Artur B. Ribeiro

Angiotensin II antagonists for hypertension: are there differences in efficacy?

We compared the antihypertensive efficacy of available drugs in the new angiotensin-II-antagonist (AIIA) class. The antihypertensive efficacy of losartan, valsartan, irbesartan, and candesartan was evaluated from randomized controlled trials (RCT) by performing a metaanalysis of 43 published RCT. These trials involved AIIA compared with placebo, other antihypertensive classes, and direct comparisons between AIIA. A weighted-average for diastolic and systolic blood pressure reduction with AIIA monotherapy, dose titration, and with addition of low-dose hydrochlorothiazide (HCTZ) were calculated. Weighted-average responder rates were also determined. The metaanalysis assessed a total of 11,281 patients. The absolute weighted-average reductions in diastolic (8.2 to 8.9 mm Hg) and systolic (10.4 to 11.8 mm Hg) blood pressure reductions (not placebo-corrected) for AIIA monotherapy were comparable for all AIIA. Responder rates for AIIA monotherapy were 48% to 55%. Dose titration resulted in slightly greater blood pressure reduction and an increase in responder rates to 53% to 63%. AIIA/hydrochlorothiazide combinations produced substantially greater reduction in systolic (16.1 to 20.6 mm Hg) and diastolic (9.9 to 13.6 mm Hg) blood pressure reductions than AIIA monotherapy and responder rates for AIIA/HCTZ combinations were 56% to 70%. This comprehensive analysis shows comparable antihypertensive efficacy within the AIIA class, a near-flat AIIA-dose response when titrating from starting to maximum recommended dose, and substantial potentiation of the antihypertensive effect with addition of HCTZ.

Ultrasonography for the Evaluation of Visceral Fat and Cardiovascular Risk

Visceral fat accumulation is associated with increased cardiovascular risk. Clinical evaluation of visceral fat is limited because of the lack of reliable and low-cost methods. To assess the correlation between ultrasonography and computed tomography (CT) for the evaluation of visceral fat, 101 obese women, age 50.5±7.7 years with a body mass index of 39.2±5.4 kg/m2, were submitted to ultrasonograph and CT scans. Visceral fat measured by ultrasonography, 1 cm above the umbilical knot, showed a high correlation with CT-determined visceral fat (r =0.67, P <0.0001). The ultrasonograph method showed good reproducibility with an intra-observer variation coefficient of <2%. Both ultrasonograph and CT visceral fat values were correlated with fasting insulin (r =0.29 and r =0.27, P <0.01) and plasma glucose 2 hours after oral glucose load (r =0.22 and r =0.34, P <0.05), indicating that ultrasonography is a useful method to evaluate cardiovascular risk. A significant correlation was also found between visceral fat by CT and serum sodium (r =0.18, P <0.05). A ultrasonograph-determined visceral-to-subcutaneous fat ratio of 2.50 was established as a cutoff value to define patients with abdominal visceral obesity. This value also identified patients with higher levels of plasma glucose, serum insulin and triglycerides and lower levels of HDL-cholesterol, which are metabolic abnormalities characteristic of the metabolic syndrome. Our data demonstrate that ultrasonography is a precise and reliable method for evaluation of visceral fat and identification of patients with adverse metabolic profile.

Treatment of Obesity Hypertension and Diabetes Syndrome

Obesity has been shown to be an independent risk factor for coronary heart disease. The insulin resistance associated with obesity contributes to the development of other cardiovascular risk factors, including dyslipidemia, hypertension, and type 2 diabetes. The coexistence of hypertension and diabetes increases the risk for macrovascular and microvascular complications, thus predisposing patients to cardiac death, congestive heart failure, coronary heart disease, cerebral and peripheral vascular diseases, nephropathy, and retinopathy. Body weight reduction increases insulin sensitivity and improves both blood glucose and blood pressure control. Metformin therapy also improves insulin sensitivity and has been associated with decreases in cardiovascular events in obese diabetic patients. Antihypertensive treatment in diabetics decreases cardiovascular mortality and slows the decline in glomerular function. However, pharmacological treatment should take into account the effects of the antihypertensive agents on insulin sensitivity and lipid profile. Diuretics and beta-blockers are reported to reduce insulin sensitivity and increase triglyceride levels, whereas calcium channel blockers are metabolically neutral and ACE inhibitors increase insulin sensitivity. For the high-risk hypertensive diabetic patients, ACE inhibition has proven to confer additional renal and vascular protection. Because hypertension and glycemic control are very important determinants of cardiovascular outcome in obese diabetic hypertensive patients, weight reduction, physical exercise, and a combination of antihypertensive and insulin sensitizers agents are strongly recommended to achieve target blood pressure and glucose levels.

Comparison of the effects of losartan and atenolol on common carotid artery intima-media thickness in patients with hypertension: results of a 2-year, double-blind, randomized, controlled study.

BACKGROUNDnHypertension induces progressive pathologic changes in the arterial wall. Experimental findings suggest that these changes, which include intima-media thickening, may be mediated, at least in part, by angiotensin II (AII).nnnOBJECTIVEnThe Losartan Vascular Regression Study (LAARS) was a double-blind, parallel-group, randomized, controlled, multicenter study designed to compare the effects of the AII antagonist losartan and the beta-blocker atenolol on ultrasonographically determined intimamedia thickness (IMT) of the common carotid artery (CCA) in patients with mild to moderate essential hypertension.nnnMETHODSnThe primary end point of the study was the yearly rate of change (YRC) from baseline of the mean IMT of the CCA (CCA-IMT(mean)) averaged over 2 years of treatment. Secondary end points included IMT of the common femoral artery and sitting systolic and diastolic blood pressures (SiSBP/SiDBP). Safety assessments of losartan and atenolol were made by statistical and clinical review of the incidence of adverse experiences as well as review of vital signs and laboratory values. A total of 414 patients with essential hypertension were screened for study inclusion at 36 study centers in Germany and Brazil. Patients received losartan (50 mg once daily) or atenolol (50 mg once daily) for 24 months. Target blood pressure (SiSBP/SiDBP <140/<90 mm Hg) was achieved by adding hydrochlorothiazide 12.5 mg once daily, doubling the dose of study drug, or adding an open-label calcium channel blocker sequentially, as needed.nnnRESULTSnOf the original 414 patients screened, 280 hypertension patients (SiDBP 95-115 mm Hg), aged 35 to 65 years, with an IMT of 0.8 to 1.5 mm of the right or left CCA, were randomized to treatment with either losartan (n = 142) or atenolol (n = 138). Both losartan and atenolol therapy produced comparable reductions in CCA-IMTmean over 24 months compared with baseline; the average YRC was -0.038 +/- 0.004 mm/y (P < or = 0.001) for losartan and -0.037 +/- 0.004 mm/y (P < or = 0.001) for atenolol. There were no significant differences between groups. Losartan showed a greater reduction of femoral artery IMT than did atenolol; the average YRC was -0.024 mm/y (P < or = 0.05) for losartan and -0.017 mm/y for atenolol (P = NS), with no significant difference between groups. Both agents produced similar significant reductions in SiSBP and SiDBP and were generally well tolerated. Approximately 7% of losartan patients had drug-related clinical adverse events, compared with 12% of atenolol patients.nnnCONCLUSIONSnThe findings of LAARS, the first large study with an AII antagonist that examined IMT, suggest that AII antagonism reverses the early stages of vascular hypertrophy in patients with hypertension. Further studies are needed to delineate the relative importance of AII antagonism versus blood pressure reduction per se in mediating the beneficial vascular effects of losartan.

Effect of blood glucose on left ventricular mass in patients with hypertension and type 2 diabetes mellitus

The aim of our prospective study was to evaluate the influence of blood glucose (BG) on left ventricular mass and diastolic function in patients with hypertension and type 2 diabetes mellitus (DM). Fifty-six hypertensive patients with type 2 DM and 26 healthy controls were investigated. They were submitted to echocardiography (ECHO) with Doppler and we calculated the mean of their fasting BG values, office blood pressure (OBP), cholesterol and fractions, and triglycerides during the previous 4 years. The diabetic patients were then followed-up for 1 year with OBP, fasting BG, and lipids measured every 2 months. After this period, the patients were again submitted to ECHO and in 22 patients (group I [GI]), reductions greater than 10% in left ventricular mass index (LVMI) were observed (122 +/- 35 v 89 +/- 23 g/m2, P < .01), whereas increases greater than 10% (group II [GII], n = 17) (94 +/- 18 v 115 +/- 27 g/m2, P < .01) or no changes (group III [GIII], n = 17) (98 +/- 16 v 99 +/- 18 g/m2, NS) in LVMI were detected in the remaining patients. The OBP values did not change during the follow-up. In GI the reduction of LVMI was associated with a BG fall from 178 +/- 36 to 147 +/- 30 mg/dL (P < .01) and a correlation was observed between BG and LVMI percent variations (delta) (r = 0.48, P < .01). No important changes in left ventricular diastolic function were observed during the follow-up. We concluded that the improvement in glycemic control may contribute to LVH regression in hypertensive patients with type 2 DM.

Obesidade visceral, hipertensão arterial e risco cárdio-renal: uma revisão

Great part of obesity adversity is due to its cardiovascular/coronary risk, particularly present in obese with visceral adiposity distribution. Visceral fat deposition is known to be associated with a greater prevalence of metabolic, neurohormonal, inflammatory and hemodynamic disorders, which together will be implicated in microvascular and target organ involvement, particularly to the cardio-renal axis. In this aspect, beyond its classical association with coronary disease, visceral obesity has been associated with left ventricular hypertrophy and microalbuminuria, which are known cardiac and nephrologic risk factors. So, therapeutic tools for obese patients, specially for those with hypertension, must accomplish the risk stratification based on body fat distribution, which will allow a more adequate therapy in terms of risk factors control as well as target organ damage monitoring.

Angiotensin II antagonists - therapeutic benefits spanning the cardiovascular disease continuum from hypertension to heart failure and diabetic nephropathy

ABSTRACT Background:u2002The cardiovascular benefits of angiotensin II antagonists (AIIAs) have been evaluated not only in terms of their ability to lower blood pressure but also on their ability to prevent strokes, cardiac events, and target organ damage. This review summarizes the body of evidence-based data demonstrating the efficacy of AIIAs across the spectrum of cardiovascular disease. Methods:u2002A PubMed/MEDLINE search of English-language articles (1990 to September 2005) was used to identify articles describing clinical studies, particularly outcome trials, or mechanisms of therapeutic action pertinent to the therapy of cardiovascular disease or nephropathy. Findings:u2002The antihypertensive efficacy of AIIAs is apparent across a wide spectrum of hypertensive patients, including black and Asian patients and patients with isolated systolic hypertension. More importantly, large outcome-based studies have demonstrated the efficacy of AIIAs across the continuum of cardiovascular disease, including hypertension, heart failure, post-myocardial infarction, and diabetic nephropathy. The Losartan Intervention For Endpoint reduction in hypertension study (LIFE), Reduction of Endpoints in Non-insulin-dependent Diabetes Mellitus with the AII Antagonist Losartan (RENAAL), and the Irbesartan Type 2 Diabetic Nephropathy Trial (IDNT) indicate that AIIAs confer cardiovascular and renal protective effects beyond their ability to lower blood pressure. These blood-pressure independent protective benefits of AIIAs may arise not only by blocking the deleterious effects of AII mediated via the AT1‐receptor but may also be due to beneficial molecule-specific effects. As a class, AIIAs are well tolerated with an overall adverse event profile generally comparable to placebo and superior to that typically seen with calcium channel blockers, ACE inhibitors, diuretics, and beta-blockers. Conclusions:u2002By utilizing the body of clinical trial evidence as a guide to rational prescribing of AIIAs, practitioners can expect to deliver clinical benefits to their patients in terms of survival, prognosis, and quality of life.BACKGROUNDnThe cardiovascular benefits of angiotensin II antagonists (AIIAs) have been evaluated not only in terms of their ability to lower blood pressure but also on their ability to prevent strokes, cardiac events, and target organ damage. This review summarizes the body of evidence-based data demonstrating the efficacy of AIIAs across the spectrum of cardiovascular disease.nnnMETHODSnA PubMed/MEDLINE search of English-language articles (1990 to September 2005) was used to identify articles describing clinical studies, particularly outcome trials, or mechanisms of therapeutic action pertinent to the therapy of cardiovascular disease or nephropathy.nnnFINDINGSnThe antihypertensive efficacy of AIIAs is apparent across a wide spectrum of hypertensive patients, including black and Asian patients and patients with isolated systolic hypertension. More importantly, large outcome-based studies have demonstrated the efficacy of AIIAs across the continuum of cardiovascular disease, including hypertension, heart failure, post-myocardial infarction, and diabetic nephropathy. The Losartan Intervention For Endpoint reduction in hypertension study (LIFE), Reduction of Endpoints in Non-insulin-dependent Diabetes Mellitus with the AII Antagonist Losartan (RENAAL), and the Irbesartan Type 2 Diabetic Nephropathy Trial (IDNT) indicate that AIIAs confer cardiovascular and renal protective effects beyond their ability to lower blood pressure. These bloodpressure independent protective benefits of AIIAs may arise not only by blocking the deleterious effects of AII mediated via the AT1-receptor but may also be due to beneficial molecule-specific effects. As a class, AIIAs are well tolerated with an overall adverse event profile generally comparable to placebo and superior to that typically seen with calcium channel blockers, ACE inhibitors, diuretics, and beta-blockers.nnnCONCLUSIONSnBy utilizing the body of clinical trial evidence as a guide to rational prescribing of AIIAs, practitioners can expect to deliver clinical benefits to their patients in terms of survival, prognosis, and quality of life.

Serum Insulin Levels, 24-Hour Blood Pressure Profile, and Left Ventricular Mass in Nonobese Hypertensive Patients

In essential hypertensive patients, considered to be insulin-resistant, a blunted decline in nocturnal blood pressure is associated with increased adrenergic tone and left ventricular mass. Since insulin stimulates the sympathetic system, we tested whether insulin resistance and insulinemia influence left ventricular mass and the 24-hour blood pressure profile. We studied 29 nonobese hypertensive patients with office diastolic pressure between 95 and 110 mm Hg and normal oral glucose tolerance test after a 4-month washout period. They were then assigned to M-mode echocardiographic evaluation and 24-hour ambulatory blood pressure monitoring. The glucose and insulin responses to a 75-g oral glucose load were compared with those obtained in 16 weight-matched normotensive control subjects. During the oral glucose tolerance test the hypertensive patients compared with control subjects presented higher levels of glucose at 60 minutes (138.7 +/- 30.3 versus 108.7 +/- 35.7 mg/dL; P < .05) and 90 minutes (114.0 +/- 23.8 versus 94.8 +/- 31.1 mg/dL; P < .05) and insulin at 60 minutes (287.1 +/- 259.4 versus 142.1 +/- 83.9 pmol/L; P < .05). However, peak insulin levels after glucose load did not correlate with ambulatory blood pressure values or left ventricular mass index. Left ventricular mass index showed significant correlation with mean sleeping systolic pressure (rs = 56, P < .05) and diurnal systolic pressure (rs = .37, P < .05) but not with mean diurnal or sleeping diastolic pressures. In conclusion, our results indicate that in nonobese hypertensive patients, insulin resistance does not have any influence on the 24-hour blood pressure profile or on left ventricular mass index.(ABSTRACT TRUNCATED AT 250 WORDS)

The Role of Angiotensin II Antagonism in Type 2 Diabetes Mellitus: A Review of Renoprotection Studies

BACKGROUNDnDiabetic nephropathy is the leading cause of end-stage renal disease (ESRD) in Western and Asian countries. Effective antihypertensive therapy reduces the rate of decline in renal function and postpones ESRD in patients with diabetic nephropathy.nnnOBJECTIVEnThis review presents evidence from studies on how blood pressure control, plasma glucose control, and the presence of proteinuria determine outcomes in diabetic patients. The role of angiotensin II (All) in the development of diabetic nephropathy and the reno- and cardiobeneficial effects of AII antagonism in patients with type 2 diabetes mellitus (DM-2) and diabetic nephropathy also are addressed.nnnMETHODSnArticles included in this review were found using a MEDLINE search for studies published from 1991 to 2001 and including the search terms diabetic nephropathy, type 2 diabetes mellitus, microalbuminuria, proteinuria, angiotensin receptor blockade, angiotensin-converting enzyme inhibition, and cardiovascular disease. Articles reporting new data, new mechanisms, major clinical trials, and our own data were included.nnnRESULTSnRecently, the Reduction of Endpoints in NIDDM (non-insulin-dependent diabetes mellitus) with the Angiotensin II Antagonist Losartan (RENAAL) trial provided sufficient data to conclude that the blockade of the All AT1 receptor with losartan confers renoprotection in patients with DM-2 and nephropathy. Similar results were obtained with irbesartan in the Irbesartan Diabetic Nephropathy Trial (IDNT) and the Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria study (IRMA 2). The results of RENAAL indicate that the renoprotective effects of losartan were attributable to effects beyond blood pressure control. In addition to the favorable impact of the All blockade on blood pressure and renal hemodynamics, the blockade of the growth-promoting, profibrotic, nonhemodynamic actions of AII also may be important for renoprotection. Intensive blood pressure control also confers cardiovascular protection in pa- tients with DM-2. Some studies suggest that the blockade of the renin-angiotensin system confers superior cardioprotective effects in patients with DM-2. The RENAAL study also showed cardioprotection with losartan, with an important reduction in the risk for first hospitalization for heart failure.nnnCONCLUSIONnEvidence supports the importance of an effective blockade of AII action for both reno- and cardioprotection in patients with DM-2.

Uric acid as a marker for renal dysfunction in hypertensive women on diuretic and nondiuretic therapy.

Hyperuricemia is a common finding in hypertensive patients, especially among those who are on diuretic therapy. However, its clinical relevance regarding cardiovascular and chronic kidney disease (CKD) has not clearly been established. The authors assessed whether, in a population of 385 hypertensive women categorized according to diuretic therapy, the stratification in quartiles by uric acid levels would identify a gradient of changes in renal function and in risk factors for cardiovascular disease. The following were evaluated: serum uric acid, glycemia, total and fractional cholesterol, triglycerides, apolipoprotein (Apo) B, Apo A‐I, and C‐reactive protein. Renal function was assessed by serum creatinine, albuminuria, and estimated glomerular filtration rate (eGFR) by the Modification of Diet in Renal Disease equation, whereas cardiovascular risk was estimated through the Framingham score. A total of 246 women were on diuretic therapy; 139 were taking other antihypertensive medications. There was a reduction in eGFR parallel to the increase in uric acid levels, regardless of diuretic use and without a concomitant increase in albuminuria. In both groups, higher uric acid levels translated into an increase in metabolic syndrome components, in markers of insulin resistance, triglyceride/high‐density lipoprotein levels, and Apo B/Apo A‐I ratios, as well as in Framingham scores. Hyperuricemia was associated with an increase in inflammatory markers only in patients on diuretic therapy. In a binary logistic regression, hyperuricemia (uric acid >6.0u2003mg/dL) was independently associated with CKD (eGFR <60u2003mL/min/1.73u2003m²) (odds ratio, 2.63; 95% confidence interval, 1.61–4.3; P<.001). In hypertensive women, the presence of hyperuricemia indicated a substantial degree of kidney dysfunction as well as a greater cardiovascular risk profile.