A Randomized, Double-Blind, Placebo-Controlled Trial to Evaluate the Effect of Enalapril in Patients With Clinical Diabetic Nephropathy

Bauer, John H.; Reams, Garry P.; Hewett, John E.; Klachko, David M.; Lau, Alisa; Messina, Catherine R.; Knaus, Vicki

doi:10.1016/s0272-6386(12)70256-1

Cited by 64 publications

(24 citation statements)

References 31 publications

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“…They may be related to a much longer drug of exposure in vivo than in in vitro assays. Still, more data are needed to ascertain whether the unexpected AGE-lowering effect of AIIR antagonists and some ACE inhibitors contribute to some of the recently demonstrated clinical and experimental benefits of these drugs (42)(43)(44)(45)(46)(47)(48)(49)(50)(51). An interaction between AGE, endothelial cell function, and nitric oxide release (29,49 -51) provides a useful framework for the exploration of these systemic effects, which are often unaccounted for by BP lowering.…”

Section: Discussionmentioning

confidence: 99%

Angiotensin II Receptor Antagonists and Angiotensin-Converting Enzyme Inhibitors Lower In Vitro the Formation of Advanced Glycation End Products

Miyata¹,

Strihou²,

Ueda³

et al. 2002

Journal of the American Society of Nephrology

282

218

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Abstract. The implication of advanced glycation end products (AGE) in the pathogenesis of atherosclerosis and of diabetic and uremic complications has stimulated a search for AGE inhibitors. This study evaluates the AGE inhibitory potential of several well-tolerated hypotensive drugs. Olmesartan, an angiotensin II type 1 receptor (AIIR) antagonist, as well as temocaprilat, an angiotensin-converting enzyme (ACE) inhibitor, unlike nifedipine, a calcium blocker, inhibit in vitro the formation of two AGE, pentosidine and N ⑀ -carboxymethyllysine (CML), during incubation of nonuremic diabetic, nondiabetic uremic, or diabetic uremic plasma or of BSA fortified with arabinose. This effect is shared by all tested AIIR antagonists and ACE inhibitors. On an equimolar basis, they are more efficient than aminoguanidine or pyridoxamine. Unlike the latter two compounds, they do not trap reactive carbonyl precursors for AGE, but impact on the production of reactive carbonyl precursors for AGE by chelating transition metals and inhibiting various oxidative steps, including carbon-centered and hydroxyl radicals, at both the pre-and post-Amadori steps. Their effect is paralleled by a lowered production of reactive carbonyl precursors. Finally, they do not bind pyridoxal, unlike aminoguanidine. Altogether, this study demonstrates for the first time that widely used hypotensive agents, AIIR antagonists and ACE inhibitors, significantly attenuate AGE production. This study provides a new framework for the assessment of families of AGE-lowering compounds according to their mechanisms of action.Advanced glycation and oxidation irreversibly modify proteins over the years and thus contribute to aging phenomena (1). Their local or generalized acceleration is associated with atherosclerosis (2-6) as well as with various diabetic (7-10) and uremic complications (11-13). Inhibition of advanced glycation end products (AGE) formation has thus become a therapeutic goal.Aminoguanidine, the first AGE inhibitor discovered in 1986 (14), and (Ϯ)-2-isopropylidenehydrazono-4-oxo-thiazolidin-5-ylacetanilide (OPB-9195) (15) are both hydrazine-derivatives. They inhibit in vitro the formation of AGE, pentosidine (16), and N ⑀ -carboxymethyllysine (CML) (17) from a variety of individual precursors, such as ribose, glucose, and ascorbate, as well as that of advanced lipoxidation end products (ALE), malondialdehyde-lysine and 4-hydroxynonenal-protein adduct (18), from arachidonate (19). They also inhibit pentosidine generation in diabetic and uremic plasma incubated for 4 wk (20).As expected, both compounds correct several biologic effects that are associated with AGE formation. In murine thymocyte and fibroblasts, they inhibit the phosphorylation of tyrosine residues of a number of intracellular proteins induced by cell surface Schiff base formation (21). Given to diabetic animal models, such as Otsuka-Long-Evans-Tokushima-Fatty (OLETF) or streptozotocin-treated rats, they reduce urinary albumin excretion and improve glomerular morphology (15,22). Oral admi...

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Section: Discussionmentioning

confidence: 99%

Angiotensin II Receptor Antagonists and Angiotensin-Converting Enzyme Inhibitors Lower In Vitro the Formation of Advanced Glycation End Products

Miyata¹,

Strihou²,

Ueda³

et al. 2002

Journal of the American Society of Nephrology

282

218

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“…However, in both studies blood pressure values were significantly lower with the ACE inhibitor treatments when compared to the respective control groups [16,17]. It is of note, that in other randomised intervention studies, in which blood pressure control was kept comparable between the study groups, there was no difference in the decline in glomerular filtration rate (GFR) when comparing ACE inhibitors to placebo [18] or a beta blocker [19]. In meta-analyses including controlled and uncontrolled studies ACE inhibitors have been reported to be more effective than other antihypertensive agents with regard to the reduction of albuminuria and proteinuria [20] but equally effective with regard to their influence on the decline of GFR in diabetic nephropathy [21].…”

Section: Patients With Iddmmentioning

confidence: 87%

Antihypertensive treatment and mortality in diabetic patients What is the evidence?

1997

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In follow-up studies patients with hypertension and non-insulin-dependent diabetes mellitus (NIDDM) have a four to sevenfold increase in total mortality when compared to non-diabetic normotensive subjects. Recently, the risk of mortality associated with hypertension in diabetes was assessed in 3648 newly diagnosed NIDDM patients [1], hypertension was present in 35 % of women and 46 % of men. When compared to normotensive diabetic patients the mortality risk associated with hypertension was doubled over a median follow-up period of 4.6 years. Cardiac events including sudden death accounted for 58 % and stroke for 13 % of all causes of death.Patients with insulin-dependent diabetes mellitus (IDDM) exhibit a dramatically reduced life expectancy when they develop diabetic nephropathy which is nearly always associated with hypertension [2]. Without antihypertensive treatment the 10-year mortality approaches 80 % in these patients and the main causes of death are myocardial infarction, cardiac failure, sudden death and stroke [3,4].Hence, there is no doubt that hypertension adds considerably to the already increased morbidity and mortality risk in NIDDM patients and is the major determinant of the prognosis in nephropathic IDDM patients. Evidence from intervention studies Patients with NIDDMTo date no prospective randomised intervention trials aiming at the relevant end points of cardiovascular morbidity and mortality have been published for hypertensive NIDDM patients. At least in Germany, the majority of these patients at diagnosis of diabetes are already above 65 years of age; until recently, there has been controversy over whether elderly patients would benefit from antihypertensive treatment. At the beginning of this decade intervention trials in older patients with essential hypertension were published including about 10 % NIDDM patients [5][6][7]. These trials have impressively shown that antihypertensive treatment with thiazide diuretics and beta blocking agents reduces morbidity and mortality both in patients with systolic and/or diastolic hypertension and gave no indication that these beneficial effects would be different in diabetic patients.The evidence from intervention trials in essential hypertension indicates that the overall benefit of antihypertensive treatment in the intervention group rises with an increase of the mortality risk in the control group. In a recent overview-evaluation of intervention trials in essential hypertension the mortality risk in the intervention group was correlated with the mortality risk in the control group and an equation for this linear correlation was proposed [8]. According to this equation it should be possible to estimate the benefit of antihypertensive treatment when the baseline risk of an untreated hypertensive population is known: y = 0.47x -2.9 (y = reduction of mortality due to antihypertensive treatment; x = mortality risk without antihypertensive treatment). Applying this equation to the increased mortality risk in newly diagnosed hypertensive NIDDM patients ...

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“…Beyond their antihypertensive benefit, ACEI slow the progression of type 1 diabetic nephropathy [139, 140]. The mechanisms of the beneficial nephroprotective activity of RAS inhibition in diabetic nephropathy are complex and still incompletely understood [24, 140, 141] and may vary somewhat between type 1 and type 2 diabetes.…”

Section: Reducing Proteinuriamentioning

confidence: 99%

Diabetic Nephropathy: The Proteinuria Hypothesis

Williams¹

2005

Am J Nephrol

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Background/Aims: Proteinuria, nearly a universal finding in progressive kidney disease, has been the subject of frequent recent analyses in the renal literature. Proteinuria is a hallmark of diabetic nephropathy: microalbuminuria is the principal early predictor for progression of diabetic glomerulopathy, and proteinuria may be viewed as a measure of the severity and promoter of progression of nephropathy. Methods: This article critically reviews for the first time the full scope of diabetic proteinuria – complex molecular mechanisms, natural history, and analysis of treatment trials – in order to address the validity of ‘the proteinuria hypothesis’, i.e., that diabetic proteinuria is a modifiable determinant of renal progression. This hypothesis is analyzed in detail, including recent studies on the primary therapy of diabetic nephropathy, renin-angiotensin blockade. Results: As fully developed, this hypothesis consists of three postulates: that higher amounts of proteinuria predict progressive loss of function, that proteinuria reduction correlates with slowing progression, and that proteinuria is a surrogate endpoint for clinical trials. The latter postulate has not before been adequately linked to growing information about the first two postulates as they apply to diabetic kidney disease. Conclusion: While diabetic nephropathy is a disease model for the potential use of proteinuria as a surrogate marker for renal progression, this shift in perspective will require prospective data from additional clinical trials, particularly of non-renin-angiotensin blocking drugs, to be complete.

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A Randomized, Double-Blind, Placebo-Controlled Trial to Evaluate the Effect of Enalapril in Patients With Clinical Diabetic Nephropathy

Cited by 64 publications

References 31 publications

Angiotensin II Receptor Antagonists and Angiotensin-Converting Enzyme Inhibitors Lower In Vitro the Formation of Advanced Glycation End Products

Angiotensin II Receptor Antagonists and Angiotensin-Converting Enzyme Inhibitors Lower In Vitro the Formation of Advanced Glycation End Products

Antihypertensive treatment and mortality in diabetic patients What is the evidence?

Diabetic Nephropathy: The Proteinuria Hypothesis

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