity and mortality. This effect is attributable primarily to the impressive and immediate reduction in the incidence of stroke, a finding reported in virtually every study of blood pressure reduction. However, the across-theboard benefit of aggressive and intensive treatment of hypertension in reducing other forms of vascular disease has been less consistent. In the Veterans Administration Cooperative Study [3], the Australian study [4], the Multiple Risk Factor Intervention Trial [5], and the important study of mild hypertension conducted in Oslo [6], no reduction in the number of deaths from myocardial infarction was demonstrable. Of all the large studies, only the Hypertension Detection and Follow-up Program was able to show such benefit [7]. This inconsistency in demonstrating even a modest benefit in the reduction of coronary artery disease prevalence and mortality rate has raised concern about the sweeping recommendations for blood pressure reduction in all hypertensive patients. None of the large-scale trials has addressed the issue of why such intervention has not led to the anticipated reduction in coronary artery disease and mortality, but there is considerable speculation regarding the possible explanations. FACTORS INFLUENCING CORONARY DISEASE AND SUDDEN DEATH
ARTERY
Over the long term, risk factors, such as those described in the Framingham Study [2], contribute to the development of coronary artery disease. Thus, an immediate reduction of elevated blood pressure-only one of the risk factors-may not have an immediate effect in reducing the risk of coronary artery disease. There are additional identifiable factors to consider. For example, if hypertension is associated with left ventricular hypertrophy, the risk of coronary disease and sudden death is increased. When hypertension is found in conjunction with an abnormal
February
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ON INITIAL ANTIHYPERTENSIVE
THERAPY-WEINBERGER
electrocardiographic finding or hypokalemia, the risk for sudden death is greater. Another factor to be resolved is the question of potential harmful effects of certain antihypertensive agents used in these various trials. In particular, diuretics have been implicated because of their potassium- and magnesium-depleting effects. The arrhythmogenie potential of such therapy has prompted a reevaluation of the treatment of hypertension. Diuretic therapy has long been the mainstay of antihypertensive treatment in the United States. This is partly because diuretics are effective antihypertensive agents in many patients, particularly in the elderly, in black hypertensive patients, and in those with congestive hear-l failure. The studies demonstrating the greatest efficacy of diuretics have often been conducted among populations in which such individuals were disproportionately represented. Studies of different populations often show the efficacy of nondiuretic antihypertensive therapy. The responses to antihypertensive therapy are now recognized to be heterogeneous and, hence, the ability to identify the mechanisms and characteristics of such responses has become an important factor in optimizing patient care. LIPID COMPONENTS
AND THEIR EFFECTS
With the elucidation of the mechanisms of lipid transport (6,9] and the regulation of plasma cholesterol [lo] and other lipid fractions, more sophisticated studies were designed to explore the role of these lipid fractions in the epidemiology of coronary disease. To summarize a massive amount of work in this area, lipid components can be evaluated in terms of total serum cholesterol, triglycerides, and high-density, low-density, and very-low-density lipoproteins. In general, elevated levels of any of the above components except high-density lipoprotein are associated with an increased risk of coronary artery disease. Elevation of high-density lipoprotein, the component involved in removal or clearance of lipid from tissues (and therefore its subsequent metabolism and excretion), is associated with a decreased coronary risk. The low-density lipoprotein fraction has been identified as the carrier of lipid to tissues, including arterial wall tissue. These concepts have been confirmed in studies of the Framingham cohort (111, as well as in other studies in the United States [12], Norway [13], and Israel [14]. Although a genetic component in lipid metabolism has been demonstrated, it is generally conceded that dietary intake of saturated fat is the major factor influencing the variability in lipid levels and, thus, the risk of coronary disease among most individuals. Epidemiologic evidence in the United States suggests a parallel decrease in the consumption of saturated fat and the prevalence of coronary artery disease. Both low-density lipoprotein and total cholesterol levels can be reduced by diet [15] or drugs. The effect of combined dietary and pharmacologic approaches on reduc-
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ON INITIAL ANTIHYPERTENSIVE
TABLE I
THERAPY-WEINBERGER
Effects of Diuretics on Lipid Components Number
Total
Of
Agent
Subjects
Chlorthalidone Chlotthalidone Hydrochlorothiazide Hydrochlorothiazide Adapted from co.05. +p 10.001.
60 40 60 47
Duration 6 1 6 1
Cholesterol Owl)
weeks year weeks year
High-Density Lipoprotein (WW
Tl9 t 15+ f15 t 12+
Triglycerides Owl) t 23’ T 36t t 26* t 39
Low-Density Lipopmtein OWW T 14 rg -
[51], with permission.
lp
tion of lipid levels was prospectively tested in the Lipid Research Clinics Coronary Primary Prevention Trial [lS]. A group of men with type II hyperlipoproteinemia who were following a cholesterol-lowering diet were randomly assigned to receive cholestyramine (a bile acid sequestrant) or placebo for an average of 7.4 years. The cholestyramine-treated group showed a significantly greater reduction (p
deleterious effect on coronary artery disease and be capable of overriding and obscuring the benefit of blood pressure reduction, preventing significant benefit to heart disease from being perceived. Diuretics. All three of the large-scale trials of antihypertensive therapy used diuretics as initial agents, following the stepped-care approach of the Veterans Administration Cooperative Study [3,5,7]. Indeed, diuretics have been the traditional drug of choice for the treatment of hypertension. The Multiple Risk Factor Intervention Trial failed to demonstrate that an intensive treatment approach used in high-risk men to reduce lipid levels through diet, to induce cessation of cigarette smoking through behavioral modification, and to control blood pressure with antihypertensive medications (beginning with hydrochlorothiazide or chlorthalidone) could reduce cardiovascular mortality rates at all levels of elevated blood pressure [5]. Although the benefit of intervention was clearly evident for those with diastolic pressures greater than 100 mm Hg, the mortality rate was not significantly lower among those individuals who entered the study with milder elevations of diastolic pressure and underwent the intensive multiple risk factor intervention [5]. Speculation by various experts has led to different interpretations of these data and their practical implications. The danger of unrecognized and asymptomatic hypokalemia has been emphasized. Kaplan [19] suggested that mild hypertension (diastolic pressure of 90 to 94 mm Hg) may not always require antihypertensive treatment. Yet, recent actuarial data suggest a progressive increase in mortality rates at diastolic pressures of more than 65 mm Hg [20]. Furthermore, nonpharmacologic forms of antihypertensive therapy, although attractive, have not been uniformly demonstrated to be effective and are difficult to implement and maintain for the average patient. A reappraisal of the effects of antihypertensive agents on cardiovascular risk factors may provide additional information regarding the controversy about the benefit of treating hypertension and coronary artery disease. Diuretics reduce blood pressure primarily by decreasing extracellular fluid volume. This is done at the expense of potassium loss unless potassium supplementation, potas-
HYPERTENSION AND ANTIHYPERTENSIVE DRUGS Several studies have shown that hypertension acts synergistically with atherosclerosis to cause cardiovascular disease [2]. Although the beneficial effects of a blood pressure reduction in preventing cardiovascular morbidity and mortality have been demonstrated in several large studies, these studies have shown a striking decrease in most forms of hypertensive vascular disease (stroke, congestive heart failure, renal failure, and aortic aneurysm and dissection) while failing to demonstrate a significant decrease in myocardial infarction [3,5,7]. Various explanations have been offered. Some experts have viewed coronary artery disease as a duration-dependent process that, once established, cannot be reversed, even though the clinical manifestations may not be apparent. Evidence from the recent studies cited earlier in this article appears to refute that concept. Another opinion is that antihypertensive therapy, or some component thereof, may have a
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TABLE II
Agent Reserpine Methyldopa Methyldopa Adapted from 10.05.
lp
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THERAPY-WEINBERGER
Effects of Sympatholytic Agents on Lipid Components Number of Subiects 15 17 17
Duration 1 year 3 months 1 year
Total Cholesterol (w/W
High-Density Lipoprotein bwdl)
45
J 7’
Triglycerides ~m!Udl)
Low-Density Lipoprotein (mg/dl) &* -
t1
[51], with permission.
sium-sparing diuretics, or a low-sodium intake is implemented. The arrhythmogenic potential of hypokalemia has been the subject of several studies [19]. Diuretics also increase blood uric acid and glucose levels and have a consistent effect on plasma lipids [21,22]. As shown in Table I, total cholesterol and triglyceride levels are increased by short-term or long-term diuretic therapy [2123], and studies with specific agents indicate that diuretics may raise low-density lipoprotein levels [23] or raise the ratio of total cholesterol to high-density lipoprotein [24]. The magnitude of lipid changes with diuretics and other antihypertensive agents may be small, but they can blunt considerably the beneficial effects of blood pressure reduction, according to the predictive value of small changes in lipids from the Framingham Study [25]. Data from lipid-lowering studies demonstrate a 2 percent decrease in the rate of coronary heart disease for a 1 percent decrease in serum cholesterol. Small increases in lipid levels pose a greater risk to younger hypertensive subjects than to the elderly population, who are more sensitive to diuretic therapy. In addition, diuretics are known to elevate blood glucose levels, which may further influence lipid levels [24]. Sympatholytic Agents. A second major group of antihypertensive agents is comprised of those that interfere with a component of the sympathetic nervous system at some point from the central to the more peripheral receptor level. The centrally acting drugs include reserpine, methyldopa, clonidine, and guanabenz. Methyldopa was found to reduce high-density lipoprotein levels and increase the ratio of total cholesterol to high-density lipoprotein in one study (Table II) [26]. However, another study of hypertensive patients with and without type II hyperlipidemia found an overall significant reduction in low-density lipoprotein levels and an increase in total triglyceride levels with methyldopa; the significance of these findings was obscured by the considerable variability among patients. When hyperlipidemic patients were considered separately, a significant decrease (p ~0.05) in low-density lipoprotein levels was seen [27]. A preliminary report by Leon et al [28] indicated that methyldopa may significantly reduce (p ~0.02) high-density lipoprotein levels after six weeks of treatment. Clonidine and guanabenz, centrally
February
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acting alpha-adrenergic agonists, have been reported to lower total cholesterol levels when given alone [29,30], but the various lipoprotein components were not measured in those studies. Furthermore, when a diuretic was added to clonidine, a significant increase in total cholesterol levels was seen [29]. The sympathetic nervous system may influence lipid metabolism in several ways. Beta receptors mediate the catecholamine stimulation of adenylate cyclase. This increases cyclic adenosine monophosphate, which activates the protein kinase, which, in turn, is responsible for activating inactive lipase. The latter converts triglycerides to free fatty acids and glycerol, energy sources for the metabolic needs of cells and tissues. inhibition of lipoprotein lipase would then be expected to increase triglyceride concentrations and decrease high-density lipoprotein levels. This situation can occur during beta-receptor blockade when adenylate cyclase activity is decreased. It can also occur as a result of a permissive effect of unopposed alpha-adrenergic stimulation [31]. Beta Blockers. As a class, beta-adrenergic blocking drugs constitute the most frequently used antisympathetic agents in the treatment of hypertension. The effects of those agents on lipid levels have been extensively studied. The six beta blockers currently available in the United States have differences in receptor specificity (beta,, beta& duration of action, lipid solubility, and intrinsic sympathomimetic activity. Most studies demonstrate increases in plasma triglyceride levels with beta blockers; all beta blockers except pindolol (having intrinsic sympathomimetic activity) have been shown to decrease highdensity lipoprotein levels. This shifts the ratio of triglycerides, total cholesterol, and high-density lipoprotein to a more atherogenic one. In the Medical Research Council Trial of mild hypertension in Great Britain, total cholesterol did not decrease as much in propranolol-treated men as it did in the placebo group [32]. In the Multiple Risk Factor Intervention Trial, the addition of propranolol to the diuretic was associated with a further significant decline (p ~0.01) in high-density lipoprotein levels and an increase in triglyceride levels (p cO.01) [33]. These observations confirm those made in several other studies, demonstrating that propranolol decreases high-density lipoprotein levels
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TABLE III Agent Propranolol Propranolol Atenolol MetoproloV propranolol Oxprenolol Nadolol Pindolol Labetalol Labetalol Adapted from l p CO.05. tp
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THERAPY-WEINBERGER
Effects of Beta Blockers on Lipid Components Number of Subjects
Duration
23 885 20 53
8 3 6 3
80 121 20 8 35
3 12 6 12 12
weeks years months months to 1 year weeks weeks months weeks weeks
Total Chotecteml No change J 6 mmol/litert f 1.5 mg/dl 4 0.06-0.36 mmol/liter J 0.08 mmol/liter 4 2 mgldl & 0.28 mmol/liter’ No change No change
J 13 percent*
4 0.04~o.18 mmol/lite+ No change t 0.04 mmollliter No change No change
Triglycerides t 24 percent* t 24.5 mg/dl* 7 0.3-0.67 mmol/liter’ t 0.1 mmol/liter t 22 percent’ t 0.02 mmollliter No change No change
Low-Density Lipoprotein -
& 0.1;0.46 mmol/liter* No change
[51], with permission.
by 10 to 20 percent and increases triglyceride levels by 25 to 100 percent [34-371. Several studies have demonstrated similar changes with atenolol, metoprolol, and oxprenolol [38]. In long-term studies with propranolol alone [37] or in combination with a thiazide diuretic [8], these changes persisted. The latter study also identified a significant decrease in high-density lipoprotein levels with combined hydrochlorothiazide and propranolol therapy [39]. Nadolol in combination with a thiazide diuretic significantly increased both cholesterol and triglyceride levels
i401. Cardioselective (beta,) blockers may have less of an effect on lipid levels than nonselective (beta, and beta.J blockers. A study of nonselective (propranolol or oxprenoloI) and cardioselective (atenolol or metoprolol) drugs showed that the latter produced smaller increases in triglyceride levels than did the nonselective drugs [31]. Significant increases (p ~0.05) in very-low-density lipoprotein and significant decreases (p ~0.01) in high-density lipoprotein levels were seen with all four agents. The low-density lipoprotein levels did not change significantly. It appears that beta blockers with intrinsic sympathomimetic activity, such as pindolol, may not significantly alter total cholesterol, high-density lipoprotein, or triglyceride levels (Table Ill) [41] and may reverse diuretic-induced increases in low-density lipoprotein levels [42]. Labetalol, a combined alpha- and beta-adrenergic blocker, is the first of a new group of adrenergic antagonists. This agent has been reported to reduce total cholesterol levels, although other studies have reported no significant changes in lipids during labetalol therapy (Table III) [43-451. The lack of typical beta blocker-induced changes in lipids seen with the combination of alpha- and beta-adrenergic blockade confirms the concept [31] that alpha-adrenergic stimulation can inhibit lipoprotein lipase. A beneficial effect on plasma lipids should then be observed when peripheral alpha-adrenergic blocking drugs such as prazosin are used. 88
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Alpha Blockers. Prazosin, a selective alpha,-blocking agent, acts as an indirect vasodilator to reduce blood pressure. Several studies with prazosin have demonstrated decreases in total cholesterol and triglyceride levels as well as increases in high-density lipoprotein levels (Table IV) [29,36,46-481. In addition, when prazosin was combined with propranolol, the latter’s effect on lipids was blunted [36]. More recent studies demonstrating the consistent beneficial effects of prazosin on plasma lipids in both short-term and long-term studies have been summarized by Lowenstein [49] and in Table IV. Another mechanism for inducing vasodilation indirectly is inhibition of angiotensin-converting enzyme activity. Studies with captopril found no change in total cholesterol or triglycerides; when this agent was combined with a thiazide diuretic, the significant increase in total cholesterol levels seen with the latter type of drug was prevented [50]. Other vasodilators, such as hydralazine and minoxidil, act directly on the blood vessel wall. Although these agents do not appear to have a direct effect on lipid metabolism, they are potent activators of the sympathetic nervous system. The stimulation of heart rate and myocardial oxygen consumption that accompanies their use may have deleterious effects in hypertensive patients with manifest or unrecognized coronary artery disease. These agents also cause salt and water retention and volume expansion by their effect on the renin-angiotensin-aldosterone system. Frequently, beta-blocking drugs and diuretics are administered simultaneously with hydralazine or minoxidil to blunt the compensatory side effects of these vasodilators. Both diuretics and beta blockers have already been described as having a potentially harmful effect on the lipid profile. COMMENTS What are the implications of all these observations and how do they influence the treatment of hypertensive patients today? Although it is generally acknowledged that Volume 80 (suppl2A)
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TABLE IV
Total Cholesterol (percent)
Of
Subjects
Duration
Prazosin
23
8 weeks
Prazosin (multistudy) Captopril
76 71
12 weeks 6 weeks
Adapted from ‘p
to 1 year
2.
3.
4.
5.
High-DenSity Lipoprotein (percent)
JQ
14.3
0 to 1 a+ No change
oto
f17+ -
Triglycerides (percent)
Low-Density Lipoprotein (percent)
116”
-
oto 110+ No change
LO
[51], with permission.
hypertension is associated with an increased risk of cardiovascular morbidity and mortality and that a reduction of elevated blood pressure is generally effective in decreasing that risk, it is now recognized that the risk of cardiovascular disease from hypertension is not evenly distributed. Hypertension is more likely to cause cardiovascular disease in those who have additional risk factors (e.g., cigarette smoking, hyperlipidemia, diabetes mellitus, hypokalemia, left ventricular hypertrophy, or electrocardiographic abnormalities). The evidence to date indicates that not all patients with mild hypertension need to be treated with drugs; not all of those treated with drugs should be treated with the same agents; and the benefit of the same degree of blood pressure lowering may not be equivalent for different drugs. In patients with mild hypertension having any of the risk factors just mentioned, the use of traditional step 1 diuretic therapy is not necessarily appropriate. Recognition of the potential hazards of mild, asymptomatic hypokalemia, hyperlipidemia, and a change in the ratio of high-density lipoprotein to low-density lipoprotein may make consideration of other drugs appropriate. Although no studies demonstrate that changes in lipid levels induced by anti-
1.
THERAPY-WEINBERGER
Effects of Vasodilators on Lipid Components Number
Asent
ON INITIAL ANTIHYPERTENSIVE
Keys A, ed: Coronary heart disease in seven countries. Circulation 1970; 41 (suppl I): l-211. Kannel WB, Dawber TR, Friedman GD, Glennon WE, McNamara PM: Risk factors in coronary heart disease: an evaluation of several serum lipids as predictors of coronary heart disease. The Framingham Study. Ann Intern Med 1964; 61: 888-899. Veterans Administration Cooperative Study Group on Antihypertensive Agents: Effects of treatment on morbidity in hypertension. II. Results in patients with diastolic blood pressure averaging QO through 114 mm Hg. JAMA 1970; 213: 11431152. Korner PI, Bauer GE, Doyle AE. et al: Untreated mild hypertension: a report by the management committee of the Australian therapeutic trial in mild hypertension. Lance1 1982; I: 185191. Multiple Risk Factor Intervention Trial Research Group: Multiple Risk Factor Intervention Trial: risk factor changes and mortality results. JAMA 1982; 248: 1465-1477.
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hypertensive therapy convey the same risk as a similar natural increase in lipid levels, it is reasonable to assume that they do so. Beta-adrenergic blocking drugs are often chosen as initial therapy for hypertensive patients with angina, but, again, the lipid effects of such agents may actually increase the potential for coronary artery disease. One agent that does not adversely affect lipid levels is prazosin. This agent can be effective as monotherapy in the treatment of mild hypertension, and its addition to diuretic or beta-blocker therapy appears to blunt or prevent the adverse effects of those agents on lipid levels. Finally, the message is clear that a reduction in blood pressure, in concert with a reduction in other risk factors that are present, is associated with reductions in both cardiovascular morbidity and mortality at even the mildest levels of blood pressure elevation. Choosing the form of antihypertensive therapy least likely to worsen existing risk factors or precipitate their occurrence should enhance the benefit of blood pressure reduction in delaying or preventing cardiovascular disease. This is especially important in the choice of the initial antihypertensive agent, since it is likely that this drug will be taken for the longest time.
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51.
Volume
beta-blocker therapy in the Medical Research Council Trial. Am J Med 1984; 76 (suppl 2A): 45-51. Lasser NL, Grandits G, Caggiula AW, et al: Effects of antihypertensive therapy on plasma lipids and lipoproteins in the Multiple Risk Factor Intervention Trial. Am J Med 1984; 76 (suppl 2A): 52-66. Bielmann P, Leduc G: Effects of metoprolol and propranolol on lipid metabolism. Int J Clin Pharmacol Biopharm 1979; 17: 378-382. Day JL, Simpson N, Metcalfe J, Page RL: Metabolic consequences of atenolol and propranolol in treatment of essential hypertension. Br Med J 1979; 1: 77-80. Leren P, Helgeland A, Holme I, Foss PO, Hjermann I, LundLarsen PG: Effect of propranolol and prazosin on blood lipids: the Oslo Study. Lancet 1980; II: 4-6. Veterans Administration Cooperative Study Group on Antihy pertensive Agents: Comparison of propranolol and hydrochlorothiazide for the initial treatment of hypertension. 1. Results of short-term titration with emphasis on racial differences in response. II. Results of long-term therapy. JAMA 1982; 248: 1996-2003; 2004-2011. Day JL, Metcalfe J, Simpson N, Lowenthal L: Adrenergic mechanisms in the control of plasma lipids in man. Am J Med 1984; 76 (suppl 2A): 94-96. Helgeland A, Hjermann I, Leren P, Enger S, Holme I: Highdensity lipoprotein cholesterol and antihypertensive drugs: the Oslo Study. Br Med J 1978; 2: 403. Freis ED: Effectiveness of nadolol versus bendroflumethiazide alone and in combination in the treatment of hypertension. In: Hollenberg N, ed. The haemodynamics of nadolol. Second International Symposium, Royal Society of Medicine International Congress Symposium Series 51. London: Academic Press, 1982; 51-57. Leren P, Eide I, Foss OP, et al: Antihypertensive drugs and blood lipids: the Oslo Study. Br J Clin Pharmacol 1982; 13: 441 s-4445. Schiffl H, Weidmann P, Mordasini R, Riesen W, Bachmann C: Reversal of diuretic-induced increases in serum lowdensity lipoprotein cholesterol by the beta blocker pindolol. Metabolism 1982; 31: 411-415. McGonigle RJS, Williams L, Murphy MJ, Parsons V: Labetafol and lipids. Lancet 1981; I: 163. Frishman WH, Michelson EL, Johnson BF, Poland MP: Multiclinic comparison of labetalol to metoprolol in treatment of mild to moderate systemic hypertension. Am J Med 1983; 75 (suppl 4A): 54-67. Pagnan A, Pessina AC, Hlede M, Zanetti G, Dal Palu 0: Effects of labetalol on lipids and carbohydrate metabolism. Pharmacol Res Commun 1979; 11: 227-236. Lowenstein J, Neusy A-J: The biochemical effects of antihypertensive agents and the impact on atherosclerosis. J Cardiovasc Pharmacol 1982; 4 (suppl2): S262-5264. Kokubu T, ltoh I, Kurita H, Ochi T, Murata K, Yuba I: Effect of prazosin on serum lipids. J Cardiovasc Pharmacol 1982; 4 (suppl 2): S228-S232. Velasco M, Silva H, Morillo J, et al: Effect of prazosin on blood lipids and on thyroid function in hypertensive patients. J Cardiovasc Pharmacol 1982; 4 (suppl 2): S225-S227. Lowenstein J: Effects of prazosin and propranolol on serum lipids in patients with essential hypertension. Am J Cardiol 1984; 53: 21 A-23A. Weinberger MH: Comparison of captopril and hydrochlorothiazide alone and in combination in mild to moderate essential hypertension. Br J Clin Pharmacol 1982; 14: 1275-131s. Weinberger MH: Antihypertensive therapy and lipids: evidence, mechanisms, and implications. Arch Intern Med 1985; 145: 1102-1105.
99 (suppl2A)
MYRON H. WEINBERGER, M.D. Indianapolis,
It is generally acknowledged that hypertension is associated with an increased risk of cardiovascular morbidlty and mortality, and that lowering elevated blood pressure is effective in reducing that risk. However, hypertension is more likely to cause cardiovascular disease in those with additional risk factors, such as cigarette smoking, hyperlipldemia, diabetes mellitus, hypokalemia, left ventricular hypertrophy, or electrocardiographic abnormalities. The evidence to date indicates that not all patients wlth mild hypertension need to bs treated with drugs; not all of those receiving drug therapy should be treated with the same drugs; and the benefit of the same degree of reduction in blood pressure may not be equivalent for different drugs. The use of traditional step 1 diuretic therapy is not uniformly appropriate. As an alternative, the vasodilator prazosin can be effective as monotherapy in the treatment of mild hypertension, and its addition to diuretic or beta blocker therapy appears to blunt or prevent the adverse effects of those agents on lipid levels. Since prazosin therapy is least likely to worsen existing risk factors or precipitate their occurrence, it should enhance the benefit of blood pressure reduction In delaying or preventing cardiovascular disease.
Indiana
From the Hypertension Research Center, Indiana University School of Medicine, Indianapolis, Indiana. Requests for reprints should be addressed to Dr. Myron H. Weinberger, Hypertension Research Center, 541 Clinical Drive, Indianapolis, Indiana 46223.
64
February
14,1966
The American
Journal
Morbidity and mortality from cardiovascular disease have been the scourge of modern industrialized society [l]. The progression of medical practice has closely paralleled both a clearer understanding of the causes of this disease and an improvement in treatment technology. Increased knowledge concerning the disease’s manifestations has led to prompt detection of the disorder and to earlier treatment of symptomatic patients. Since many individuals did not survive their initial cardiovascular episode, attention during the first 50 years of the 20th century was directed primarily toward the diagnosis of coronary artery disease and the treatment of angina. With improvement in physical facilities and emergency therapeutic approaches, it is now possible to save many of the patients who have acute myocardial infarction and who would have died otherwise. Wellequipped ambulances and coronary care units and well-trained personnel to staff these facilities have improved immediate survival rates. Although surgical intervention to treat coronary artery lesions can limit the symptoms of this disease, its ability to extend life span is not well established. These aooroaches have not imoacted on the develooment of cor. . onary artery disease since they were directed toward intervention in those with established symptomatic disease. One of the most important advances in controlling cardiovascular disease in general, and coronary artery disease in particular, has been the
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precise definition of risk factors, since such identification helps to prevent disease or limit the progression of existing disease. The Framingham Study was a landmark study in this regard [2]. It not only delineated the isolated risks of elevated blood pressure, elevated cholesterol, obesity, diabetes mellitus, cigarette smoking, and age, but it also emphasized the synergistic interactions of these factors. During the past 20 years, much emphasis has been placed on the detection and treatment of hypertension as a major risk factor for cardiovascular disease-a factor that is eminently treatable. Recently, several large-scale trials have been conducted, each seeking to demonstrate, in a slightly different manner or population, the benefits to be gained from an aggressive treatment approach to hypertension and blood pressure reduction at different levels of risk. As a whole, these studies have indeed confirmed the long-acknowledged advantage of reducing elevated blood pressure, namely, a decrease in cardiovascular morbidity and mortality. This effect is attributable primarily to the impressive and immediate reduction in the incidence of stroke, a finding reported in virtually every study of blood pressure reduction. However, the across-theboard benefit of aggressive and intensive treatment of hypertension in reducing other forms of vascular disease has been less consistent. In the Veterans Administration Cooperative Study [3], the Australian study [4], the Multiple Risk Factor Intervention Trial [5], and the important study of mild hypertension conducted in Oslo [6], no reduction in the number of deaths from myocardial infarction was demonstrable. Of all the large studies, only the Hypertension Detection and Follow-up Program was able to show such benefit [7]. This inconsistency in demonstrating even a modest benefit in the reduction of coronary artery disease prevalence and mortality rate has raised concern about the sweeping recommendations for blood pressure reduction in all hypertensive patients. None of the large-scale trials has addressed the issue of why such intervention has not led to the anticipated reduction in coronary artery disease and mortality, but there is considerable speculation regarding the possible explanations. FACTORS INFLUENCING CORONARY DISEASE AND SUDDEN DEATH
ARTERY
Over the long term, risk factors, such as those described in the Framingham Study [2], contribute to the development of coronary artery disease. Thus, an immediate reduction of elevated blood pressure-only one of the risk factors-may not have an immediate effect in reducing the risk of coronary artery disease. There are additional identifiable factors to consider. For example, if hypertension is associated with left ventricular hypertrophy, the risk of coronary disease and sudden death is increased. When hypertension is found in conjunction with an abnormal
February
14,1666
ON INITIAL ANTIHYPERTENSIVE
THERAPY-WEINBERGER
electrocardiographic finding or hypokalemia, the risk for sudden death is greater. Another factor to be resolved is the question of potential harmful effects of certain antihypertensive agents used in these various trials. In particular, diuretics have been implicated because of their potassium- and magnesium-depleting effects. The arrhythmogenie potential of such therapy has prompted a reevaluation of the treatment of hypertension. Diuretic therapy has long been the mainstay of antihypertensive treatment in the United States. This is partly because diuretics are effective antihypertensive agents in many patients, particularly in the elderly, in black hypertensive patients, and in those with congestive hear-l failure. The studies demonstrating the greatest efficacy of diuretics have often been conducted among populations in which such individuals were disproportionately represented. Studies of different populations often show the efficacy of nondiuretic antihypertensive therapy. The responses to antihypertensive therapy are now recognized to be heterogeneous and, hence, the ability to identify the mechanisms and characteristics of such responses has become an important factor in optimizing patient care. LIPID COMPONENTS
AND THEIR EFFECTS
With the elucidation of the mechanisms of lipid transport (6,9] and the regulation of plasma cholesterol [lo] and other lipid fractions, more sophisticated studies were designed to explore the role of these lipid fractions in the epidemiology of coronary disease. To summarize a massive amount of work in this area, lipid components can be evaluated in terms of total serum cholesterol, triglycerides, and high-density, low-density, and very-low-density lipoproteins. In general, elevated levels of any of the above components except high-density lipoprotein are associated with an increased risk of coronary artery disease. Elevation of high-density lipoprotein, the component involved in removal or clearance of lipid from tissues (and therefore its subsequent metabolism and excretion), is associated with a decreased coronary risk. The low-density lipoprotein fraction has been identified as the carrier of lipid to tissues, including arterial wall tissue. These concepts have been confirmed in studies of the Framingham cohort (111, as well as in other studies in the United States [12], Norway [13], and Israel [14]. Although a genetic component in lipid metabolism has been demonstrated, it is generally conceded that dietary intake of saturated fat is the major factor influencing the variability in lipid levels and, thus, the risk of coronary disease among most individuals. Epidemiologic evidence in the United States suggests a parallel decrease in the consumption of saturated fat and the prevalence of coronary artery disease. Both low-density lipoprotein and total cholesterol levels can be reduced by diet [15] or drugs. The effect of combined dietary and pharmacologic approaches on reduc-
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ON INITIAL ANTIHYPERTENSIVE
TABLE I
THERAPY-WEINBERGER
Effects of Diuretics on Lipid Components Number
Total
Of
Agent
Subjects
Chlorthalidone Chlotthalidone Hydrochlorothiazide Hydrochlorothiazide Adapted from co.05. +p 10.001.
60 40 60 47
Duration 6 1 6 1
Cholesterol Owl)
weeks year weeks year
High-Density Lipoprotein (WW
Tl9 t 15+ f15 t 12+
Triglycerides Owl) t 23’ T 36t t 26* t 39
Low-Density Lipopmtein OWW T 14 rg -
[51], with permission.
lp
tion of lipid levels was prospectively tested in the Lipid Research Clinics Coronary Primary Prevention Trial [lS]. A group of men with type II hyperlipoproteinemia who were following a cholesterol-lowering diet were randomly assigned to receive cholestyramine (a bile acid sequestrant) or placebo for an average of 7.4 years. The cholestyramine-treated group showed a significantly greater reduction (p
deleterious effect on coronary artery disease and be capable of overriding and obscuring the benefit of blood pressure reduction, preventing significant benefit to heart disease from being perceived. Diuretics. All three of the large-scale trials of antihypertensive therapy used diuretics as initial agents, following the stepped-care approach of the Veterans Administration Cooperative Study [3,5,7]. Indeed, diuretics have been the traditional drug of choice for the treatment of hypertension. The Multiple Risk Factor Intervention Trial failed to demonstrate that an intensive treatment approach used in high-risk men to reduce lipid levels through diet, to induce cessation of cigarette smoking through behavioral modification, and to control blood pressure with antihypertensive medications (beginning with hydrochlorothiazide or chlorthalidone) could reduce cardiovascular mortality rates at all levels of elevated blood pressure [5]. Although the benefit of intervention was clearly evident for those with diastolic pressures greater than 100 mm Hg, the mortality rate was not significantly lower among those individuals who entered the study with milder elevations of diastolic pressure and underwent the intensive multiple risk factor intervention [5]. Speculation by various experts has led to different interpretations of these data and their practical implications. The danger of unrecognized and asymptomatic hypokalemia has been emphasized. Kaplan [19] suggested that mild hypertension (diastolic pressure of 90 to 94 mm Hg) may not always require antihypertensive treatment. Yet, recent actuarial data suggest a progressive increase in mortality rates at diastolic pressures of more than 65 mm Hg [20]. Furthermore, nonpharmacologic forms of antihypertensive therapy, although attractive, have not been uniformly demonstrated to be effective and are difficult to implement and maintain for the average patient. A reappraisal of the effects of antihypertensive agents on cardiovascular risk factors may provide additional information regarding the controversy about the benefit of treating hypertension and coronary artery disease. Diuretics reduce blood pressure primarily by decreasing extracellular fluid volume. This is done at the expense of potassium loss unless potassium supplementation, potas-
HYPERTENSION AND ANTIHYPERTENSIVE DRUGS Several studies have shown that hypertension acts synergistically with atherosclerosis to cause cardiovascular disease [2]. Although the beneficial effects of a blood pressure reduction in preventing cardiovascular morbidity and mortality have been demonstrated in several large studies, these studies have shown a striking decrease in most forms of hypertensive vascular disease (stroke, congestive heart failure, renal failure, and aortic aneurysm and dissection) while failing to demonstrate a significant decrease in myocardial infarction [3,5,7]. Various explanations have been offered. Some experts have viewed coronary artery disease as a duration-dependent process that, once established, cannot be reversed, even though the clinical manifestations may not be apparent. Evidence from the recent studies cited earlier in this article appears to refute that concept. Another opinion is that antihypertensive therapy, or some component thereof, may have a
66
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14,1996
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SYMPOSIUM
TABLE II
Agent Reserpine Methyldopa Methyldopa Adapted from 10.05.
lp
ON INITIAL ANTIHYPERTENSIVE
THERAPY-WEINBERGER
Effects of Sympatholytic Agents on Lipid Components Number of Subiects 15 17 17
Duration 1 year 3 months 1 year
Total Cholesterol (w/W
High-Density Lipoprotein bwdl)
45
J 7’
Triglycerides ~m!Udl)
Low-Density Lipoprotein (mg/dl) &* -
t1
[51], with permission.
sium-sparing diuretics, or a low-sodium intake is implemented. The arrhythmogenic potential of hypokalemia has been the subject of several studies [19]. Diuretics also increase blood uric acid and glucose levels and have a consistent effect on plasma lipids [21,22]. As shown in Table I, total cholesterol and triglyceride levels are increased by short-term or long-term diuretic therapy [2123], and studies with specific agents indicate that diuretics may raise low-density lipoprotein levels [23] or raise the ratio of total cholesterol to high-density lipoprotein [24]. The magnitude of lipid changes with diuretics and other antihypertensive agents may be small, but they can blunt considerably the beneficial effects of blood pressure reduction, according to the predictive value of small changes in lipids from the Framingham Study [25]. Data from lipid-lowering studies demonstrate a 2 percent decrease in the rate of coronary heart disease for a 1 percent decrease in serum cholesterol. Small increases in lipid levels pose a greater risk to younger hypertensive subjects than to the elderly population, who are more sensitive to diuretic therapy. In addition, diuretics are known to elevate blood glucose levels, which may further influence lipid levels [24]. Sympatholytic Agents. A second major group of antihypertensive agents is comprised of those that interfere with a component of the sympathetic nervous system at some point from the central to the more peripheral receptor level. The centrally acting drugs include reserpine, methyldopa, clonidine, and guanabenz. Methyldopa was found to reduce high-density lipoprotein levels and increase the ratio of total cholesterol to high-density lipoprotein in one study (Table II) [26]. However, another study of hypertensive patients with and without type II hyperlipidemia found an overall significant reduction in low-density lipoprotein levels and an increase in total triglyceride levels with methyldopa; the significance of these findings was obscured by the considerable variability among patients. When hyperlipidemic patients were considered separately, a significant decrease (p ~0.05) in low-density lipoprotein levels was seen [27]. A preliminary report by Leon et al [28] indicated that methyldopa may significantly reduce (p ~0.02) high-density lipoprotein levels after six weeks of treatment. Clonidine and guanabenz, centrally
February
14, 1986
acting alpha-adrenergic agonists, have been reported to lower total cholesterol levels when given alone [29,30], but the various lipoprotein components were not measured in those studies. Furthermore, when a diuretic was added to clonidine, a significant increase in total cholesterol levels was seen [29]. The sympathetic nervous system may influence lipid metabolism in several ways. Beta receptors mediate the catecholamine stimulation of adenylate cyclase. This increases cyclic adenosine monophosphate, which activates the protein kinase, which, in turn, is responsible for activating inactive lipase. The latter converts triglycerides to free fatty acids and glycerol, energy sources for the metabolic needs of cells and tissues. inhibition of lipoprotein lipase would then be expected to increase triglyceride concentrations and decrease high-density lipoprotein levels. This situation can occur during beta-receptor blockade when adenylate cyclase activity is decreased. It can also occur as a result of a permissive effect of unopposed alpha-adrenergic stimulation [31]. Beta Blockers. As a class, beta-adrenergic blocking drugs constitute the most frequently used antisympathetic agents in the treatment of hypertension. The effects of those agents on lipid levels have been extensively studied. The six beta blockers currently available in the United States have differences in receptor specificity (beta,, beta& duration of action, lipid solubility, and intrinsic sympathomimetic activity. Most studies demonstrate increases in plasma triglyceride levels with beta blockers; all beta blockers except pindolol (having intrinsic sympathomimetic activity) have been shown to decrease highdensity lipoprotein levels. This shifts the ratio of triglycerides, total cholesterol, and high-density lipoprotein to a more atherogenic one. In the Medical Research Council Trial of mild hypertension in Great Britain, total cholesterol did not decrease as much in propranolol-treated men as it did in the placebo group [32]. In the Multiple Risk Factor Intervention Trial, the addition of propranolol to the diuretic was associated with a further significant decline (p ~0.01) in high-density lipoprotein levels and an increase in triglyceride levels (p cO.01) [33]. These observations confirm those made in several other studies, demonstrating that propranolol decreases high-density lipoprotein levels
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TABLE III Agent Propranolol Propranolol Atenolol MetoproloV propranolol Oxprenolol Nadolol Pindolol Labetalol Labetalol Adapted from l p CO.05. tp
ON INITIAL ANTIHYPERTENSIVE
THERAPY-WEINBERGER
Effects of Beta Blockers on Lipid Components Number of Subjects
Duration
23 885 20 53
8 3 6 3
80 121 20 8 35
3 12 6 12 12
weeks years months months to 1 year weeks weeks months weeks weeks
Total Chotecteml No change J 6 mmol/litert f 1.5 mg/dl 4 0.06-0.36 mmol/liter J 0.08 mmol/liter 4 2 mgldl & 0.28 mmol/liter’ No change No change
J 13 percent*
4 0.04~o.18 mmol/lite+ No change t 0.04 mmollliter No change No change
Triglycerides t 24 percent* t 24.5 mg/dl* 7 0.3-0.67 mmol/liter’ t 0.1 mmol/liter t 22 percent’ t 0.02 mmollliter No change No change
Low-Density Lipoprotein -
& 0.1;0.46 mmol/liter* No change
[51], with permission.
by 10 to 20 percent and increases triglyceride levels by 25 to 100 percent [34-371. Several studies have demonstrated similar changes with atenolol, metoprolol, and oxprenolol [38]. In long-term studies with propranolol alone [37] or in combination with a thiazide diuretic [8], these changes persisted. The latter study also identified a significant decrease in high-density lipoprotein levels with combined hydrochlorothiazide and propranolol therapy [39]. Nadolol in combination with a thiazide diuretic significantly increased both cholesterol and triglyceride levels
i401. Cardioselective (beta,) blockers may have less of an effect on lipid levels than nonselective (beta, and beta.J blockers. A study of nonselective (propranolol or oxprenoloI) and cardioselective (atenolol or metoprolol) drugs showed that the latter produced smaller increases in triglyceride levels than did the nonselective drugs [31]. Significant increases (p ~0.05) in very-low-density lipoprotein and significant decreases (p ~0.01) in high-density lipoprotein levels were seen with all four agents. The low-density lipoprotein levels did not change significantly. It appears that beta blockers with intrinsic sympathomimetic activity, such as pindolol, may not significantly alter total cholesterol, high-density lipoprotein, or triglyceride levels (Table Ill) [41] and may reverse diuretic-induced increases in low-density lipoprotein levels [42]. Labetalol, a combined alpha- and beta-adrenergic blocker, is the first of a new group of adrenergic antagonists. This agent has been reported to reduce total cholesterol levels, although other studies have reported no significant changes in lipids during labetalol therapy (Table III) [43-451. The lack of typical beta blocker-induced changes in lipids seen with the combination of alpha- and beta-adrenergic blockade confirms the concept [31] that alpha-adrenergic stimulation can inhibit lipoprotein lipase. A beneficial effect on plasma lipids should then be observed when peripheral alpha-adrenergic blocking drugs such as prazosin are used. 88
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The Awtwrican Journal d Medlctne
Alpha Blockers. Prazosin, a selective alpha,-blocking agent, acts as an indirect vasodilator to reduce blood pressure. Several studies with prazosin have demonstrated decreases in total cholesterol and triglyceride levels as well as increases in high-density lipoprotein levels (Table IV) [29,36,46-481. In addition, when prazosin was combined with propranolol, the latter’s effect on lipids was blunted [36]. More recent studies demonstrating the consistent beneficial effects of prazosin on plasma lipids in both short-term and long-term studies have been summarized by Lowenstein [49] and in Table IV. Another mechanism for inducing vasodilation indirectly is inhibition of angiotensin-converting enzyme activity. Studies with captopril found no change in total cholesterol or triglycerides; when this agent was combined with a thiazide diuretic, the significant increase in total cholesterol levels seen with the latter type of drug was prevented [50]. Other vasodilators, such as hydralazine and minoxidil, act directly on the blood vessel wall. Although these agents do not appear to have a direct effect on lipid metabolism, they are potent activators of the sympathetic nervous system. The stimulation of heart rate and myocardial oxygen consumption that accompanies their use may have deleterious effects in hypertensive patients with manifest or unrecognized coronary artery disease. These agents also cause salt and water retention and volume expansion by their effect on the renin-angiotensin-aldosterone system. Frequently, beta-blocking drugs and diuretics are administered simultaneously with hydralazine or minoxidil to blunt the compensatory side effects of these vasodilators. Both diuretics and beta blockers have already been described as having a potentially harmful effect on the lipid profile. COMMENTS What are the implications of all these observations and how do they influence the treatment of hypertensive patients today? Although it is generally acknowledged that Volume 80 (suppl2A)
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TABLE IV
Total Cholesterol (percent)
Of
Subjects
Duration
Prazosin
23
8 weeks
Prazosin (multistudy) Captopril
76 71
12 weeks 6 weeks
Adapted from ‘p
to 1 year
2.
3.
4.
5.
High-DenSity Lipoprotein (percent)
JQ
14.3
0 to 1 a+ No change
oto
f17+ -
Triglycerides (percent)
Low-Density Lipoprotein (percent)
116”
-
oto 110+ No change
LO
[51], with permission.
hypertension is associated with an increased risk of cardiovascular morbidity and mortality and that a reduction of elevated blood pressure is generally effective in decreasing that risk, it is now recognized that the risk of cardiovascular disease from hypertension is not evenly distributed. Hypertension is more likely to cause cardiovascular disease in those who have additional risk factors (e.g., cigarette smoking, hyperlipidemia, diabetes mellitus, hypokalemia, left ventricular hypertrophy, or electrocardiographic abnormalities). The evidence to date indicates that not all patients with mild hypertension need to be treated with drugs; not all of those treated with drugs should be treated with the same agents; and the benefit of the same degree of blood pressure lowering may not be equivalent for different drugs. In patients with mild hypertension having any of the risk factors just mentioned, the use of traditional step 1 diuretic therapy is not necessarily appropriate. Recognition of the potential hazards of mild, asymptomatic hypokalemia, hyperlipidemia, and a change in the ratio of high-density lipoprotein to low-density lipoprotein may make consideration of other drugs appropriate. Although no studies demonstrate that changes in lipid levels induced by anti-
1.
THERAPY-WEINBERGER
Effects of Vasodilators on Lipid Components Number
Asent
ON INITIAL ANTIHYPERTENSIVE
Keys A, ed: Coronary heart disease in seven countries. Circulation 1970; 41 (suppl I): l-211. Kannel WB, Dawber TR, Friedman GD, Glennon WE, McNamara PM: Risk factors in coronary heart disease: an evaluation of several serum lipids as predictors of coronary heart disease. The Framingham Study. Ann Intern Med 1964; 61: 888-899. Veterans Administration Cooperative Study Group on Antihypertensive Agents: Effects of treatment on morbidity in hypertension. II. Results in patients with diastolic blood pressure averaging QO through 114 mm Hg. JAMA 1970; 213: 11431152. Korner PI, Bauer GE, Doyle AE. et al: Untreated mild hypertension: a report by the management committee of the Australian therapeutic trial in mild hypertension. Lance1 1982; I: 185191. Multiple Risk Factor Intervention Trial Research Group: Multiple Risk Factor Intervention Trial: risk factor changes and mortality results. JAMA 1982; 248: 1465-1477.
February
14,1999
hypertensive therapy convey the same risk as a similar natural increase in lipid levels, it is reasonable to assume that they do so. Beta-adrenergic blocking drugs are often chosen as initial therapy for hypertensive patients with angina, but, again, the lipid effects of such agents may actually increase the potential for coronary artery disease. One agent that does not adversely affect lipid levels is prazosin. This agent can be effective as monotherapy in the treatment of mild hypertension, and its addition to diuretic or beta-blocker therapy appears to blunt or prevent the adverse effects of those agents on lipid levels. Finally, the message is clear that a reduction in blood pressure, in concert with a reduction in other risk factors that are present, is associated with reductions in both cardiovascular morbidity and mortality at even the mildest levels of blood pressure elevation. Choosing the form of antihypertensive therapy least likely to worsen existing risk factors or precipitate their occurrence should enhance the benefit of blood pressure reduction in delaying or preventing cardiovascular disease. This is especially important in the choice of the initial antihypertensive agent, since it is likely that this drug will be taken for the longest time.
6.
7.
8.
9.
10.
11.
Helgeland A. Hjermann I, Leren P, Holme I: Possible metabolic side effects of beta-adrenergic blocking drugs. Br Med J 1978; 1: 828. Hypertension Detection and Follow-up Program Cooperative Group: Five-year findings of the hypertension detection and follow-up program. I. Reduction in mortality of persons with high blood pressure, including mild hypertension. JAMA 1979; 242: 2562-2571. Fredrickson DS, Levy RI, Lees RS: Fat transport in lipoproteinsan integrated approach to mechanisms and disorders. N Engl J Med 1967; 276: 34-44. Goldstein JL, Brown MS: The lowdensity lipoprotein pathway and its relation to atherosclerosis. Annu Rev Biochem 1977: 46: 897-930. Brown MS, Kovanen PT, Goldstein JL: Regulation of plasma cholesterol by lipoprotein receptors. Science 1981; 212: 628-635. Gordon T, Castelli WP, Hjortland MC, Kannel WB, Dawber TR: High-density lipoprotein as a protective factor against coro-
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12.
13.
14.
15.
16.
17.
18.
19. 20. 21. 22. 23.
24.
25. 26.
27.
28.
29.
30.
31.
32.
70
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