Aims To determine whether the beneficial effects of carvedilol on insulin resistance (IR) are affected by the concomitant use of insulin sensitizers [thiazolidinediones (TZDs) and metformin].Methods Changes in HbA(1c) and homeostasis model assessment-insulin resistance (HOMA-IR) were assessed over 5 months, comparing carvedilol with metoprolol tartrate according to insulin sensitizer (TZDs and metformin) use.Results In TZD/metformin users, carvedilol patients showed a 5.4% decrease [95% confidence interval (CI) -11.9, 1.6; P = 0.13] and metoprolol tartrate patients showed a 2.8% decrease (95% CI -8.5, 3.2; P = 0.35) in HOMA-IR. The -2.6% difference between treatments was not significant (95% CI -10.7, 6.2; P = 0.55). In contrast, those not taking TZD/metformin experienced a 13.2% increase in HOMA-IR on metoprolol tartrate (95% CI 3.2, 24.1; P < 0.01) and a 4.8% decrease in HOMA-IR on carvedilol (95% CI -14.6, 6.0; P = 0.37), with a significant treatment difference of -15.9% favouring carvedilol (95% CI -26.6, -3.6; P = 0.01). There was no significant treatment interaction for the use of TZD/metformin and HbA(1c). A statistically significant treatment difference was observed for HbA(1c) after 5 months favouring carvedilol after adjusting for insulin sensitizer use (-0.11%, 95% CI -0.214, -0.009; P = 0.03).Conclusions In patients with diabetes and hypertension not taking insulin sensitizers, the use of metoprolol tartrate resulted in a worsening of insulin resistance, an effect not seen with carvedilol. However, in TZD/metformin users the difference between the beta-blockers was not statistically significant.

AIM:The Glycemic Effect in Diabetes Mellitus: Carvedilol-Metoprolol Comparison in Hypertensives (GEMINI) trial compared the metabolic effects of two beta-blockers in people with type 2 diabetes and hypertension treated with renin-angiotensin system (RAS) blockade and found differences in metabolic outcomes. In this paper, we report the results of a prespecified secondary analysis of GEMINI that sought to determine the effect of these two beta-blockers on commonly reported symptoms. METHODS:The Diabetes Symptom Checklist (DSC), a self-report questionnaire measuring the occurrence and perceived burden of diabetes-related symptoms, was completed by GEMINI participants at baseline and at the end of the study (maintenance month 5). The DSC assessed symptoms in eight domains: psychology (fatigue), psychology (cognitive), neuropathy (pain), neuropathy (sensory), cardiology, ophthalmology, hyperglycaemia and hypoglycaemia. RESULTS:Comparison of the mean change in self-reported diabetes-related symptoms indicated a significant treatment difference favouring carvedilol over metoprolol tartrate in overall symptom score (-0.08; 95% CI -0.15, -0.01; p = 0.02) and in the domains for hypoglycaemia symptoms (-0.12; 95% CI -0.23, -0.02; p = 0.02) and hyperglycaemia symptoms (-0.16; 95% CI -0.27, -0.05; p = 0.005). Carvedilol resulted in fewer perceived diabetes-related symptoms in patients with diabetes and hypertension. CONCLUSION:Carvedilol resulted in a lower perceived burden of diabetes-related symptoms in patients with type 2 diabetes and hypertension. The addition of a well-tolerated beta-blocker to RAS blockade may improve hypertension treatment and quality of life in patients with diabetes.

Background: Chronic kidney disease is common in older patients with hypertension.Objective: To compare rates of coronary heart disease (CHID) and end-stage renal disease (ESRD) events; to determine whether glomerular filtration rate (GFR) independently predicts risk for CHID; and to report the efficacy of first-step treatment with a calcium-channel blocker (amlodipine) or an angiotensin-converting enzyme inhibitor (lisinopril), each compared with a diuretic (chlorthalidone), in modifying cardiovascular disease (CVD) outcomes in high-risk patients with hypertension stratified by GFR. 6.0%, respectively). A baseline GFR of less than 53 mL/min per 1.73 m(2) (compared with > 104 mL/min per 1.73 m(2)) was independently associated with a 32% higher risk for CHD. Amlodipine was similar to chlorthalidone in reducing CHID (16.0% vs. 15.2%, respectively; hazard ratio, 1.06 [95% Cl, 0.89 to 1.27]), stroke, and combined CVD (CHID, coronary revascularization, angina, stroke, heart failure, and peripheral arterial disease), but less effective in preventing heart failure. Lisinopril was similar to chlorthalidone in preventing CHID (15.1% vs. 15.2%, respectively; hazard ratio, 1.00 [Cl, 0.84 to 1.20]), but was less effective in reducing stroke, combined CVD events, and heart failure.Design: Post hoc subgroup analysis.Setting: Multicenter randomized, double-blind, controlled trial.Participants: Persons with hypertension who were 55 years of age or older with 1 or more risk factors for CHID and who were stratified into 3 baseline GFR groups: normal or increased ( >= 90 mL/min per 1.73 m(2); n = 8126 patients), mild reduction (60 to 89 mL/min per 1.73 m(2); n = 18 109 patients), and moderate or severe reduction (< 60 mL/min per 1.73 m(2); n = 5662 patients).Interventions: Random assignment to chlorthalidone, amlodipine, or lisinopril.Measurements: Rates of ESRD, CHID, stroke, and combined CVD (CHID, coronary revascularization, angina, stroke, heart failure, and peripheral arterial disease).Results: In participants with a moderate to severe reduction in GFR, 6-year rates were higher for CHID than for ESRD (15.4% vs. Limitations: Proteinuria data were not available, and combination therapies were not tested.Conclusions: Older high-risk patients with hypertension and reduced GFR are more likely to develop CHID than to develop ESRD. A low GFR independently predicts increased risk for CHID. Neither amlodipine nor lisinopril is superior to chlorthalidone in preventing CHID, stroke, or combined CVD, and chlorthalidone is superior to both for preventing heart failure, independent of level of renal function.

BACKGROUNDThe African American Study of Kidney Disease and Hypertension was a multicenter trial of African Americans with hypertensive kidney disease randomized to an angiotensin-converting enzyme inhibitor (ramipril), a beta-blocker (metoprolol succinate), or a calcium channel blocker (amlodipine besylate). We compared the incidence of type 2 diabetes mellitus (DM) and the composite outcome of impaired fasting glucose or DM (IFG/DM) for the African American Study of Kidney Disease and Hypertension interventions.METHODSCox regression models were used to evaluate (post hoc) the association of the randomized interventions and the relative risk (RR) of DM and IFG/DM and to assess the RR of DM and IFG/DM by several prerandomization characteristics.RESULTSAmong 1017 participants, 147 (14.5%) developed DM; 333 (42.9%) of 776 participants developed IFG/DM. Respective DM event rates were 2.8%, 4.4%, and 4.5% per patient-year in the ramipril-, amlodipine-, and metoprolol-treated groups. The RRs of DM with ramipril treatment were 0.53 (P = .001) compared with metoprolol treatment and 0.49 (P = .003) compared with amlodipine treatment. Respective IFG/DM event rates were 11.3%, 13.3%, and 15.8% per patient-year in the ramipril-, amlodipine-, and metoprolol-treated groups. The RRs of IFG/DM with ramipril treatment were 0.64 (P<.001) compared with metoprolol treatment and 0.76 (P = .09) compared with amlodipine treatment. The RRs of DM and IFG/DM with amlodipine treatment compared with metoprolol treatment were 1.07 (P = .76) and 0.84 (P = .26), respectively.CONCLUSIONRamipril treatment was associated with a significantly lower risk of DM in African Americans with hypertensive kidney disease than amlodipine or metoprolol treatment.

Context Few cardiovascular outcome data are available for blacks with hypertension treated with angiotensin-converting enzyme (ACE) inhibitors or calcium channel blockers (CCBs).Objective To determine whether an ACE inhibitor or CCB is superior to a thiazide-type diuretic in reducing cardiovascular disease (CVD) incidence in racial subgroups.Design, Setting, and Participants Prespecified subgroup analysis of ALLHAT, a randomized, double-blind, active-controlled, clinical outcome trial conducted between February 1994 and March 2002 in 33 357 hypertensive US and Canadian patients aged 55 years or older (35% black) with at least 1 other cardiovascular risk factor.Interventions Anti hypertensive regimens initiated with a CCB (amlodipine) or an ACE inhibitor (lisinopril) vs a thiazide-type diuretic (chlorthalidone). Other medications were added to achieve goal blood pressures (BPs) less than 140/90 mm Hg.Main Outcome Measures The primary outcome was combined fatal coronary heart disease (CHD) or nonfatal myocardial infarction (MI), analyzed by intention-to-treat. Secondary outcomes included all-cause mortality, stroke, combined CVD (CND death, nonfatal MI, stroke, angina, coronary revascularization, heart failure [HF], or peripheral vascular disease), and end-stage renal disease.Results No significant difference was found between treatment groups for the primary CHD outcome in either racial subgroup. For amlodipine vs chlorthalidone only, HF was the only prespecified clinical outcome that differed significantly (overall: relative risk [RR], 1.37; 95% confidence interval [Cl], 1.24-1.51; blacks: RR, 1.46; 95% CI, 1.24-1.73; nonblacks: RR, 1.32; 95% CI, 1.17-1.49; P<.001 for each comparison) with no difference in treatment effects by race (P=.38 for interaction). For lisinopril vs chlorthalidone, results differed by race for systolic BP (greater decrease in blacks with chlorthalidone), stroke, and combined CVD outcomes (P<.001, P=.01, and P=.04, respectively, for interactions). In blacks and nonblacks, respectively, the RRs for stroke were 1.40 (95% CI, 1.17-1.68) and 1.00 (95% CI, 0.85-1.17) and for combined CVD were 1.19 (95% CI, 1.09-1.30) and 1.06(95% CI, 1.00-1.13). For HF, the RRs were 1.30 (95% CI, 1.10-1.54) and 1.13 (95% CI, 1.00-1.28), with no significant interaction by race. Time-dependent BP adjustment did not significantly alter differences in outcome for lisinopril vs chlorthalidone in blacks.Conclusions In blacks and nonblack subgroups, rates were not lower in the amlodipine or lisinopril groups than in the chlorthalidone group for either the primary CHD or any other prespecified clinical outcome, and diuretic-based treatment resulted in the lowest risk of heart failure. While the improved outcomes with chlorthalidone were more pronounced for some outcomes in blacks than in nonblacks, thiazide-type diuretics remain the drugs of choice for initial therapy of hypertension in both black and nonblack hypertensive patients.

Increases in the cardiovascular risk marker microalbuminuria are attenuated by blood pressure reduction using blockers of the renin-angiotensin system. Such changes in microalbuminuria have not been observed when beta-blockers are used. A prespecified secondary end point of the Glycemic Effects in Diabetes Mellitus Carvedilol-Metoprolol Comparison in Hypertensives (GEMINI) trial was to examine the effects of different beta-blockers on changes in albuminuria in the presence of renin-angiotensin system blockade. Participants with hypertension and type 2 diabetes were randomized to either metoprolol tartrate (n=737) or carvedilol (n=498) in blinded fashion after a washout period of all antihypertensive agents except for angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. Blinded medication was titrated to achieve target blood pressure, with a-5 month follow-up period. The current analysis examined microalbuminuria, using spot urine albumin:creatinine, in participants who had values at screening and trial end. A greater reduction in microalbuminuria was observed for those randomized to carvedilol (-16.2%Delta; 95% confidence interval, -25.3, -5.9; P=0.003). Of those with normoalbuminuria at baseline, fewer progressed to microalbuminuria on carvedilol versus metoprolol (20 of 302 [6.6%] versus 48 of 431 [11.1%], respectively; P=0.03). Microalbuminuria development was not related to differences in blood pressure or achievement of blood pressure goal (68% carvedilol versus 67%, metoprolol). Presence of metabolic syndrome at baseline was the only independent predictor of worsening albuminuria throughout the study (P=0.004). Beta-blockers have differential effects on microalbuminuria in the presence of renin-angiotensin system blockade. These differences cannot be explained by effects on blood pressure or alpha1-antagonism but may relate to antioxidant properties of carvedilol.

While left ventricular (LV) structure and function differ between hypertensive women and men, it remains unclear whether sex affects regression of LV hypertrophy with antihypertensive treatment. We analysed paired echocardiograms in 500 men and 347 women enrolled in the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study at baseline and after 12 months of antihypertensive treatment with either losartan or atenolol. At enrolment, 177 women and 242 men were randomized to losartan-based treatment and 161 women and 247 men were randomized to atenolol-based treatment (sex difference=NS). After 12 months of antihypertensive treatment, blood pressure was lowered similarly in women (152/83 from 174/97 mmHg) and men (149/85 from 173/99 mmHg; both P<0.001, sex difference=NS), without significant change in body weight in either sex. Cardiac output and pulse pressure/stroke volume were equivalently reduced in both sexes (−0.2 vs −0.1 l/min and both –0.20 mmHg/ml/m2, respectively; both P=NS). Absolute LV mass change after 12 months of antihypertensive treatment was greater in men than in women (−30 vs −24 g, P=0.01). However, after adjusting for baseline LV mass and randomized study treatment, LV mass reduction was greater in women than in men (−33 vs −23 g, P=0.001). LV mass regression was greater in women, by 8.0±2.8 g, after adjusting for baseline LV mass and randomized study treatment. After consideration of baseline LV mass and randomized study treatment, antihypertensive treatment regressed LV hypertrophy more in women. Further studies are needed to identify the mechanisms and prognostic implications of this sex-related difference.

Context Anti hypertensive therapy is well established to reduce hypertension-related morbidity and mortality, but the optimal first-step therapy is unknown.Objective To determine whether treatment with a calcium channel blocker or an angiotensin-converting enzyme inhibitor lowers the incidence of coronary heart disease (CHD) or other cardiovascular disease (CVD) events vs treatment with a diuretic.Design The Anti hypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), a randomized, double-blind, active-controlled clinical trial conducted from February 1994 through March 2002.Setting and Participants A total of 33 357 participants aged 55 years or older with hypertension and at least 1 other CHD risk factor from 623 North American centers.Interventions Participants were randomly assigned to receive chlorthalidone, 12.5 to 25 mg/d (n= 15255); amlodipine, 2.5 to 10 mg/d (n =9048); or lisinopril, 10 to 40 mg/d (n=9054) for planned follow-up of approximately 4 to 8 years.Main Outcome Measures The primary outcome was combined fatal CHD or nonfatal myocardial infarction, analyzed by intent-to-treat. Secondary outcomes were all-cause mortality, stroke, combined CHD (primary outcome, coronary revascularization, or angina with hospitalization), and combined CVD (combined CHD, stroke, treated angina without hospitalization, heart failure [HF], and peripheral arterial disease).Results Mean follow-up was 4.9 years. The primary outcome occurred in 2956 participants, with no difference between treatments. Compared with chlorthaliclone (6-year rate, 11.5%), the relative risks (RRs) were 0.98 (95% Cl, 0.90-1.07) for amlodipine (6-year rate, 11.3%) and 0.99 (95% Cl, 0.91-1.08) for lisinopril (6-year rate, 11.4%). Likewise, all-cause mortality did not differ between groups. Five-year systolic blood pressures were significantly higher in the amlodipine (0.8 mm Hg, P=.03) and lisinopril (2 mm Hg, P<.001) groups compared with chlorthaliclone, and 5-year diastolic blood pressure was significantly lower with amlodipine (0.8 mm Hg, P<.001). For amlodipine vs chlorthaliclone, secondary outcomes were similar except for a higher 6-year rate of HF with amlodipine (10.2% vs 7.7%; RR, 1.38; 95% Cl, 1.25-1.52). For lisinopril vs chlorthaliclone, lisinopril had higher 6-year rates of combined CVD (33.3% vs 30.9%; RR, 1.10; 95% Cl, 1.05-1.16); stroke (6.3% vs 5.6%; RR, 1.15; 95% Cl, 1.02-1.30); and HF (8.7% vs 7.7%; RR, 1.19; 95% Cl, 1.07-1.31).Conclusion Thiazide-type diuretics are superior in preventing 1 or more major forms of CVD and are less expensive. They should be preferred for first-step antihypertensive therapy.

Hypertension is an important risk factor for cardiovascular disease (CVD) in patients with normal renal function. After reviewing over two decades of clinical trial data and an even longer history of epidemiologic data, multiple consensus panels worldwide have made recommendations for the aggressive treatment of hypertension using both lifestyle modification and drug therapy. These data and recommendations provide the basis of the recommendations for preventing CVD in patients with renal disease. Most patients should have elevated blood pressure (BP) lowered to less than 140 mm Hg systolic and less than 90 mm Hg diastolic. Earlier and more aggressive intervention is recommended in high-risk hypertensive patients with risk factors (especially diabetes mellitus) or evidence of target organ damage or clinical CVD. Lifestyle changes are indicated as either initial therapy or concomitant therapy in all hypertensive patients to lower BP and to normalize other CVD risk factors. There is general agreement that clinical outcome data from controlled clinical trials should guide the selection of antihypertensive agents. Currently, these data are only available for thiazide diuretics and beta-blockers for most hypertensive patients with normal renal function and for the dihydropyridine calcium channel blockers in older hypertensive patients with isolated systolic hypertension. However, data may support the use of other agents in hypertensives with selected comorbidity (eg, ACE inhibitors in heart failure, beta-blockers after myocardial infarction, and so forth). However, with only 25% of hypertensive patients controlled to less than 140/90 mm Hg, achieving blood pressure control remains the most important goal in managing hypertension in this population.

African Americans have excess hypertension and end-stage renal disease presumed due to hypertension compared to Caucasians. The AASK was designed to examine the impact of antihypertensive therapies and two levels of blood pressure control on the rate of decline of GFR in African Americans with presumed hypertensive renal disease. During the pilot phase of the trial, eligible participants were requested to undergo renal biopsy to assess the underlying lesions in this population. Eighty-eight hypertensive (diastolic BP > 95 mm Hg) non-diabetic African American patients between the ages of 18 to 70 years, with GFR between 25 to 70 ml/min/1.73 m2 and without marked proteinuria were assessed for possible renal biopsy. Forty-three patients did not undergo renal biopsy due to refusal or contraindications. Adequate renal biopsies were obtained in 39 of the remaining 46 patients. Biopsy findings were analyzed and then compared to clinical parameters. The 39 patients studied, 29 men and 10 women, were on average 53.0 +/- 11.0 years old, and had a MAP of 109 +/- 15 mm Hg and GFR 51.7 +/- 13.6 ml/min/1.73 m2 (not significantly different from nonbiopsied patients). Thirty-eight of these 39 biopsies showed arteriosclerosis and/or arteriolosclerosis, severity on average 1.5 +/- 0.9 and 1.5 +/- 0.8, respectively on a 0 to 3+ scale. Interstitial fibrosis was moderate, 1.3 +/- 0.9 (0 to 3+ scale). Segmental glomerulosclerosis was present in five biopsies, and in one patient, biopsy and clinical findings were consistent with idiopathic focal segmental glomerulosclerosis. Additional lesions included mesangiopathic glomerulonephritis in one patient, basement membrane thickening suggestive of diabetic nephropathy in one, and cholesterol emboli in two cases. Arteriolar and arterial sclerosis were tightly linked, and correlated with interstitial fibrosis and the reciprocal of serum creatinine. Global glomerulosclerosis was extensive, involving on average 43 +/- 26% of glomeruli. The extent of this lesion did not correlate with degree of arteriolar or arterial thickening, but did correlate with systolic blood pressure (P = 0.0174), the reciprocal of serum creatinine (P = 0.0009), serum cholesterol (P = 0.0129) and interstitial fibrosis (P < 0.0001). These data underscore that renal biopsies in non-diabetic hypertensive African-Americans with mild to moderate renal insufficiency in the absence of marked proteinuria are overwhelmingly likely to show renal vascular lesions consistent with the clinical diagnosis of hypertensive nephrosclerosis.