Renoprotection in Type 2 diabetes: blockade of the renin-angiotensin system with angiotensin II receptor blockers (2001)

JRAAS 2001;2:170–3 Introduction Diabetic nephropathy accounts for the largest number of patients with end-stage renal disease (ESRD) in the UK, Europe, Japan and the United States. Despite growing evidence for the importance of blood pressure (BP) and glycaemic control in disease progression, the incidence of ESRD secondary to diabetic nephropathy continues to rise. The worldwide prevalence of diabetes is increasing steadily and the majority, in the developed world, have Type 2 diabetes. Hypertension and microalbuminuria (30–300 mg albumin/24 hours) are frequently present, even from the time of diagnosis. Microalbuminuria progresses over 5–10 years to proteinuria (>300 mg of protein/24 hours) in 20–40% of patients. Persistent proteinuria is the hallmark of diabetic nephropathy and is accompanied by a progressive decline in glomerular filtration rate (GFR). Heavy proteinuria and co-existing hypertension both accelerate the rate of progression to ESRD. Microalbuminuria is a strong predictor of cardiovascular morbidity and mortality in Type 2 diabetics. Indeed, the leading cause of death in diabetics is cardiovascular disease. Type 2 diabetics have the same excess risk of myocardial infarction (MI) as non-diabetics who have previously had a myocardial infarct. Furthermore, the combination of diabetes and hypertension is associated with an approximately 4-fold increase in cardiovascular risk when compared with the non-diabetic normotensive population. Treatment strategies in diabetics aim to slow the onset and progression of renal disease and other microvascular complications and to reduce the associated excess cardiovascular risk. In Type 1 diabetics with proteinuria or microalbuminuria, blockade of the renin-angiotensin system (RAS) with angiotensin-converting enzyme inhibitors (ACE-I) improves renal outcome. ACE-I are renoprotective, in that they afford protection against progressive proteinuria and renal insufficiency, which is independent of, and probably additive to, their BP-lowering effect. There is now a consensus opinion that ACE-I, when well tolerated, should be used as first line therapy in this group.Their role in Type 2 diabetics, however, is not yet fully established. In 1993, Ravid reported that the ACE-I, enalapril, stabilised plasma creatinine and urinary albumin excretion in 94 normotensive,Type 2 diabetics with microalbuminuria and normal renal function. More recently, the MICRO-HOPE study demonstrated that ramipril reduced cardiovascular mortality and early renal disease progression in individuals with both Type 1 and Type 2 diabetes. This effect appeared to be greater than might be attributable to the decrease in BP in the ramipril-treated group, although the potential contribution of BP reduction in this study remains contentious. Other studies have compared ACE-I with other antihypertensives, with varying outcomes on the observed rates of diabetic complications and mortality. The UKPDS trial stratified treatment intensities in hypertensive Type 2 diabetics, specifying BP targets of below either 150/80 mmHg or 180/105 mmHg. These targets were achieved with either an ACE-I, captopril, or a beta-blocker, atenolol, as the main treatment. In the lower BP group, there was a reduction in the risk of death related to diabetes, progression of diabetic nephropathy and deterioration in visual acuity. However, further analysis of the outcome data in the lower blood pressure group showed no difference between those treated with the ACE inhibitor or beta blocker. Both of these agents inhibit the renin-angiotensin system and there was no comparison, in this study, with a regimen that did not block the renin-angiotensin system. Despite the number of trials conducted to date, there remains controversy over which agent, if any, offers superior renal or cardiovascular protection in Type 2 diabetics. The question also remains as to whether blockade of the RAS will confer similar benefits in Type 2 as in Type 1 diabetics. Furthermore, it may be that BP reduction itself is more important than the treatment used to achieve it.These important questions and unresolved issues have provided the background for three prospective clinical trials, which evaluated the effect of angiotensin II receptor blockers (ARBs) on cardiovascular and renal outcomes, specifically in Type 2 diabetics.The results of these trials have now been published simultaneously in the New England Journal of Medicine.