The metabolic effects of diuretics and other antihypertensive drugs: a perspective as of 1989

International Elsevier

CARD10

Journal

of Cardiology,

143

28 (1990) 143-150

01109

Review

.

The metabolic effects of diuretics and other antihypertensive drugs: a perspective as of 1989 E.B. Raftery Cardiology Department

and Division of Cardiovascular

Diseases, Northwick Park Hospital and Clinical Research Centre, Harrow. U.K.

(Received and accepted 12 January 1990)

Raftery EB The metabolic effects of diuretics and other hypertensive drugs: a perspective as of 1989. Int J Cardiol 1990;28:143-150. Active treatment has produced a dramatic decline in the ‘mechanical’ complications of hypertension (haemorrhagic stroke, congestive heart failme, renal failure, and aortic dissection) but has had no effect on the ‘thrombotic’ complications (thrombotic stroke, and myocardial infarction). There is a growing body of opinion that this failure is related to changes in the metabolism of lipoproteins and carbohydrates induced by anti-hypertensive drugs, which actively counteract the beneficial effects of a lowered blood pressure. The literature on this subject is extensive, but the results are inconclusive and much remains to be learned. In the light of present knowledge, it would appear to be prudent to choose anti-hypertensive drugs with care, concentrating upon proven agents which produce minimal biochemical disturbances, rather than using drugs which are known to have marked effects on lipoprotein metabolism.

Key words: Hypertension;

Drug treatment;

Diuretic

Introduction

There is strong evidence linking hypertension with an increase in the risk of premature coronary arterial disease. But, although effective antihypertensive treatment has reduced the incidence of cerebrovascular accidents and congestive heart failure, it has had little or no effect on the incidence of myocardial infarction [l-3], while two clinical studies have shown a small increase in the number of myocardial infarctions occurring dur-

Correspondence to: Dr. E.B. Raftexy, Cardiology Dept. and Div. of Cardiovascular Diseases, Northwick Park Hospital and Clinical Research Centre, Watford Road, Harrow HA1 3 UJ, U.K. 0167-5273/90/%03.50

ing diuretic treatment [4,5]. Because hypertension is treated early with the intention of preventing all its complications, including myocardial infarction, these results are particularly disconcerting. Why do the drugs which treat hypertension so effectively fail to prevent one of its most lethal complications? A possible explanation is that some antihypertensive drugs have other pharmacological effects which reverse their potential benefits. A growing body of opinion suggests that drug-induced metabolic changes may be a key issue, and that such changes, although most clearly associated with diuretics, are common to a range of antihypertensive drugs. These changes influence the metabolism of lipoproteins and carbohydrates, the excretion of sodium, potassium, and calcium, and the mechanisms regulating the plasma content

0 1990 Elsevier Science Publishers B.V. (Biomedical Division)

144

of uric acid. In particular, changes in glucose and lipid metabolism could increase an individual’s risk of coronary arterial disease, thereby offsetting the long-term beneficial cardiovascular effects . of lowered blood pressure [6]. Lipoprotein metabolism Diuretics. The thiazide diuretics are by far the most widely used “first-line" antihypertensive drugs, and all can cause adverse shifts in lipoprotein patterns. Hydrochlorothiazide, for example, increases the plasma concentrations of both cholesterol and triglyceride; studies of its effects on lipoprotein distribution shown increases in the levels of very low and low density lipoproteins, and corresponding decreases in the levels of high density lipoprotein (although the changes are unpredictable in the case of the high density lipoprotein) [7,9]. Similar effects have been associated with polythiazide, cyclopenthiazide, clopamide, bendroflumethiazide, mefruside, and chlorthalidone [lo]. Whether or not these changes in lipids are dose-dependent is unclear, but in some studies [ll] as many as one third of patients may fail to show any significant alteration. Interestingly, the increases in levels of total triglyceride and cholesterol occurring during treatment with chlorthalidone persist, even when patients are given a lipid-lowering diet [ll]. In contrast, the hyperlipidaemic effects of other thiazide diuretics respond to dietary changes [7,8]. Whether or not a fat-reduced diet, together with a thiazide given in low dosage, is a rational combination remains to be established, but it is probably wise to avoid long-term treatment with chlorthalidone. The effect of the “loop” diuretics on serum lipids has not been as thoroughIy investigated as that of the thiazides. During short-term treatment, frusemide raises levels of total cholesterol and triglyceride to much the same extent as hydrochlorothiazide, but depresses the high density fraction of cholesterol rather more [12,13]. During continued treatment with frusemide, total cholesterol and triglyceride levels tend to fall after their initial increase [13]. The level of high density cholesterol, on the other hand, falls by around 15%, and remains low [14]. The limited information available suggests that

the newer “loop” diuretics, xipamide and piretanide, influence serum lipids in much the same way as frusemide [9,15]. The effects on the lipid profile of the potassium-sparing diuretics (spironolactone, triamterene and amiloride) have not been extensively investigated. Spironolactone has little or no effect on serum lipoproteins [16], and in combination with a “loop” diuretic or thiazide the hyperlipidaemic effects of the latter drugs predominate [I71. The mdoline diuretic indapamide, although resembling the thiazides in its site and mechanism of action, has less effect on lipoprotein metabolism. Indeed, most studies have shown that indapamide, administered up to 24 months, has no effect on serum lipids [6,18-211, suggesting that it may be preferable to either the thiazides or the loop diuretics as first line treatment for mild to moderate hypertension. Diuretic-induced lipid changes probably reflect the enhancement of catecholamine and insulin secretion by these drugs, and the consequent increase in synthesis of very low density lipoproteins in the liver [22,23]. Lipoprotein lipase activity is unaffected by diuretics, so catabolism of the very low density moieties proceeds unhindered, and serum levels of low density lipoprotein (and of total cholesterol) increase. Long-term studies are required to clarify the pathological and prognostic significance of the changes in lipoproteins induced by diuretics, but the long-term neutral effects observed with certain agents appear promising. Beta-blockers. The lipid changes associated with the beta-blockers vary according to their pharmacological profile. Non-selective antagonists, typified by propranolol, raise the level of total triglycerides but have little or no effect on total cholesterol [24]. They do, however, shift the distribution of cholesterol between the lipoprotein fractions, reducing the concentration of high density fats and increasing levels of the low density variants [25]. The combination of a non-selective beta-blocker with a thiazide diuretic is a popular form of second-line antihypertensive therapy. It is disconcerting to find that such a combination

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disturbs lipid patterns to a greater extent than either component used alone, with substantial depression of the high density fraction and marked hypertriglyceridaemia [26]. Beta-l selective drugs, like atenolol, affect serum lipids in much the same way as the non-selective agents, although the changes tend to be less pronounced [lo]. Those adrenoceptor antagonists, which possess intrinsic sympathomimetic activity, like acebutolol [28,29] or pindolol [27], have practically no effect on serum lipoproteins; indeed pindolol may increase the levels of the high density fraction of cholesterol, with a possible reduction in overall cardiovascular risk [27,30]. The effect of most beta-blockers on lipids is due to the inhibition of lipoprotein lipase which results from an unopposed alpha adrenergic response [31,32]. The consequent reduction in catabolism of very low density lipoproteins is responsible for both the increase in triglyceride level and the fall in this type of cholesterol. Adrenoceptor antagonists with intrinsic sympathomimetic activity, on the other hand, increase lipoprotein lipase activity and have the reverse effect [30]. Other antihypertensive drugs. The two most widely prescribed antihypertensive drugs with alpha-antagonist activity, prazosin and labetalol (which antagonises both alpha- and beta-receptors), have less effect on lipoproteins than either the beta-blockers or the diuretics [33,34]. Several studies with prazosin have failed to show any detrimental shift in lipid patterns and comparative trials with beta-blockers show that is lowers both total and low density cholesterol, while increasing the concentration of the beneficial high density fraction [35,36]. The centrally-acting antihypertensive drugs, methyldopa and clonidine, have differing effects on plasma lipids. Methyldopa elevates total triglyceride levels in patients with normal serum cholesterol, but not in those with hypercholesterolaemia, in whom it tends to lower cholesterol levels [37]. Clonidine (and the related drug guanabenz), on the other hand, reduces the levels of low density cholesterol, total cholesterol and triglycerides, and raises the concentration of high density cholesterol [38]. Like the alpha-blockers,

the beta-blockers with intrinsic sympathomimetic activity, and the indoline diuretic indapamide, clonidine has the potential to reduce the coronary risk associated with hyperlipidaemia. The established calcium channel blockers verapamil, nifedipine, nitrendipine, nicardipine and diltiazem seem to leave serum lipids unchanged, and it is unlikely that any of the newer drugs under development will differ significantly from those already in use in this respect [lo]. Similarly, the inhibitors of the angiotensin converting enzyme captopril, enalapril, and lisinopril have no effect on serum lipids [39,40]. Interestingly, these drugs can counteract the hypercholesterolaemia induced by the thiazide diuretics, giving the combination of a thiazide and an inhibitor of angiotensin converting enzyme theoretical advantages over the more traditional pairing of a thiazide with a beta-blocker [39,41]. Further studies are required to establish whether the short-term observations are maintained during longer-term therapy.

TABLE

1

Lipids, lipoproteins, and antihypertensives.

DW Diuretics thiazides loops indapamide K+ sparing Beta-blockers non-selective selective with ISA (pindolol, acebutolol) Alpha-blockers prazosin labetalol Ca’+ antagonists a ACE inhibitors a

TC

TG

HDL

VLDL

LDL

++ +

+ +

-

0 ?

0 ?

0 ?

+ + 0 ?

+ + 0 ?

i? +

++ +

--

++ +

++ +

0

0

0

0

0

0 0 0

0 + 0 0

0 0 0 0

0 0 0 0

0 0 0 0

0

a Short term studies, no data on long-term treatment. TC = total cholesterol; TG = total triglycerides; HDL = high density lipoprotein cholesterol; LDL = low density lipoproteins; VLDL = very low density lipoproteins: ? = equivocal results; 0 = no change; - = small reduction; -- = large reduction; + = small increase; + + = large increase.

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Table 1 summarizes the influence of different antihypertensive drugs on serum lipids and lipoproteins. What is the practical significance of these drug-induced lipoprotein shifts? In a typical patient with mild to moderate hypertension, treatment with a thiazide diuretic would probably raise low density cholesterol by about 15%, and total triglycerides by roughly 20%. The increase in total cholesterol (and probably also triglycerides) confers an increased risk of cardiovascular complications which might reverse the benefits of blood pressure reduction. Thus, drug-induced lipid shifts may not be mere biochemical curiosities but may have important implications for the management of hypertensive patients. In such a situation, a drug with a favourable effect on the lipid profile which has been established by long-term studies should be preferred when considering cardiovascular protection in the hypertensive patient. Among the beta-blockers, those with a high intrinsic sympathomimetic activity such as pindolol and acebutolol, might be preferred, whereas when the choice is to use a diuretic, indapamide might be the logical choice. Carbohydrate intolerance. Disturbances of carbohydrate metabolism are exclusively associated with diuretics: There is little evidence that other antihypertensive drugs have any significant long term effects. More patients are treated with diuretics, however, than with any of the other agents, so the clinical significance of their diabetogenie effect deserves serious attention. Loss of control in previously stable diabetics after a few months of treatment with a thiazide diuretic is well recognised; During long-term treatment with thiazides, up to 30% of patients develop abnormal glucose tolerance and, although clinically significant deterioration is usually confined to “pre-diabetic” individuals or poorly controlled diabetics, it can occur in non-diabetic patients as well [42,43]. The diabetogenic effect is reversible, and within a year of the withdrawal of treatment glucose tolerance will have returned to normal in two thirds of patients [43]. There is some interesting evidence of a link between hypokalaemia and glucose intolerance during thiazide treatment; when the lowest effective doses are used, both hypokalaemia and

carbohydrate disturbances can be avoided [44,45]. This suggests that electrolyte imbalance may be a necessary component of thiazide-induced glucose intolerance, a suggestion that gains support from the results of short-term studies showing that glucose intolerance can be reversed by the correction of diuretic-induced potassium depletion [46]. The mechanisms underlying thiazide-induced disturbances in carbohydrate metabolism are still obscure. The drugs may decrease both insulin secretion and tissue sensitivity to insulin, and they inhibit hepatic phosphodiesterase thereby accelerating cyclic AMP-mediated glycolysis, but the relative importance of these actions remains to be established [47,48]. Glucose intolerance is probably less frequent with the “loop” diuretics than with the thiazides. Although frusemide has been shown to inhibit insulin release in response to an intravenous glucose load [48], in long-term use neither frusemide nor the other “loop” diuretics are associated with significant carbohydrate disturbances [49]. Similarly, the indoline diuretic, indapamide, has no adverse effect on glucose tolerance in either diabetic or non-diabetic hypertensive patients during long-term treatment. This was observed in several studies investigating the effects of indapamide on oral glucose tolerance and repeated measurements of insulinaemia and glycaemia [18,50-521. The effects of the potassium-sparing diuretics on glucose tolerance have not been investigated, but since they are usually administered in combination with a thiazide any effect of the potassium-sparing component would probably be overwhelmed by the diabetogenic effect of the thiazide. Glucose intolerance has been associated with increases in the incidence of coronary artery disease and in total mortality [53,54]. This could, therefore, contribute to the lower than expected improvement in coronary risk recorded in hypertensive patients treated with thiazide diuretics. Impaired glucose metabolism induced by decreased insulin secretion has been reported in non-insulin-dependent diabetics during antihypertensive therapy with non-selective beta-blockers. These agents may prolong and/or mask the symptoms of hypoglycaemic attacks [55]. In addition, studies with certain calcium antagonists such as

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nifedipine have shown a short term impaired cose tolerance in diabetic patients [56].

glu-

Effects on electrolytes Diuretics can induce hyponatraemia, together with hypokalaemia and alkalosis, despite a normal body content of exchangeable sodium, and in the absence of dehydration. In these circumstances the underlying mechanism is the passage of sodium from the extracellular fluid in an attempt to correct diuretic-induced intracellular hypokalaemia ]571. Perhaps the clinical condition most often complicated by diuretic-induced hyponatraemia is congestive heart failure, where low plasma sodium levels can be accompanied by an increase in whole body sodium content. Although the sequence can be initiated by volume depletion during diuretic treatment, there are probably other unidentified, non-osmotic, contributory factors [58]. The belief that diuretic-induced hypokalaemia predisposes to potentially fatal ventricular arrhythmias underlies the common reluctance to use adequate doses of diuretics in patients with uncomplicated essential hypertension. This concern derives principally from the results of the “MRFIT” trial which suggested that American thiazide diuretics were associated with an increase in sudden cardiac deaths in a subgroup of patients who had minor electrocardiographic abnormalities at entry [3]. The study was not designed, however, to determine the relationship between thiazides and sudden death, and this association, which emerged from a retrospective analysis of the data, is unconvincing. It has not, so far, been confirmed by any independent investigation, and none of the similar studies that have been conducted provide any evidence that diuretics increase mortality in patients with resting electrocardiographic abnormalities. Furthermore, in none of these studies (including “MRFIT”) was there any correlation between diuretic dosage or serum potassium levels, and deaths from ischaemic heart disease [l-3]. The available evidence provides no support for the view that diuretic-induced hypokalaemia is a potentially lethal complication. Nevertheless, the

view remains widely held, and is responsible for the general prescribing of both potassium supplements and potassium-sparing diuretics. In patients at high risk from diuretic-induced hypokalaemia (which includes cirrhotics, oedematous patients with hepatic or cardiac disease, the elderly, diabetics, those taking steroids, and those who have just experienced a myocardial infarction), diuretics can be given intermittently, dietary potassium can be increased, or potassium-sparing diuretics can be used. In younger patients with uncomplicated essential hypertension treated with the lowest effective dose of a thiazide diuretic, hypokalaemia is rare. Only if plasma potassium falls below 3.0 mmol/l is active correction necessary, and a potassiumsparing diuretic is usually more effective than a potassium supplement.

Uric acid

Asymptomatic hyperuricaemia is common during treatment with all diuretics, probably because of a diuretic-induced reduction of the extracellular fluid volume. Although more than 50% of patients treated with diuretics for long periods may have hyperuricaemia, less than 2% will develop the symptoms of gout [59]. Diuretic-induced gout responds to treatment with anti-inflammatory drugs just as predictably as primary gout, and allopurinol can be added to the diuretic regimen to maintain long-term control of plasma urate levels. There is a correlation between hyperuricaemia and hypertension [60], which raises the possibility that raised serum uric acid levels are an independent risk factor for coronary heart disease. The evidence is unconvincing, some groups claiming that uric acid is an independent factor (albeit one conferring a low degree of risk) [61], and others denying that any such relationship exists [62]. There is, on balance, no convincing evidence that the hyperuricaemia induced by long-term diuretic therapy offsets any of the benefits resulting from the effective control of hypertension. No case of gouty nephritis resulting from diuretic therapy has ever been reported.

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Conclusions So, what are the clinical implications of the metabolic effects of antihypertensive drugs and how should prescribing practices be altered to take them into account? Diuretic and betablocker-induced lipid shifts may well reverse some of the reduction in cardiovascular risk associated with controlling blood pressure, and it is as well to take this into account until more information on the significance of these changes becomes available. If diuretic therapy is preferred, the merits of indapamide, which seems to have a more favourable metabolic profile than the thiazides or “loop” diuretics, should be considered. Careful consideration should certainly be given before prescribing thiazide diuretics to diabetic hypertensives, and to patients who may be pre-diabetic. The importance of the disturbances in carbohydrate metabolism induced by antihypertensive drugs is less obvious than that of the lipid shifts, and the effects of diuretics on electrolytes are probably of rather less importance. Long-term studies in large patient population are required, nonetheless, to determine the full impact on cardiovascular disease of these biochemical changes induced by antihypertensive agents. Diuretic-induced hyperuricaemia probably has no long-term significance. None of the metabolic effects of antihypertensive drugs should be regarded as biochemical curiosities. They can effect both the well-being and long-term prognosis of hypertensive patients and should be given serious consideration in the selection of appropriate therapy for individual patients.

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