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Assistant Professor of Medicine
Division of Nephrology
University of Virginia Health System
Diabetes is among the leading causes of endstage renal disease (ESRD) worldwide. In the USA it is responsible for more than 40% of cases of ESRD. ESRD affects at least 16% of those with diabetes, and its overall annual incidence has been increasing steadily over the past decade. The increase in the number of patients with ESRD has been accompanied by a rise in total healthcare expenditure.
The number of patients diagnosed with ESRD is small compared with the magnitude of patients at risk for ESRD. According to the National Health and Nutrition Examination Survey (NHANES III) data, it is estimated that 10.9 million individuals in the USA have chronic kidney disease (CKD) with serum creatinine above 133mmol/l (>1.5 mg/dl).(1) Development of diabetic nephropathy, as evidenced by microalbuminuria, is associated with an increase in mortality.(2,3)
Hypertension and diabetic nephropathy
Factors such as hyperglycaemia, hypertension, baseline albumin excretion rate (AER) and serum cholesterol have been identified as risk factors for the development and progression of diabetic nephropathy and have become targets for treatment of this condition.(4–7) Hypertension has long been established as one of the major risk factors for the progression of nephropathy associated with both type 1 and type 2 diabetes. Reduction of blood pressure by different classes of antihypertensives has clearly been associated with a decline in AER.(8–11) For the type 2 diabetic individuals enrolled in the United Kingdom Prospective Diabetes Study (UKPDS), a 10mmHg difference in systolic and 5mmHg difference in diastolic blood pressure was associated with a 37% reduction in microvascular endpoints. At six years, significantly fewer patients in the tight blood pressure control group, as compared with the conventional group, developed microalbuminuria.(8) In 2003 the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC-7) recommended a blood pressure goal of <130/80mmHg in treating hypertensive individuals with diabetes or chronic kidney disease, as compared with <140/90mmHg for hypertensive nondiabetic patients.(12) The same goal in treatment of diabetic patients was recommended by the American Diabetes Association in 2002.(13) To achieve this goal, the majority of patients will require three or more antihypertensives agents.
Although reduction of blood pressure below the recommended levels is the goal, it appears that not all antihypertensives are the same in regards to renoprotection. Recent trials have clearly shown that using a dihydropyridine calcium channel blocker for treatment of hypertension in diabetic and nondiabetic individuals with nephropathy, as a single agent and without blockade of the renin–angiotensin–aldosterone system (RAAS), is associated with worse outcomes.(14,15) Several trials have demonstrated the benefits of using the inhibitors of the RAAS in diabetic individuals with nephropathy.
This system was once thought to be composed only of renin, an enzyme that breaks down angiotensinogen to angiotensin I, which in turn is converted to angiotensin II by the action of angiotensin-converting enzyme (ACE). Recent discoveries have unfolded unexpected dimensions of the RAAS, demonstrating a more complex system than previously understood. These discoveries include cloning of the angiotensin II (Ang-II) type 2 (AT2) receptor and its possible role in antiproliferation, vasodilatation and apoptosis, demonstrating a receptor for renin,(16) discovery of angiotensin-converting enzyme 2 (ACE-2), which is not inhibited by the converting enzyme inhibitors,(17) and discovery of angiotensin 1–7. Tissue RAAS has been demonstrated locally in the vasculature, heart and kidney. Diabetic individuals are thought to have an activated intrarenal RAAS.(18,19) Elevated local concentrations of Ang-II, the active component of this system, result in vasoconstriction, increased intraglomerular pressure, activation of intracellular enzymes such as protein kinase C and growth factors such as transforming growth factor-beta (TGF-beta), and an increase in production of reactive oxygen species. These changes will eventually result in the development of albuminuria and an imbalance between production and degradation of the mesangial matrix, resulting in mesangial expansion and eventually glomerulosclerosis. These actions of Ang-II are mediated through activation of its type 1 (AT1) receptors.
Angiotensin-converting enzyme inhibitors (ACE-Is)
ACE-Is act by blocking the conversion of Ang-I to Ang-II. Although it has been shown that alternative pathways, such as chymase, are capable of converting Ang-I to Ang-II, the significance of these other pathways is not clear. It appears that different converting enzymes are prominent in different tissues. Treatment with ACE-Is is also associated with elevation of bradykinin levels, which is partly responsible for their antihypertensive effects,(20) as well as side-effects such as cough and angio-oedema. Blockage of the RAAS by using ACE-Is has been associated with reduction of morbidity and mortality in patients with risk factors for coronary artery disease,(21) hypertension, heart failure(22,23) and postmyocardial infarction.(24,25) Almost two decades ago animal studies demonstrated that ACE-Is reduce the intraglomerular and transcapillary pressures in diabetic animals. As a result, the glomerular structural abnormalities and proteinuria were prevented by the use of an ACE-I.(26) Human studies have since confirmed the antiproteinuric effects of this class of antihypertensives. (27–31) In a randomised controlled trial of type 1 diabetic individuals with proteinuria, use of captopril was associated with a 48% reduction in the incidence of doubling the serum creatinine and a 50% reduction in the rate of death, ESRD or renal transplantation.(32) However, a similar study demonstrating beneficial effects of ACE-Is in reduction of hard renal outcomes of doubling serum creatinine or ESRD in type 2 diabetic patients with proteinuria has not yet been published. The occurrence of side-effects, such as cough and angio-oedema, and the finding of a high Ang-II concentration after prolonged use of these agents are reasons to search for a more protective and safer alternative.
Angiotensin receptor blockers (ARBs)
ARBs act by blocking the actions of angiotensin II on its type 1 (AT1) receptors. As a result of the receptor blockade, the concentrations of Ang-II will rise. Hypothetically, in this situation Ang-II could possibly act on its AT2 receptors and result in vasodilatation and antiproliferation. Recent large-scale randomised, placebo-controlled trials have demonstrated the effectiveness of ARBs in reduction of urinary albumin excretion (UAE) as well as doubling of serum creatinine and ESRD in type 2 diabetic patients with microalbuminuria and proteinuria. MicroAlbuminuria Reduction with VALsartan (MARVAL) compared valsartan versus amlodipine in 332 type 2 hypertensive patients with microalbuminuria.(33) In that study, 24 weeks of treatment with valsartan and not amlodipine was associated with a significant reduction in albuminuria. Thirty per cent of valsartan-treated individuals, compared with 14.5% of amlodipine-treated ones, normalised their albuminuria.(33) Irbesartan, another drug from this class, reduced the development of overt nephropathy in a dose-dependent fashion in 590 hypertensive type 2 diabetic patients with microalbuminuria.(34) Two years of treatment with irbesartan at a dose of 300mg/day was associated with a relative risk reduction of 70% and an absolute risk reduction of 9.7% in the development of overt proteinuria compared with placebo.(34) The same drug was used in the Irbesartan Diabetic Nephropathy Trial (IDNT) to treat 1,715 proteinuric type 2 patients for an average of 2.6 years and was associated with a 33% reduction (p=0.003) in the incidence of doubling the serum creatinine, and a 23% reduction in the incidence of ESRD (p=0.07), compared with the placebo group.(15) Finally, the Reduction in End Points in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) trial compared losartan with other antihypertensive agents (except for ACE-Is) in 1,513 hypertensive proteinuric type 2 diabetic patients.(35) In this study, 3.4 years of treatment with losartan was associated with a 25% reduction in the incidence of doubling of the serum creatinine and a 28% reduction in the incidence of ESRD.(35) IDNT and RENAAL are the only large-scale, randomised, controlled trials in proteinuric type 2 diabetic patients demonstrating the effectiveness of a drug in reducing renal outcomes, such as doubling serum creatinine or ESRD.
Since cardiovascular mortality is the leading cause of death among patients with diabetic nephropathy, it seems vital to investigate the potential benefits of ARBs in cardiovascular protection as well. In comparison with ACE-Is, the data on the benefits of ARBs in cardiovascular protection are scarce. The Losartan Heart Failure Survival Trial (ELITE-II) showed that treatment of heart failure with captopril or losartan resulted in similar reductions of all-cause mortality, sudden death or resuscitated arrest in elderly patients.(36) Also, among the subgroup of 366 patients in the Valsartan in Chronic Heart Failure Trial (Val-Heft) who could not tolerate ACE-Is, treatment with valsartan alone resulted in a reduction of 33% in all-cause mortality.(37) The Losartan Intervention For Endpoint reduction in hypertension study (LIFE) was specifically designed to address the issue of cardiovascular protection by an ARB.(38,39) Of the 1,195 hypertensive diabetic patients with left ventricular hypertrophy enrolled in the LIFE trial, 4.8 years of treatment with losartan was associated with a 24% reduction in composite endpoint of cardiovascular morbidity and mortality compared with treatment with atenolol.(39) There was also a 37% reduction in cardiovascular mortality associated with losartan compared with atenolol. The rates of total mortality and hospitalisation for heart failure and albuminuria were also significantly lower in the losartan group.(39) Among the nondiabetic patients enrolled in the LIFE trial (n=7,998), treatment with losartan was associated with 25% lower incidence of new-onset diabetes compared with atenolol.(38)
All ARBs were well tolerated in these studies without any major side-effects. Side-effects such as cough and angio-oedema, although possible, are not commonly seen with the use of these medications. This class of antihypertensives is recommended by the American Diabetes Association and considered the drug of choice in the treatment of hypertensive type 2 diabetic patients with micro- or macroalbuminuria.(40)
Diabetic nephropathy is the most common cause of ESRD. Microalbuminuria is associated with higher rates of cardiac complications and mortality. Patients with ESRD secondary to diabetes have significantly lower survivals compared with nondiabetic patients. Cardiovascular (CV) causes are the major cause of morbidity and mortality in patients with diabetic nephropathy. Hypertension is a major risk factor for progression of nephropathy in diabetes. The renin– angiotensin system plays a central role in the development and progression of diabetic nephropathy. Several studies have demonstrated antiproteinuric effects of blocking the RAAS. ACE-Is and ARBs reduce UAE in both type 1 and type 2 diabetes. Recent randomised controlled trials have shown that the use of ARBs in proteinuric type 2 diabetics will slow the progression of nephropathy and postpone the development of ESRD. A few recent trials have demonstrated the CV benefits of ARBs as well.