• Elevations in the levels of total serum cholesterol, triglycerides, and low-density lipoproteins increase the risk of coronary artery disease and atherogenesis. High-density lipoproteins (HDLs) are beneficial in removing lipid from tissues. High-risk men adhering to a diet and/or receiving cholestyramine to lower their elevated lipid levels had lowering of cardiac mortality. Hypertension is also a major risk factor for cardiovascular disease and for accelerated atherosclerosis. The benefit of blood pressure reduction may not be consistent in decreasing cardiovascular morbidity and mortality among all mildly hypertensive persons. Many antihypertensive agents may raise undesirable lipid fractions and/or lower HDL levels, enhancing the risk of cardiovascular disease, while others have few negative effects. Thus, the antihypertensive agent chosen may modify lipid levels and cardiovascular risk in hypertensive patients. (Arch Intern Med1985;145:1102-1105)

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Antihypertensive Therapy and Lipids: Evidence, Mechanisms, and Implications

• Hypertension is a major risk factor for arteriosclerotic vascular disease. Despite intensive antihypertensive Intervention, the risk of cardiovascular disease has not declined appreciably. Many of the antihypertensive agents have been shown to elevate total serum cholesterol and triglyceride levels or lower the high-density lipoprotein-cholesterol level. Thus, the antihypertensive agents chosen may negate the beneficial effects of a lower blood pressure. Our purpose is to review all available antihypertensive medications and their influence on lipoprotein metabolism. Choosing the antihypertensive therapy least likely to worsen or precipitate other known cardiovascular risk factors is important. Cost and side effect profiles must also be considered in choosing the best antihypertensive regimen for your patients. (Arch Intern Med1988;148:1280-1288)

The effects of antihypertensive agents on serum lipids and lipoproteins.

Atenolol is a selective beta 1-adrenoceptor antagonist with a duration of activity of at least 24 hours. The scope of therapeutic use of the drug has been expanded and become better defined since it was first reviewed in the Journal in 1979. Atenolol is effective and generally well tolerated in patients with all grades of hypertension. Data from comparative studies show that when administered orally, atenolol reduces blood pressure to a similar extent, and in a similar proportion of patients, as usual therapeutic doses of other beta-adrenoceptor antagonists (such as acebutolol, celiprolol, betaxolol, indenolol, metoprolol, nadolol, pindolol, propranolol, tertatolol), angiotensin converting enzyme (ACE) inhibitors (e.g. captopril, enalapril and lisinopril), calcium antagonists (e.g. amlodipine, diltiazem, felodipine, isradipine, nitrendipine, nifedipine, verapamil), doxazosin, ketanserin and alpha-methyldopa. Atenolol effectively lowers blood pressure in elderly patients with hypertension and in women with hypertension associated with pregnancy, and improves objective and subjective indices in patients with stable angina pectoris. Oral atenolol is used for preventing recurrence of supraventricular arrhythmias once control is achieved by intravenous administration of atenolol. Early intervention with intravenous atenolol followed by oral maintenance therapy reduces infarct recurrence and cardiovascular mortality in patients with known or suspected myocardial infarction. There is also encouraging evidence of reduced mortality from cardiovascular disease during long term therapy with atenolol in patients with hypertension. Atenolol is well tolerated in most patients. Increases in plasma levels of both total triglycerides and very low density lipoprotein (VLDL) triglycerides have accompanied atenolol therapy although the clinical relevance, if any, of longer term metabolic effects has yet to be determined. Its low lipid solubility and limited brain penetration results in a lower incidence of central nervous system effects than that associated with propranolol. After many years of clinical usage atenolol is a well established treatment option in several areas of cardiovascular medicine such as mild to moderate hypertension and stable angina pectoris. Furthermore, it has also shown potential in the treatment of some cardiac arrhythmias and has been associated with reduced cardiovascular mortality in patients with hypertension and in patients with myocardial infarction.

Atenolol. A reappraisal of its pharmacological properties and therapeutic use in cardiovascular disorders.

Potassium-losing diuretic drugs, when used in the treatment of hypertension, cause unfavourable short term alterations in blood lipid and lipoprotein concentrations. The disturbance is characterised by increases in total cholesterol of 4 to 13%, in low density lipoprotein (LDL) cholesterol of 7 to 29%, in very-low density lipoprotein (VLDL) cholesterol of 7 to 56%, and in total triglyceride of 14 to 37%. The disturbance is variable among patients and over time in individual patients; it is absent in some. In long term treatment the data are fragmentary, but total cholesterol and triglycerides usually return to baseline values or below. The variability of the lipid response to diuretics has several consequences: firstly, it necessitates a sizeable study population (minimum of 30 patients) in order to document convincingly its presence or absence; secondly, lipoprotein fractions must be examined to define the pattern of the disturbance; and thirdly, the subsidence of the diuretic-induced lipid effects in long term treatment may be more apparent than real because even larger decreases have been noted in untreated groups in the few studies that wisely included these important controls for comparison. While the cause of the lipid-lipoprotein aberration is unclear, existing data suggest that certain attributes of the study population influence the response, i.e. age, habitual diet, hormonal milieu (gender), baseline cholesterol concentrations, and induced glucose intolerance. The apparent absence of lipid alterations with indapamide needs to be substantiated and compared with low doses of a standard thiazidetype drug. The lipid-lipoprotein effects of diuretics seem inconsequentially small, but they may contribute to the disappointing failure of diuretic-based regimens to lower the incidence of coronary heart disease in hypertensive patients. Nevertheless, diuretic-based treatment remains the only therapeutic regimen of proven benefit to congestive heart failure in patients with hypertension, and it is superior to β-blockade in preventing stroke. Hence, alternative antihypertensive drug regimens must be compared prospectively with diuretics in order to verify any theoretic superiority.

The effects of antihypertensive drugs on serum lipids and lipoproteins, I. Diuretics.

Uric acid (UA) is the final product of purine catabolism in man, and it is excreted mainly by the kidneys when renal function is not impaired. Consequently, serum (S) UA increases as a function of purine intake, and it varies inversely to uricosuria. The latter variable diminishes in response to low-sodium intakes and vice versa. Insofar as the diet is not usually controlled in studies in which the response of SUA to drugs is evaluated, most reports are to be considered cautiously. Common diuretics elevate SUA in healthy subjects, hypertensives and patients with heart failure, apparently by elevating net UA reabsorption in the nephronal proximal tubule. This drug action, which becomes noticeable shortly after the institution of treatment and remains throughout it, starts at low doses (e.g., 12.5 mg hydrochlorothiazide or 1.25 mg bendrofluazide once daily in subjects with uncomplicated hypertension) and increases in dose-dependent fashion. Beta-blockers tend to elevate SUA. The angiotensin-converting enzyme (ACE) inhibitors captopril, enalapril and ramipril have been found to increase uricosuria mildly, likely by lowering the net reabsorption of UA in the proximal tubule. These three drugs and lisinopril can blunt the rise in SUA provoked by diuretics in hypertensives if used at sufficiently high doses relative to the dose of the diuretic. The angiotensin II antagonist losartan augments uricosuria mildly and thereby decreases SUA. The cardiovascular implications of the response of SUA to drugs remain speculative. Uric acid can scavenge various reactive oxygen species and thus reduce oxidative stress, which seems to contribute to the development and/or progress of various cardiovascular conditions, including hypertension, atherosclerosis and heart failure. Consequently, it may be theorised that the elevations in SUA induced by diuretics might contribute to the established favourable action of these agents on cardiovascular prognosis. Conversely, diuretic-induced increases in SUA are to be considered detrimental according to an old hypothesis that maintains that SUA is a cardiovascular risk factor; this construct is largely based upon the results of selected epidemiological undertakings. The cardiovascular implications of the effects of drugs on SUA, if any, should be elucidated through purposive research.

Cardiovascular Drugs and Serum Uric Acid

The effects on blood lipids and uric acid of six different antihypertensive drugs used alone, and of five different combinations of two antihypertensive drugs, are reported here. Prazosin significantly lowered serum low density lipoprotein and very low density lipoprotein (LDL + VLDL) cholesterol and total triglycerides while maintaining high density lipoprotein (HDL) levels. Atenolol lowered LDL + VLDL cholesterol slightly. Both pindolol and hydrochlorothiazide (HCTZ) were neutral, while oxprenolol increased total triglycerides. Propranolol lowered HDL cholesterol and increased total triglycerides and uric acid. The combination of prazosin plus pindolol has a direct favorable lipid profile, while the combination of propranolol plus HCTZ lowered HDL cholesterol and increased total triglycerides. The combination of propranolol plus prazosin lowered HDL cholesterol, but to a lesser degree than propranolol alone, which suggests that prazosin was not able to completely counteract the negative effects of propranolol on HDL. Methyldopa plus HCTZ, and HCTZ plus amiloride were neutral with regard to effects on blood lipids. It is suggested that the metabolic effects of antihypertensive drugs could be of special importance in the long-term treatment of mild hypertension.

Holme I

Papers

Antihypertensive drugs and blood lipids: the Oslo study.