Blood lipid levels and Antihypertensive Therapy

WILLIAM C. ROBERTS, MD

I n the 1970s massive educational and therapeutic programs were carried out in the U.S. to determine how many of its citizens had systemic hypertension and to treat effectively those who did. These programs have been highly successful. The major direct conse- quence of systemic hypertension, namely stroke, is clearly decreasing in frequency; dissection of the aor- ta, another direct consequence of systemic hyperten- sion, may be decreasing in frequency; and the fre- quency of fatal coronary artery disease is decreasing, but how much of its decrease is attributable to better control of systemic hypertension is uncertain.

In the mid 198Os, emphasis on blood lipid lowering was added to that of blood pressure lowering. The results of the Lipid Research Clinics-Coronary Pri- mary Prevention Trial (LRC-CPPT] were published in January 1984 and they established conclusively that the lowering of the plasma total cholesterol level, at least when initially considerably elevated (>285 mg/ dl), was associated with a decrease in heart attack fre- quency.l Given these and prior intervention results and also the wealth of epidemiologic data, substantial educational efforts are being undertaken to identify all citizens in the U.S. with hypercholesterolemia and to treat effectively those above certain levels (roughly total plasma cholesterol >22O mg/dl for persons <3O years of age and >240 mg/dl for persons >40 years of age). More definitive detailed recommendations are expected in the near future. The results of this cam- paign on blood cholesterol levels will not be known for several years, but any population-wide lowering of blood cholesterol levels surely will have important beneficial effects on the frequency of symptomatic coronary artery disease.

The most important finding from the LRC-CPPT study was that every 1% decrease in the plasma total cholesterol level was associated with a 2% decrease in the frequency of fatal coronary artery disease, non- fatal acute myocardial infarction or both (Fig. 1). This monumental study (3,086 men enrolled, 193,000 clinic visits, 1,055,OOO clinic data forms, 341,000 blood tests, 72,000 electrocardiograms and >$150 million cost)- the most important cardiologic study of this decade in

From the Pathology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland.

my view-also showed that the appearance of angina pectoris, congestive heart-failure, resuscitated cardiac arrest or a positive exercise stress test, as well as the need for coronary artery bypass grafting, was signifi- cantly less in the group randomized to lipid-lowering therapy (cholestyramine] compared with the group randomized to placebo. A corollary to this finding is that every 1% increase in plasma total cholesterol lev- el causes a 2% increase in heart attack frequency [Fig. 1). There is substantial data to indicate that the risk of heart attack is proportional to the serum [or plasma) total cholesterol level, or more precisely, the low den- sity lipoprotein (LDL) cholesterol level: the higher the level, the greater the risk.2

Thus, for patients receiving therapy for many years for any condition it is important that the total cholester- ol and LDL cholesterol levels do not increase and that

I -20 -16 -12 -6 -4 +4 +0 +12 +16 +20

HEART ATTACK FREQUENCY (%) FIGURE 1. Effect of increasing or decreasing plasma total choles- terol (TC) level on heart attack (fatal coronary artery disease or nonfatal acute myocardial infarction) frequency. From the Lipid Research Clinics-Coronary Primary Prevention Trial.

33E

34E A SYMPOSIUM: HYPERTENSION-THE PREVENTABLE CARDIOVASCULAR RISK FACTOR

TABLE I Effects of Antihypertensive Drugs on Serum Lipids and Lipoproteins.

TC TG HDLC LDLC

Diuretics Thiazide t t - t Spironolactone f f lndapamide f f

/3 blockers -

Without ISA - t 1 - With ISA f+ ++ f*

fi+P c) f* U

Sympatholytics Prazosin Clonidine ! Guanabenz

1 r: z c* i

Methyldopa t, c* *-,

ACE inhibitors f* c, ff

Calcium blockers cf - ++

ACE = angiotensin converting enzyme; HDLC = high density lipoprotein cholesterol; ISA = intrinsic sympathomimetic activity; LDLC = low density lipoprotein cholesterol; TC = total cholesterol; TG = triglycerides.

From reference 25.

the high density lipoprotein (HDL) cholesterol level does not decrease. The largest group of patients most likely to receive medical therapy over many years, of course, are those with systemic hypertension and most of them are asymptomatic. Of the 160 million U.S. citizens >20 years of age, it is estimated that 60 million (37%) have a systemic arterial blood pressure >140/90 mm Hg. It is also known that persons with untreated systemic hypertension have higher total and LDL cho- lesterol and lower HDL cholesterol levels than do nor- motensive subjects of similar age and sex.3

Several studies have examined the effects of vari- ous antihypertensive medicines on blood lipid levels4 -26 (Table I). Most studies have shown that diuretics raise the blood total and LDL cholesterol levels and lower the HDL cholesterol levels4-l8 Some,l* but not a11,24 studies have shown that the levels appear to re- turn to baseline or below by 12 months and do not increase to 4 years thereafter. A recent studyZ4 to 42 months disclosed that serum total cholesterol, LDL cholesterol and triglyceride levels were significantly more elevated at each 6-month interval to 42 months than at baseline in patients treated with hydrochloro- thiazide. /3 blockers without intrinsic sympathomimet- ic activity raise the blood triglyceride and lower the HDL cholesterol levels. They have little to no effect on the total or LDL cholesterol levels but they do raise the total-to-HDL cholesterol ratio. p blockers with intrin- sic sympathomimetic activity (acebutolol, pindolol), however, do not raise the blood triglyceride or lower the HDL cholesterol levels and they do not change or they slightly lower the total and LDL cholesterol lev- e1s.20-22 The elevations of blood lipid levels by diure- tics appear to be reversed by administering a p blocker with intrinsic sympathomimetic activity simultaneous- ly.12 Calcium antagonists and converting enzyme in- hibitors do not adversely affect blood lipid levels on a short-term basis; long-term data are not yet available.27

Most studies on the effects of antihypertensive drugs on the blood lipid levels are short term (512 months), most did not have 3 different determinations of blood lipid levels before initiation of antihyperten- sive therapy-a requirement to be reasonably (75%) certain of the baseline level,2*-some were not ran- domized prospective studies and most were compli- cated by more than 1 drug being given simultaneously. Thus, more information is required to be certain of long-term effects of various antihypertensive medi- cines on blood lipid levels. It would be ideal to have a drug that not only decreased elevated blood pressure levels but also simultaneously lowered blood lipid lev- els. Lacking this ideal antihypertensive agent at pre- sent, it is important that blood pressure lowering not be accompanied by blood lipid raising.

References 1. Lipid Research Clinics Program. The Lipid Research Clinics Coronary Primary Prevention Trial Results. I. Reduction in incidence of coronary heart disease. II. The relationship of reduction in incidence of coronary heart disease to cholesterol lowering. JAMA 1984;251:351-374. 2. Grundy SM. Can dietary change prevent coronary heart disease? Prog Cardiol 1981;10:13-21. 3. MacMahon SW, Macdonald GJ, Blacket RB. Plasma lipoprotein levels in treated and untreated hypertensive men and women. The National Heart Foundation of Australia Risk Factor Prevalence Study. Arteriosclerosis 1985;5:391-396. 4. Schoenfeld MR, Goldberger E. Hypercholesterolemia induced by thia- zides: a pilot study. Curr Ther Res 1964;6:180-184. 5. Ames RP, Hill P. Elevation of serum lipid levels during diuretic therapy of hypertension. Am / Med 1976;61:748-757. 6. Kannel WB, Gordon T, McGee D. Diuretics and serum cholesterol. Lancet 1977;1:13t32-1363. 7. Helgeland A, Hjermann I, Holme I, Leren P. Serum triglycerides and serum uric acid in untreated and thiazide-treated patients with mild hyper- tension. The Oslo study. Am J Med 2978;64:34-38. 8. Goldman AI, Steel BW, Schnaper HW, Fritz A, Frohlich ED, Perry MH. Serum lipoprotein levels during chlorthalidone therapy: a Veterans Adminis- tration-National Heart, Lung, and Blood Institute cooperative study on anti- hypertensive therapy: mild hypertension. TAMA 1980;244:1691-1695. 9. Grimm RH, Leon AS, Hunninghake DB, Lenz K, Hannan P, Blackburn H. Effects of thiazide diuretics on plasma lipids and Iipoproteins in mildly hyper- tensive patients: a double-blind controlled trial. Ann Intern Med 1981;94:7-II. 10. Amery A, Birkenhager W, Bulpitt C, Clement D, Deruyltere M, De Schalp- dryver A, Dollery C, Fagare R, Foretle F, Forte J. Influence of anti-hyperten- sive theropy on serum cholesterol in elderly hypertensive patients. Acta Cordiol 1982;37:235-244. 11. Veterans Administration Cooperative Study Group on Antihypertensive Agents, Comparison of propranolol and hydrochlorothiazide for initial treat- ment of hypertension. I. Results of short-term titration with emphasis on racial differences in response. II. Results of long-term treatment. JAMA 1982; 248:2004-2011. 12. Schiffl H, Weidmann P, Mordasini R, Riesen W, Bachmann C. Reversal of diuretic-induced increases in serum low-density-lipoprotein cholesterol by the beta blocker pindolol. Metabolism 1982;31:411-415. 13. Williams WR, Borhani NO, Schnaper HW, Schneider KA, Slotkoff L, on behalf of the Hypertension Detection and Follow-Up Program [HDFP) Coop- erative Group. The relationship between diuretics and serum cholesterol in HDFP participants (abstr). {ACC 1983;1:623. 14. Weidmann P, Gerber A, Mordasini R. Effects of antihypertensive therapy on serum lipoproteins. Hypertension 1983;5:III-120-111-131. 15. Lasser NL, Grandits G, Caggiula AW, Cutler JA, Grimm RH Jr, Kuller LH, Sherwin RW, Stamler J. Effects of antihypertensive therapy on plasma lipids and lipoproteins in the Multiple Risk Factor Intervention Trial. Am J Med 1984;76:suppl:52-66. 16. Ames RP. Coronary heart disease and the treatment of hypertension: impact of diuretics on serum lipids and glucose. r Cardiovasc Pharmacol 1984:6:5466-5473. 17. Weinberger MH. Antihypertensive therapy and lipids. Evidence, mecha- nisms, and implications. Arch Intern Med 1985;145:1102-1105. 18. Burris JF, Freis ED. Thiazides do not cause long-term increases in serum lipid concentrations. Arch Intern Med 1985;345:2264-2266. 19. Wallace RB, Hunninghake DB, Chambless LE, Heiss G, Wahl P, Barrett- Connor E. A screening survey of dyslipoproteinemias associated with pre- scription drug use. The Lipid Research Clinics Program Prevalence Study.

September 18, 1987 THE AMERICAN JOURNAL OF CARDIOLOGY Volume 60 35E

Circulation 1986;73:suppI 1:1-70-I-79. 20. van Brummelen P. The relevance of intrinsic sympathomimetic activity for P-blocker-induced changes in plasma lipids. f Cardiovasc Pharmacol 19F33;5:551-555. 21. Leren P. Effect of alpha- and beta-blocker therapy on blood lipids: Euro- pean experience. Am f Med 1984:76:67-71. 22. Giuntoli F, Scalabrino A, Galeone F, Birindelli A, Natali A, Panigada G, Saba P. Antihypertensive and metabolic effects of a long-term treatment with acebutolol. Curr Ther Res 1984;36:188-194. 23. Lehtonen A. Effect of beta blockers on blood lipid profile. Am Heart 1 1985;109:1192-1196. 24. Middeke M, Weisweiler P, Schwandt P, Holzgreve H. Serum lipoproteins

during antihypertensive therapy with beta blockers and diuretics: a con- trolled long-term comparative trial. Clin Cordial 1987;10:94-98. 25. Chobanian AV. Effects of beta blockers and other antihypertensive drags on cardiovascular risk. Am f Cardiol 1987;59:48F-52F. 26. Nakamura H. Effects of antihypertensive drags on plasma lipids. Am f Cardiol 1987;60:24E-28E. 27. Pool PE, Seagren SC, Sale1 AF, Skalland ML. Effects of diltiazem on serum lipids, exercise performance and blood pressure: randomized, douhle- blind placebo-controlled evaluation for systemic hypertension. Am / Cardiol 1985;56:86H-91H. 28. Blackburn H. Coronary risk factors. How to evaluate and manage them. Ear J Cardiol 1975;2/3:249-283.