Effects of Losartan on Renal and Cardiovascular Outcomes in Patients with Type 2 Diabetes and Nephropathy

Brenner, Barry M.; Cooper, Mark E.; Zeeuw, Dick de; Keane, William F.; Mitch, William E.; Parving, Hans Henrik; Remuzzi, Giuseppe; Snapinn, Steven; Zhang, Zhonxin; Shahinfar, Shahnaz

doi:10.1056/nejmoa011161

Cited by 6,284 publications

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“…77 The RAAS is thought to have a central function in the pathogenesis of this disease, evidenced by numerous studies showing that RAAS blockade by ACEIs and AT 1 receptor blockers slows the progression of DN. [3][4][5][6] However, these treatments do not halt the progression of this disease. Thus, the underlying mechanisms for progression of DN continue even in patients treated with accepted therapies.…”

Section: Testing Aliskiren In Animal Modelsmentioning

confidence: 99%

“…This heralded the therapeutic control of BP by inhibiting the RAAS at its first and rate-limiting step. However, RAAS blockade is also effective for treating renal disease [3][4][5][6] and the efficacy of aliskiren for this purpose is currently being investigated. Accordingly, the subject of this review is to summarize the preclinical evidence for renoprotection by aliskiren, and to discuss recently published information on the possible mechanism(s) for these benefits.…”

Section: Introductionmentioning

confidence: 99%

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New insights into the renoprotective actions of the renin inhibitor aliskiren in experimental renal disease

Feldman

2010

Hypertens Res

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The renin-angiotensin-aldosterone system (RAAS) has a central function in the regulation of blood pressure. Aliskiren, the first direct renin inhibitor to be approved for the treatment of hypertension, blocks the RAAS at its point of activation. As renin inhibition acts at the top of the RAAS cascade, this mechanism has been proposed to offer advantages over existing modes of RAAS blockade. The RAAS is also considered to be a major factor in the pathogenesis of many renal diseases, especially diabetic nephropathy (DN), the main cause of end-stage renal disease. Existing therapies to block the RAAS slow the progression of DN, but they do not halt the disease. Therefore, more effective modes of interventions are needed. Studies to determine the efficacy of aliskiren in human renal disease are in progress. This review summarizes in vivo studies in which the efficacy of aliskiren was tested in experimental models of renal disease, and presents in vitro studies that provide insights into the possible mechanisms by which aliskiren confers renoprotection in animals. These works are discussed in the framework of the intrarenal RAAS and suggest that aliskiren may act by unique renoprotective mechanisms. Keywords: aliskiren; kidney; mechanism; nephropathy; renin INTRODUCTIONThe renin-angiotensin-aldosterone system (RAAS) is an ancient pathway 1 that has evolved into a central mechanism by which mammalian blood pressure (BP) and fluid homeostasis are regulated. Research in this field started with the discovery in 1898 by Tigerstedt and Berman 2 that a renal extract when injected into rabbits induced a rapid increase in systemic BP. Subsequent work over many years established the RAAS as a pivotal contributor to cardiorenal diseases. Hence, inhibitors of the middle and distal portions of the RAAS pathway, angiotensin-converting enzyme (ACE) inhibitors (ACEI) and AT 1 receptor blockers, respectively, have become mainstay therapies for treating hypertension. In 2007, aliskiren, the first direct renin inhibitor (DRI), was approved for the treatment of hypertension. This heralded the therapeutic control of BP by inhibiting the RAAS at its first and rate-limiting step. However, RAAS blockade is also effective for treating renal disease 3-6 and the efficacy of aliskiren for this purpose is currently being investigated. Accordingly, the subject of this review is to summarize the preclinical evidence for renoprotection by aliskiren, and to discuss recently published information on the possible mechanism(s) for these benefits. As it is well recognized that there is a tissue as well as circulating RAAS, 7 the preclinical actions of aliskiren will be discussed in the context of the intrarenal RAAS and the potential for its inhibition by aliskiren.

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Section: Testing Aliskiren In Animal Modelsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

New insights into the renoprotective actions of the renin inhibitor aliskiren in experimental renal disease

Feldman

2010

Hypertens Res

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“…[63][64][65][66][67][68][69][70][71] The protein leakage in diabetic hypertensive patients has been attributed to endothelial dysfunction, which is present in both diabetes and hypertension. 72 Microalbuminuria in type II diabetic, 73 or nondiabetic hypertensive 74 patients has been associated, besides renal failure, with cardiovascular complications.…”

Section: Diabetic Nephropathymentioning

confidence: 99%

“…In the other, 1513 type II diabetic, hypertensive patients were randomized to losartan 50-100 mg once daily (n ¼ 751) or placebo (n ¼ 762) and followed for 3.4 years. 71 In both studies, additional drugs could be added for better blood pressure control. The losartan-based regimen decreased, doubling the baseline serum creatinine level by 25% vs placebo (P ¼ 0.006), and ESRD by 28% vs placebo (P ¼ 0.002), but had no effect on death rate.…”

Section: Diabetic Nephropathymentioning

confidence: 99%

Current status of angiotensin receptor blockers for the treatment of cardiovascular diseases: focus on telmisartan

Chrysant

Desai

2005

J Hum Hypertens

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Poorly controlled hypertension is a major risk for cardiovascular morbidity and mortality, strokes, heart failure and renal failure. Despite these devastating complications, blood pressure control of p140/90 mmHg, which is above the current standard, is very poor worldwide, accounting for 34% of hypertensive patients in the United States, and 6% in other countries. The reasons for this poor control of blood pressure include lack of aggressive treatment by physicians, especially for the systolic blood pressure, drug selection and patient compliance. The blood pressure follows a circadian rhythm and is the highest between 0600 to 1200 h, when most complications occur. Long-acting drugs that extend their action to cover this vulnerable period are preferable, especially those that block the renin-angiotensin-aldosterone system, such as ACE inhibitors and angiotensin receptor blockers, and are the most effective in controlling blood pressure and preventing or reducing its cardiovascular and renal complications. With respect to the angiotensin receptor blockers, telmisartan has been demonstrated by several studies to be the longest acting among its class of drugs and to effectively prevent the early morning rise of blood pressure.

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“…The American Diabetes Association, the European Society of Hypertension and the Japanese Society of Hypertension recommend the use of angiotensin‐converting enzyme inhibitors or angiotensin receptor blockers (ARBs) as a first choice for type 2 diabetes patients with hypertension3, 4, 5. These drugs decrease not only the risk of macroangiopathy6, 7, 8, but also other diabetic complications9, 10, 11, 12, 13. Furthermore, these drugs also delay the onset of diabetes14, 15, 16.…”

Section: Introductionmentioning

confidence: 99%

Switching from low‐dose thiazide diuretics to sodium–glucose cotransporter 2 inhibitor improves various metabolic parameters without affecting blood pressure in patients with type 2 diabetes and hypertension

Kimura

Sanada

Shimoda

et al. 2017

J of Diabetes Invest

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Aims/IntroductionSodium–glucose cotransporter 2 (SGLT2) inhibitors function to increase urinary glucose excretion and improve glycemic control in individuals with type 2 diabetes mellitus. SGLT2 inhibitors, as well as diuretics, increase urinary volume, which leads to the reduction of blood pressure. The aim of the present study was to compare the effects of SGLT2 inhibitor and thiazide diuretic on blood pressure, metabolic parameters and body mass composition.Materials and MethodsA total of 31 participants were enrolled in the present study. We switched from thiazide diuretics to an SGLT2 inhibitor, ipragliflozin, in participants with type 2 diabetes and hypertension whose blood pressure was controlled with thiazide diuretics. Three months after the switch, we evaluated the effects of such switching on blood pressure, various metabolic parameters and body mass composition.ResultsThere was no significant difference in blood pressure from baseline to 3 months later. However, glycated hemoglobin, fasting plasma glucose and uric acid were significantly decreased after the switch. Body mass index and visceral fat area were also significantly reduced after the switch. Furthermore, urinary albumin excretion was also significantly decreased after the switch.ConclusionsSwitching from thiazide diuretic to an SGLT2 inhibitor, ipragliflozin, markedly improved various metabolic parameters and body mass composition without affecting blood pressure in participants with type 2 diabetes and hypertension.

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Effects of Losartan on Renal and Cardiovascular Outcomes in Patients with Type 2 Diabetes and Nephropathy

Cited by 6,284 publications

References 27 publications

New insights into the renoprotective actions of the renin inhibitor aliskiren in experimental renal disease

New insights into the renoprotective actions of the renin inhibitor aliskiren in experimental renal disease

Current status of angiotensin receptor blockers for the treatment of cardiovascular diseases: focus on telmisartan

Switching from low‐dose thiazide diuretics to sodium–glucose cotransporter 2 inhibitor improves various metabolic parameters without affecting blood pressure in patients with type 2 diabetes and hypertension

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