Diuretics Revisited—Again

Within the past 3 months, two former patients and one colleague who is knowledgeable in the management of hypertension have consulted with me about their “resistant hypertension.” They had been under treatment for several years and were concerned about their lack of response to medication.

The physician had been taking two or, on some occasions, three different medications; so were the other two people. None had been given a diuretic on a consistent basis. The physician expressed particular concern about the metabolic effects of diuretics—increased lipid levels, adverse effects on glucose metabolism, effects on arrhythmias, and so forth. He was reluctant to use them and had only dabbled with homeopathic doses on a few occasions.

All three cases have happy endings. Medication was adjusted and a small dose of a thiazide diuretic was added in each case; blood pressures were controlled at goal levels. But it took a lot of convincing. Even in 2001, after years of good news about diuretics, physicians are reluctant to use them. One must ask, “Why?”

A thiazide diuretic may not be the drug of choice for every patient, but clearly physicians are still not using these medications appropriately. This, despite many recent articles, including many repetitive papers that we and others have written, refuting the misconceptions that: 1) the use of these agents does not result in a decrease in morbidity or mortality from cardiovascular disease; 2) they are poorly tolerated; and 3) their use results in significant adverse metabolic effects. ¹ , ² , ³ , ⁴ , ⁵ There had been too much emphasis on the negative aspects of these agents, ⁶ , ⁷ , ⁸ , ⁹ , ¹⁰ and too little emphasis on their benefits, to eradicate the stigma, even after many years of positive reports. As the results of new trials were published, demonstrating that the use of diuretics not only effectively lowered blood pressure but also reduced morbidity/mortality, and as each new Joint National Committee (JNC) Report on Detection, Evaluation, and Treatment of High Blood Pressure was released, recommending diuretics as appropriate initial therapy, their use continued to decrease. ¹¹ , ¹² A large part of this trend had nothing to do with science.

The efforts to promote newer medications by emphasizing misconceptions had been effective. ¹³ , ¹⁴ Newer medications have proven to be well tolerated and results of therapy are excellent, but diuretic‐based programs have been shown to be as effective or more so than other regimens, not just in lowering blood pressure but also in improving outcome. ¹⁵ In addition, most of the studies with other agents have demonstrated that goal blood pressures could not be achieved without the addition of a diuretic. ¹⁶ , ¹⁷ Yet these agents have not been used in patients who need them. Hence, it is necessary to reiterate what has previously been written over and over again and ignored or forgotten by many physicians.

ADVERSE EFFECTS OF DIURETICS: FACT OR FICTION?

One extreme example of the literature regarding diuretics is an article in the October, 1989 issue of The American Heart Journal: “Diuretics elevate blood sugar, cause overt diabetes, induce diabetic ketoacidosis, elevate total cholesterol and LDL‐C [low‐density lipoprotein cholesterol], and worsen left ventricular hypertrophy. They are contraindicated in patients with hyperglycemia, hyperlipidemia and coronary heart disease.” ⁷ In numerous redundant publications, it has been pointed out that careful review of the clinical trials has demonstrated a minimal, if any, adverse effect of diuretics on lipid levels over time, even in higher doses (the equivalent of 50 mg or more/day of hydrochlorothiazide). ² , ⁴ , ⁵ A short‐term (6–9 month) increase in cholesterol and LDL levels may occur, but these changes are not sustained and do not appear to be of clinical significance. In numerous (often duplicated) publications, it has been pointed out that the use of diuretics in clinical trials did not result in an increase in blood glucose levels over time and, at most, was associated with an approximate increase in new‐onset diabetes of only 0.5%. ⁴ , ⁵ , ¹⁸ One large, case‐control study ¹⁹ revealed no difference in the occurrence of diabetes between diuretic use and use of other antihypertensive drugs, despite the realization that these medications may increase insulin resistance in hypertensive individuals who already may be insulin‐resistant. Diuretics in large doses may cause hypokalemia, ²⁰ but carefully controlled studies have not confirmed the original contention that this results in significant arrhythmias. ²¹ , ²² In numerous papers, often duplicated, it has been pointed out that, despite the comments of some investigators, lowering blood pressure with diuretics results in regression of left ventricular hypertrophy. ²³ , ²⁴ , ²⁵ The use of diuretics in clinical trials, in both the young and the elderly, has resulted in a decrease not only in cerebrovascular but also in cardiovascular events. ²⁵ , ²⁷ , ²⁸

COMPARATIVE STUDIES

Recent studies comparing diuretics to long‐acting calcium channel blockers, either a dihydropyridine (nifedipine GITS [gastrointestinal treatment system]), ²⁹ a nondihydropyridine (verapamil SR [sustained release]), ³⁰ or a moderately long‐acting dihydropyridine (isradipine) ³¹ have shown a reduction in cardiovascular events that is equivalent or superior with a diuretic. A review of clinical trials in middle‐aged or older diabetics, in which diuretic‐based regimens were compared to angiotensin‐converting enzyme (ACE) inhibitors or calcium channel blocker‐based programs, also indicated equivalent benefits. ³² Interestingly, most of the clinical trials—whether they involved treatment regimens based on a diuretic, β blocker, ACE inhibitor, or calcium channel blocker—have not been studies of monotherapy.

COMBINATION THERAPY

It is well known that any antihypertensive drug, whether a diuretic or other agent, is effective only about 50% of the time. Diuretics and calcium channel blockers appear to be more effective in elderly and black patients; ACE inhibitors and β blockers are generally more effective in young Caucasians. ³³ However, despite attempts to select an appropriate drug on the basis of demographic criteria, the majority of patients require the use of more than one drug to achieve goal blood pressures of <140/90 mm Hg (or even lower in diabetics or patients with renal disease). The JNC has repeatedly suggested that if a diuretic is not used as initial treatment, it should be included as a second‐step drug. Hence, the proliferation of combination therapy: β blocker/diuretic, ACE inhibitor/diuretic, angiotensin II receptor blocker/diuretic. One study suggested that patients who received combination therapy that did not include a diuretic achieved less effective blood pressure control than those whose regimen included a diuretic. A recent review ³⁴ reported that diuretics reduced stroke to a greater degree than did other agents, and patients on two‐ or three‐drug regimens that included a diuretic had fewer strokes than individuals on therapy that did not include a diuretic. All of these data confirm the benefits of diuretic therapy. It is time for more physicians to recognize this.

FINAL THOUGHTS

We are concerned about patient adherence; we are concerned about resistant hypertension. Dr. Irvine Page, one of the pioneers of the modern therapy of hypertension, commented in Modern Medicine in 1988, “There are hypertensives who are resistant to treatment, but they are few. The resistance, I'm afraid, lies more with the physician who failed to monitor carefully enough the course of the patient's blood pressure.” If more patients were either given a diuretic as initial therapy or had a diuretic added as second‐step therapy if goal blood pressure was not achieved with an ACE inhibitor, β blocker, angiotensin receptor blocker, or calcium channel blocker, the number of patients who respond to therapy would be considerably higher. There would be fewer cases of “resistant hypertension.”

Many of the patients who do not achieve goal pressures are those with persistently elevated systolic blood pressure. Recent data strongly suggest that systolic blood pressure elevation presents a greater cardiovascular risk than elevated diastolic blood pressure in patients over 50–55 years of age. Systolic elevation is becoming more common as our population ages. It has been demonstrated that the use of thiazide diuretics will effect an equivalent decrease, or greater reduction in systolic blood pressure, than many of the other available agents.

A further comment: quality of life studies have demonstrated that the use of diuretics will not interfere with the enjoyment of life—on the contrary, there may be an improvement with these medications. ³⁵

The message is clear: we have numerous effective, well tolerated medications. Occasionally, when drugs go “off patent” or are “old,” they are forgotten. I remember one day about 15–20 years ago, when a top executive of a major pharmaceutical company turned to me and said, “Why do you keep defending the use of diuretics? They are drugs of the past.” The answer is that diuretics were drugs of the past; they are drugs of the present and of the future. If we use them more often and combine them with other medications more appropriately, adherence rates will increase and, importantly, there is a good chance that morbidity/mortality results will improve still further. Although there are reasons why some of our patients do not respond to therapy, withholding of a diuretic should not be one of them.