The Atherogenic Risk of Antihypertensive Therapy

ROBERT M. STARK, M.D.

Greenwich, Connecticut

From the Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, and the Greenwich Hospital, Greenwich, Connecticut. Requests for reprints should be addressed to Dr. Robert M. Stark, Cardiology Section, Greenwich Hospital, Greenwich, Connecticut 06830.

The past 20 years have demonstrated the unqualified success of antihypertensive therapy in reducing morbidity and mortality from cardiovascular and cerebrovascular disease [1]. Evidence mounts, however, that certain antihypertensive agents may, themselves, have an adverse effect on the development and progression of car- diovascular disease. The dramatic reductions in the incidence of cerebrovascular events and congestive heart failure among patients receiving antihypertensive therapy [1-4] have not been paralleled by similar reductions in cardiac morbidity or mortality [2-5]. Several lines of evidence now point to the possibility that adverse metabolic changes are induced by certain antihypertensive drugs. These changes may offset, negate, or even reverse the potential benefit afforded by successful blood pressure control.

CLINICAL TRIALS

The results of large-scale clinical trials involving patients receiving long- term antihypertensive therapy all indicate a marked differential in effec- tiveness in preventing cerebrovascular versus cardiovascular events. The Oslo Hypertension Study [2] showed a significantly higher incidence of coronary events occurring among patients receiving thiazide-based antihypertensive therapy. Of particular note was a 9.4 percent increase in serum glucose and a 26 percent increase in serum triglyceride concen- tractions in the treated patients. There was a concomitant reduction in incidence of stroke and vascular events in the group receiving therapy.

The Australian Therapeutic Trial showed no significant improvement in the rate of myocardial infarction mortality among hypertensive patients treated with thiazides or thiazides plus sympatholytic agents [3]. The Hypertension Detection and Followup Program [4] compared the efficacy of diuretic-based stepped-care versus "referral care" in patients with mild hypertension. Blood pressure control was measurably better in the stepped-care group, but the resulting 45 percent reduction in stroke mor- tality was accompanied by only a 25 percent reduction in cardiovascular deaths.

The Multiple Risk-Factor Intervention Trial similarly compared thiazide- based stepped-care plus multiple risk-factor intervention Versus "usual care" by the patients' personal physicians. Among 8,000 high-risk men studied, there was no effect on mortality from coronary heart disease in the group of mildly hypertensive patients receiving thiazide-based stepped therapy [5]. Similar results were seen in the British Medical Re- search Council Trial in which either thiazides or beta-blockers were com- pared with placebo in patients with mild hypertension [6]. Incidence of

86 January 29, 1988 The American Journal of Medicine Volume 84 (suppl 1B)

SYMPOSIUM ON INDAPAMIDE--STARK

aneurysms, strokes, and cerebrovascular mortality was significantly reduced in the treated groups, whereas cardi- ovascular mortality rates were not. The European Work- ing Party Trial succeeded in showing a significant de- crease in both stroke and cardiac events among treated patients, but the study was limited to patients starting ther- apy after the age of 60 [7].

The International Prospective Primary Prevention Study [8] showed a significant difference when the degree of improvement in stroke incidence was compared with that for myocardial infarction in a group of over 6,000 hyper- tensive patients. The incidence of cerebrovascular events was reduced by 43 percent, whereas cardiac events were reduced by only 24 percent among the patients achieving at least a 5-mm Hg reduction in diastolic blood pressure, regardless of whether the therapy was based on thiazides or beta-blockers.

POSSIBLE MECHANISMS

It has been suggested that antihypertensive therapy may have an effect on progression of coronary atherosclerosis that is somewhat different from its effect on cerebrovascu- lar atherosclerosis [2,6]. It is also possible that stroke may represent a more "mechanical" complication of elevated arterial pressure, whereas myocardial infarction repre- sents a more "metabolic" manifestation of cholesterol deposition and plaque formation. It does appear that the more mechanical entities such as subarachnoid hemor- rhage, aneurysms, or vascular dissections are prevented to a greater degree than are myocardial infarctions. But the potential importance of metabolic effects of antihyper- tensive drugs must be considered.

The process of arterial wall plaque formation has been retarded in cholesterol-fed rabbits treated with propranolol [9]. The calcium channel blocker, verapamil, has also been found to be protective in experimental atherogenesis [10]. Related studies are underway on the potential effect of calcium channel blockers on entry of calcium into the smooth muscle cells of developing atherosclerotic plaques.

METABOLIC EFFECTS

Much is already known about the metabolic disturbances associated with beta-blocker and diuretic-based antihy- pertensive therapy. Thiazide diuretics may cause glucose intolerance and raise serum cholesterol levels through their induction of partial insulin-resistance [11]. In most tissues, insulin not only mediates glucose uptake but also exerts a tonic inhibitory effect on lipolysis (Figure 1 ). Thia- zide-induced insulin-resistance can result in increased li- polysis, increased levels of serum free fatty acids, and increased hepatic synthesis of very low-density lipopro- tein which, in turn, is converted by plasma lipoprotein lip- ase to low-density lipoprotein. Thiazide therapy has been

Insulin Resistance °e T ° ° e ec'

Increased lipolysis

Increased hepatic • VLDL synthesis

l lipoprotein lipase /

Increased serum VLOL t (Increased triglyceride)

Increased serum free fatty acids

Increased serum LDL P (Increased cholesterol)

(LDL) Inlernalizalion inlo somatic ceils =

Figure 1. Proposed mechanism for the impairment of glu- cose and lipid metabolism mediated by thiazide-induced insufin resistance. Adapted from [12].

associated with increases of 5 to 7 percent in low-density lipoprotein cholesterol, 12 to 19 mg/dl in total cholesterol, and 23 to 39 mg/dl in serum triglycerides [12,13]. Adverse changes in the ratio of total cholesterol to high-density lipoprotein cholesterol have also been observed during therapy with thiazides [12]. Indapamide, a thiazide-like diuretic of the indoline class, does not appear to cause significant changes in the various serum lipoprotein frac- tions [14-16].

Beta-blockers increase serum triglyceride levels by 25 to 100 percent, and decrease high-density lipoprotein cholesterol levels by up to 20 percent [17]. Evidence is mounting to support the concept that serum triglyceride and high-density lipoprotein cholesterol levels are regu- lated, in large part, by alpha- and beta-adrenergic stimuli that modulate the activity of specific lipases [18]. Accord- ing to this still-emerging schema, beta-adrenergic stimuli are thought to activate cyclic-AMP in specific target cells such as hepatocytes, adipocytes, and vascular endothe- lium. The activated c-AMP, in turn, increases the activity of cellular and plasma lipases, which hydrolyze triglycer- ide into free fatty acids.

Alpha-adrenergic agonists and beta-adrenergic block- ers appear to oppose this effect, and can therefore pro- mote the accumulation of triglyceride-rich particles such as very low-density lipoprotein. High-density lipoprotein particles, which derive in part from the breakdown of very low-density lipoprotein particles, appear to decrease in concentration in patients treated with beta-blockers. This effect is not normally observed in hypertensive patients treated with centrally acting alpha-adrenergic agonists such as clonidine, guanabenz, and methyldopa; or with beta-blockers having intrinsic sympathomimetic activity, such as pindolol.

January 29, 1988 The American Journal of Medicine Volume 84 (suppl 1B) 87

SYMPOSIUM ON INDAPAMIOE--STARK

TABLE I Effects of Antihypertensive Drugs on Lipid Levels

Drug TC TG HDL LDL

Diuretics Thiazide T" T 0 1" Indapamide 0 0 0 0

Beta-adrenergic blockers Without ISA 0 t 1 0 With ISA 0 0 0 0

Sympatholytics ~ 0 0 J, ACE inhibitors 0 0 0 0 Calcium antagonists 0 0 0 0

TC = total serum cholesterol; TG = serum triglyceride; HDL = high-density lipoprotein cholesterol; LDL = low-density lipoprotein cholesterol; ISA = intrinsic sympathomimetic activity; ACE = angiotensin-converting enzyme. "T = raised lipid levels; 0 = no change; ~ = lowered lipid levels. Adapted from [19].

COMMENTS

Evidence mounts that metabol ic changes induced by cer- tain ant ihypertensive drugs may outweigh the beneficial effects ach ieved by successful b lood pressure reduction. This may hold special s igni f icance for pat ients with pre- exist ing cholesterol or t r ig lycer ide elevat ions, those with

carbohydrate intolerance, or younger pat ients who may be facing long-term therapy. In these patients, it may be prudent to select ant ihyper tensive agents having a lower potent ial for inducing such metabo l ic changes (Table I).

Indapamide, a th iazide- l ike diuret ic with an indol ine ring structure, appears to lack the th iaz ide- type effect on serum lipids and g lucose tolerance. Central ly act ing a lpha-adrenerg ic agents such as c lonidine or guanabenz, sympatholy t ics like reserpine or methy ldopa [19], and beta-b lockers possessing intrinsic sympa thomimet i c ac- tivity, such as pindolol and labetolol [13,19], do not appear to have the adverse effect on h igh-densi ty l ipoprotein and tr ig lycer ides that is character ist ic of the beta-blockers. Calc ium channel blockers, as a class, also do not appear to have signif icant effects on carbohydrate or lipid metab- ol ism [20], as is also the case for the angiotensin-convert - ing enzyme inhibitors, captopri l and enalapr i l . Recogni t ion of these factors may lead to greater indiv idual izat ion and, perhaps, improved eff icacy for ant ihyper tensive reg imens in the managemen t of the pat ient 's overal l card iovascular risk profi le.

ACKNOWLEDGMENT

I thank Mrs. Carmel Fedors and Ms. Judy Keller of the Greenwich Hospital Library for their invaluable assistance with this project.

REFERENCES

1. Cooperative Study Group on Antihypertensive Agents: Effects of treatmenl on morbidity in hypertension. JAMA 1967; 202: 1028-1034.

2. Helgeland A: Treatment of mild hypertension: a five-year con- trolled drug trial. The Oslo Study. Am J Med 1980; 69: 725- 732.

3. Report by the Management Committee: The Australian Thera- peutic Trial in Mild Hypertension. Lancet 1980; h 1261-1267.

4. The Hypertension Detection and Followup Program Group: The effect of treatment on mortality in mild hypertension. N Engl J Med 1982; 307: 976-980.

5. Multiple Risk-Factor Intervention Trial Research Group: Multiple Risk Factor Intervention Trial. JAMA 1982; 248: 1465- 1471.

6. Medical Research Council Working Party: Medical Research Council Trial of Treatment of Mild Hypertension: principal re- sults. Br Med J 1985; 291: 97-104.

7. European Working Party: Mortality and morbidity results from the European Working Party on High Blood Pressure in the Elderly Trial. Lancet 1985; I: 1349-1354.

8. The International Prospective Primary Prevention Study in Hy- pertensive (IPPPSH) Collaboration Group: Cardiovascular risk and risk-factors in a randomized trial based on the beta- blocker oxprenolol: the IPPPSH. J Hypertens 1985; 3: 379- 392.

9. Chobanian AV, Brecher P, Chan C: Effects of propranolol on atherogenesis in the cholesterol-fed rabbit. Circ Res 1985; 56: 755-762.

10. Rouleau J, Parmley WW, Stevens J: Verapamil suppresses ath- erosclerosis in cholesterol-fed rabbits. J Am Coil Cardiol

1983; I: 1453-1460. 11. Ames RP: Negative effects of diuretic drugs on metabolic risk

factors for coronary heart disease: possible alternative drug therapies. Am J Cardiol 1983; 51: 632-638.

12. Ames RP: Metabolic disturbances increasing the risk of coro- nary heart disease during diuretic-based antihypertensive therapy: lipid alterations and glucose metabolism. Am Heart J 1983; 106: 1207-1214.

13. Weinberger MH: Antihypertensive therapy and lipids. Am J Med 1986; 80 (suppl 2A): 64-70.

14. Perry HM Jr: Some wrong-way chemical changes during antihy- pertensive treatment: comparison of indapamide and related agents. Am Heart J 1983; 106: 251-257.

15. Meyer-Sabellek W, Gotzen R, Heitz J, Arntz HR, Schulte KL: Serum lipoprotein levels during long-term treatment of hyper- tension with indapamide. Hypertension 1985; 7(suppl II): 170- 174.

16. Osei K, Holland G, Falke JM: Indapamide: effect on apoprotein, lipoprotein, and glucoregulation in ambulatory diabetic pa- tients. Arch Intern Med 1986; 146: 1973-1977.

17. Weinberger MH: Antihypertensive therapy and lipids: evidence, mechanisms and implications. Arch Intern Med 1985; 145: 1102-1105.

18. Sachs FM, Dzau V J: Adrenergic effects on plasma lipoprotein metabolism. Am J Meal 1986; 80 (suppl 2A): 71-81.

19. Chobanian AV: Antihypertensive drugs and atherosclerosis. J Clin Hypertens 1986; 3: 148S-157S.

20. Wade S, Nakayama M, Masaki V: Effects of diltiazem on serum lipids: comparison with beta-blockers. Clin Ther 1982; 5:163- 173.

88 January 29, 1988 The American Journal of Medicine Volume 84 (suppl 1B)