This Article Extract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Messerli, F. H. Articles by Julius, S. Search for Related Content PubMed Articles by Messerli, F. H. Articles by Julius, S. Related Collections Cardiovascular Pharmacology Type 2 diabetes Glucose intolerance Clinical Studies Epidemiology

(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

	Introduction

Top Introduction Diabetes and Blood Pressure New-Onset Diabetes With Thiazide... Meta-Analysis of Diuretic-Based... New-Onset Diabetes With β... Differences Among... Does Drug-Associated Diabetes... Does Concomitant Renin... Antihypertensive Therapy and... Weight Change and... β-Blockade in the Young... Other Adverse Effects of... Morbidity and Mortality... Pseudoantihypertensive Effect... Physicians' Perception: The Myth... Cost-Effectiveness Outcome Evidence Versus... Conclusions References

 
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

	Diabetes and Blood Pressure

Top Introduction Diabetes and Blood Pressure New-Onset Diabetes With Thiazide... Meta-Analysis of Diuretic-Based... New-Onset Diabetes With β... Differences Among... Does Drug-Associated Diabetes... Does Concomitant Renin... Antihypertensive Therapy and... Weight Change and... β-Blockade in the Young... Other Adverse Effects of... Morbidity and Mortality... Pseudoantihypertensive Effect... Physicians' Perception: The Myth... Cost-Effectiveness Outcome Evidence Versus... Conclusions References

 
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.

	New-Onset Diabetes With Thiazide Diuretics

Top Introduction Diabetes and Blood Pressure New-Onset Diabetes With Thiazide... Meta-Analysis of Diuretic-Based... New-Onset Diabetes With β... Differences Among... Does Drug-Associated Diabetes... Does Concomitant Renin... Antihypertensive Therapy and... Weight Change and... β-Blockade in the Young... Other Adverse Effects of... Morbidity and Mortality... Pseudoantihypertensive Effect... Physicians' Perception: The Myth... Cost-Effectiveness Outcome Evidence Versus... Conclusions References

 
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.

	Meta-Analysis of Diuretic-Based Studies

Top Introduction Diabetes and Blood Pressure New-Onset Diabetes With Thiazide... Meta-Analysis of Diuretic-Based... New-Onset Diabetes With β... Differences Among... Does Drug-Associated Diabetes... Does Concomitant Renin... Antihypertensive Therapy and... Weight Change and... β-Blockade in the Young... Other Adverse Effects of... Morbidity and Mortality... Pseudoantihypertensive Effect... Physicians' Perception: The Myth... Cost-Effectiveness Outcome Evidence Versus... Conclusions References

 
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/SE²). Heterogeneity was assessed visually with funnel plots, Q (²) statistics, and/or I² 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 Laird¹³ was applied to calculate overall differences. Publication bias was estimated with the weighted regression test of Egger.

View larger version (32K): [in this window] [in a new window]   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.

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).

View larger version (22K): [in this window] [in a new window]   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.

	New-Onset Diabetes With β-Blockers

Top Introduction Diabetes and Blood Pressure New-Onset Diabetes With Thiazide... Meta-Analysis of Diuretic-Based... New-Onset Diabetes With β... Differences Among... Does Drug-Associated Diabetes... Does Concomitant Renin... Antihypertensive Therapy and... Weight Change and... β-Blockade in the Young... Other Adverse Effects of... Morbidity and Mortality... Pseudoantihypertensive Effect... Physicians' Perception: The Myth... Cost-Effectiveness Outcome Evidence Versus... Conclusions References

 
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).

View larger version (33K): [in this window] [in a new window]   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.

View larger version (21K): [in this window] [in a new window]   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.

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.

View larger version (22K): [in this window] [in a new window]   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.

	Differences Among Antihypertensive Drugs

Top Introduction Diabetes and Blood Pressure New-Onset Diabetes With Thiazide... Meta-Analysis of Diuretic-Based... New-Onset Diabetes With β... Differences Among... Does Drug-Associated Diabetes... Does Concomitant Renin... Antihypertensive Therapy and... Weight Change and... β-Blockade in the Young... Other Adverse Effects of... Morbidity and Mortality... Pseudoantihypertensive Effect... Physicians' Perception: The Myth... Cost-Effectiveness Outcome Evidence Versus... Conclusions References

 
The Glycemic Effects in Diabetes Mellitus: Carvedilol-Metoprolol Comparison in Hypertensives (GEMINI) trial¹⁴ 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 Meyer¹⁵ 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).

View larger version (21K): [in this window] [in a new window]   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.

	Does Drug-Associated Diabetes Mellitus Increase Morbidity and Mortality?

Top Introduction Diabetes and Blood Pressure New-Onset Diabetes With Thiazide... Meta-Analysis of Diuretic-Based... New-Onset Diabetes With β... Differences Among... Does Drug-Associated Diabetes... Does Concomitant Renin... Antihypertensive Therapy and... Weight Change and... β-Blockade in the Young... Other Adverse Effects of... Morbidity and Mortality... Pseudoantihypertensive Effect... Physicians' Perception: The Myth... Cost-Effectiveness Outcome Evidence Versus... Conclusions References

 
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.

1. 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.
   
2. 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."
   
3. 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.
   
4. 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.
   
5. 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.
   
6. 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.

View this table: [in this window] [in a new window]   Table. Pooled Relative Risk of Cardiovascular Event Based on Our Meta-Analysis

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.

	Does Concomitant Renin-Angiotensin System Blockade Reduce the Risk of New-Onset Diabetes Associated With Diuretics and β-Blockers?

Top Introduction Diabetes and Blood Pressure New-Onset Diabetes With Thiazide... Meta-Analysis of Diuretic-Based... New-Onset Diabetes With β... Differences Among... Does Drug-Associated Diabetes... Does Concomitant Renin... Antihypertensive Therapy and... Weight Change and... β-Blockade in the Young... Other Adverse Effects of... Morbidity and Mortality... Pseudoantihypertensive Effect... Physicians' Perception: The Myth... Cost-Effectiveness Outcome Evidence Versus... Conclusions References

 
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.

	Antihypertensive Therapy and Dyslipoproteinemia

Top Introduction Diabetes and Blood Pressure New-Onset Diabetes With Thiazide... Meta-Analysis of Diuretic-Based... New-Onset Diabetes With β... Differences Among... Does Drug-Associated Diabetes... Does Concomitant Renin... Antihypertensive Therapy and... Weight Change and... β-Blockade in the Young... Other Adverse Effects of... Morbidity and Mortality... Pseudoantihypertensive Effect... Physicians' Perception: The Myth... Cost-Effectiveness Outcome Evidence Versus... Conclusions References

 
The effects of antihypertensive therapy on serum lipids were analyzed by Kasiske et al²⁵ 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

	Weight Change and Antihypertensive Therapy

Top Introduction Diabetes and Blood Pressure New-Onset Diabetes With Thiazide... Meta-Analysis of Diuretic-Based... New-Onset Diabetes With β... Differences Among... Does Drug-Associated Diabetes... Does Concomitant Renin... Antihypertensive Therapy and... Weight Change and... β-Blockade in the Young... Other Adverse Effects of... Morbidity and Mortality... Pseudoantihypertensive Effect... Physicians' Perception: The Myth... Cost-Effectiveness Outcome Evidence Versus... Conclusions References

 
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 al²⁸ 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.

	β-Blockade in the Young Hypertensive Patient

Top Introduction Diabetes and Blood Pressure New-Onset Diabetes With Thiazide... Meta-Analysis of Diuretic-Based... New-Onset Diabetes With β... Differences Among... Does Drug-Associated Diabetes... Does Concomitant Renin... Antihypertensive Therapy and... Weight Change and... β-Blockade in the Young... Other Adverse Effects of... Morbidity and Mortality... Pseudoantihypertensive Effect... Physicians' Perception: The Myth... Cost-Effectiveness Outcome Evidence Versus... Conclusions References

 
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.

	Other Adverse Effects of β-Blockers and Diuretics

Top Introduction Diabetes and Blood Pressure New-Onset Diabetes With Thiazide... Meta-Analysis of Diuretic-Based... New-Onset Diabetes With β... Differences Among... Does Drug-Associated Diabetes... Does Concomitant Renin... Antihypertensive Therapy and... Weight Change and... β-Blockade in the Young... Other Adverse Effects of... Morbidity and Mortality... Pseudoantihypertensive Effect... Physicians' Perception: The Myth... Cost-Effectiveness Outcome Evidence Versus... Conclusions References

 
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.

	Morbidity and Mortality Reduction With β-Blockers and Diuretics

Top Introduction Diabetes and Blood Pressure New-Onset Diabetes With Thiazide... Meta-Analysis of Diuretic-Based... New-Onset Diabetes With β... Differences Among... Does Drug-Associated Diabetes... Does Concomitant Renin... Antihypertensive Therapy and... Weight Change and... β-Blockade in the Young... Other Adverse Effects of... Morbidity and Mortality... Pseudoantihypertensive Effect... Physicians' Perception: The Myth... Cost-Effectiveness Outcome Evidence Versus... Conclusions References

 
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

	Pseudoantihypertensive Effect and the β-Blocker Hypertension Paradox

Top Introduction Diabetes and Blood Pressure New-Onset Diabetes With Thiazide... Meta-Analysis of Diuretic-Based... New-Onset Diabetes With β... Differences Among... Does Drug-Associated Diabetes... Does Concomitant Renin... Antihypertensive Therapy and... Weight Change and... β-Blockade in the Young... Other Adverse Effects of... Morbidity and Mortality... Pseudoantihypertensive Effect... Physicians' Perception: The Myth... Cost-Effectiveness Outcome Evidence Versus... Conclusions References

 
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, Kjekshus⁴¹ 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.

	Physicians’ Perception: The Myth of Cardioprotection

Top Introduction Diabetes and Blood Pressure New-Onset Diabetes With Thiazide... Meta-Analysis of Diuretic-Based... New-Onset Diabetes With β... Differences Among... Does Drug-Associated Diabetes... Does Concomitant Renin... Antihypertensive Therapy and... Weight Change and... β-Blockade in the Young... Other Adverse Effects of... Morbidity and Mortality... Pseudoantihypertensive Effect... Physicians' Perception: The Myth... Cost-Effectiveness Outcome Evidence Versus... Conclusions References

 
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.

	Cost-Effectiveness

Top Introduction Diabetes and Blood Pressure New-Onset Diabetes With Thiazide... Meta-Analysis of Diuretic-Based... New-Onset Diabetes With β... Differences Among... Does Drug-Associated Diabetes... Does Concomitant Renin... Antihypertensive Therapy and... Weight Change and... β-Blockade in the Young... Other Adverse Effects of... Morbidity and Mortality... Pseudoantihypertensive Effect... Physicians' Perception: The Myth... Cost-Effectiveness Outcome Evidence Versus... Conclusions References

 
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.

	Outcome Evidence Versus Surrogate End Point

Top Introduction Diabetes and Blood Pressure New-Onset Diabetes With Thiazide... Meta-Analysis of Diuretic-Based... New-Onset Diabetes With β... Differences Among... Does Drug-Associated Diabetes... Does Concomitant Renin... Antihypertensive Therapy and... Weight Change and... β-Blockade in the Young... Other Adverse Effects of... Morbidity and Mortality... Pseudoantihypertensive Effect... Physicians' Perception: The Myth... Cost-Effectiveness Outcome Evidence Versus... Conclusions References

 
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.

	Conclusions

Top Introduction Diabetes and Blood Pressure New-Onset Diabetes With Thiazide... Meta-Analysis of Diuretic-Based... New-Onset Diabetes With β... Differences Among... Does Drug-Associated Diabetes... Does Concomitant Renin... Antihypertensive Therapy and... Weight Change and... β-Blockade in the Young... Other Adverse Effects of... Morbidity and Mortality... Pseudoantihypertensive Effect... Physicians' Perception: The Myth... Cost-Effectiveness Outcome Evidence Versus... Conclusions References

 
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, β-blockers should no longer be used for initial therapy in hypertension. In patients with advanced hypertensive cardiovascular disease, the benefits of lowering blood pressure outweigh the small metabolic adverse events associated with diuretics and, in some specific cases, even with β-blockers. However, in uncomplicated hypertension, neither diuretics nor β-blockers are acceptable for first-line treatment. Not quite unexpectedly, Thomas Sydenham’s dictum of primum nil nocere also applies to first-line antihypertensive therapy.

	Acknowledgments

 
Disclosures

Dr Messerli reports having served as an ad hoc consultant/speaker for the following organizations: Abbott, GSK, Novartis, Pfizer, AstraZeneca, Bayer, Boehringer Ingelheim, BMS, Forest, Sankyo, Merck, Mars, and Sanofi. Dr Julius reports having served as a consultant to Novartis and Servier and having received lecture fees from Novartis and Merck and grant support from AstraZeneca and Novartis. Dr Bangalore has no disclosures.

	References

Top Introduction Diabetes and Blood Pressure New-Onset Diabetes With Thiazide... Meta-Analysis of Diuretic-Based... New-Onset Diabetes With β... Differences Among... Does Drug-Associated Diabetes... Does Concomitant Renin... Antihypertensive Therapy and... Weight Change and... β-Blockade in the Young... Other Adverse Effects of... Morbidity and Mortality... Pseudoantihypertensive Effect... Physicians' Perception: The Myth... Cost-Effectiveness Outcome Evidence Versus... Conclusions References

 
1. Report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure: a cooperative study. JAMA. 1977; 237: 255–261.[Abstract/Free Full Text]

2. The 1984 Report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med. 1984; 144: 1045–1057.[Abstract/Free Full Text]

3. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, Jones DW, Materson BJ, Oparil S, Wright JT Jr, Roccella EJ. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA. 2003; 289: 2560–2572.[Abstract/Free Full Text]

4. CDC’s Diabetes Program. National Diabetes Surveillance System: prevalence of diabetes. Available at: http://www.ede.gov/diabetes/statistics/prev/national/source.htm. Accessed January 8, 2007.

5. Gress TW, Nieto FJ, Shahar E, Wofford MR, Brancati FL. Hypertension and antihypertensive therapy as risk factors for type 2 diabetes mellitus: Atherosclerosis Risk in Communities Study. N Engl J Med. 2000; 342: 905–912.[Abstract/Free Full Text]

6. Conen D, Ridker PM, Mora S, Buring JE, Glynn RJ. Blood pressure and risk of developing type 2 diabetes mellitus: the Women’s Health Study. Eur Heart J. 2007; 28: 2937–2943.[Abstract/Free Full Text]

7. Upchurch SL, Brosnan CA, Meininger JC, Wright DE, Campbell JA, McKay SV, Schreiner B. Characteristics of 98 children and adolescents diagnosed with type 2 diabetes by their health care provider at initial presentation. Diabetes Care. 2003; 26: 2209.[Free Full Text]

8. Furberg CD, Wright JT, Davis BR, Cutler JA, Alderman M, Black H, Cushman W, Grimm R, Haywood LJ, Franz Leenen F, Oparil S, Perry HM, Probstfield J, Whelton P, Payne G, Nwachuku C, Gordon D, Proschan M, Frommer P, Einhorn P, Hawkins CM, Ford C, Pressel S, Piller L, Lusk C, Bettencourt J, Kimmel B, Geraci T, Walsh S, Rahman M, Juratovac A, Pospisil R, Brennan K, Carroll L, Sullivan S, Barone G, Christian R, Feldman S, Lucente T, Lewis CE, Jenkins K, McDowell P, Johnson J, Kingry C, Letterer R, Margolis K, Holland L, Jaeger-Fox B, Williamson J, Louis G, Ragusa P, Williard A, Ferguson RS, Tanner J, Eckfeldt J, Crow R, Pelos J; ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 283: 1967–1975.

9. Messerli FH, Weber MA. Long-term cardiovascular consequences of diuretics vs calcium channel blockers vs angiotensin-converting enzyme inhibitors. JAMA. 2003; 289: 2067–2068.[Free Full Text]

10. Lindholm LH, Persson M, Alaupovic P, Carlberg B, Svensson A, Samuelsson O. Metabolic outcome during 1 year in newly detected hypertensives: results of the Antihypertensive Treatment and Lipid Profile in a North of Sweden Efficacy Evaluation (ALPINE study). J Hypertens. 2003; 21: 1563–1574.[CrossRef][Medline] [Order article via Infotrieve]

11. Bradburn MJ, Deeks JJ, Altman DG. Sbe24: METAN: an alternative meta-analysis command. Stata Tech Bull Reprints. 1998; 8: 86–100.

12. Galbraith RF. A note on graphical presentation of estimated odds ratios from several clinical trials. StatMed. 1988; 7: 889–894.

13. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986; 7: 177–188.[CrossRef][Medline] [Order article via Infotrieve]

14. Bakris GL, Fonseca V, Katholi RE, McGill JB, Messerli FH, Phillips RA, Raskin P, Wright JT Jr, Oakes R, Lukas MA, Anderson KM, Bell DS. Metabolic effects of carvedilol vs metoprolol in patients with type 2 diabetes mellitus and hypertension: a randomized controlled trial. JAMA. 2004; 292: 2227–2236.[Abstract/Free Full Text]

15. Elliott WJ, Meyer PM. Incident diabetes in clinical trials of antihypertensive drugs: a network meta-analysis. Lancet. 2007; 369: 201–207.[CrossRef][Medline] [Order article via Infotrieve]

16. Verdecchia P, Reboldi G, Angeli F, Borgioni C, Gattobigio R, Filippucci L, Norgiolini S, Bracco C, Porcellati C. Adverse prognostic significance of new diabetes in treated hypertensive subjects. Hypertension. 2004; 43: 963–969.[Abstract/Free Full Text]

17. Alderman MH, Cohen H, Madhavan S. Diabetes and cardiovascular events in hypertensive patients. Hypertension. 1999; 33: 1130–1134.[Abstract/Free Full Text]

18. Davey Smith G, Bracha Y, Svendsen KH, Neaton JD, Haffner SM, Kuller LH. Incidence of type 2 diabetes in the randomized multiple risk factor intervention trial. Ann Intern Med. 2005; 142: 313–322.[Abstract/Free Full Text]

19. Almgren T, Wilhelmsen L, Samuelsson O, Himmelmann A, Rosengren A, Andersson OK. Diabetes in treated hypertension is common and carries a high cardiovascular risk: results from a 28-year follow-up. J Hypertens. 2007; 25: 1311–1317.[CrossRef][Medline] [Order article via Infotrieve]

20. Aksnes TA, Kjeldsen SE, Rostrup M, Omvik P, Hua TA, Julius S. Impact of new-onset diabetes mellitus on cardiac outcomes in the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial population. Hypertension. 2007; 50: 467–473.[Abstract/Free Full Text]

21. Kostis JB, Wilson AC, Freudenberger RS, Cosgrove NM, Pressel SL, Davis BR. Long-term effect of diuretic-based therapy on fatal outcomes in subjects with isolated systolic hypertension with and without diabetes. Am J Cardiol. 2005; 95: 29–35.[CrossRef][Medline] [Order article via Infotrieve]

22. Pepine CJ, Handberg EM, Cooper-DeHoff RM, Marks RG, Kowey P, Messerli FH, Mancia G, Cangiano JL, Garcia-Barreto D, Keltai M, Erdine S, Bristol HA, Kolb HR, Bakris GL, Cohen JD, Parmley WW. A calcium antagonist vs a non-calcium antagonist hypertension treatment strategy for patients with coronary artery disease: the International Verapamil-Trandolapril Study (INVEST): a randomized controlled trial. JAMA. 2003; 290: 2805–2816.[Abstract/Free Full Text]

23. Cooper-Dehoff R, Cohen JD, Bakris GL, Messerli FH, Erdine S, Hewkin AC, Kupfer S, Pepine CJ. Predictors of development of diabetes mellitus in patients with coronary artery disease taking antihypertensive medications (findings from the INternational VErapamil SR-Trandolapril STudy [INVEST]). Am J Cardiol. 2006; 98: 890–894.[CrossRef][Medline] [Order article via Infotrieve]

24. Bakris G, Molitch M, Hewkin A, Kipnes M, Sarafidis P, Fakouhi K, Bacher P, Sowers J. Differences in glucose tolerance between fixed-dose antihypertensive drug combinations in people with metabolic syndrome. Diabetes Care. 2006; 29: 2592–2597.[Abstract/Free Full Text]

25. Kasiske BL, Ma JZ, Kalil RS, Louis TA. Effects of antihypertensive therapy on serum lipids. Ann Intern Med. 1995; 122: 133–141.[Abstract/Free Full Text]

26. Sharma AM, Pischon T, Hardt S, Kunz I, Luft FC. Hypothesis: beta-adrenergic receptor blockers and weight gain: a systematic analysis. Hypertension. 2001; 37: 250–254.[Abstract/Free Full Text]

27. Messerli FH, Bell DS, Fonseca V, Katholi RE, McGill JB, Phillips RA, Raskin P, Wright JT Jr, Bangalore S, Holdbrook FK, Lukas MA, Anderson KM, Bakris GL; GEMINI Investigators. Body weight changes with beta-blocker use: results from GEMINI. Am J Med. 2007; 120: 610–615.[CrossRef][Medline] [Order article via Infotrieve]

28. Scholze J, Grimm E, Herrmann D, Unger T, Kintscher U. Optimal treatment of obesity-related hypertension: the Hypertension-Obesity-Sibutramine (HOS) study. Circulation. 2007; 115: 1991–1998.[Abstract/Free Full Text]

29. Lindholm LH, Carlberg B, Samuelsson O. Beta blockers in primary hypertension: do age and type of beta-blocker matter? J Hypertens. 2006; 24: 2143–2145.[Medline] [Order article via Infotrieve]

30. Wiysonge CS, Bradley H, Mayosi BM, Maroney R, Mbewu A, Opie LH, Volmink J. Beta-blockers for hypertension. Cochrane Database Syst Rev. 2007: CD002003.

31. Messerli FH, Grossman E. Beta-blocker therapy and depression. JAMA. 2002; 288: 1845–1846.[Free Full Text]

32. Hawkins RG, Houston MC. Is population-wide diuretic use directly associated with the incidence of end-stage renal disease in the United States? A hypothesis. Am J Hypertens. 2005; 18: 744–749.[CrossRef][Medline] [Order article via Infotrieve]

33. Reungjui S, Hu H, Mu W, Roncal CA, Croker BP, Patel JM, Nakagawa T, Srinivas T, Byer K, Simoni J, Wesson D, Sitprija V, Johnson RJ. Thiazide-induced subtle renal injury not observed in states of equivalent hypokalemia. Kidney Int. 2007; 72: 1483–1492.[CrossRef][Medline] [Order article via Infotrieve]

34. Rovin BH, Hebert LA. Thiazide diuretic monotherapy for hypertension: diuretic’s dark side just got darker. Kidney Int. 2007; 72: 1423–1426.[CrossRef][Medline] [Order article via Infotrieve]

35. Grossman E, Messerli FH, Goldbourt U. Does diuretic therapy increase the risk of renal cell carcinoma? Am J Cardiol. 1999; 83: 1090–1093.[CrossRef][Medline] [Order article via Infotrieve]

36. Lindholm LH, Carlberg B, Samuelsson O. Should beta blockers remain first choice in the treatment of primary hypertension? A meta-analysis. Lancet. 2005; 366: 1545–1553.[CrossRef][Medline] [Order article via Infotrieve]

37. Messerli FH, Grossman E, Goldbourt U. Are beta-blockers efficacious as first-line therapy for hypertension in the elderly? A systematic review. JAMA. 1998; 279: 1903–1907.[Abstract/Free Full Text]

38. Bangalore S, Messerli FH, Kostis JB, Pepine CJ. Cardiovascular protection using beta blockers: a critical review of the evidence. J Am Coll Cardiol. 2007; 50: 563–572.[Abstract/Free Full Text]

39. Dahlof B, Sever PS, Poulter NR, Wedel H, Beevers DG, Caulfield M, Collins R, Kjeldsen SE, Kristinsson A, McInnes GT, Mehlsen J, Nieminen M, O'Brien E, Ostergren J. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial. Lancet. 2005; 366: 895–906.[CrossRef][Medline] [Order article via Infotrieve]

40. Messerli FH, Grossman E, Leonetti G. Antihypertensive therapy and new onset diabetes. J Hypertens. 2004; 22: 1845–1847.[CrossRef][Medline] [Order article via Infotrieve]

41. Kjekshus JK. Importance of heart rate in determining beta-blocker efficacy in acute and long-term acute myocardial infarction intervention trials. Am J Cardiol. 1986; 57: 43F–49F.[CrossRef][Medline] [Order article via Infotrieve]

42. Bangalore S, Sawhney S, Messerli FH. Heart rate and anti-hypertensive therapy: the β-blocker paradox. J Am Coll Cardiol. In press.

43. Williams B, Lacy PS, Thom SM, Cruickshank K, Stanton A, Collier D, Hughes AD, Thurston H, O'Rourke M. Differential impact of blood pressure–lowering drugs on central aortic pressure and clinical outcomes: principal results of the Conduit Artery Function Evaluation (CAFE) study. Circulation. 2006; 113: 1213–1225.[Abstract/Free Full Text]

44. Kaboli PJ, Shivapour DM, Henderson MS, Barnett MJ, Ishani A, Carter BL. Patient and provider perceptions of hypertension treatment: do they agree? J Clin Hypertens. 2007; 9: 416–423.[CrossRef]

45. National Collaborating Centre for Chronic Conditions. Hypertension: Management of Hypertension in Adults in Primary Care: Partial Update. London, UK: Royal College of Physicians; 2006.

46. POEM*: diuretics should be first line treatment for hypertension. BMJ. 2003;327:DOI:10.1136/bmj.327.7413.0-e Accessed May 12, 2008.

---

 

Response to Messerli et al

Jeffrey A. Cutler, MD, MPH; Barry R. Davis, MD, PhD

The article by Messerli and colleagues argues against first-line diuretic treatment for those with stage I hypertension on the basis of selective evidence from many nonrandomized studies and analyses. The crux of their case gives undue weight to small differences in new-onset diabetes among antihypertensive drug treatments. We disagree with this point for the following reasons: (1) As the authors acknowledge (but fail to incorporate in their conclusions), type 2 diabetes mellitus is a surrogate outcome and is important primarily because of its status as a risk factor, presumably causal, for cardiovascular-renal outcomes. Thiazide-type diuretics have an advantage over other drugs as a first-step treatment for prevention of such outcomes. In ALLHAT, these advantages persisted in subgroups of patients with diabetes or the metabolic syndrome. (2) The cause of the diabetes epidemic is increasing overweight/obesity and physical inactivity. The epidemic can be reversed in the population, and diabetes can be prevented (and treated in its early stage) in the individual by attention to these factors. (3) Most new-onset diabetes in diuretic-treated patients is not diuretic induced. Cases that are can likely be prevented by avoiding significant potassium depletion. There are no direct data on diuretic-induced diabetes and cardiovascular risk. The authors purport to refute JNC7, a broadly based set of consensus, evidence-based guidelines. The process for generating a JNC8 is getting under way, and we are confident that the best evidence will prevail. We have no major disagreement with these authors regarding a secondary role for β-blockers, despite the deficiencies in evidence regarding non-atenolol β-blockers.

	Footnotes

 
The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.

This article is Part II of a 2-part article. Part I appears on page 2691.

This article has been cited by other articles:

				M. E. Ernst and M. Moser Use of Diuretics in Patients with Hypertension N. Engl. J. Med., November 26, 2009; 361(22): 2153 - 2164. [Full Text] [PDF]

				N. M. Kaplan The Choice of Thiazide Diuretics: Why Chlorthalidone May Replace Hydrochlorothiazide Hypertension, November 1, 2009; 54(5): 951 - 953. [Full Text] [PDF]

				C. J. Lavie, F. H. Messerli, and R. V. Milani Beta-blockers as first-line antihypertensive therapy the crumbling continues. J. Am. Coll. Cardiol., September 22, 2009; 54(13): 1162 - 1164. [Full Text] [PDF]

				M. Klapholz {beta}-Blocker Use for the Stages of Heart Failure Mayo Clin. Proc., August 1, 2009; 84(8): 718 - 729. [Abstract] [Full Text] [PDF]

				J. T. Wright Jr, J. L. Probstfield, W. C. Cushman, S. L. Pressel, J. A. Cutler, B. R. Davis, P. T. Einhorn, M. Rahman, P. K. Whelton, C. E. Ford, et al. ALLHAT Findings Revisited in the Context of Subsequent Analyses, Other Trials, and Meta-analyses Arch Intern Med, May 11, 2009; 169(9): 832 - 842. [Abstract] [Full Text] [PDF]

				F. H. Messerli and S. Bangalore Antihypertensive Efficacy of Aliskiren: Is Hydrochlorothiazide an Appropriate Benchmark? Circulation, January 27, 2009; 119(3): 371 - 373. [Full Text] [PDF]

				D. Rosskopf and M. C. Michel Pharmacogenomics of G Protein-Coupled Receptor Ligands in Cardiovascular Medicine Pharmacol. Rev., December 1, 2008; 60(4): 513 - 535. [Abstract] [Full Text] [PDF]

				T. Shafi, L. J. Appel, E. R. Miller III, M. J. Klag, and R. S. Parekh Changes in Serum Potassium Mediate Thiazide-Induced Diabetes Hypertension, December 1, 2008; 52(6): 1022 - 1029. [Abstract] [Full Text] [PDF]

				M. B. Fowler Hypertension, Heart Failure, and Beta-Adrenergic Blocking Drugs J. Am. Coll. Cardiol., September 23, 2008; 52(13): 1073 - 1075. [Full Text] [PDF]

This Article Extract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Messerli, F. H. Articles by Julius, S. Search for Related Content PubMed Articles by Messerli, F. H. Articles by Julius, S. Related Collections Cardiovascular Pharmacology Type 2 diabetes Glucose intolerance Clinical Studies Epidemiology