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Among patients with impaired glucose tolerance, the short-acting insulin secretagogue nateglinide did not reduce the incidence of diabetes over the course of 5 years. Nateglinide also did not reduce the risk of cardiovascular events. Therefore, nateglinide does not have a place in the management of impaired glucose tolerance. Among patients with impaired glucose tolerance, the short-acting insulin secretagogue nateglinide did not reduce the incidence of diabetes over the course of 5 years. Nateglinide also did not reduce the risk of cardiovascular events. Persons with impaired glucose tolerance are at increased risk for type 2 diabetes mellitus and cardiovascular disease 1 – 3 ; therefore, treatments that might reduce the incidence of diabetes and associated cardiovascular disease and death are potentially important. 3 The risk of diabetes is reduced with lifestyle interventions that involve increasing physical activity and reducing weight 4 – 6 and with metformin, 6 acarbose, 7 or rosiglitazone 8 therapy, but no trials to date have been powered to consider cardiovascular outcomes. Among persons with type 2 diabetes, reducing glycemia results in a small reduction in the risk of major macrovascular events. 9 Glucose levels after a glucose challenge, . . .

In this large clinical trial, the angiotensin-receptor blocker valsartan reduced the risk of diabetes in patients with impaired glucose tolerance. However, the effect was small, and there was no reduction in the rate of cardiovascular events. Thus, impaired glucose tolerance is probably best managed with lifestyle intervention. In this large clinical trial, the angiotensin-receptor blocker valsartan reduced the risk of diabetes in patients with impaired glucose tolerance. However, the effect was small, and there was no reduction in the rate of cardiovascular events. Patients with impaired glucose tolerance have an increased risk of type 2 diabetes mellitus and cardiovascular disease. 1 – 3 Interventions that might reduce the incidence of diabetes and associated rates of death and complications from cardiovascular causes in such patients are therefore of importance. 3 Several trials have shown that lifestyle modification, including increased physical activity and weight loss, reduces the risk of diabetes, although these trials did not evaluate cardiovascular outcomes. 3 – 8 Certain drugs, including metformin, acarbose, and rosiglitazone, also reduce the incidence of diabetes, although their effect on cardiovascular events is uncertain. 6 , 9 , 10 Another pharmacologic approach to reducing the . . .

This study investigated whether an angiotensin-receptor blocker (olmesartan) would delay microalbuminuria in patients with type 2 diabetes and normoalbuminuria. Olmesartan was associated with a delayed onset of microalbuminuria, even though blood pressure control in both groups was excellent. Diabetic nephropathy is an increasingly common cause of end-stage renal disease, 1 and the development and rate of renal deterioration are most closely related to the patient's blood pressure. Guideline committees worldwide concur that the blood pressure in patients with diabetes and chronic kidney disease should be kept at 130/80 mm Hg or less. 2 Microalbuminuria is predictive of diabetic nephropathy and premature cardiovascular disease 3 – 5 ; therefore, European and American guidelines recommend that patients with diabetes be tested for microalbuminuria. 6 , 7 Overactivity of the renin–angiotensin system has been implicated in the deterioration of renal function in patients with diabetic nephropathy and . . .

Increased excretion of albumin in urine might be a marker of the various pathophysiological changes that arise in patients with heart failure. Therefore our aim was to assess the prevalence and prognostic value of a spot urinary albumin to creatinine ratio (UACR) in patients with heart failure. UACR was measured at baseline and during follow-up of 2310 patients in the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) Programme. The prevalence of microalbuminuria and macroalbuminuria, and the predictive value of UACR for the primary composite outcome of each CHARM study—ie, death from cardiovascular causes or admission to hospital with worsening heart failure—and death from any cause were assessed. 1349 (58%) patients had a normal UACR, 704 (30%) had microalbuminuria, and 257 (11%) had macroalbuminuria. The prevalence of increased UACR was similar in patients with reduced and preserved left ventricular ejection fractions. Patients with an increased UACR were older, had more cardiovascular comorbidity, worse renal function, and a higher prevalence of diabetes mellitus than did those with normoalbuminuria. However, a high prevalence of increased UACR was still noted among patients without diabetes, hypertension, or renal dysfunction. Elevated UACR was associated with increased risk of the composite outcome and death even after adjustment for other prognostic variables including renal function, diabetes, and haemoglobin A 1c. The adjusted hazard ratio (HR) for the composite outcome in patients with microalbuminuria versus normoalbuminuria was 1·43 (95% CI 1·21–1·69; p<0·0001) and for macroalbuminuria versus normoalbuminuria was 1·75 (1·39–2·20; p<0·0001). The adjusted values for death were 1·62 (1·32–1·99; p<0·0001) for microalbuminuria versus normoalbuminuria, and 1·76 (1·32–2·35; p=0·0001) for macroalbuminuria versus normoalbuminuria. Treatment with candesartan did not reduce or prevent the development of excessive excretion of urinary albumin. Increased UACR is a powerful and independent predictor of prognosis in heart failure. AstraZeneca.

Urinary neutrophil gelatinase-associated lipocalin (Ngal or lipocalin 2) is a very early and sensitive biomarker of kidney injury. Here we determined the origin and time course of Ngal appearance in several experimental and clinically relevant renal diseases. Urinary Ngal levels were found to be markedly increased in lipoatrophic- and streptozotocin-induced mouse models of diabetic nephropathy. In the latter mice, the angiotensin receptor blocker candesartan dramatically decreased urinary Ngal excretion. The reabsorption of Ngal by the proximal tubule was severely reduced in streptozotocin-induced diabetic mice, but upregulation of its mRNA and protein in the kidney was negligible, compared to those of control mice, suggesting that increased urinary Ngal was mainly due to impaired renal reabsorption. In the mouse model of unilateral ureteral obstruction, Ngal protein synthesis was dramatically increased in the dilated thick ascending limb of Henle and N was found in the urine present in the swollen pelvis of the ligated kidney. Five patients with nephrotic syndrome or interstitial nephritis had markedly elevated urinary Ngal levels at presentation, but these decreased in response to treatment. Our study shows that the urinary Ngal level may be useful for monitoring the status and treatment of diverse renal diseases reflecting defects in glomerular filtration barrier, proximal tubule reabsorption, and distal nephrons.

Chronic heart failure (CHF) is an important cause of hospital admission and death. Poor adherence to medication is common in some chronic illnesses and might reduce the population effectiveness of proven treatments. Because little is known about adherence in patients with CHF and about the consequences of non-adherence, we assessed the association between adherence and clinical outcome in the CHARM (Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity) programme. CHARM was a double-blind, randomised, controlled clinical trial, comparing the effects of the angiotensin receptor blocker candesartan with placebo in 7599 patients with CHF. Median follow-up was 38 months. The proportion of time patients took more than 80% of their study medication was defined as good adherence and 80% or less as poor adherence. We used a Cox proportional hazards regression model, with adherence as a time-dependent covariate in the model, to examine the association between adherence and mortality in the candesartan and placebo groups. We excluded 187 patients because of missing information on adherence. In the time-dependent Cox regression model, after adjustment for predictive factors (demographics, physiological and severity-of-illness variables, smoking history, and number of concomitant medications), good adherence was associated with lower all-cause mortality in all patients (hazard ratio [HR] 0·65, 95% CI 0·57–0·75, p<0·0001). The adjusted HR for good adherence was similar in the candesartan (0·66, 0·55–0·81, p<0·0001) and placebo (0·64, 0·53–0·78, p<0·0001) groups. Good adherence to medication is associated with a lower risk of death than poor adherence in patients with CHF, irrespective of assigned treatment. This finding suggests that adherence is a marker for adherence to effective treatments other than study medications, or to other adherence behaviours that affect outcome. Understanding these factors could provide an opportunity for new interventions, including those aimed at improving adherence.

Atrial fibrillation (AF) is frequent in patients with chronic heart failure (CHF). Experimental and small patient studies have demonstrated that blocking the renin-angiotensin-aldosterone system may prevent AF. In the CHARM program, the effects of the angiotensin receptor blocker candesartan on cardiovascular mortality and morbidity were evaluated in a broad spectrum of patients with symptomatic CHF. CHARM provided the opportunity to prospectively determine the effect of candesartan on the incidence of new AF in this CHF population. 7601 patients with symptomatic CHF and reduced or preserved left ventricular systolic function were randomized to candesartan (target dose 32 mg once daily, mean dose 24 mg) or placebo in the 3 component trials of CHARM. The major outcomes were cardiovascular death or CHF hospitalization and all-cause mortality. The incidence of new AF was a prespecified secondary outcome. Median follow-up was 37.7 months. A conditional logistic regression model for stratified data was used. 6379 patients (83.9%) did not have AF on their baseline electrocardiogram. Of these, 392 (6.15%) developed AF during follow-up, 177 (5.55%) in the candesartan group and 215 (6.74%) in the placebo group (odds ratio 0.812, 95% CI 0.662-0.998, P = .048). After adjustment for baseline covariates, the odds ratio was 0.802 (95% CI 0.650-0.990, P = .039). There was no heterogeneity of the effects of candesartan in preventing AF between the 3 component trials ( P = .57). Treatment with the angiotensin receptor blocker candesartan reduced the incidence of AF in a large, broadly-based, population of patients with symptomatic CHF.

Angiotensin II Type 1 Receptor Blockade Improves β-Cell Function and Glucose Tolerance in a Mouse Model of Type 2 Diabetes Kwan Yi Chu 1 , Tung Lau 1 , Per-Ola Carlsson 2 and Po Sing Leung 1 1 Department of Physiology, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong, China 2 Departments of Medical Cell Biology and Medical Sciences, Uppsala University, Uppsala, Sweden Address correspondence and reprint requests to Professor P. S. Leung, PhD, Department of Physiology, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong. E-mail: psleung{at}cuhk.edu.hk Abstract We identified an angiotensin-generating system in pancreatic islets and found that exogenously administered angiotensin II, after binding to its receptors (angiotensin II type 1 receptor [AT1R]), inhibits insulin release in a manner associated with decreased islet blood flow and (pro)insulin biosynthesis. The present study tested the hypothesis that there is a change in AT1R expression in the pancreatic islets of the obesity-induced type 2 diabetes model, the db/db mouse, which enables endogenous levels of angiotensin II to impair islet function. Islets from 10-week-old db/db and control mice were isolated and investigated. In addition, the AT1R antagonist losartan was administered orally to 4-week-old db/db mice for an 8-week period. We found that AT1R mRNA was upregulated markedly in db/db islets and double immunolabeling confirmed that the AT1R was localized to β-cells. Losartan selectively improved glucose-induced insulin release and (pro)insulin biosynthesis in db/db islets. Oral losartan treatment delayed the onset of diabetes, and reduced hyperglycemia and glucose intolerance in db/db mice, but did not affect the insulin sensitivity of peripheral tissues. The present findings indicate that AT1R antagonism improves β-cell function and glucose tolerance in young type 2 diabetic mice. Whether islet AT1R activation plays a role in the pathogenesis of human type 2 diabetes remains to be determined. AT1R, angiotensin II type 1 receptor KRBB, Krebs-Ringer bicarbonate buffer OGTT, oral glucose tolerance test RAS, renin-angiotensin system Footnotes Accepted November 10, 2005. Received August 8, 2005. DIABETES

This study aimed to determine whether early administration of drugs that block the renin–angiotensin system slows the progression of change in glomerular mesangial fractional volume and retinopathy progression of two steps or more, according to the retinopathy severity scale. Early blockade of the renin–angiotensin system did not modify nephropathy progression in patients with type 1 diabetes but had important effects in slowing retinopathy. Early blockade of the renin–angiotensin system did not modify nephropathy progression in patients with type 1 diabetes but had important effects in slowing retinopathy. Diabetic nephropathy, responsible for more than 45% of cases of end-stage renal disease in the United States, 1 may be structurally advanced once albuminuria becomes detectable. 2 , 3 Blockers of the renin–angiotensin system are more effective than other antihypertensive agents in slowing nephropathy progression in patients who have proteinuria, diabetes mellitus, and a reduced glomerular filtration rate (GFR), 4 – 6 and such blockers can also decrease proteinuria in patients with diabetes. 7 Although the reduction of proteinuria in patients with diabetes has been associated with a reduction in the rate of decline in GFR in small studies, 8 this association has not been systematically tested; . . .

The dysfunction of the renin-angiotensin system (RAS) has been observed in coronavirus infection disease (COVID-19) patients, but whether RAS inhibitors, such as angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II type 1 receptor blockers (ARBs), are associated with clinical outcomes remains unknown. COVID-19 patients with hypertension were enrolled to evaluate the effect of RAS inhibitors. We observed that patients receiving ACEI or ARB therapy had a lower rate of severe diseases and a trend toward a lower level of IL-6 in peripheral blood. In addition, ACEI or ARB therapy increased CD3 and CD8 T cell counts in peripheral blood and decreased the peak viral load compared to other antihypertensive drugs. This evidence supports the benefit of using ACEIs or ARBs to potentially contribute to the improvement of clinical outcomes of COVID-19 patients with hypertension.