The problem

The prevalence of end-stage renal disease (ESRD) in the USA is increasing at an alarming rate - it's doubled in the last 10 years. Nearly all the increase is due to nephropathy associated with type 2 diabetes. With no obvious increase in the rate of kidney donations for transplantation, most of the new cases in the next decades will be treated with dialysis, indefinitely. Already, 6% of the US Medicare budget is used for ESRD; all this emphasizes the need for steps to prevent it, and this is the subject of 3 articles and a recent editorial in the New England Journal of Medicine.

A possible solution

Obviously, control of hyperglycemia and hypertension is key. There are numerous approaches - specific medication, and stringent lifestyle changes (diet, exercise). In considering antihypertensive medications, there is evidence that angiotensin-converting-enzyme (ACE) inhibitors slow progress of ESRD in type 1 diabetes more efficiently than other drugs. However, there are fewer data to support their efficacy in type 2 diabetes. The studies just published show that 2 "cousins" of ACE-inhibitors, the angiotensin-receptor blocking drugs irbesartan and losartan, are indeed effective in type 2 diabetic patients at risk.

Angiotensin-receptor antagonists trials

In the first study¹ , irbesartan was given to patients with type 2 diabetes and hypertension who had normal glomerular filtration rates (GFR), but low-grade proteinuria. 590 patients were randomized to receive 150 mg daily or 300 mg daily of irbesartan, or placebo. The primary end-point, onset of diabetic nephropathy within 2 years, showed hazards ratios of 0.30 and 0.61 for irbesartan 150 and 300 mg, respectively, compared with placebo as 1.0. The drug was associated with a dose-dependent decrease in proteinuria, but no significant changes in GFR. Blood pressures were only marginally affected in this study design - the average group blood pressures over the 2 years were 144/83 mmHg for placebo, 143/83 mmHg for 150 mg, and 141/83 mmHg for 300 mg irbesartan.

The other two studies employed type 2 diabetic hypertensive patients with more pronounced proteinuria and established renal insufficiency. In one² , losartan (50 to 100 mg daily) was compared in a double-blind, randomized study with placebo, both being taken with conventional antihypertensive drugs, for a mean of 3.4 years. During the study period losartan significantly reduced the incidences of doubling of serum creatinine levels and ESRD, but had no effect on the death rate. Admissions for heart failure were significantly reduced, and proteinuria declined by 35%.

The third study³ compared irbesartan (300 mg daily) with amlodipine (10 mg daily) and placebo, in a randomized design over 2.6 years. Similar benefits with regard to the incidences of doubling of creatinine levels and ESRD, but again there was no reduction in cardiovascular events or mortality during the study period.

In all three studies, the benefits clearly exceeded those that could be attributed to changes in blood pressure. On average, there was a delay in the onset of ESRD of about 2 years. It is likely that the blockade of the renin-angiotensin-aldosterone system achieved with these drugs led to decreases in the glomerular capillary pressure and in the fibroproliferative actions of angiotensin and aldosterone.

Consequences

It has long been assumed that renin-angiotensin-aldosterone blockade would slow nephropathy in type 2 diabetics, even without benefit of large clinical studies like these. The editorial considers why ACE inhibitors have not been studied in this way, and concludes that this is probably related to the expense of such studies and the impending lapse of patent coverage for ACE inhibitors; also, proteinuria (a relatively easy parameter to measure) has only recently been accepted as a reliable indicator of the severity of ESRD.

If, indeed, ACE inhibitors and angiotensin-receptor blockers have equivalent beneficial effects in patients at risk, decisions about which to prescribe should be based on side effects and cost. The troubling cough provoked by ACE inhibitors in 5-20% of patients may be a reason to select an angiotensin-receptor blocker. On the other hand, the relative cheapness of ACE inhibitors has led to one expert recommendation that all middle-aged type 2 diabetics should be prescribed a drug from this class, regardless of their base-line renal status.

In spite of these encouraging results, it must be remembered that the benefits achieved represent a postponement, but not total prevention, of ESRD. We still need more effective approaches - apart from the obvious ones - to prevent type 2 diabetes in the first place.