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Thiazide-Type Diuretics and β-Adrenergic Blockers as First-Line Drug Treatments for Hypertension

2008; Lippincott Williams & Wilkins; Volume: 117; Issue: 20 Linguagem: Inglês

10.1161/circulationaha.107.709931

1524-4539

Jeffrey A. Cutler, Barry R. Davis,

Sodium Intake and Health

HomeCirculationVol. 117, No. 20Thiazide-Type Diuretics and β-Adrenergic Blockers as First-Line Drug Treatments for Hypertension Free AccessArticle CommentaryPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessArticle CommentaryPDF/EPUBThiazide-Type Diuretics and β-Adrenergic Blockers as First-Line Drug Treatments for Hypertension Jeffrey A. Cutler, MD, MPH and Barry R. Davis, MD, PhD Jeffrey A. CutlerJeffrey A. Cutler From the National Heart, Lung, and Blood Institute, Bethesda, Md (J.A.C.), and the University of Texas Health Science Center at Houston School of Public Health, Houston, Tex (B.R.D.). and Barry R. DavisBarry R. Davis From the National Heart, Lung, and Blood Institute, Bethesda, Md (J.A.C.), and the University of Texas Health Science Center at Houston School of Public Health, Houston, Tex (B.R.D.). Originally published20 May 2008https://doi.org/10.1161/CIRCULATIONAHA.107.709931Circulation. 2008;117:2691–2705Systemic arterial hypertension affects 72 million US adults and an additional hundreds of millions of persons worldwide.1,2 Most of these are candidates for pharmacological treatment to reduce risk of cardiovascular disease (CVD) events, based primarily on a very large body of epidemiological and intervention research in humans. Because of this high prevalence and the cardiovascular consequences of untreated or inadequately treated hypertension, the selection of drugs for initial and continuing, long-term treatment has large public health and economic implications. Fortunately, such decisions and the expert recommendations that seek to guide them can call on evidence from 4 decades of randomized multicenter clinical trials evaluating effects of treatment on clinical CVD. We summarize that evidence in this article, in approximate chronological order, and we comment on the related treatment guidelines. We close with some of the major clinical questions yet to be resolved.Response by Messerli et al p 2705Trials of Blood Pressure ReductionBefore the current era beginning in the early 1990s of emphasis on positive-control trials, which directly compare different drug regimens, there were 3 decades of trials that compared an active regimen with placebo or, in a few cases, "usual care." For most of this period, the mainstay of treatment was generally a thiazide-type diuretic (hereinafter called thiazides) or, to a lesser extent, a β-adrenergic blocker (termed β-blockers). With few exceptions, these trials, especially those with high statistical power and thiazide-based regimens, showed benefit for CVD outcomes.3–8 This evidence, which provided a basis for recommending thiazides or β-blockers as first-step drugs in most editions of US guidelines through 1997,9 needs to continue to be given due weight in practice and practice guidelines.The largest and most consistent benefits from the earlier trials were for stroke and (where reported) heart failure. Benefits for coronary heart disease (CHD) were less clear, and commentators frequently speculated that potentially adverse metabolic effects—on potassium (for diuretics), lipids, and glucose—of thiazides and β-blockers were related to this shortfall in reducing CHD outcomes. Two reports in the early 1990s reduced concern about the CHD shortfall considerably. A meta-analysis of essentially all randomized antihypertensive treatment trials with clinical events outcomes, placed in an epidemiological context to address the question of what effects would be expected on the basis of risks of various events at different blood pressure (BP) levels, showed that treatment significantly reduced nonfatal myocardial infarction (MI) or CHD death (major CHD) by 14%, which represented approximately two thirds of the epidemiological expectation.10,11 The authors attributed the shortfall to the short duration of treatment in the trials, averaging ≈2 to 3 years to CHD events, which was a plausible conclusion. Shortly thereafter, the Systolic Hypertension in the Elderly Program (SHEP) reported that a thiazide-based regimen (using low-dose chlorthalidone) not only reduced fatal and nonfatal stroke by 36% but also lowered major CHD by 27%.8The results of these trials have also provided a basis for guidelines on drug choice through indirect comparisons among trials and groups of trials. Subsequent to SHEP, the similarly designed Systolic Hypertension in Europe (Syst-Eur) trial reported that treatment with a dihydropyridine calcium channel blocker (CCB) as the main drug reduced BP, stroke, and all cardiac events to an extent similar to that in SHEP.12 However, neither the effects on CHD or heart failure were separately statistically significant. For angiotensin-converting enzyme (ACE) inhibitors, there was no large trial focused on hypertension, but several trials reported that these drugs reduced mortality and morbidity in patients with heart failure and/or CHD13–16; the Studies of Left Ventricular Dysfunction (SOLVD) prevention trial showed that enalapril lowered the risk of MI and overt heart failure in patients with reduced ejection fraction.17 The size of the heart failure effect was, however, only 20%, in contrast with the 49% benefit in SHEP.18These newer trials provided important added justification for earlier recommendations concerning use of CCBs and ACE inhibitors as first-line drugs in treating hypertension in the 1988 Report of the Joint National Committee (JNC) on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.19 However, both JNCV and JNCVI recommended thiazides and β-blockers as preferred initial drugs for antihypertensive treatment.9,20 As in the case of ACE inhibitors, the trials of secondary prevention of heart disease continued to play a large role in the thinking about benefits of β-blockers in hypertension.Despite all of these factors, that is, the weight of the evidence, the consensus incorporated in JNC recommendations, and the low acquisition costs of several generic agents, the use of thiazides and β-blockers to treat hypertension declined dramatically after 1981–1983 through the early 1990s (Figure 1).21 These trends can be attributed to the following: (1) concerns raised regarding metabolic effects; (2) results of trials that used doses of thiazides much higher than in general use today22; and (3) effective marketing of newer patented drugs, in part based on their effects on intermediate markers of various disease processes. Thiazide dosing issues were eventually addressed on the basis of the dose-response curves for BP effects versus potassium depletion, the SHEP trial results, and, most persuasively, by a meta-analysis that separated use of "low-dose" (actually, low-to-moderate dose) from high-dose thiazides among cardiovascular events trials.23 Nevertheless, it was increasingly recognized that large, direct comparison trials would be needed to provide a solid scientific basis for drug selection. One of the first such trials, and the largest in terms of total study population as well as patients per treatment arm, was the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Download figureDownload PowerPointFigure 1. Percentage of drug mentions by class of antihypertensive agent, 1982–1993.21 Data from IMS America.59 Reprinted from Manolio et al,21 with permission. Copyright 1995, American Medical Association.The Continuing Case for Thiazide- Type DiureticsDirect Comparison TrialsALLHAT: Design and Prespecified OutcomesALLHAT was designed to address the issue of which class of drugs should be used for initial therapy for hypertension. It was planned as a practice-based trial to mirror community treatment of hypertension, obtain sufficient patients, and capture the diversity of hypertensive patients (by age, sex, ethnicity, and diabetic status). More specifically, the study was a randomized, double-blind, multicenter clinical trial, designed to determine whether the incidence of CHD is reduced in high-risk patients with hypertension by a CCB (represented by amlodipine), an ACE inhibitor (represented by lisinopril), or an α-blocker (represented by doxazosin), each compared with diuretic treatment (represented by chlorthalidone).24 The overall findings of the trial showed that CHD risk was not improved for any of the 3 newer agents compared with chlorthalidone25,26 and that total mortality was also similar for the 4 groups (Tables 1 and 2). Table 1. Clinical Outcomes by Antihypertensive Treatment Group25ChlorthalidoneAmlodipineLisinoprilAmlodipine/ChlorthalidoneLisinopril/ChlorthalidoneNo. of Total Events6-Year Rate per 100 Persons (SE)No. of Total Events6-Year Rate per 100 Persons (SE)No. of Total Events6-Year Rate per 100 Persons (SE)RR (95% CI)Z ScorePRR (95% CI)Z ScorePCHD includes nonfatal MI and fatal CHD; end-stage renal disease: kidney disease death, kidney transplant, or start of chronic renal dialysis; and heart failure: fatal, nonfatal hospitalized, or treated. Adapted from Reference 25, with permission. Copyright 2002, American Medical Association.*Nonfatal MIs comprise 64% to 66% of the primary outcome.†Combined CHD indicates CHD death, nonfatal MI, coronary revascularization procedures, and hospitalized angina. Combined CVD indicates CHD death, nonfatal MI, stroke, coronary revascularization procedures, hospitalized or treated angina, treated or hospitalized heart failure, and peripheral arterial disease (hospitalized or outpatient revascularization).‡Proportional hazards assumption violated; data are RRs from a 2×2 table.Primary end point CHD*136211.5 (0.3)79811.3 (0.4)79611.4 (0.4)0.98 (0.90–1.07)−0.460.650.99 (0.91–1.08)−0.240.81Secondary end points All-cause mortality220317.3 (0.4)125616.8 (0.5)131417.2 (0.5)0.96 (0.89–1.02)−1.270.201.00 (0.94–1.08)0.120.90 Combined CHD†245119.9 (0.4)146619.9 (0.5)150520.8 (0.5)1.00 (0.94–1.07)0.040.971.05 (0.98–1.11)1.350.18 Stroke6755.6 (0.2)3775.4 (0.3)4576.3 (0.3)0.93 (0.82–1.06)−1.090.281.15 (1.02–1.30)2.310.02 Combined CVD†394130.9 (0.5)243232.0 (0.6)251433.3 (0.6)1.04 (0.99–1.09)1.550.121.10 (1.05–1.16)3.78<0.001 End-stage renal1931.8 (0.1)1292.1 (0.2)1262.0 (0.2)1.12 (0.89–1.40)0.980.331.11 (0.88–1.38)0.870.38 diseaseComponents of secondary outcomes Heart failure8707.7 (0.3)70610.2 (0.4)6128.7 (0.4)1.38 (1.25–1.52)6.29<0.0011.19 (1.07–1.31)‡3.33<0.001 Hospitalized/fatal7246.5 (0.3)5788.4 (0.4)4716.9 (0.4)1.35 (1.21–1.50)5.37<0.0011.10 (0.98–1.23)‡1.590.11 heart failure Angina (hospitalized156712.1 (0.3)95012.6 (0.4)101913.6 (0.4)1.02 (0.94–1.10)0.420.671.11 (1.03–1.20)2.590.01 or treated) Angina (hospitalized)10788.6 (0.3)6308.4 (0.4)6939.6 (0.4)0.98 (0.89–1.08)−0.410.681.09 (0.99–1.20)1.850.06 Coronary11139.2 (0.3)72510.0 (0.4)71810.2 (0.4)1.09 (1.00–1.20)1.880.061.10 (1.00–1.21)1.950.05 revascularizations Peripheral arterial5104.1 (0.2)2653.7 (0.2)3114.7 (0.4)0.87 (0.75–1.01)−1.860.061.04 (0.90–1.19)0.480.63 disease (hospitalized or treated)Table 2. Outcomes in the BP Component of ALLHAT by Treatment Group as of February 15, 200026OutcomesTotal No. of Patients With Outcomes4-Year Rate per 100 (SE)RR (D/C), 95% CIZ ScoreP*Chlorthalidone GroupDoxazosin GroupChlorthalidone Group (n=15 255)Doxazosin Group (n=9061)Adapted from Reference 26, with permission from Lippincott Williams & Wilkins. Copyright 2003, American Heart Association.*To adjust for multiple comparisons, compare the P value with 0.018 rather than 0.05.†Combined CHD includes CHD death, nonfatal MI, coronary revascularization procedures, and hospitalized angina.‡Combined CVD includes CHD death, nonfatal MI, stroke, coronary revascularization procedures, hospitalized or treated angina, treated or hospitalized CHF, and peripheral arterial disease (hospitalized, or outpatient revascularization).§Proportional hazards assumption violated; numbers given are RRs.CHD (nonfatal MI+fatal CHD)8184997.76 (0.30)7.91 (0.39)1.03 (0.92–1.15)0.490.62All-cause mortality125876910.51 (0.32)11.04 (0.43)1.03 (0.94–1.13)0.680.50 Cardiovascular5513774.74 (0.22)5.60 (0.32)1.15 (1.01–1.32)2.150.03 MI1841051.65 (0.13)1.76 (0.19)0.96 (0.76–1.22)−0.320.75 Definite CHD57390.54 (0.08)0.54 (0.10)1.16 (0.77–1.74)0.700.49 Possible CHD62430.50 (0.08)0.63 (0.11)1.17 (0.79–1.73)0.790.43 Stroke92760.79 (0.10)1.25 (0.16)1.39 (1.03–1.89)2.140.03 Heart failure59420.60 (0.09)0.65 (0.11)1.20 (0.81–1.78)0.910.36 Other cardiovascular97720.88 (0.10)1.12 (0.15)1.25 (0.92–1.70)1.440.15 Noncardiovascular5613174.82 (0.23)4.72 (0.30)0.95 (0.83–1.09)−0.670.50 Cancer3141622.78 (0.18)2.43 (0.21)0.87 (0.72–1.05)−1.430.15 Kidney disease12120.11 (0.04)0.24 (0.09)1.69 (0.76–3.77)1.290.20 Accident/suicide/homicide39280.33 (0.06)0.40 (0.09)1.21 (0.75–1.97)0.780.44 Other noncardiovascular1961151.75 (0.14)1.84 (0.19)0.99 (0.79–1.25)−0.080.93 Unknown146751.37 (0.13)1.18 (0.16)0.87 (0.66–1.15)−1.000.32Combined CHD†1642104014.87 (0.39)16.00 (0.53)1.07 (0.99–1.16)1.820.07Stroke4343254.08 (0.22)5.49 (0.35)1.26 (1.10–1.46)3.200.001Combined CVD‡2829194725.09 (0.48)28.56 (0.64)1.20 (1.13–1.27)6.13<0.001 Heart failure (fatal, hospitalized, treated)5465845.35 (0.26)8.89 (0.42)1.80 (1.61–2.02)§10.27<0.001 Heart failure (fatal, hospitalized)4404344.41 (0.24)6.63 (0.37)1.66 (1.46–1.89)§7.72 1 drug, diuretics should generally be part of any antihypertensive regimen. With regard to applicability of these conclusions, although ALLHAT was conducted in high-risk patients to ensure that enough outcome events would occur during the study to detect important treatment differences, its findings (just as those from most trials) can and should be reasonably extrapolated beyond the exact sample in which it was conducted.BP Differences in ALLHATOne of the main criticisms of ALLHAT was that its outcome findings (especially the subgroup findings for stroke) could be explained by observed BP differences among treatment groups. The chlorthalidone-based regimen happened to be the most effective in reducing clinical outcomes and, to a small degree, in BP lowering (Figure 2).25Download figureDownload PowerPointFigure 2. Mean systolic and diastolic BP by year during follow-up.25 Reprinted from Reference 25, with permission. Copyright 2002, American Medical Association.Meta-regressions of effects of BP differences on trial results27 suggest that they offer a partial explanation, except for heart failure. In ALLHAT, the small differences in achieved mean systolic BP and diastolic BP (<1 mm Hg) between the amlodipine and chlorthalidone groups overall and the lisinopril and chlorthalidone groups in nonblack persons should have had a negligible effect on cardiovascular event rates. In these respective comparisons, the observed rates of heart failure were higher with amlodipine (relative risk [RR]=1.38; 95% CI, 1.25 to 1.52) and lisinopril (RR=1.15; 95% CI, 1.01 to 1.30) than with chlorthalidone.25Extrapolating Findings to Drugs Within a ClassCould the ALLHAT results be extrapolated to other drugs of the same class? For α-blockers, ACE inhibitors, and dihydropyridine CCBs, such extrapolation seems reasonable.28 Data from studies using various thiazide-type diuretics (chlorthalidone, hydrochlorothiazide, indapamide, and bendrofluazide) suggest similar benefits among equivalent doses of all thiazide-type diuretics tested in CVD prevention trials against placebo, usual care, or another drug class.5,6,8,29–34 However, a few studies suggest that the longer duration of action of chlorthalidone may provide some advantage in CVD prevention over hydrochorothiazide.22,35Results From Other TrialsAfter the ALLHAT results appeared, several other active comparator trials were reported. The Second Australian National Blood Pressure Study (ANBP2), a practice-based open-label trial, was the only other large trial besides ALLHAT to compare diuretic-based (hydrochlorothiazide recommended) with ACE inhibitor–based (enalapril recommended) antihypertensive treatment.34 A total of 6083 participants, aged 65 to 84 years, were treated and followed up for a mean of 4.1 years. The primary end point was a composite of all cardiovascular events (including recurrent events, an unusual design) plus all-cause mortality. Cardiovascular events included major coronary events, stroke and transient ischemic attacks, heart failure (not otherwise defined), acute occlusion of any other major artery, and dissecting or ruptured aortic aneurysm. The results for the primary end point favored the ACE inhibitor group with marginal significance (RR, 0.89; 95% CI, 0.79 to 1.00; P=0.05). The corresponding results with the use of first cardiovascular event had essentially the same RR (P=0.07). The RR for heart failure was 0.85 (95% CI, 0.62 to 1.18; P=0.33). Frohlich36 weighed the supposedly conflicting results of ANBP2 and ALLHAT, suggesting possible explanations such as the patients studied (many more black patients in ALLHAT) and the specific drugs used. Additionally, there were almost 8 times as many cardiovascular events in the 2 comparable arms in ALLHAT as in ANBP2, and only ALLHAT was double blind. ANBP2 used a prospective, randomized, open-label, blinded end point (PROBE) design, increasing the potential for bias in the reporting of events (the rates of some outcomes might have been "expected" to be lower with the ACE inhibitor) even though ANBP2 relied on end point committee–adjudicated outcomes. Doses of agents in ANBP2 were left up to the local investigator and were not reported; thus, it is not possible to assess whether appropriate doses of hydrochlorothiazide were used. Even given the possible biases, however, the results of ANBP2 are consistent with those of ALLHAT if the upper confidence limit for the RR in ANBP2 is compared with the estimates of RR in ALLHAT.37The International Nifedipine GITS study [Intervention as a Goal in Hypertension Treatment (INSIGHT)] was the other large trial besides ALLHAT to compare diuretic-based (co-amilozide) with CCB-based (nifedipine) antihypertensive treatment on cardiovascular mortality and morbidity in high-risk patients with hypertension.33 It was a randomized, double-blind trial in 6321 patients aged 55 to 80 years with hypertension. Patients had at least 1 additional cardiovascular risk factor and were randomly assigned to nifedipine (30 to 60 mg in a long-acting gastrointestinal-transport system [GITS] formulation) or co-amilozide (hydrochlorothiazide 25 to 50 mg plus amiloride). The primary outcome was cardiovascular death, MI, heart failure, or stroke. Primary outcomes occurred in 200 patients (6.3%) in the nifedipine group and in 182 (5.8%) in the co-amilozide group (RR=1.10; 95% CI, 0.91 to 1.34; P=0.35). The CCB was not superior to the diuretic in preventing cardiovascular morbidity and mortality. Nonfatal heart failure was more common in the CCB arm (RR=2.20; 95% CI, 1.07 to 4.49; P=0.028). There were only 3 fatal heart failure events: 2 in the CCB arm and 1 in the diuretic arm.Further Details on Heart Failure in ALLHATAnother major ALLHAT criticism concerned the heart failure findings. Specifically, were the findings real, and could they be explained by withdrawal from antihypertensive medications, such as diuretics and ACE inhibitors, on entry into ALLHAT?Several articles have addressed these 2 questions in detail.38–41 The reliability of the heart failure diagnosis during the trial was examined in depth via the ALLHAT Heart Failure Validation Study (HFVS).40 This study was designed to validate and elucidate the significance of heart failure events in ALLHAT. This study involved all hospitalized heart failure events and relevant hospital records related to these events. Cardiology fellows, external to ALLHAT and blinded to treatment assignment, centrally abstracted the documentation for each heart failure hospitalization (2778 in 1935 patients; 2 independent reviews per case). ALLHAT and Framingham criteria were assigned by a computer algorithm; the reviewers also rendered a global clinical judgment. Percent agreements with site physician diagnoses were 71%, 80%, and 84% for ALLHAT, Framingham, and reviewers' judgment, respectively. On the basis of these 3 criteria, RRs (95% CI) for new-onset hospitalized heart failure compared with chlorthalidone were, respectively, 1.46 (1.27 to 1.68), 1.42 (1.25 to 1.62), and 1.45 (1.28 to 1.64) for amlodipine; 1.18 (1.02 to 1.28), 1.13 (0.99 to 1.30), and 1.15 (1.01 to 1.32) for lisinopril (Figure 3); and 1.79 (1.51 to 2.11), 1.71 (1.46 to 2.00), and 1.80 (1.55 to 2.10) for doxazosin.40Download figureDownload PowerPointFigure 3. Incident hospitalized (Hosp) heart failure (HF) outcomes by antihypertensive treatment group (amlodipine/lisinopril vs chlorthalidone).40 *Prespecified end point of treated, hospitalized, or fatal heart failure. Reprinted from Einhorn et al,40 with permission. Copyright 2007, Elsevier.Although there was early divergence of the heart failure incidence curves in ALLHAT, it continued after the first year for doxazosin and amlodipine versus chlorthalidone. For lisinopril versus chlorthalidone, the curves also separated early but appeared to converge between years 6 and 7.25 Diagnostic analysis revealed that the proportional hazards assumption of constant relative risk over time was not valid.39 A more appropriate model showed that RRs of amlodipine or lisinopril versus chlorthalidone during year 1 were 2.22 (1.69 to 2.91; P<0.001) and 2.08 (1.58 to 2.74; P<0.001); after year 1, they were 1.22 (1.08 to 1.38; P<0.001) and 0.96 (0.85 to 1.10; P=0.58) (Figure 4).39Download figureDownload PowerPointFigure 4. Cumulative event rates for hospitalized (Hosp)/fatal heart failure (HF) by treatment group.39In addition, information about previous medication use was collected on the hospitalized and fatal cases of heart failure as a follow-up to the HFVS.41 When case-only design theory was used to assess interactions,42 the analyses did not support an effect of preentry diuretic use on the observed heart failure differences. However, the addition of second- and third-line drugs (≈30% at year 1) probably contributed to the lessening of the divergence starting at 6 to 12 months after randomization. Given these additional examinations, the original conclusions remained the same. Thiazide-type diuretics should be the preferred first-step therapy for prevention of heart failure in high-risk patients with hypertension.Diabetes in ALLHATAs noted above, the initial ALLHAT reports showed consistent findings for those in the prespecified subgroups with and without a baseline history of diabetes.25,26 A subsequent report on comparisons among the chlorthalidone, amlodipine, and lisinopril arms utilized baseline fasting glucose levels in addition to history to classify participants into those with diabetes, impaired fasting glucose (110 to 125 mg/dL), and fasting normoglycemia. Results were similar in all 3 subgroups, showing, in particular, the superiority of chlorthalidone for heart failure and the absence of any outcome (including end-stage renal disease) for which another arm was superior.43Among those without diabetes mellitus (DM) at baseline, the mean fasting glucose was ≈93.5 mg/dL. Changes in fasting glucose and percentage of incident diabetes mellitus (IDM) at 4 years, although not prespecified outcomes, were +10.8 mg/dL and 11.0% in the chlorthalidone group; +9.3 mg/dL and 9.3% in the amlodipine group, and +6.8 mg/dL and 7.8% in the lisinopril group, respectively.25 It was observed that these and other metabolic differences did not translate into any overall disadvantage for the diuretic arm during the mean follow-up of 4.9 years (range, 4 to 8 years). Nevertheless, further epidemiological-type analyses were conducted to examine the association of glucose changes with CVD and renal outcomes.44 There was no significant association of 2-year fasting glucose change with subsequent events, overall or in the chlorthalidone arm separately. In addition, among those who developed IDM by 2 years compared with those who did not, there was no significant increase in subsequent risk for any major disease outcomes except CHD, eg, the RRs for all CVD combined were 1.04 (95% CI, 0.80 to 1.35) for all arms and 0.96 (0.66 to 1.37) for chlorthalidone; for total mortality, they were 1.31 (0.96 to 1.81) and 1.05 (0.66 to 1.67), respectively. For CHD, the risk associated with IDM was 1.64 (1.15 to 2.33) overall but only 1.46 (0.88 to 2.42) in the chlorthalidone arm (Figure 5). Download figureDownload PowerPointFigure 5. Cox regression models showing the hazard ratios (95% CIs) associated with IDM during the first 2 years of follow-up on subsequent CVD and renal end points in those without DM at baseline.44 All hazard ratios controlled for treatment group (total cohort), 2-year blood pressure, age, race, sex, smoking status, baseline fasting glucose level, baseline body mass index, 2-year serum potassium level, and atenolol and statin administration at 2 years. NA indicates not applicable (too few events for analysis). Reprinted from Barzilay et al,44 with permission. Copyright 2006, American Medical Association.Is this tendency for IDM occurring during low/moderate-dose chlorthalidone treatment to impart less risk for adverse clinical events than during other regimens real? If so, what could be the explanation? First, in the only other long-term follow-up data in treated hypertensive patients that are relatively uncontaminated with concomitant drugs, the findings in the SHEP 14-year extended follow-up study showed a similar phenomenon: a contrast between an increased CVD risk associated with IDM in the placebo arm but not in the chlorthalidone arm.45 Second, it must be recognized that in a typical hypertensive population, the great majority of IDM that occurs while taking a thiazide is not drug induced but is due to typical causes of type 2 diabetes and therefore would be expected to carry the same risk as any such occurrence. From ALLHAT data on IDM at 4 years, such a fraction can be estimated as 83%, if it is assumed that the CCB is metabolically neutral.46 If only 1 of 5 cases of IDM in patients prescribed a thiazide is due to the drug but these cases cannot be separated from the majority, the lower risk in such patients would serve to somewhat lower but not eliminate the overall DM-associated risk.For the reason why thiazide-induced IDM could carry less risk than "naturally occurring" DM, one needs to consider the abundant, but mostly older and often forgotten, literature on potassium depletion and glucose disorders.46,47 To the extent that glucose disorders are due to this mechanism, it is plausible that its natural history is quite different. Furthermore, as pointed out in Reference 46, "In the diuretic-treated patient hypokalemia is likely to be intermittent, due to dietary and drug adherence variation, and potassium-sparing therapeutic intervention [which] may also translate to dysglycemia that is intermittent…and thus confer little risk of diabetic complications."Network Meta-AnalysisThe role of the efficacy of various antihypertensive therapies used as first-line agents in preventing major cardiovascular disease outcomes has been assessed with network meta-analysis.48 This type of analysis combines direct within-trial, between-drug comparisons with indirect evidence from the other trials. The indirect comparisons, which preserve the within-trial randomized findings, were constructed from trials that had 1 treatment in common.Data were combined from 42 clinical trials that included 192 478 patients randomized to 7 major treatment strategies, including placebo. For all outcomes, low-dose diuretics were superior to placebo (Figure 6): CHD (RR, 0.79; 95% CI, 0.69 to 0.92); congestive heart failure (RR, 0.51; 95% CI, 0.42 to 0.62); stroke (RR, 0.71; 0.63 to 0.81); CVD events (RR, 0.76; 95% CI, 0.69 to 0.83); CVD mortality (RR, 0.81; 95% CI, 0.73 to 0.92); and total mortality (RR, 0.90; 95% CI, 0.84 to 0.96). None of the other first-line treatment strategies—β-blockers, ACE inhibitors, CCBs, α-blockers, and angiotensin receptor blockers—was significantly better than low-dose diuretics for any outcome. BP changes were similar between comparison treatments. On the basis of this network meta-analysis, the authors concluded that low-dose diuretics were the most effective first-line treatment for preventing the occurrence of CVD morbidity and mortality. Download figureDownload PowerPointFigure 6. Network meta-analysis of first-line treatment strategies in randomized controlled clinical trials in hypertension.48 Asterisks, placed after the closed parentheses of the