Long-Term Safety ofAntihypertensive Therapy

Ehud Grossman and Franz H. Messerli

Lowering blood pressure (BP) in hypertensivepatients reduces morbidity and mortality. Howeverthe long-term safety of some antihypertensiveagents was a matter of concern. Diuretic, the goldstandard treatment in hypertension may impairglucose tolerance and thereby accelerate the de-velopment of diabetes mellitus. It was also asso-ciated with increased cardiovascular mortality indiabetic patients. However, recent evidenceshowed that low-medium dose of thiazide diureticespecially when given in combination with potassi-um sparing agent is effective in reducing BP andcardiovascular morbidity and mortality. Beta block-ers are less effective than other antihypertensiveagents in the elderly. Therefore they may beappropriate as a first choice in young and middle-age hypertensives, and in those with fast heart rate,but they should not be considered appropriate asthe first-line therapy in the elderly with uncompli-cated hypertension. Several years ago a plethora ofpublications showed that short-acting calciumantagonists may increase the risk for myocardialinfarction and cancer. A few years ago two studiesshowed that calcium antagonists are less effectivethan angiotensin converting enzyme inhibitors inpreventing cardiovascular events in diabetic hyper-tensive patients. However, recent results from largeprospective randomized studies showed that calci-um antagonists reduce cardiovascular morbidityand mortality in diabetic and non-diabetic hyper-tensive patients. Some investigators have sug-gested that angiotensin receptor blockers (ARBs)may increase the risk of myocardial infarction

in hypertensive patients. However, recent metaanalyses refuted this conclusions and showed thatARBs are probably as effective as other antihyper-tensive agents in prevention of myocardial infarc-tion. Despite the concern that has been raisedregarding the long-term safety of some antihyper-tensive agents, it is clear that lowering BP is safeand beneficial.n 2006 Elsevier Inc. All rights reserved.

Hypertension is one of the major risk factorsfor cardiovascular morbidity and mortality.

It is clear that lowering blood pressure is ben-

eficial1-5; however, there are still some doubts

regarding the long-term safety of antihyperten-

sive therapy. We will discuss some of the doubts

and show what is clearly safe and what is still

open to debate.

Diuretics

Numerous prospective studies attested to the

safety and efficacy of thiazide diuretics in reducing

morbidity and mortality in hypertensive pa-

tients.1,2 However, the safety of diuretics in diabetic

hypertensive patients has been questioned.

Fifteen years ago, Warram et al6 showed that

in diabetic hypertensive patients, the risk ofcardiovascular mortality was 3.8-fold higher in

those treated with diuretics than in those who

were not treated. In contrast later, prospective

studies showed that diuretics reduced cardiovas-

cular morbidity and mortality in elderly diabetic

hypertensive patients.7-9 The old belief that di-

uretics may paradoxically increase cardiovascu-

lar morbidity and mortality can be put to rest inview of the recent evidence of clear benefit. In

the past, a high dose of diuretic was used, which

may account for lack of benefit, whereas in more

recent studies, a low- to medium-dose diuretic

with or without potassium-sparing agents was

used. It is well accepted that the low to medium

dose of diuretic is effective in lowering blood

Progress in Cardiovascular Diseases, Vol. 49, No. 1 (July/August), 2006: pp 16-2516

From the Internal Medicine D and Hypertension Unit,

The Chaim Sheba Medical Center, Tel-Hashomer, Affil-iated to the Sackler School of Medicine Tel-Aviv

University, Israel, and Division of Cardiology, St. Luke’s-

Roosevelt Hospital, NY.

Address reprint requests to Ehud Grossman, InternalMedicine D and Hypertension Unit, The Chaim Sheba

Medical Center, Tel-Hashomer, 52621 Israel.

E-mail: gross-e@zahav.net.il

0033-0620/$ - see front mattern 2006 Elsevier Inc. All rights reserved.

doi:10.1016/j.pcad.2006.06.002

pressure with minimal side effects. Increasing

the dose adds very little to the control of blood

pressure, whereas it increases substantially the

rate of side effects such as hypokalemia, hypo-

natremia, hyperuricemia, hypercholesterolemia,

and so on.10 Similarly, the risk of sudden cardiacdeath was low in diuretic users when the dose

was low and a potassium-sparing agent was

added.11 The rationale of adding a potassium-

sparing agent to a thiazide is supported by the

recent evidence that addition of aldosterone

antagonists to optimal treatment reduces cardio-

vascular morbidity and mortality in patients with

congestive heart failure.12,13 It seems that thecontroversy regarding the long-term efficacy and

safety of diuretics in hypertension has been

resolved by using a low- to medium-dose

diuretic with the option of adding a potassium-

sparing agent. Recently, aldosterone antagonist

has been included in the regimen of resistant

hypertension.14 The combination of thiazide with

an aldosterone antagonist may be very effectivein lowering blood pressure and reducing the risk

of hypokalemia and sudden death.15 However,

this combination, particularly when given with

an angiotensin-converting enzyme (ACE) inhib-

itor, may expose patients to hyperkalemia.16

Thus, close follow-up of serum potassium levels

may increase the safety of diuretics.

Diuretics may impair glucose tolerance anddecrease insulin sensitivity and thereby acceler-

ate the development of diabetes mellitus.17 This

deleterious effect of diuretic may take time and

can be blunted by the combination with an ACE

inhibitor.18 Most prospective randomized trials

in hypertension last 4 to 6 years and therefore

provide little if any information as to long-term

safety of diuretics. Many patients are exposed toblood pressure–lowering drugs for many de-

cades, and drug-induced changes could be

cumulative. This is potentially true with the

adverse metabolic effects that are seen with the

diuretics.19 Clearly, the increased risk of new

onset diabetes with diuretics, single or in

combination, will not translate into increased

morbidity and mortality in a study lasting 4 to6 years.9 After decades, however, sustained dia-

betes may have an important impact on cardio-

vascular morbidity and mortality.20

Long-term treatment with thiazide diuretics

may increase the risk for renal cell carcinoma.21

The risk is higher in women than in men and

seems to increase in parallel with the duration of

diuretic exposure.21 This risk of carcinogenicity

is unlikely to be discovered in short-term

(4-6 years) prospective, randomized trials be-

cause similar to other carcinogenic substances(tobacco), the exposure needed exceeds 2 dec-

ades. Diuretics have the longest track record of

any antihypertensive drug class and therefore

have been intensively scrutinized. The benefit of

lowering blood pressure should therefore be

weighed against the potential long-term adverse

effects of diuretics.

bbb-Blockers in the Treatmentof Hypertension

Until the recent publication of the Joint National

Committee 7 (JNC 7), diuretics and b-blockers

were both recommended as the drug of choice for

essential hypertension.22 Although numerous

epidemiologic studies attest to the safety andefficacy of diuretics in this regard, the data for

b-blockers are sketchy and unconvincing. In fact,

the available data suggest that the clinical benefits

of b-blockers are poorly documented and that

b-blockers may be inefficacious in the elderly,

who account for a large segment of the hyperten-

sive population.23 Monotherapy with a b-blocker

in the elderly does not reduce morbidity andmortality compared with placebo. The British

Medical Research Council 2 Trial, a randomized,

placebo-controlled, single-blinded study in

patients aged 65 to 74 years, clearly documented

that although blood pressure was lowered effec-

tively by the cardioselective b-blocker atenolol,

morbidity and mortality of the b-blocker group

did not differ from that of the placebo group.2

Moreover, patients who received the combination

of b-blockers and diuretics fared consistently

worse than those receiving diuretics alone.24 In

a previous meta-analysis, we showed that

b-blocker–based therapy does not reduce cardio-

vascular disease, coronary heart disease, and total

mortality in elderly hypertensive patients.23 The

Losartan Intervention For Endpoint reduction inhypertension study showed that atenolol-based

therapy is inferior to losartan-based therapy in

elderly hypertensive patients with electrocardio-

gram-documented left ventricular hypertro-

phy.25,26 In the recent Anglo-Scandinavian

LONG-TERM SAFETY OF ANTIHYPERTENSIVE THERAPY 17

Cardiac Outcomes Trial-Blood Pressure Lower-

ing Arm, atenolol-based regimen was less effec-

tive in preventing cardiovascular events and

induced more diabetes mellitus than amlodi-

pine-based regimen.27,28 In a recent meta-analy-

sis that compared treatment with b-blockers toother antihypertensive drugs, the relative risk of

stroke was 16% higher for b-blockers than for

other drugs.29,30 Thus, despite their having a

beneficial effect on the surrogate end point, that

is, blood pressure, b-blocker therapy failed to

favorably affect the real end point, that is, strokes

and cardiac events in elderly.

Similarly, in a large case control study, the riskof sudden cardiac death was distinctly higher in

elderly patients receiving either b-blocker as

monotherapy or in combination with a thiazide

diuretic than in patients receiving other therapy

(calcium antagonists, ACE inhibitors, potassium-

sparing diuretics).31 This would indicate that

b-blocker therapy does needlessly expose

millions of elderly hypertensive patients to ad-verse effects and cost while not conferring any

benefit whatsoever. In all studies in the geriatric

population, wherein b-blockers were implied to

reduce morbidity and mortality, they were used in

combination with a diuretic. Thus, in the Swedish

STOP Trial,3 more than two thirds of the patients

were receiving combination therapy, and no

information was available regarding the effectsof b-blocker monotherapy. In the Systolic Hyper-

tension in the Elderly Program Study, only 32%

of patients were receiving atenolol (or reserpine),

all of these in combination with a diuretic.1 A

subanalysis by Kostis et al32 did not identify any

additional benefits attributable to atenolol (or

reserpine) that were independent of the ones

conferred by the diuretic. In the study of Coopeand Warrender,33 which demonstrated a signifi-

cant reduction in the rate of strokes, 70% of

patients in the treatment group were receiving

atenolol, and 60% were receiving bendrofluazide.

None of these studies allows us to conclude that

either b-blocker alone or b-blocker with the

diuretic regimen did indeed significantly and

independently impact morbidity and mortality.Nevertheless, some indirect evidence suggests

that b-blockers may have benefits in middle-

aged and younger patients. In all 3 trials

(Medical Research Council, International Pro-

spective Primary Prevention Study in Hyperten-

sion, and Heart Attack Primary prevention in

Hypertension),34-36 the rate of myocardial in-

farction (MI), stroke, and cardiovascular death

was not very different in a b-blocker regimen

than with a diuretic regimen. A meta-analysis

analyzing the 3 studies showed a decreasingtrend in total cardiovascular mortality in men by

14% and an increasing trend in women by 16%

in the b-blocker group when compared with the

non–b-blocker group.37 Thus, there is still doubt

whether a b-blocker is adequate as one of the

first drugs of choice for hypertension.

The use of b-blockers became even more of a

question in diabetic hypertensive patients. TheNational High Blood Pressure Education Program

Working Group38 recommended in 1994 to avoid

the use of b-blockers in diabetic hypertensive

patients because they can have adverse effects on

peripheral blood flow and mask symptoms of

hypoglycemia. However, the results from the UK

Prospective Diabetes Study39 showed that block-

ers are as effective as ACE inhibitors in reducingcardiovascular events in diabetic hypertensive

patients. It seems that b-blockers may be appro-

priate as a first choice treatment in young and

middle-age hypertensives and in those with fast

heart rate, but it should not be considered

appropriate as the first-line therapy in the elderly

with uncomplicated hypertension.

The class of b-blockers is heterogeneous, and ithas been debated whether all the drugs in the

class are the same. It has been shown that

metoprolol and carvedilol are effective in con-

gestive heart failure. Nonetheless, the recent

Carvedilol or Metoprolol European Trial showed

a superiority of carvedilol over metoprolol in

patients with congestive heart failure.40 However,

the design of the study does not allow one toconclude that carvedilol is superior because

blood pressure levels were lower in the carvedi-

lol-treated group and metoprolol was used in

a subtherapeutic dose. In addition, in the re-

cent Glycemic Effects in Diabetes Mellitus:

Carvedilol-Metoprolol Comparison in Hyper-

tensives Study in diabetic hypertensive patients

who were treated with a blocker of the reninangiotensin system, carvedilol had a less detri-

mental effect on glycemic indices than did

metoprolol.41 Similarly, nebivolol may differ

from other b-blockers because of its vasodilating

properties. Thus, the question whether the

GROSSMAN AND MESSERLI18

efficacy and safety of all b-blockers are equal is

still pertinent, and only a well designed head-to-

head comparative study with 2 b-blockers will be

able to resolve the uncertainty.

Calcium Antagonists

Calcium antagonists are widely used as antihy-

pertensive agents. They are liked by physicians

and patients because of their efficacy, metabolic

neutrality, and clean side-effect profile. Several

years ago, a plethora of publications showed that

hypertensive patients treated with short-acting

calcium antagonists are at increased risk for MIand have a higher mortality rate compared with

patients treated with other antihypertensive

drugs.42-45 Moreover, calcium antagonists have

been accused of increasing the risk of cancer

among hypertensive patients.46,47 Because these

studies were uncritically extrapolated to all

calcium antagonists as a class, they cast doubt

on the safety and efficacy of these drugs, alarmedpatients, and frustrated physicians. Recent pro-

spective randomized studies attested to the

safety of calcium antagonists.9,27,48-51 Moreover,

they showed clearly that calcium antagonists

are beneficial in reducing cardiovascular mor-

bidity and mortality.4,9,27,48-50,52 Calcium antag-

onists are less effective than diuretics and ACE

inhibitors in preventing congestive heart fail-ure9,50,52 and less effective than blockers of the

renin angiotensin system in preventing renal

failure.53,54 However, they are equally effective

as renin angiotensin system blockers in reducing

cardiovascular morbidity and mortality.9,48,55

Diabetes mellitus is common among hyper-

tensive patients and is devastating to the

cardiovascular system.56 The risk of stroke orany cardiovascular event is almost doubled when

the hypertensive patient has diabetes mellitus.57

Lowering blood pressure markedly decreases the

rate of cardiovascular events and renal deterio-

ration in these patients.51,58-60 A few years ago,

2 studies showed that calcium antagonists are less

effective than ACE inhibitors in preventing

cardiovascular events in diabetic hypertensivepatients.61,62 These results cast doubt on the

safety and efficacy of calcium antagonists in

diabetic hypertensive patients. However, recent

results from large prospective randomized stud-

ies8,9,63,64 showed that calcium antagonists re-

duce cardiovascular morbidity and mortality in

diabetic hypertensive patients. We recently

showed that calcium antagonists are as effective

as diuretics and ACE inhibitors in reducing

cardiovascular morbidity and mortality in dia-

betic hypertensive patients.65 Thus, it seems thatcalcium antagonists are less effective than other

agents in preventing congestive heart failure and

perhaps renal deterioration, but they are safe

and clearly reduce cardiovascular morbidity and

mortality in hypertensive patients with or with-

out diabetes mellitus.

Angiotensin-ConvertingEnzyme Inhibitors

Angiotensin-converting enzyme inhibitors be-

came very popular in the treatment of hyperten-

sion because in addition to lowering blood

pressure, they prolong life in patients with

congestive heart failure,66-70 they prevent renal

deterioration in patients with diabetic nephrop-athy and with nondiabetic renal failure,53,71-76

and they reduce morbidity and mortality in high-

risk patients.77-79 Despite their advantages in

subgroups of patients, they were not superior to

other agents in prospective randomized trials in

hypertensive patients.9,39,48,80 Surprisingly, in

several studies, ACE inhibitors were even less

effective than the conventional therapy or di-uretic in preventing first stroke.9,80,81 In the

recent perindopril protection against recurrent

stroke study (PROGRESS) Trial in patients with

cerebrovascular disease, combination therapy of

a diuretic (indapamide) and ACE inhibitor

(perindopril) reduced the risk of stroke by 43%

when compared with placebo.82 However, perin-

dopril alone, despite lowering systolic bloodpressure by 5 mm Hg, decreased stroke risk

only by a nonsignificant 5%. It is possible that

the benefit observed in high-risk patients was

related to blood pressure reduction and not

to the specific effect of ACE inhibition.83 This

assumption is supported by the observation of

Svensson et al84 that the mild blood pressure

fall observed in the clinic in the ramipril-treatedgroup of the Heart Outcomes Prevention Evalu-

ation (HOPE) Study underestimated the true

blood pressure fall. Despite the controversy on

whether the beneficial effects of ACE inhibitors

are related to blood pressure reduction or to the

LONG-TERM SAFETY OF ANTIHYPERTENSIVE THERAPY 19

intrinsic effect of ACE inhibition, it seems safe to

recommend ACE inhibitors for many hyperten-

sive patients. It should be noted that most

patients benefit from the combination of ACE

inhibitor and diuretic.

Angiotensin Receptor Blockers

Blocking the renin angiotensin aldosterone sys-

tem with ACE inhibitors reduces cardiovascular

morbidity and mortality in patients with high

cardiovascular risk.78,79 Moreover, ACE inhibi-

tors reduce the risk of recurrent stroke in patients

with a history of stroke or transient ischemicattack.82 However, ACE inhibitors enhance pros-

taglandin synthesis and decrease the degradation

of bradykinin,85,86 which may be responsible for

their adverse effects. An alternative way to block

the renin angiotensin aldosterone system is by

the new class of drugs, the angiotensin II receptor

blockers (ARBs), that block angiotensin II activity

at the receptor site. This class has been shownto be safe, well tolerated, and effective for

blood pressure control in young and elderly

patients.87-90 Recently, several studies showed

that this class of drugs confers renal benefits in

patients with diabetic nephropathy,54,91 reduces

the rate of stroke in hypertensive patients better

than the conventional treatment,25,26,92 and is

effective in patients with congestive heart fail-ure.93-99 However, the recent Valsartan Antihy-

pertensive Long-term Use Evaluation Study

showed that the angiotensin receptor blocker

valsartan is less effective than the calcium

antagonist, amlodipine, in preventing MI. After

this study, some investigators have suggested that

ARBs may increase the risk of MI in hypertensive

patients.100,101 However, recent meta-analysesrefuted this conclusion and showed that ARBs

are probably as effective as other antihypertensive

agents in the prevention of MI.102,103

aaa-Blockers

a-Blockers had great promise in the treatment

of hypertension because in addition to loweringblood pressure, they improve insulin resistance

and lipid profile.104,105 However, the recent

results of the Antihypertensive and Lipid-

Lowering Treatment to Prevent Heart Attack

Trial (ALLHAT) study showed that a-blockers

are less effective than diuretics in preventing

cardiovascular events, mainly heart failure.106

Because of these results, the National Institutes

of Health recommended not to use a-blocker as

the first drug of choice in hypertension. It is

noteworthy that the systolic blood pressure washigher by 2 mm Hg in the doxazosin-treated

patients of the ALLHAT than in the diuretic-

treated patients, and the high rate of heart failure

began very shortly after randomization.106 The

ALLHAT results with lisinopril were similar to

the results with a-blockers,9 but the ACE in-

hibitor remained a safe and effective first

choice in hypertensive patients. Thus, it seemsthat a-blocker is a safe antihypertensive agent,

but because of the ALLHAT results, it should not

be used as the first antihypertensive drug; how-

ever, it still can be used as an add-on therapy.

The Importance of New OnsetDiabetes with Antihypertensive Agents

Recent prospective studies have shown that the

rate of developing diabetes mellitus in hyper-

tensive patients is different with various drugs. A

variety of studies documented that long-term

diuretic therapy, particularly when combined

with a b-blocker, diminishes glucose tolerance

and increases the risk of new onset diabetes.

Conversely, as we have learned from recenttrials, treatment with antihypertensive drugs

such as blockers of the renin angiotensin system

or calcium antagonists seems to decrease this

risk.19 However, it must be emphasized that new

onset diabetes was not a prespecified primary

end point in any of these prospective, random-

ized trials. The recent Antihypertensive Treat-

ment and Lipid Profile in a North of SwedenEfficacy Evaluation Study107 was designed to

compare the effects of antihypertensive therapy

on glucose metabolism in almost 400 patients

with uncomplicated hypertension who had

never been treated. Patients were randomized

to either an ARB (with addition of calcium

antagonist, if needed) or to a thiazide diuretic

(and a b-blocker, if needed). After only 1 year offollow-up, 18 patients in the diuretic arm

reached diagnostic criteria of the metabolic

syndrome, and 9 had developed frank diabetes.

The corresponding numbers in the ARB arm

were 5 and 1.

GROSSMAN AND MESSERLI20

In the ALLHAT9 Study, about 10% of the total

study population of patients developed new onset

diabetes during the 4 to 6 years duration of the

study. Of note, the risk of becoming diabetic was

between 40% and 65% higher in patients on

chlorthalidone-based therapy than in patients onlisihopril-based therapy, and between 18% and

30% higher in patients on chlorthalidone than in

those on amlodipine. These metabolic differences

did not translate into more cardiovascular events

or into higher all-cause mortality in the chlortha-

lidone group during the 4 to 6 years of the study.

However, antihypertensive therapy is most often

life-long, and a follow-up lasting a few years isunlikely to give us any information as to the

cardiovascular morbidity and mortality related to

drug-associated diabetes.

The recent thorough study of Verdecchia et al20

has thrown some light on this issue. The authors

report an up to 16 years follow-up of almost 800

initially untreated hypertensive patients, 6.5% of

whom had diabetes at the onset, and 5.8% ofwhom developed new onset diabetes throughout

the study. The fasting blood glucose at entry as

well as diuretic treatment on follow-up were

independent, powerful predictors of new-onset

diabetes ( P b .0001 and P b .004, respectively).

Most importantly, compared with subjects who

never developed diabetes, the risk for cardiovas-

cular disease during the follow-up was verysimilar in patients who developed diabetes (odds

ratio, 2.92; 95% confidence interval, 1.33-6.41;

P = .007) and in the group that had preexisting

diabetes (odds ratio, 3.57; 95% confidence inter-

val, 1.65-7.73; P = .001). Patients with new onset

diabetes and those with a prior diagnosis of

diabetes were almost 3 times as likely to develop

subsequent cardiovascular disease than thosewho remained free of diabetes. These provocative

findings show again that antihypertensive therapy

with a thiazide diuretic, and if needed in combi-

nation with a b-blocker, confers a substantial risk

of new onset diabetes, and more importantly, that

patients who have become diabetic will suffer

all the adverse sequel of this disease. Subject

to contrast, a recent reanalysis of the SystolicHypertension in the Elderly Program by Kostis

et al showed no increased risk of patients who

developed diabetes while they were on chlortha-

lidone.108 The discrepancy between the 2 studies

remains essentially unexplained.

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