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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Renin angiotensin system inhibitor therapy is seldom offered to individuals who have diabetes and advanced chronic kidney disease because of safety concerns. In this post hoc, secondary analysis of the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) trial, angiotensin antagonism risk/benefit profile was assessed in 1513 individuals with type 2 diabetes and overt nephropathy. Incidence of ESRD, hospitalizations for heart failure, withdrawals for adverse events, and proteinuria during losartan or conventional treatment were compared within three tertiles of baseline serum creatinine concentration (highest, 2.1 to 3.6 mg/dl; middle, 1.6 to 2.0 mg/dl; lowest, 0.9 to 1.6 mg/dl). Losartan decreased the risk of ESRD by 24.6, 26.3, and 35.3% in highest, middle, and lowest tertiles, respectively. For every 100 patients with serum creatinine >2.0, 1.6 to 2.0, or <1.6 mg/dl, respectively, 4 yr of losartan therapy was estimated to save 18.9, 8.4, and 2.9 ESRD events and US$1,502,855, US$1,021,770, and US$528,591 costs for renal replacement therapy. Losartan also decreased the hospitalizations for heart failure by 50.2 and 45.1, in the highest and middle tertile, respectively. Withdrawals for adverse events other than heart failure were comparable between tertiles and treatment groups. Proteinuria decreased more on losartan than on placebo in all tertiles (highest, 24 versus -8%; middle, 16 versus -8%; lowest, 15 versus -10%). In proteinuric individuals with type 2 diabetes, losartan therapy reduced ESRD and hospitalizations for heart failure and was well tolerated at all levels of renal function. Angiotensin II antagonism is a suitable and well-tolerated treatment for individuals with type 2 diabetes even with GFR levels approaching renal replacement therapy.
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PMID:Continuum of renoprotection with losartan at all stages of type 2 diabetic nephropathy: a post hoc analysis of the RENAAL trial results. 1557 15

We discuss combination therapy with angiotensin receptor antagonists (angiotensin receptor blockers; ARBs) and thiazide diuretics in light of the independent actions of both types of agents, and the adverse effects of both agents independently and in the context of the physiologic synergy achieved in using these agents together. ARBs counteract many of the adverse events associated with the use of thiazide diuretics and have been shown to reduce the occurrence of new-onset diabetes mellitus. We also review outcome trials in patients with hypertension (such as LIFE [Losartan Intervention For Endpoint reduction in hypertension], VALUE [Valsartan Antihypertensive Long-term Use Evaluation], and SCOPE [Study on COgnition and Prognosis in the Elderly]), in which losartan, valsartan, and candesartan cilexetil were used in combination with hydrochlorothiazide. Fixed combination ARB/hydrochlorothiazide agents make sense as initial therapy for patients in whom BP is >20/10 mm Hg above goal.
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PMID:Fixed-dose combinations in the management of hypertension: defining the place of angiotensin receptor antagonists and hydrochlorothiazide. 1563 34

Rates of type 2 diabetes mellitus are increasing worldwide at an explosive rate. This "epidemic" is largely driven by a concomitant obesity epidemic, which is seen not only in affluent countries, but in industrializing countries as well, concomitant with the rapid change toward Western life-style patterns worldwide. Recent clinical trials such as Heart Outcomes Prevention Evaluation (HOPE), Losartan Intervention for Endpoint reduction (LIFE), and Study of Cognition and Prognosis in the Elderly (SCOPE) have indicated that blocking the renin-angiotensin system (RAS) may reduce the risk of developing type 2 diabetes mellitus. This effect may be explained by a variety of diabetogenic factors, which seem to be moderated by angiotensin II, such as free fatty acids (FFA) and the phenomena of adipocyte differentiation, as well as inflammation and oxidative damage. Insulin resistance, usually present in cases of impaired glucose tolerance, is the major identifiable defect in subjects at risk for type 2 diabetes. Elevated FFA levels result in reduced activation of phosphoinositol-3 kinase, an enzyme that is essential for normal insulin-stimulated glucose uptake. This reduction is potentiated by angiotensin II and consequently insulin-stimulated glucose uptake is improved by RAS inhibition. Furthermore, blockade of the angiotensin II AT(1)-receptor has been shown to stimulate the differentiation of adipocytes that store FFAs, which leads to reduced plasma FFA levels and decreased insulin resistance. There are also data suggesting that AT(1)-receptor blockade reduces inflammatory activation and the production of reactive oxygen species (ROS), a major factor in the pathophysiology of diabetes and a major cardiovascular risk factor. Both proinflammatory molecules and ROS increase the risk of insulin resistance and atherogenesis. It is thought that FFAs and hyperglycemia increase ROS production and oxidative stress, leading to the activation of signaling molecules such as nuclear factor kappa-B and other mediators of stress-sensitive pathways, which increases insulin resistance and will lead to beta-cell dysfunction and diabetic complications during the longer term. Inhibiting the RAS seems to have an effect on several steps in this cascade. There is an obvious need for large-scale clinical trials specifically designed to assess the protective benefits of blocking the RAS in individuals at risk of developing type 2 diabetes. Two such trials on the prevention of type 2 diabetes are ongoing, the Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medications (DREAM) study and the more ambitious Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial, which is also assessing prevention of cardiovascular events.
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PMID:Of the renin-angiotensin system and reactive oxygen species Type 2 diabetes and angiotensin II inhibition. 1569 26

Hypertension is a powerful risk factor for cardiovascular (CV) morbidity and mortality; therefore, blood pressure (BP) lowering plays a central role in reducing the cardiovascular complications of hypertension, including stroke. Recent outcomes studies--Losartan Intervention For Endpoint reduction in hypertension, Reduction of Endpoints in Non-insulin-dependent Diabetes Mellitus with the Angiotensin II Antagonist Losartan, and the Irbesartan Type 2 Diabetic Nephropathy Trial--suggest that some angiotensin II antagonists are associated with CV and renal effects beyond their ability to lower BP in patients with hypertension or diabetic nephropathy and may play a role in the prevention of new-onset type 2 diabetes. Angiotensin II antagonists are associated with a wide variety of vascular, cardiac, and renal effects, as well as molecule-specific effects independent of those induced by the angiotensin-I receptor. These actions may offer a mechanistic explanation for the outcome benefits observed in patients with hypertension or diabetic nephropathy. Angiotensin-converting enzyme inhibitors and calcium-channel blockers may also have effects that are not completely explained by differences in the antihypertensive response to these agents, but the evidence is less robust. Collectively, these findings suggest that management of patients with hypertension, with or without diabetes or renal disease, should no longer be viewed as simply a matter of correcting elevated BP. Antihypertensive agents that possess CV benefits beyond their BP-reducing effects should be used to prevent the development of end-organ damage.
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PMID:Do angiotensin II antagonists provide benefits beyond blood pressure reduction? 1602 Apr 2

We hypothesized that losartan was superior to atenolol in reducing cardiovascular events in a lower-risk group (LRG) versus a higher-risk group (HRG) of patients in a Losartan Intervention For Endpoint reduction (LIFE) substudy, independently of blood pressure (BP) reduction. In a post hoc analysis, we designated 4282 patients as LRG on the basis of: (1) no previous cardiovascular disease (coronary, cerebral, peripheral vascular disease); (2) no diabetes; (3) no isolated systolic hypertension; and (4) inclusion of the lowest 3 quartiles of electrocardiographically documented left ventricular hypertrophy. The HRG consisted of 4911 remaining patients who did not qualify for the LRG. In the LRG, losartan was superior to atenolol in reducing stroke: hazard ratio (HR), 0.72 (95% confidence interval [CI], 0.53 to 0.98); new-onset diabetes (HR, 0.74 [95% CI, 0.58 to 0.93]; and new-onset atrial fibrillation: HR, 0.69 (95% CI, 0.51 to 0.92), all P<0.05 but not composite end points or cardiovascular mortality (both P=NS). In the HRG, losartan was superior to atenolol in reducing composite end points: HR, 0.82 (95% CI, 0.71 to 0.94), P<0.01; cardiovascular mortality: HR, 0.77 (95% CI, 0.62 to 0.95), P<0.05; stroke: HR, 0.75 (95% CI, 0.61 to 0.92), P<0.01; new-onset diabetes: HR, 0.76 (95% CI, 0.60 to 0.96), P<0.05; and new-onset atrial fibrillation: HR, 0.71 (95% CI, 0.58 to 88), P<0.05. Test for interaction of treatment with LRG versus HRG was not significant for composite end point, stroke, or atrial fibrillation, but was for cardiovascular mortality (P=0.018). Achieved systolic BP reduction favored losartan over atenolol by -1.8 mm Hg in LRG (P=NS) and -0.7 mm Hg (P=0.001) in HRG, but no significant differences occurred in diastolic or mean BP in either group. In conclusion, losartan compared with atenolol reduces the risk of stroke, new-onset diabetes, and new-onset atrial fibrillation in the LRG and the HRG.
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PMID:Cardiovascular morbidity and mortality in hypertensive patients with lower versus higher risk: a LIFE substudy. 1611 47

Angiotensin receptor blockers (ARBs), also known as sartans, block the activation of angiotensin type 1 receptors and have a recognised role in the treatment of heart failure and nephropathy. Since 2002, there have been three major outcome trials of ARBs in hypertension. We performed a meta-analysis to evaluate the impact of ARB on major outcomes. Randomised controlled trials of ARBs in hypertensive subjects with an average follow-up of at least 2 years and at least 100 major cardiovascular events were included. For each trial, the ARB used, number and characteristics of subjects, baseline and change in blood pressure, cardiovascular and noncardiovascular outcomes were recorded. Three trials involving 29 375 subjects were included in the meta-analysis. In Losartan Intervention For Endpoint (LIFE) and Study on Cognition and Prognosis in the Elderly (SCOPE) but not in Valsartan Antihypertensive Long-term Use Evaluation trial (VALUE), an ARB reduced the occurrence of the primary end point and stroke compared to control. Compared to other antihypertensive drugs, ARB treatment was associated with no significant change in all-cause mortality (relative risk ratio (RRR) 0.96, 95% CI: 0.88-1.06, P = 0.45). There was an increase in myocardial infarction (RRR, 1.12, 95% CI: 1.01-1.26, P = 0.041), but a decrease in new-onset diabetes mellitus (RRR, 0.80, 95% CI: 0.74-0.86, P < 0.0000001). In conclusion, the reduction in new-onset diabetes partly offsets any increase in the risk of myocardial infarction. Most hypertensive patients require more than one class of drugs. Small differences in treatment outcome should not over-ride the importance of good blood pressure control.
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PMID:Meta-analysis of large outcome trials of angiotensin receptor blockers in hypertension. 1675 2

Angiotensin II plays a central role in the pathogenesis and progression of proteinuric nephropathies and related cardiovascular complications. Losartan is a selective non-peptide angiotensin Type 1-receptor blocker (ARB) with unique uricosuric effect, not shared by other ARBs. Losartan has demonstrated renoprotective effects in animals and humans with diabetic and non-diabetic renal diseases similar to those of angiotensin-converting enzyme inhibitors, with a lower incidence of dry cough and angioneurotic oedema. A reduced incidence of cerebrovascular events and diabetes has been reported in hypertensive patients with left ventricular hypertrophy on losartan therapy compared with patients treated with atenolol. Whether ARBs have superior cardioprotective effects, compared with other blood pressure medications, is still unknown. Combined angiotensin-converting enzyme inhibitor and ARB therapy improves renal outcomes in non-diabetic nephropathies more than single drug renin-angiotensin system inhibition. Whether this also applies to diabetic nephropathy and related cardiovascular outcomes is still unknown.
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PMID:Inhibition of the renin-angiotensin system and cardio-renal protection: focus on losartan and angiotensin receptor blockade. 1614 12

We sought to study the risk factors for heart failure (HF) and the relation between antihypertensive treatment with losartan and the first hospitalization for HF in patients with diabetes mellitus in the Losartan Intervention For Endpoint reduction in hypertension (LIFE) and Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) studies. We evaluated 1,195 patients with hypertension, left ventricular hypertrophy, and diabetes from the LIFE study and 1,513 patients with type 2 diabetes and nephropathy from the RENAAL study. The comparative treatments were atenolol in the LIFE study and placebo in the RENAAL study. Patients with a history of HF were excluded from this analysis. Losartan significantly reduced the incidence of first hospitalizations for HF versus placebo in the RENAAL study (hazard ratio 0.74, p=0.037) and versus atenolol in the LIFE study (hazard ratio 0.57, p=0.019). Patients enrolled in the RENAAL study were at a higher risk of developing HF (hazard ratio for RENAAL vs LIFE diabetics 3.0, p<0.0001). The significant, independent baseline risk factors for the development of HF in the RENAAL study were urinary albumin/creatinine ratio, age, peripheral vascular disease, the Cornell product, body mass index, and previous angina; in the LIFE study they were the Cornell product, previous myocardial infarction, peripheral vascular disease, baseline atrial fibrillation, alcohol use (inverse relation), and urinary albumin/creatinine ratio. The beneficial effect of losartan on the reduction of risk for hospitalization for new HF was demonstrated in patients who were at high renal and/or high cardiovascular risk.
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PMID:Hospitalizations for new heart failure among subjects with diabetes mellitus in the RENAAL and LIFE studies. 1631 Apr 35

Analysis of the biologic effects of erythropoietin and pathophysiology of chronic kidney diseases (CKD) suggests that treatment with erythropoiesis-stimulating agents (ESA) could slow the progression of CKD. By decreasing hypoxia and oxidative stress, it could prevent the development of interstitial fibrosis and the destruction of tubular cells. It could have direct protective effects on tubular cells through its antiapoptotic properties. It could help maintain the integrity of the interstitial capillary network through its effects on endothelial cells. Thus, suggesting that correcting anemia with ESA could slow the progression of CKD is biologically plausible. In patients with CKD, three small prospective studies and a retrospective study have suggested that treatment with ESA may have protective effects. Post-hoc analysis of the Reduction in Endpoints in Noninsulin-dependent Diabetes Mellitus with the Angiotensin II Antagonist Losartan study has also shown that anemia was an independent risk factor for progression of nephropathy in patients with type 2 diabetes. In addition, a large clinical trial, which had to be stopped prematurely because of labeling change for subcutaneous administration of epoetin alfa, suggests that complete normalization of hemoglobin levels is safe in CKD patients not on dialysis and without severe cardiovascular disease. Thus, it seems reasonable to advocate starting a large randomized, prospective study to determine if normalization of hemoglobin concentration can effectively slow the progression of CKD.
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PMID:Anemia management and chronic renal failure progression. 1633 82

Insulin resistance (IR) and diabetes increase the risk of acute myocardial infarction (MI). Angiotensin receptor blockers (ARBs) have been shown to reduce the risk of cardiovascular events in patients with hypertension and diabetes, and to be beneficial after a large MI. Whether pretreatment with ARBs is beneficial in acute MI is unknown. We evaluated whether pre-, peri-, and post-MI treatment with the ARB losartan improved the outcome in the IR Zucker fatty rat (ZFR). ZFR (n=264) received either losartan (3 mg/kg daily) or vehicle for 7 d prior to MI. Early (24 h) protocol (n=31): ventricular arrhythmias were evaluated post-MI using continuous ambulatory ECG monitoring. Late (38 d) protocol (n=233): losartan was increased to 10 mg/kg daily 10 d post-MI and to 30 mg/kg daily 20 d post-MI. Blood glucose, cardiac hemodynamics and remodeling, GLUT-4, fetal gene expression, and survival were evaluated. In large-MI rats, losartan improved early survival (43% vs. 27% in controls, p=0.01) and late survival (23% vs.15% in controls, p=0.02). Improved early survival was associated with a reduction in ventricular arrhythmias. Losartan reduced pulmonary congestion, cardiac hypertrophy, and fetal gene expression in the absence of statistically significant changes in ventricular dilatation and hemodynamics. Blood glucose and cardiac GLUT-4 expression did not change with losartan. In IR ZFR, losartan improves post-MI survival, likely as a result of an early reduction in ventricular arrhythmias. There was also an associated reduction in pulmonary congestion, hypertrophy, and fetal gene expression.
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PMID:Losartan and acute myocardial infarction in insulin-resistant Zucker fatty rats: reduced ventricular arrhythmias and improved survival. 1639 7


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