benefits of diuretic-based low-cost antihypertensive therapy

High Blood Press Cardiovasc Prev 2005; 12 (2): 73-78REVIEW ARTICLE 1120-9879/05/0002-0073/$34.95/0

© 2005 Adis Data Information BV. All rights reserved.

Benefits of Diuretic-Based Low-CostAntihypertensive TherapyGiovanni de Simone and Oreste de Divitiis

Department of Clinical and Experimental Medicine, Federico II University, Naples, Italy

Contents

Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 731. Efficacy of Diuretics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 742. Effect of the Metabolic Toxicity of Diuretics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 753. Mechanisms of Thiazide-Induced Deterioration in Glucose Disposal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 764. Use of Anti-Aldosterone Diuretics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 765. Economic Implications of the JNC VII . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 776. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77

Recent trials demonstrate that blood pressure must be optimally controlled to reduce the risk of cardiovascu-Abstractlar mortality and morbidity in the population, and combination treatment is preferable to single medications.Diuretics are a constant component of the antihypertensive regimen to effectively decrease blood pressure, ageneral practical behaviour that is supported by most large trials, which demonstrate the superiority of diureticsin preventing adverse cardiovascular outcomes (with special evidence for heart failure). Consistent with thisstrong evidence, the JNC VII (Joint National Committee VII) still indicates diuretics as the first line ofantihypertensive therapy. The main argument used against this indication is the metabolic toxicity of diuretics(deterioration of insulin resistance is a common condition among patients with hypertension), which has beenrepeatedly proven. One factor that might aggravate glucose metabolism during diuretic therapy is the underesti-mated effect of hypokalaemia, which interferes with glucose-stimulated insulin release. There is evidence thatindividuals presenting with hypokalaemia after 1 year of treatment (SHEP [Systolic Hypertension in the ElderlyProgram]) do not experience the reduction in cardiovascular events achieved among those who do not develophypokalaemia. Among other beneficial effects, correction of hypokalaemia prevents or significantly reducesthiazide-induced hyperglycaemia. Some experiments suggest that thiazide diuretics should be given at lowdoses, possibly together with K+-saving medications, including ACE inhibitors, angiotensin II type 1 (AT1)receptor antagonists or K+-sparing diuretics. Low doses of anti-aldosterone diuretics have been used successfullyin resistant hypertension and have demonstrated effects on blood pressure similar to, or even better than,enalapril or losartan. There are concerns regarding the use of anti-aldosterone diuretics because of the increasedrate of hospitalization for hyperkalaemia after the RALES (Randomized ALdactone Evaluation Study). Howev-er, this information should be weighted for the assessment of renal function, often deteriorated in heart failure.There are indications that when renal function is still normal, early anti-aldosterone treatment might help toprevent hyperkalaemia. Eventually, economic implications should be considered in the choice of diuretics,taking into account that the (theoretical) single-medication yearly cost of antihypertensive therapy goes from€10 with chlortalidone 12.5mg to about €380 with the most expensive ‘new’ medications. However, financialand social costs related to the prevalence and incidence of arterial hypertension as well as to any othercardiovascular risk factors should take into account the financial and social burden of laboratory examinations,visits, adverse effects, hospitalisations and their frequency, and indirect costs due to temporary loss of workforce, which is an issue that should be resolved by ad hoc studies that balance the immediate money saving withthe potential increased cost of antihypertensive management.

74 de Simone & de Divitiis

1. Efficacy of Diuretics ity in controlling blood pressure. In fact, the difference in riskprofile versus the lisinopril arm achieved statistical significanceonly for elderly and African American participants.Many comments have been issued about similarities and differ-

The ALLHAT findings confirm and highlight the importanceences between 2003 American and European guidelines for theof findings from the SHEP (Systolic Hypertension in the Elderlymanagement of arterial hypertension,[1,2] especially after the publi-Program).[10] The SHEP was a placebo-controlled trial designed tocation of the ALLHAT (Antihypertensive and Lipid-Loweringassess the ability of treatment with low-dose chlortalidone as theTreatment to Prevent Heart Attack Trial).[3-5] Both guidelinesstep 1 medication to reduce the risk of stroke in 4736 elderlyagree that the majority of hypertensive patients require more thanpatients with isolated systolic hypertension, over an average fol-one medication to achieve optimal blood pressure control and,low-up of 4.5 years. Atenolol was the second drug used in theconsistent with the most recent findings, there is no need anymoretreatment. The incidence of stroke was markedly reduced, by 36%,for expensive, large clinical trials to demonstrate the superiority ofin the treated arm. The reduction in the incidence of combinedone single medication over another.[3,6] What is clear now is thatcardiovascular diseases (secondary endpoint) was even greater.blood pressure must be optimally controlled to reduce the risk of

cardiovascular mortality and morbidity in the population, no mat- Another relevant finding from the ALLHAT concerns the inci-ter which combination of medications is used. Comparison be- dence of congestive heart failure, which was substantially lesstween single medications is substantially academic and conceals with chlortalidone than with either amlodipine or lisinopril. Thethe reality: in all trials and in most circumstances comparison is emphasis given to this result has been criticised, as it was a postbetween combinations, rather than single medications. For in- hoc, secondary endpoint, which might be difficult to reliablystance, in the LIFE (Losartan Intervention For Endpoint reduction assess.[4,11] Congestive heart failure is a clinical diagnosis based onin hypertension) study,[6] the combination of losartan with low- a combination of nonspecific symptoms and signs, which are notdose hydrochlorothiazide and the combination of atenolol with the interchangeable and many criteria may be adopted for diagnosis.same diuretic were compared. Not all standardised guidelines have the same efficacy, as recently

The difference between the JNC VII (Joint National Committee shown.[12] Thus, without predefined criteria it is possible that theVII) and the ESC/ESH (European Society of Cardiology/European risk of misdiagnosis might also increase, although this has neverSociety of Hypertension) 2003 guidelines, often presented as been proven. Even taking into account the potential pitfalls associ-being substantial, is in the importance that Americans still place on ated with the diagnosis of congestive heart failure, this secondarydiuretic therapy, which is based on the results of the ALLHAT.[3] endpoint remains substantially important and cannot be ignored.

The ALLHAT was a randomised, double-blind, multicentre Congestive heart failure is the true terminal stage in the evolu-clinical institutional trial, entirely sponsored by the National tion of hypertensive heart disease. Left ventricular (LV) hypertro-Heart, Lung, and Blood Institute (NHLBI),[3] and was designed to phy is a risk factor for coronary heart disease,[13] which candetermine whether the occurrence of fatal or nonfatal coronary progress to systolic dysfunction when remodelling occurs afterheart disease is lower for high-risk hypertensive patients treated myocardial infarction. However, LV hypertrophy can also pro-with amlodipine, lisinopril, doxazosin or chlortalidone. The proto- gress directly to heart failure without the intermediate steps ofcol was also approved by a review committee that was indepen- coronary heart disease and, in this instance, is often characteriseddent of the NHLBI.[7] The ALLHAT recruited 9000–15 000 par- by preserved normal ejection fraction,[14] a clinical presentationticipants per intervention arm (total: 33 357), and the follow-up that is increasingly observed[15] because of both the aging of thewas quite long (4–8 years). The doxazosin arm was closed prema- population and the relative ability to prevent myocardial infarc-turely because of higher mortality.[8] Despite a number of impor- tion. Through these two evolutionary pathways, hypertension can,tant limitations of this study,[4,9] the overall impact of its findings therefore, explain most of the financial and social burden associat-remains very high. ed with congestive heart failure. Even when the difficulty of

The baseline characteristics of the ALLHAT participants were correctly diagnosing congestive heart failure is considered,[12] it issubstantially similar in the three arms completing the study. likely that the possible diagnostic errors are uniformly distributedChlortalidone was significantly more effective than both among arms. Thus, the reduced incidence of congestive heartamlodipine and lisinopril in achieving optimal control of blood failure obtained with chlortalidone in the ALLHAT should bepressure at year 1 and year 2 and was more effective than lisinopril given due consideration. Because LV hypertrophy is the bestin blood pressure control at years 3, 4 and 5 (all p < 0.001). predictor of congestive heart failure,[16,17] the ALLHAT findingConsistent with the better control of blood pressure, chlortalidone also brings to mind the evidence that diuretics can reduce LV masstended to provide 10% more protection against combined fatal and at least as well as, and perhaps better than, other antihypertensivenonfatal coronary heart disease than lisinopril, whereas protection medications. This effect is more evident in direct comparisonswas similar for amlodipine, although less evident than its superior- than in meta-analyses.[18-20]

© 2005 Adis Data Information BV. All rights reserved. High Blood Press Cardiovasc Prev 2005; 12 (2)

Diuretic-Based Low-Cost Antihypertensive Therapy 75

In the TOMHS (Treatment Of Mild Hypertension Study), five were aware of the patients’ treatment. In addition, no informationactive treatments (acebutolol, amlodipine, chlortalidone, dox- was available on medication doses and metabolic control of sub-azosin and enalapril) were compared in terms of blood pressure jects (i.e. K+ levels). The comparison with the ALLHAT has beencontrol and reduction of LV mass; the study included a placebo debated and the interpretation of the tiny difference betweencontrol and a programme of intense and monitored lifestyle inter- medications has been criticised.[27-30]

vention.[21] In this study, the additional effect of each medication2. Effect of the Metabolic Toxicity of Diureticswas measured compared with the effect of lifestyle intervention.

After 1 year, chlortalidone was the medication achieving the mostThe most recurrent criticism of all trials showing the superiority

effective reduction of LV mass compared with lifestyle modifica-of diuretics over other medications in controlling blood pressure

tion alone. This reduction included a consistent decrease in bothconcerns the worsening of glucose metabolism resulting from

LV chamber dimension and wall thickness. In the Veterans Ad-thiazide effects.[4,31,32] It is convincingly argued that the complica-

ministration study, conducted in an overwhelmingly Africantions after onset of de novo diabetes mellitus take decades to

American population, Gottdiener et al.[22] avoided using combina-develop, and the 2- to 6-year timeframe of clinical trials[33] cannot

tions in order to compare the pure effect of different classes ofreally detect these complications. Recently, this has also been

antihypertensive medications (captopril, hydrochlorothiazide, ate-shown in a study documenting that the prevalence of retinal

nolol, clonidine, diltiazem and prazosin) on regression of LVchanges in diabetes is 20-fold greater after 20 years than after 10

hypertrophy and found that only diuretic therapy achieved a sig-years from initial diagnosis.[34] This criticism might, therefore, be

nificant regression of LV hypertrophy, whatever level of baselinejustified.

LV mass was considered. In contrast, the effect of captopril andThe ALLHAT authors report a higher incidence of diabetes inatenolol, the other drugs that significantly decreased LV mass in

the diuretic group, which did not, however, affect the results.[3]this study, was evident only at the highest level of baseline LV

This finding was confirmed by another long-term study examiningmass.the relationship between diabetes and long-term follow-up[15] in

The findings of meta-analyses conducted on randomised con- elderly hypertensive subjects (SHEP).[35] The authors found that,trolled trials did not contrast substantially with those obtained while diuretics do raise the risk of diabetes, cardiovascular mortal-from the direct comparisons, confirming that diuretics can produce ity was still almost 15% lower in patients treated with a low-dosean average reduction in LV mass of 8%, only slightly smaller than diuretic compared with placebo. However, the SHEP is limited inthe decrease obtained on average with ACE inhibitors.[19,20]

its lack of comparison with other active medications. Neverthe-Overall, the ALLHAT study confirmed most results of previous less, as has been stated, this apparent inconsistency is possibly

large trials comparing ‘old’ with ‘new’ drugs. related to the relatively short follow-up. Paralleling the strongIn a short review, Kjeldsen et al.[23] showed that every attempt criticism about the use of secondary endpoints, including incident

to demonstrate the superiority of the new medications over the old congestive heart failure and diabetes, some inconsistency can be(diuretics and β-blockers) has been unsuccessful. The LIFE study noted. While findings concerning congestive heart failure arewas designed for a critical type of hypertensive patient at high risk widely criticised as ‘soft’,[36] there is emphasis on the secondaryof cardiovascular events, because it required the presence of finding of the increased incidence of diabetes with diuretics.[37-39]

electrocardiographically documented LV hypertrophy.[24] The This concern is, however, also confirmed by some recent evidenceLIFE study, in fact, demonstrated the superiority of losartan versus of the dangerous effect of incident diabetes in patients with arterialatenolol in preventing cerebrovascular events (not myocardial hypertension.[32]

infarction), but this result was largely obtained by a combination The remarkable success of diuretics in all large trials despitewith diuretics – a pharmacological association that is considered this ‘toxic’ effect on glucose metabolism should lead to a consider-near perfect in its synergistic mechanism.[25] ation of alternative hypotheses. Alexander et al.[40] reported that,

Immediately after the ALLHAT report, the Second Australian among the NHANES III (Third National Health and NutritionNational Blood Pressure Study,[26] a large trial on hypertension in Examination Survey) participants with diabetes, the prevalence ofan elderly population followed up by family practitioners, reported coronary heart disease was increased compared with participantsa very marginal superiority (p = 0.05) of ACE inhibitors over with the metabolic syndrome but without diabetes. However,diuretics in the prevention of combined fatal and nonfatal cardio- individuals with diabetes without the metabolic syndrome had novascular events and all-cause mortality, which was particularly greater prevalence of coronary heart disease than those withevident in men (as a post hoc analysis). Although receiving less neither diabetes nor the metabolic syndrome. In the NHANES III,criticism than the ALLHAT, this trial was not as carefully de- the most frequent component of the metabolic syndrome in diabet-signed. It was an open-label study and some observational bias ic participants was high blood pressure. To be consistent withmight have affected the judgment of family practitioners, who these findings and to explain the success of diuretics despite their



evident toxic effect on glucose homeostasis, we need to consider diabetes does not require an increase in insulin infusion to main-the possibility that, if blood pressure is optimally controlled, the tain glucose uptake compared with baseline levels, over a range ofworsening of glucose homeostasis might not have such a signifi- glucose uptake rates between approximately 2.5 and 12 mg/kg/cant negative effect on prognosis in an unselected population. At min.[50] In an interesting experiment, Natali et al.[51] demonstratedthe same time, we cannot exclude that correction of metabolic that clamping K+ under iso-osmolar conditions boosts the insulinabnormalities might further improve the prognosis to a level that secretory response to glucose. However, in the same experiment, itsurpasses the benefit of the optimal control of blood pressure was shown that forcing K+ levels could also increase the aldoster-achieved with diuretic-based therapy; however, each of these one response. Overall, this experiment suggests that thiazide di-possibilities needs to be tested. In this scenario, it should also be uretics should be given at low doses, possibly together with K+-considered that to achieve optimal control of blood pressure com- preserving medications, including ACE inhibitors, angiotensin IIbination therapy must almost invariably include diuretics,[4] even type 1 (AT1) receptor antagonists and K+-sparing diuretics.in patients with diabetes. Among K+-sparing diuretics, preference should be given to aldos-

terone-receptor inhibitors.3. Mechanisms of Thiazide-Induced Deterioration inGlucose Disposal 4. Use of Anti-Aldosterone Diuretics

An important consideration to be highlighted is that deteriora- Low doses of spironolactone (12.5–25mg) have been adminis-tion in insulin resistance, a quite common condition among hyper- tered to patients with resistant hypertension and with or withouttensive subjects, and progression to diabetes “is not a gradual primary hyperaldosteronism.[52] The decrease in both systolic anddownward drift in glucose levels but an abrupt and, generally, diastolic blood pressure was marked in subjects either with orirreversible phenomenon”.[41] Promoted by long-standing insulin without hyperaldosteronism. In another study,[53] eplerenone, aresistance, diabetes is finally triggered because of the failure of β- relatively new anti-aldosterone medication, was compared withcell function. Thus, in hypertensive subjects, insulin resistance enalapril over a wide range of doses (25–200mg vs 5–40mg) andneeds to be associated with abnormal insulin secretion for diabetes demonstrated similar effects on blood pressure (with perhaps ato develop. slightly better, albeit nonsignificant, control of systolic blood

One factor that might aggravate glucose metabolism during pressure). In another randomised controlled trial,[54] eplerenonetherapy with diuretics is the underestimated effect of hy- reduced blood pressure (by 13mm Hg for systolic and 10mm Hgpokalaemia, which interferes with glucose-stimulated insulin re- for diastolic blood pressure) significantly more than losartanlease, a condition that might be worsened by an association with β- (6mm Hg and 7mm Hg, respectively), an effect that was similar inadrenergic blockade.[41,42] African Americans and Caucasians, although statistically signifi-

As stated in section 1, the SHEP demonstrated the ability of cant only in the former and substantially larger group.therapy with diuretics to reduce systolic hypertension and prevent There are, however, concerns regarding the use of aldosteronecardiovascular complications.[10] However, within the group of receptor inhibitors, which has increased dramatically[55] after theparticipants receiving diuretics, the few individuals presenting publication of the RALES (Randomized ALdactone Evaluationwith hypokalaemia after 1 year of observation (n = 151 of 2102, or Study).[56] Among patients with heart failure, the hospitalisation7%) did not show the same reduction in cardiovascular events rate for hyperkalaemia followed the increase in spironolactoneachieved among those who did not develop hypokalaemia.[43] prescriptions, rising from 2.4 per 1000 patients in 1994 to 11.0 perThus, the SHEP confirmed that hypokalaemia should be consid- 1000 patients in 2001, while the associated mortality rose from 0.3ered as the main complication of therapy with diuretics. Among per 1000 to 2.0 per 1000 patients.[55] However, as is also pointedother beneficial effects, including improvement in blood pressure out on many occasions,[57-59] in this study patients had at least classcontrol, the correction of hypokalaemia prevents or significantly III New York Heart Association (NYHA) heart failure and noreduces thiazide-induced hyperglycaemia.[44-46] In fact, when very information was provided on renal function, a factor that is alsolow-dose diuretics are given and hypokalaemia is prevented, glu- relevant in treatment with ACE inhibitors.[60] In addition to thecose metabolism is not affected even in diabetic patients.[47] Low- number of relatively simple strategies that can be adopted todose indapamide has been indicated as a diuretic with a low prevent hyperkalaemia,[60] there is also some indication that whenhypokalaemic effect and, therefore, a reduced effect on plasma renal function is still normal early treatment might help to preventglucose.[48,49] hyperkalaemia.[61] Together with drawing attention to this impor-

Therefore, the mechanism of potential toxicity with thiazide tant topic, it is also important to underline again that this debatediuretics seems to be at least partly related to an imbalance in developed with regard to treatment for class III–IV NYHA heartinsulin release rather than insulin resistance. Administration of failure patients, not for arterial hypertension, a condition thathydroflumethiazide 75mg for 2 weeks in patients with type 1 might easily be managed before renal impairment occurs.


Diuretic-Based Low-Cost Antihypertensive Therapy 77

5. Economic Implications of the JNC VII 6. Conclusions

Although this issue should not be the primary concern of a Arguments regarding the use of a diuretic as a first step inphysician, the enormous gap in costs between medications should antihypertensive therapy is an academic exercise, because verybe considered if doctors wish to contribute to the preservation of few hypertensive patients can be optimally controlled withoutthe public health system in Europe. Figure 1 shows the economic pharmacological combinations that include a diuretic. Whetherimplications of the ALLHAT-related choice of the JNC VII to give many or most hypertensive patients need expensive medicationspriority to diuretics in the treatment of hypertension and considers instead of cheap but very effective treatment remains to be fullyboth low and high doses of many popular antihypertensive medi- elucidated.cations according to the annual cost in Italy of a theoretical one-drug regimen. The differences range from about €10 with Acknowledgementschlortalidone 12.5mg to about €380 with amlodipine 10mg.

Addition of low-dose spironolactone to low-dose chlortalidone Dr de Simone has served occasionally as a consultant for the GIENNEwould increase the annual cost of antihypertensive therapy to pharamaceutical company. Dr de Divitiis has no conflicts of interest that are

directly relevant to the content of this review.approximately €50, similar to the cost of atenolol 50 mg/day andwell below that of the cheapest monotherapy with ‘new’ drugs,including indapamide, a relatively new diuretic. References

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Irbesartan (150)Losartan (50)Amlodipine (10)Perindopril (4)Ramipril (5)Indapamide SR (1.5)Atenolol (100)Clortalidone (25)

High doseLow dose

Cos

t of m

onot

hera

py/p

atie

nt/y

ear

(€)

400

300

200

100

0

Fig. 1. Annual cost of antihypertensive monotherapy in Italy. The name ofthe drug and the commercial dose (mg) are shown.



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