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Query: UMLS:C0011860 (type 2 diabetes)
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Diabetic nephropathy is the leading cause of end-stage kidney disease in the United States. The majority of these cases are attributed to those with type 2 diabetes. Elevated blood pressure, proteinuria, and increased activity of the renin-angiotensin-aldosterone system (RAAS) play a major role in the development and progression of chronic kidney disease attributed to diabetes mellitus. Moreover, drugs that inhibit angiotensin II synthesis or block the angiotensin II type I receptor lower blood pressure, reduce proteinuria, and improve outcomes in patients with chronic kidney disease caused by diabetes. This article highlights improvements in the current management of diabetic nephropathy afforded by agents that inhibit the RAAS, discusses their limitations, and considers novel strategies to prevent onset and progression of diabetic nephropathy. Current opinions concerning combination drug therapy with agents that block the RAAS at multiple sites, as well as combining calcium channel blockers with either angiotensin-converting enzyme inhibitors or angiotensin II receptor antagonists, are also discussed.
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PMID:Appropriate drug therapy for improving outcomes in diabetic nephropathy. 1264 62

Cardiovascular disease (CVD) is a major determining factor of morbidity and mortality in type 2 diabetic patients. Hypertension, which accompanies diabetes in more than 70% of cases, contributes to increased prevalence of CVD events in this group of patients. Results from the United Kingdom Prospective Diabetes Study (UKPDS) indicated that reduction of elevated blood pressure might decrease CVD morbidity and mortality more than reduction of hyperglycemia. Activation of circulating and tissue renin-angiotensin system (RAS) contributes to the development of both hypertension and insulin resistance in patients with the cardiometabolic syndrome. Angiotensin-converting enzyme (ACE) inhibitor therapy in patients with the cardiometabolic syndrome may improve insulin action as well as lessen CVD. In clinical trials, ACE inhibitors have been shown to be more efficient than other antihypertensive medications (i.e., calcium channel blockers) in the reduction of CVD morbidity and mortality in hypertensive diabetics. In this article, we summarize possible mechanisms by which ACE inhibition may improve insulin resistance, coagulation/clotting, and vascular function abnormalities, and postpone or even prevent the development of type 2 diabetes in hypertensive patients.
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PMID:Role of ACE inhibitors in treating hypertensive diabetic patients. 1264 81

In type 1 diabetes, hypertension is closely linked to the development of nephropathy. An association of hypertension and the impact of hypertension on the clinical course of type 2 diabetes, including the development of vascular complications, has been well established. However, the association with nephropathy in type 2 diabetes is less clear. Despite that, antihypertensive treatment has a crucial impact on the course of nephropathy in both types of diabetes. In this article, we discuss recent evidence focusing on the nephroprotective potential of various classes of antihypertensive agents and confront it with current recommendations for the treatment of hypertension in diabetic patients with nephropathy. Unlike type 1 diabetes, where the nephroprotection could be a good sole measure for assessing the efficiency of a particular agent or their combination, defining of the optimal antihypertensive agent or agents in type 2 diabetes requires consideration of both cardiovascular, cerebrovascular, and nephroprotective potentials of such a treatment. In both types of diabetes, recent data support the use of inhibitors of the renin-angiotensin system with or without diuretics as the initial therapy. In type 1 diabetes, additional beneficial effect can be expected from calcium channel blockers (CCBs). In type 2 diabetic patients, combining more agents may be necessary early in the course of nephropathy to affect both micro- and macrovascular targets. beta blockers should be applied early to enhance cardioprotectivity, followed by CCBs to achieve goal blood pressure. Although not supported by all recent data, aggressive blood pressure control (< 130/75 mm Hg) is warranted. Furthermore, multifactorial intervention targeting metabolic derangements and lifestyle, is a necessary complimentary measure that must accompany antihypertensive treatment.
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PMID:Treatment of hypertension in diabetic patients with nephropathy. 1264 7

Where shall we place angiotensin receptor blockers in the scheme of the prevention of diabetic nephropathy? Only the results of a large, randomized double-blind trial with a comparable and appropriate alternative would prove therapeutic efficacy. The results of several trials with angiotensin-converting enzyme (ACE) inhibitors have proven them to be the standard of care for diabetics and their kidneys. As reviewed in this article, the results of three large such clinical trials have recently been completed with angiotensin receptor blockers in patients with type 2 diabetes mellitus. Initial results appear favorable. However, whether angiotensin blockers have more to offer than ACE inhibitors is still speculative. The renin-angiotensin system plays an important role in the pathogenesis of diabetic nephropathy. Since alternative pathways to ACE have been uncovered in the formation of angiotensin II, inhibition at the final end point would provide favored blockade. Because angiotensin receptor blockers do provide this specific blockade, they offer far more promise than ACE inhibitors.
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PMID:Angiotensin receptor blockers in diabetic nephropathy. 1264 9

Renal involvement in patients with type 2 diabetes will (probably) be one of the most important clinical problems for nephrologists to face during the next few years. Unlike type 1 diabetes, in type 2 diabetes the renal damage has not yet been well defined at both clinical and pathological levels. Pathological examination of renal biopsies has displayed different patterns of renal damage including diabetic glomerulosclerosis (Class 1), mostly chronic vascular changes (Class 2) and superimposed glomerular diseases (Class 3a) or unrelated to diabetic glomerulosclerosis (Class 3b). Despite the large number of papers published in this field, the actual prevalence and outcome of the different histological classes still remain to be established. Reported discrepancies are most likely caused by ethnic and geographic factors. However, as documented by a recent study carried out on a large number of patients, the prevalence of histological patterns is also greatly influenced by the policy for performing renal biopsies adopted at the various nephrological centers. Although the natural history of type 2 glomerulosclerosis (Class 1) still remains to be defined, those patients with clinical nephropathy and impairment of renal function have very poor outcome with a high rate of mortality and progression to uremia. Moreover, when diabetic glomerulosclerosis is complicated by superimposed glomerular diseases (Class 3a) the prognosis is much worse. On the contrary, when glomerular diseases are not associated with glomerulosclerosis lesions (Class 3b) the prognosis is markedly better. During the last ten years controlled studies have shown that the outcome in type 1 diabetic nephropathy has improved as a result of the use of drugs inhibiting the renin-angiotensin system. Although it is likely that this type of drug might also favourably influence the outcome of type 2 diabetic nephropathy, any conclusive evidence is presently still lacking.
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PMID:[Renal damage in type 2 diabetes]. 1264 81

The goal of antihypertensive therapy is to provide effective treatment that can be sustained lifelong, while lowering elevated blood pressure and preventing hypertensive end-organ damage and mortality. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II antagonists (AIIAs) control blood pressure as well as other available classes of antihypertensive drugs. The ACE inhibitors have been demonstrated to reduce the incidence of stroke, reverse left ventricular hypertrophy, and improve congestive heart failure symptomatology and mortality to a similar degree as diuretics and beta-adrenergic blockers. ACE inhibitors reduce postmyocardial infarction recurrence, improve congestive heart failure symptomatology and mortality, and slow the progression of glomerular renal disease. The AIIAs reverse left ventricular hypertrophy. Several of these agents have been shown to improve congestive heart failure symptomology and mortality, to reduce the occurrence of early atherosclerotic vascular disease, and to slow the progression of renal failure in type 2 diabetes mellitus nephropathy. One AIIA has reduced the incidence of end-stage renal disease in non-insulin-dependence diabetes mellitus nephropathy over 3 years. Ideally, antihypertensive therapy should maintain or improve the patients quality of life without creating side effects or adverse laboratory effects. Among the available nine classes of antihypertensive drugs, ACE inhibitors and the AIIAs come close to meeting the description of an ideal drug. AIIAs and ACE inhibitors, two classes of antihypertensive drugs that reduce the activity of the renin-angiotensin II system, should be among the preferred first-step drugs for the treatment of hypertension.
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PMID:Drugs that interrupt the renin-angiotensin system should be among the preferred initial drugs to treat hypertension. 1267 27

Diabetic nephropathy is one of the most frequent causes of end-stage renal disease (ESRD), and, in recent years, the number of diabetic patients entering renal replacement therapy has dramatically increased. The magnitude of the problem has led to numerous efforts to identify preventive and therapeutic strategies. In normoalbuminuric patients, optimal glycemic control (HbA(1c) lower than 7.5%) plays a fundamental role in the primary prevention of ESRD [weighted mean relative risk reduction (RRR) approximately 37% for metabolic control versus trivial renoprotection for intensive anti-hypertensive therapy or ACE-inhibitors (ACE-I)]. In the microalbuminuric stage, strict glycemic control probably reduces the incidence of overt nephropathy (weighted mean RRR approximately 50%), while blood pressure levels below 130/80 mmHg are recommended according to the average blood pressure levels obtained in various studies. In normotensive patients, ACE-I markedly reduce the development of overt nephropathy almost regardless of blood pressure levels; in hypertensive patients, ACE-I are less clearly active (weighted mean RRR approximately 23% versus other drugs), whereas angiotensin-receptor blockers (ARB) appear strikingly renoprotective. Once overt proteinuria appears, it is uncertain whether glycemic control affects the progression of nephropathy. In type 1 diabetes, various anti-hypertensive treatments, mainly ACE-I, are effective in slowing down the progression of nephropathy; in type 2 diabetes, two recent studies demonstrate that ARB are superior to conventional therapy or calcium channel blockers (CCB). In clinical practice, pharmacological tools are not always used to the best benefit of the patients. Therefore, clinicians and patients need to be educated regarding the renoprotection of drugs inhibiting the renin-angiotensin system (RAS) and the overwhelming importance of achieving target blood pressure.
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PMID:Treatment of diabetic nephropathy in its early stages. 1267 78

Overfeeding of rodents leads to increased local formation of angiotensin II due to increased secretion of angiotensinogen from adipocytes. Whereas angiotensin II promotes adipocyte growth and preadipocyte recruitment, increased secretion of angiotensinogen from adipocytes also directly contributes to the close relationship between adipose-tissue mass and blood pressure in mice. In contrast, angiotensin II acts as an antiadipogenic substance in human adipose tissue, and the total increase in adipose-tissue mass may be more important in determining human plasma angiotensinogen levels than changes within the single adipocyte. However, as increased local formation of angiotensin II in adipose tissue may be increased especially in obese hypertensive subjects, a contribution of the adipose-tissue renin-angiotensin system to the development of insulin resistance and hypertension is conceivable in humans, but not yet proven. Insulin resistance may be aggravated by the inhibition of preadipocyte recruitment, which results in the redistribution of triglycerides to the liver and skeletal muscle, and blood pressure may be influenced by local formation of angiotensin II in perivascular adipose tissue. Thus, although the mechanisms are still speculative, the beneficial effects of ACE-inhibition and angiotensin-receptor blockade on the development of type 2 diabetes in large clinical trials suggest a pathophysiological role of the adipose-tissue renin-angiotensin system in the metabolic syndrome.
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PMID:The adipose-tissue renin-angiotensin-aldosterone system: role in the metabolic syndrome? 1267 68

The theoretical advantages of the angiotensin II receptors blockers (ARB) are slowly but progressively becoming a reality for patients with congestive heart failure. ARB are recommended in patients who cannot take ACE inhibitors as a plausible alternative for modulating the renin angiotensin system. After the recently published Val-HeFT trial, the addition of an ARB (valsartan) can be considered in patients who remain severely symptomatic despite optimal therapy in order to reduce hospitalization for heart failure and improve symptoms particularly if the patients cannot tolerates beta-blockers. Among patients with type 2 diabetes and no clinical signs of congestive heart failure ARB (losartan) are able to reduce the probability of developing congestive heart failure.
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PMID:[Angiotensin receptor antagonists and ACE inhibitors in heart failure: alternative or combined therapies?]. 1269 71

Aggressive therapy for patients with type 2 diabetes mellitus and renal disease is warranted given the natural history of this disease. Although antagonizing the renin-angiotensin system is clearly important, how this is accomplished is of considerable controversy. On the one hand, recent clinical trials of patients with type 2 diabetes mellitus with renal disease demonstrate unequivocally the renal protective effect of angiotensin receptor blockers (ARBs). Although the results of the recently published LIFE trial are encouraging, inconsistencies have been observed with ARBs in reducing cardiovascular end points. On the other hand, angiotensin-converting enzyme inhibitors have a dramatic effect in reducing cardiovascular events but have not been shown convincingly to reduce progression of renal disease in patients with type 2 diabetes mellitus. These studies leave us in a quandary as to the optimal initial treatment regimen for patients with type 2 diabetes mellitus and renal disease despite the recent recommendations from the American Diabetes Association (Alexandria, Va). Given the fact that many of these individuals will require administration of multiple antihypertensive agents, perhaps the initial treatment with a combination of an ARB and angiotensin-converting enzyme inhibitor affords optimal cardiovascular and renal protection for patients with type 2 diabetes mellitus and renal disease. Future clinical trials should be designed to address this issue.
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PMID:Combination therapy with angiotensin-converting enzyme inhibitors and angiotensin receptor antagonists in the treatment of patients with type 2 diabetes mellitus. 1274 99


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