Circulation. 2008;117:2706-2715
doi: 10.1161/CIRCULATIONAHA.107.695007
(Circulation. 2008;117:2706-2715.)
© 2008 American Heart Association, Inc.
Controversies in Cardiovascular Medicine |
Should β-blockers and diuretics remain as first-line therapy for hypertension?
Risk/Benefit Assessment of β-Blockers and Diuretics Precludes Their Use for First-Line Therapy in Hypertension
Franz H. Messerli, MD;
Sripal Bangalore, MD, MHA;
Stevo Julius, MD
From the Department of Medicine, Division of Cardiology, St Luke’s–Roosevelt Hospital and Columbia University College of Physicians and Surgeons, New York, NY (F.H.M., S.B.), and the Department of Internal Medicine, University of Michigan, Ann Arbor (S.J.).
Reprint requests to Franz H. Messerli, MD, Division of Cardiology, St Luke’s–Roosevelt Hospital, Columbia University College of Physicians and Surgeons, 1000 10th Ave, Suite 3B-30, New York, NY 10019. E-mail fmesserli{at}aol.com
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Introduction
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In 1977, the first report of the Joint National Committee (JNC)
on Detection, Evaluation, and Treatment of High Blood Pressure
was published.
1 On the basis of the available information, the
committee suggested an algorithm in which the "first step drugs
should usually be a thiazide diuretic." The algorithm suggested
either reserpine, methyldopa, or propranolol as a second step.
In 1984, JNC III recommended β-blockers as a class for
first-line therapy on an equal basis with the thiazide diuretics.
2 From then on, in all the subsequent JNC reports until JNC 7
in 2003, β-blockers and diuretics remained first-line antihypertensive
drugs.
3 JNC 7 suggested that thiazide diuretics should be used
as initial therapy in most patients. If these were not tolerated
or contraindicated, then a β-blocker, on an equal basis
with angiotensin-converting enzyme (ACE) inhibitors, angiotensin
receptor inhibitors, and calcium antagonists, could be substituted.
Thus, according to JNC 7, both thiazides and β-blockers
are meant to be given to hypertensive patients regardless of
their risk factor status and regardless of their concomitant
metabolic abnormalities.
Response by Cutler and Davis p 2715
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Diabetes and Blood Pressure
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Within the same time frame, from 1980 to 2004, the prevalence
of diabetes more than doubled in the United States, and almost
10% of people aged >20 years are currently suffering from
this disease.
4 Patients with hypertension are known to be at
a higher risk of developing new-onset diabetes than are normotensive
subjects.
5,6 In the Atherosclerosis Risk in Communities (ARIC)
study, type 2 diabetes was almost twice as likely to develop
in hypertensive than in normotensive subjects.
5 In the Women’s
Health Study, in a prospective cohort of 38 172 women free of
diabetes and cardiovascular disease, baseline blood pressure
and blood pressure progression were strong and independent predictors
of incident type 2 diabetes.
6 Women with baseline hypertension
had a hazard ratio for incident diabetes in the 4-year follow-up
of 2.39 (95% CI, 1.95 to 2.93).
6
Conversely, hypertension is exceedingly common in patients with type 2 diabetes, even in children and adolescents. Upchurch et al7 reported that 55% of young people had systolic blood pressures >90 percentile at the time of diagnosis of type 2 diabetes. In fact, hypertension at diagnosis was as much as 8 times more common in adolescents with type 2 diabetes compared with those with type 1 diabetes. Thus, hypertension begets type 2 diabetes, and, conversely, diabetes begets hypertension.
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New-Onset Diabetes With Thiazide Diuretics
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In the Antihypertensive and Lipid-Lowering Treatment to Prevent
Heart Attack Trial (ALLHAT),
10% of all patients developed new-onset
diabetes throughout the 4- to 5-year duration of the study.
8 However, this percentage was between 18% and 40% higher in patients
in the chlorthalidone arm than in those in the amlodipine and
lisinopril arms, respectively.
9 In the Antihypertensive Treatment
and Lipid Profile in a North of Sweden Efficacy Evaluation (ALPINE)
study,
10 hypertensive patients who had never been treated before
were randomized to either candesartan-based therapy (plus amlodipine
if needed) or thiazide-based therapy (plus atenolol if needed).
After only 1 year, 18 patients in the diuretic group fulfilled
criteria of the metabolic syndrome, and 9 had developed new-onset
diabetes. The corresponding numbers in the candesartan arm were
5 and 1, respectively.
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Meta-Analysis of Diuretic-Based Studies
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Figure 1 shows the results of a meta-analysis we prepared for
this review. We conducted a MEDLINE/PUBMED/EMBASE search of
studies using the terms
diuretics and
hypertension. We limited
our search to studies in human subjects and English language
in peer-reviewed journals from 1966 to October 2007. All randomized
controlled trials of patients with hypertension treated with
diuretic therapy with follow-up for at least 1 year and that
reported the incidence of new-onset diabetes were included.
Statistical analysis was done with the use of standard software
(Stata 9.0, Stata Corporation) with the METAN program.
11 The
pooled effect for each grouping of trials was derived from the
point estimate for each separate trial weighted by the inverse
of the variance (1/SE
2). Heterogeneity was assessed visually
with funnel plots, Q (
2) statistics, and/or I
2 statistics.
12 If trials were homogeneous (
P>0.05), a fixed-effect model
was used to calculate pooled effect sizes. Otherwise, a random-effect
model of DerSimonian and Laird
13 was applied to calculate overall
differences. Publication bias was estimated with the weighted
regression test of Egger.
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Figure 1. Relative risk of new-onset diabetes mellitus in studies using diuretics against other agents (including placebo). We performed a meta-analysis of all randomized controlled trials of patients on diuretics for hypertension with follow-up for at least 1 year and that reported the incidence of new-onset diabetes. The sizes of the data markers relate to study sample size and the inverse of the SE of each study. EWPHE indicates European Working Party for Hypertension in the Elderly; ACEi, ACE inhibitors; CCB, calcium channel blockers; ANBP-2, Second Australian National Blood Pressure Study; and INSIGHT, Intervention as a Goal in Hypertension Treatment.
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In the analysis of 6 trials enrolling 30 842 patients with hypertension, diuretics resulted in a 32% increased risk of new-onset diabetes compared with placebo or non–β-blocker antihypertensive agents. Compared with placebo, diuretics resulted in a strong trend toward a 22% increased risk of new-onset diabetes, suggesting that the risk is due to the medication itself. When compared with antihypertensive agents other than β-blockers, diuretics conferred a 35% increased risk of new-onset diabetes. We also performed a meta-regression analysis to evaluate the relationship between follow-up duration of therapy and the risk of new-onset diabetes. The risk of new-onset diabetes increased with increasing duration of diabetic therapy with these agents (Figure 2).
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Figure 2. Relative risk of new-onset diabetes mellitus in the studies using diuretics as a function of follow-up duration. Meta-regression analysis was performed to evaluate the relationship between risk of new-onset diabetes mellitus and the length of follow-up of patients on diuretic therapy. The diameter of the circles represents the variance of the relative risk of each individual trial. The line represents the regression fit with 95% CI for the effect sizes. Abbreviations are as defined in Figure 1 legend.
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New-Onset Diabetes With β-Blockers
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The prodiabetic effect of the β-blockers has been less
well documented. In the ARIC study, hypertensive patients taking
β-blockers had a 28% increased risk of developing diabetes
compared with those hypertensive subjects who did not take any
medication.
5
Meta-Analysis of β-Blocker–Based Studies
Figures 3 and 4
shows the results of our meta-analysis of all randomized controlled trials enrolling patients with hypertension treated with β-blocker therapy with a follow-up for at least 1 year and that reported the incidence of new-onset diabetes. We conducted a MEDLINE/PUBMED/EMBASE search of studies using the terms adrenergic beta antagonists, beta blockers, and hypertension. We limited our search to studies in human subjects and English language in peer-reviewed journals from 1966 to October 2007. In the analysis of 6 trials enrolling 55 675 patients with hypertension, β-blockers conferred a 32% increased risk of new-onset diabetes compared with placebo or nondiuretic antihypertensive agents. When compared with nondiuretic antihypertensive agents, β-blockers resulted in a 31% increased risk of new-onset diabetes (Figure 3). The risk of new-onset diabetes with β-blockers increased with duration of therapy (Figure 4).
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Figure 3. Relative risk of new-onset diabetes mellitus in studies using β-blockers (BB) against other agents (including placebo). We performed a meta-analysis of all randomized controlled trials of patients on β-blockers for hypertension with follow-up for at least 1 year and that reported the incidence of new-onset diabetes. The sizes of the data markers relate to study sample size and the inverse of the SE of each study. MRC indicates Medical Research Council; MRC-O, Medical Research Council trial of treatment of hypertension in older adults; AASK, African American Study of Kidney Disease and Hypertension; ASCOT, Anglo-Scandinavian Cardiac Outcomes Trial; and LIFE, Losartan Intervention For End point reduction in hypertension trial. Other abbreviations are as defined in Figure 1 legend.
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Figure 4. Relative risk of new-onset diabetes mellitus in the studies using β-blockers as a function of follow-up duration. Meta-regression analysis was performed to evaluate the relationship between risk of new-onset diabetes mellitus and the length of follow-up of patients on β-blocker therapy. The diameter of the circles represents the variance of the relative risk of each individual trial. The line represents the regression fit with 95% CI for the effect sizes. Abbreviations are as defined in Figure 1 and Figure 3 legends.
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However, in the mixed β-blocker/diuretic trials, in which patients could be randomized to a β-blocker, a diuretic, or their combination, β-blockers/diuretics resulted in an 11% increased risk of new-onset diabetes compared with other antihypertensive agents (Figure 5). Of note, neither in ALLHAT nor in any of the aforementioned analyzed studies was new-onset diabetes a predefined end point. This requires a cautious interpretation of the data.
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Figure 5. Relative risk of new-onset diabetes mellitus in studies using β-blockers (BB) or diuretics (mixed trials) against other agents (including placebo). We performed a meta-analysis of all randomized controlled trials of patients on β-blockers/diuretics for hypertension with follow-up for at least 1 year and that reported the incidence of new-onset diabetes. The sizes of the data markers relate to study sample size and the inverse of the SE of each study. CAPPP indicates Captopril Prevention Project; NORDIL, the Nordic Diltiazem study; and STOP-2, the second Swedish Trial in Old Patients with Hypertension. Other abbreviations are as defined in Figure 1 legend.
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Differences Among Antihypertensive Drugs
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The Glycemic Effects in Diabetes Mellitus: Carvedilol-Metoprolol
Comparison in Hypertensives (GEMINI) trial
14 reported that with
regard to metabolic adverse effects, not all β-blockers
seem to be created equal. In patients with hypertension and
type 2 diabetes who were treated with a blocker of the renin-angiotensin
system, the addition of carvedilol, compared with metoprolol,
had a favorable effect on glycemic control, insulin resistance,
microalbuminuria, and body weight. In a recent thorough and
comprehensive network meta-analysis, Elliott and Meyer
15 documented
the odds ratio of new-onset diabetes to be 0.85, 0.90, 1.05,
1.25, and 1.34 with angiotensin receptor blockers, ACE inhibitors,
calcium antagonists, β-blockers, and diuretics, respectively,
with placebo having a reference value of 1.0 (
Figure 6).
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Figure 6. Risk of new-onset diabetes mellitus with antihypertensive treatment. ARB indicates angiotensin receptor blocker; ACE-I, ACE inhibitor; and CCB, calcium channel blocker. Reprinted from Elliott and Meyer,15 with permission. Copyright 2007, Lancet.
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Does Drug-Associated Diabetes Mellitus Increase Morbidity and Mortality?
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In regard to the clinical significance of drug-associated new-onset
diabetes, the ALLHAT investigators attempted to reassure us
by stating that "overall these metabolic differences did not
translate into more cardiovascular events or into higher all-cause
mortality in the chlorthalidone group."
8 This is a correct but
perhaps somewhat myopic statement. We should consider that antihypertensive
therapy is lifelong and that a follow-up period of 4 to 6 years,
as was the case in ALLHAT, is unlikely to give us any clues
regarding the long-term sequelae of the diabetes risk associated
with either β-blockers or diuretics.
9
Several studies have scrutinized this critical issue, as follows.
- Verdecchia et al16 reported a 16-year follow-up of almost 800 initially untreated hypertensive patients, 6.5% of whom had diabetes at the onset and 5.8% of whom developed new-onset diabetes throughout the study. Fasting blood sugar at entry and diuretic treatment on follow-up were independent predictors of new-onset diabetes (P<0.0001 and P<0.004, respectively). Compared with subjects who never developed diabetes, the risk for cardiovascular disease during the follow-up was very similar in patients who developed diabetes (odds ratio, 2.92; 95% CI, 1.33 to 6.41; P=0.007) and in the group that had preexisting diabetes (odds ratio, 3.57; 95% CI, 1.65 to 7.73; P=0.001). Patients with new-onset diabetes and those with a previous diagnosis of diabetes were almost 3-fold more likely to develop subsequent cardiovascular disease than those who remained free of diabetes.
- In a study involving almost 7000 patients, Alderman et al17 showed that cardiovascular disease increased in hypertensive diuretic users who developed hyperglycemia even when blood pressure was well controlled. The authors stated, "Cardiovascular disease incidence has a direct dose response relation with diuretic used with frequent users having the highest rate."
- In the 11 645-patient Multiple Risk Factor Intervention Trial (MRFIT),18 the occurrence of new-onset diabetes was increased by >30% in diuretic-treated patients and showed an excess mortality risk in the 18-year posttrial follow-up.
- Almgren et al19 followed a population sample of 7500 men in which 20.4% of treated hypertensive patients developed diabetes. New-onset diabetes implied a significant increased risk for stroke, myocardial infarction, and mortality (hazard ratio, 1.67, 1.66, and 1.42, respectively). The authors concluded that diabetes in treated hypertensive patients was alarmingly common and carried a high risk for cardiovascular complications and mortality.
- Aksnes et al,20 in the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) study, compared patients with diabetes at baseline and new-onset diabetes with patients who did not develop diabetes (5250, 9995, and 1298 patients, respectively). Patients with new-onset diabetes had significantly higher cardiac morbidity, especially more congestive heart failure, than those without diabetes (hazard ratio, 1.43). Patients were followed up for an average of 4.2 years only.
- In contrast to the aforementioned 5 studies, Kostis et al,21 in a follow-up of the Systolic Hypertension in the Elderly Program (SHEP), found no significant increase in cardiovascular events in patients who had diabetes associated with chlorthalidone therapy. In fact, these patients had a better prognosis than those who had preexisting diabetes, and diuretic treatment in subjects who had diabetes was strongly associated with lower long-term cardiovascular mortality and total mortality. Thus, at present, the exact clinical significance of diuretic-associated diabetes remains unknown, with 5 studies showing a detrimental outcome and 1 study showing a neutral outcome.
In the present analysis using studies that reported the end point of new-onset diabetes, the risks for other events—all-cause mortality, cardiovascular mortality, myocardial infarction, stroke, and heart failure—are detailed in the Table. Compared with non–β-blocker antihypertensive agents, diuretics did not provide any incremental benefit for the end points of all-cause mortality, cardiovascular mortality, myocardial infarction, and stroke but conferred a 33% reduction in heart failure. The heart failure end point was driven mainly by the ALLHAT trial. Given the heterogeneity in the definition of heart failure used in various studies, the results should be interpreted with caution. Similarly, compared with nondiuretic antihypertensive agents, β-blocker therapy resulted in an 8% increased risk of all-cause mortality and 30% increased risk of stroke.
Conceivably, new-onset diabetes associated with diuretics and/or β-blockers may be reversible on discontinuation of the offending drug(s). Thus, treatment withdrawal could potentially separate the drug-induced new-onset diabetes from spontaneously occurring new-onset diabetes. However, the risk of new-onset diabetes continues to increase with duration of therapy (Figure 4), and diabetes has been identified as a coronary heart disease equivalent. Because antihypertensive therapy is prescribed to prevent coronary heart disease, it seems counterintuitive to select drug classes that indeed have the exact opposite effect, ie, that can induce a coronary risk equivalent.
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Does Concomitant Renin-Angiotensin System Blockade Reduce the Risk of New-Onset Diabetes Associated With Diuretics and β-Blockers?
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Over the past few years, we have come to realize that even patients
with uncomplicated hypertension may need
2 drugs to bring their
blood pressure under control. Because most often diuretics are
prescribed in combination with other drugs such as ACE inhibitors
or angiotensin receptor blockers, it has been argued that these
drugs, by mitigating hypokalemia associated with the thiazides,
may abolish some metabolic adverse effects. However, in the
International Verapamil-Trandolapril (INVEST) study, the addition
of hydrochlorothiazide in a dose-dependent way increased the
risk of new-onset diabetes in patients treated with either atenolol
or verapamil.
22,23 The metabolic effects of the thiazide diuretics
in combination with renin-angiotensin system blockade were further
investigated in the Study of Trandolapril/Verapamil SR and Insulin
Resistance (STAR) study,
24 in which patients with the metabolic
syndrome were randomized to either verapamil/trandolapril or
losartan/hydrochlorothiazide. At the end of 1 year, losartan/hydrochlorothiazide
increased plasma glucose significantly more than verapamil/trandolapril
after all oral glucose tolerance testing. The differences were
more pronounced with high-dose combinations than with low-dose
combinations.
Similarly, in the GEMINI study,14 in which all patients were treated with a blocker of the renin-angiotensin system, we observed significant differences in glycosylated hemoglobin and insulin resistance between patients on metoprolol and those on carvedilol. Thus, the presence of an ACE inhibitor or an angiotensin receptor blocker did not abolish the effects of β-blockade on metabolic parameters. Most recently, the Avoiding Cardiovascular Events in Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trial, which compared the fixed combination of benazepril/amlodipine with benazepril/hydrochlorothiazide in more than 10 000 patients, was stopped prematurely because of a 20% reduction in cardiovascular mortality in the amlodipine/benazepril arm. Thus the ACCOMPLISH data, in hypertension complicated by multiple risk factors, clearly establishes outcome superiority for a CCB/ACE inhibitor combination over an ACE inhibitor/diuretic combination, thereby relegating the thiazides to third-line therapy.
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Antihypertensive Therapy and Dyslipoproteinemia
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The effects of antihypertensive therapy on serum lipids were
analyzed by Kasiske et al
25 in a meta-analysis of 474 clinical
trials in >65 000 patients. Diuretics caused a relative increase
in cholesterol levels that was more pronounced with higher doses
and worse in black patients than in nonblacks. Chlorthalidone
caused a greater increase in low-density lipoprotein cholesterol
than did other diuretics. β-Blockers caused an increase
in triglyceride levels that was smaller for agents with intrinsic
sympathetic activity. A beneficial effect on total cholesterol,
low-density lipoprotein cholesterol, and triglycerides was seen
with the
-blockers, and a beneficial effect on triglycerides
and in diabetic patients on total cholesterol was seen with
ACE inhibitors. Calcium antagonists had no effects on lipids.
Although, as with new-onset diabetes, the long-term effects
of these drug-associated changes are not known, it seems unlikely
that the increase in total cholesterol and triglycerides with
diuretics and β-blockers, respectively, will be beneficial.
In GEMINI, there were distinct differences in total cholesterol
and triglycerides between the metoprolol arm and the carvedilol
arm, indicating again that blockade of the renin-angiotensin
system did not abolish the effect of β-blockers on lipoproteins.
14 Significantly more patients had to be started on a statin in
the metoprolol arm than in the carvedilol arm.
14
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Weight Change and Antihypertensive Therapy
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Sharma et al,
26 in a systematic analysis of prospective randomized
controlled trials, found that β-blockers increased body
weight by a median of 1.2 kg; weight gain occurred primarily
during the first few months. Of note, not all β-blockers
seem to cause weight gain equally. We recently showed no significant
weight gain in the GEMINI study in patients on carvedilol, whereas
with metoprolol, after 6 months the average weight increased
by 1.2 kg.
27 Recently, Scholze et al
28 compared a weight loss
regimen with sibutramine in a 16-week, double-blind, placebo-controlled,
randomized, multicenter study of 171 obese hypertensive patients
who were randomized to 3 different antihypertensive regimens
(felodipine/ramipril, verapamil/trandolapril, or metoprolol/hydrochlorothiazide).
Overall weight loss and reduction of abdominal obesity were
markedly attenuated in the metoprolol/hydrochlorothiazide group
compared with the other 2 groups. Similarly, improvement in
glucose tolerance and hypertriglyceridemia with weight loss
was abrogated in the metoprolol/hydrochlorothiazide cohort compared
with the other 2 arms. This would indicate that antihypertensive
combination therapy with a renin-angiotensin system blocker
and a calcium blocker facilitates weight loss with a sibutramine
regimen significantly more than does a β-blocker/diuretic–based
regimen. This is further evidence against β-blocker/diuretic
treatment for hypertension, especially in the large majority
of overweight and obese patients.
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β-Blockade in the Young Hypertensive Patient
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Because numerous studies have shown that the young borderline
hypertensive patient is characterized by an elevated cardiac
output and an "inappropriately" normal total peripheral resistance,
it was thought that β-blockade would be the most "physiological"
antihypertensive therapy in this patient population. However,
a "normalization" of hemodynamics does not necessarily prevent
the transition from borderline to more established hypertension.
In addition, the ALPINE study taught us that, if anything, young
patients (aged <55 years) were more susceptible to the development
of new-onset diabetes with diuretic-based therapy than patients
aged >55 years.
29 Similarly, total cholesterol increased
with diuretic therapy in the younger ALPINE study population,
whereas it fell in those aged >55 years. Thus, β-blockers
are not more beneficial (or less detrimental) in the young than
they are in the older patient.
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Other Adverse Effects of β-Blockers and Diuretics
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Neither β-blockers nor diuretics are well tolerated antihypertensive
drugs. In most systematic analyses, they fare consistently worse
than blockers of the renin-angiotensin system and calcium antagonists.
In the Cochrane meta-analysis, the withdrawal rate of patients
treated with β-blockers was twice as high as the rate in
patients treated with diuretics.
30 Our analysis allowed us to
calculate that for every stroke or heart attack prevented, 3
patients remained impotent and 8 experienced fatigue to the
extent that they withdrew from such therapy.
31 Clearly, this
is not an acceptable risk/benefit ratio for a completely asymptomatic
disease such as stage 1 hypertension.
The question of nephrotoxicity of long-term thiazide diuretic therapy continues to surface.32–35 Because most prospective studies last 6 years at most, solid documents attesting to the safety of diuretic therapy (and of all antihypertensive drugs) are lacking. Similarly, the issue of carcinogenicity with long-term diuretic therapy has not been resolved. We reported in a meta-analysis an association between diuretic use and renal cell carcinoma with a pooled odds ratio of 1.54 in 10 independent case-control studies and 3 cohort studies.35 The association between renal cell carcinoma and diuretic therapy remains a concern because the renal tubular cell, ie, the cell that turns cancerous, is also the main target of the diuretic pharmacological effect. Because diuretic-associated carcinogenicity seemed to be cumulative in some studies, it may be yet another reason not to expose young patients to years and decades of thiazide therapy. Clearly, however, the issue of carcinogenicity with hypertension and/or antihypertensive therapy is exceedingly complex, and hasty conclusions should be avoided.
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Morbidity and Mortality Reduction With β-Blockers and Diuretics
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The efficacy of β-blockers in reducing morbidity and mortality
in hypertension has come into question recently.
36–38 Most "evidence" used in current guidelines for hypertension
stems from extrapolation from post–myocardial infarction
studies or cohorts of hypertensive patients specifically selected
for high cardiovascular risk. For many years, extensive marketing
efforts by the pharmaceutical industry have planted the seeds
of β-blockers being "cardioprotective." However, in uncomplicated
hypertension, particularly in the elderly, outcome data with
β-blockers showed either no benefit or even harm.
37–39
We are not debating that thiazide diuretics are powerful drugs that repeatedly have been shown to reduce morbidity and mortality in high-risk established essential hypertension such as, for example, in the ALLHAT study. Clearly, in this setting, the benefits of therapy distinctly outweigh the low-grade negative metabolic adverse effects of the thiazides. Thus, unlike with β-blockers, the risk/benefit ratio with thiazide diuretics, specifically chlorthalidone, remains acceptable in such patients, and they should be considered candidates for such therapy. We should also remember that in the elderly, who are exposed to these drugs for a limited time, the metabolic adverse effects may be more acceptable than in the comparatively younger patient. However, in the younger patients with stage 1 hypertension who will be exposed to antihypertensive therapy for decades, the trade-off of lowering blood pressure at the expense of increasing the risk of new-onset diabetes by up to 10% yearly is not acceptable. This is particularly true given that there are efficacious and safe antihypertensive drugs other than diuretics and β-blockers that do not increase the risk of new-onset diabetes or dyslipoproteinemia.40
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Pseudoantihypertensive Effect and the β-Blocker Hypertension Paradox
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In hypertension as well as coronary heart disease, heart rate
has been shown to be a blood pressure–independent risk
factor for morbidity and mortality. Conversely, Kjekshus
41 has
shown that the benefit of β-blockers in the post–myocardial
infarction population is related to the negative chronotropic
effect: the slower the heart rate, the greater is the reduction
in mortality. A similar observation was made in congestive heart
failure, in which β-blockers remain a cornerstone in the
therapeutic arsenal. Thus, heart rate lowering by β-blockade
increased the survival rate in congestive heart failure as well
as in coronary artery disease. In contrast, we recently showed
that in hypertension, β-blockade–induced bradycardia
had a detrimental effect. In a meta-analysis of almost 80 000
patients in 9 trials, heart rate correlated negatively with
cardiovascular mortality, nonfatal myocardial infarction, stroke,
and heart failure (all
P<0.0001).
42 The reason for this hypertension
paradox may have to do with the reflected pulse wave. This wave
should ideally return toward the heart during diastole to augment
diastolic filling. If it returns earlier during the cardiac
cycle (as is the case with β-blocker–induced bradycardia),
it amplifies the outgoing pressure wave and leads to an increase
in central aortic pressure. As a result, central aortic pressure
will be lowered less than brachial pressure, as was seen in
the Conduit Artery Function Evaluation (CAFÉ) study.
43 Atenolol-based treatment was significantly less effective than
amlodipine-based treatment in lowering aortic systolic pressure
and pulse pressure despite identical brachial pressure in both
treatment arms. This pseudoantihypertensive effect could explain
why β-blocker–based strategies are less effective
than alternative treatments at regressing end-organ damage and
in preventing stroke. This pseudoantihypertensive effect could
also explain why β-blocker–induced bradycardia may
not necessarily be beneficial in hypertensive patients.
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Physicians’ Perception: The Myth of Cardioprotection
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In a recent survey, Veterans Affairs physicians were asked the
question, "Which of the following class of drugs has been proven
to reduce mortality in hypertensive patients?" β-Blockers,
with 78%, received, by far, the highest vote, followed by ACE
inhibitors (65%), diuretics (53%), and calcium channel blockers
(17%).
44 This is a sad state of the art given that only diuretics
and calcium channel blockers have been shown to reduce morbidity
and mortality against placebo in hypertension. Obviously, the
myth of universal cardioprotection by β-blockade, a seed
initially planted by the pharmaceutical industry, is alive and
doing well. This is also documented by the fact that year after
year, the β-blocker market has continued to grow, and >100
million prescriptions for β-blockers are written every
year in the United States alone, a number that has doubled over
the past decade.
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Cost-Effectiveness
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The compliance of patients with medication depends on multiple
factors, including economic costs of the drugs. Previously,
the guideline committees endorsed thiazides and β-blockers
as first-line agents given the actual cost of medication. However,
such an approach does not take into consideration the efficacy
and effectiveness of medication. An ideal cost-effectiveness
analysis should consider the relative effectiveness of different
drugs on clinical outcomes, the direct and indirect costs associated
with long-term sequelae with the medications (such as development
of diabetes), and the actual cost of the drug itself. Such a
formal cost-effectiveness analysis was performed by the National
Institute for Health and Clinical Excellence. On the basis of
their health-economic model, they concluded that for 65-year-old
men and women with an annual cardiovascular disease risk of
2%, heart failure risk of 1%, and diabetes risk of 1.1%, the
most cost-effective initial drug in this group was a calcium
antagonist.
45 β-Blockers were the least cost-effective
option. Given the metabolic adverse effects of β-blockers,
its direct and indirect costs, and the direct and indirect costs
of increased stroke risk in the elderly, β-blockers are
not cost-effective for this indication.
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Outcome Evidence Versus Surrogate End Point
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Glycemia, lipids, and blood pressure are well-known surrogate
end points that correlate reasonably well with outcome, ie,
morbidity and mortality. However, instances of clear-cut surrogate
end point failure have been documented for all 3 of these markers.
Thus, the fact that β-blockers and diuretics have a negative
impact on glycemia and lipids should be interpreted with caution
as long as we have no solid prospective data firmly connecting
surrogate end point with outcome.
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Conclusions
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Under the heading "Bottom Line," there was an anonymous statement
in a widely read medical journal: "It can’t get clearer.
Diuretics—the least expensive and most effective agents—should
be the first line treatment for almost everyone with hypertension,
including patients with diabetes."
46 We beg to differ and think
that the time has come to differentiate patients with stage
1 hypertension from those with a more advanced stage of the
disease. Because of their inefficacy and multiple adverse effects,<
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Introduction
Diabetes and Blood Pressure