Sunday, September 27, 2009

Early RAS-blockade in type 1 diabetes slows retinal damage, but not kidney damage

Early renin-angiotensin system (RAS) blockade in patients with type 1 diabetes slows the progression of retinopathy, but does not affect nephropathy according to a long-term controlled trial.

Diabetic nephropathy is responsible for a significant proportion of cases of end-stage renal disease, and there is evidence that once it is clinically detectable by the presence of albuminuria, drugs that block the RAS are effective in slowing its progression. Despite the lack of trial evidence for value in patients without overt nephropathy, it has therefore been accepted that RAS blockade at all stages will be beneficial in reducing diabetic nephropathy. This trial aimed to test that concept over the longer term using a hard clinical outcome measure: it was partly-industry sponsored, but designed, carried out, analysed, and written-up without industry input.

Participants were patients with type 1 diabetes, normotensive, and with normal albuminuria. Exclusion criteria included glomerular filtration rate (GFR) of less than 90ml/min (80ml/min for strict vegans) and urinary albumin excretion greater than 20microgm/min; a two-week placebo run-in period was used to exclude those poorly compliant with treatment (<85% of doses taken). Eligible patients were randomised to treatment with enalapril 10mg, losartan 50mg, or placebo daily for a study duration of five years. Drug doses were doubled during the study on the basis of trial data published after it started. Primary outcome measured actual kidney damage over the study period by determining change in the fraction of glomerular volume occupied by mesangium in kidney-biopsy specimens. Secondary renal outcomes included incidence of microalbuminuria and GFR. Retinopathy progress was assessed in those for whom lack of baseline (within one year of randomisation) retinopathy could be confirmed: the measure for this outcome was a progression on a retinopathy severity scale of two steps or more.

A total of 1,065 patients was screened for eligibility - most (n=707) declined to participate and 73 were ineligible, leaving 285 randomised participants. Of these, 256 were available for the renal outcome (29 had no exit biopsy, mostly due to withdrawal of consent/loss to follow-up), and 223 for the retinal outcome (32 no baseline photograph; 30 no final photograph, mostly due to withdrawal/loss).

There was no significant difference between the groups in the primary outcome: change in mesangial fractional volume per glomerulus over the 5-year period was 0.016 units in the placebo group compared to 0.005 units in the enalapril group (P=0.38) and 0.026 units in the losartan group (P=0.26). Albumin excretion rate increased significantly from baseline only in the losartan group, and the 5-year cumulative incidence of microalbuminuria was 6% in the placebo group, 4% in the enalapril group, and 17% in the losartan group (P=0.01 by the log-rank test vs. placebo). GFR declined at a similar rate in all three groups (6.6 to 8.9 ml/min).

Both enalapril and losartan reduced the rate of retinopathy progression compared to placebo: rates over five years were 25%, 21%, and 38% respectively, for odds ratios vs. placebo of 0.35 (95% CI, 0.14 to 0.85) and 0.30 95(% CI, 0.12 to 0.73) respectively. These differences were independent of differences in blood pressure.

There were three serious adverse events related to biopsy, all of which resolved, and three deaths unrelated to the study drugs or procedures. Chronic cough occurred in 12 patients receiving enalapril, 6 receiving losartan, and 4 on placebo.

The authors conclude that early RAS blockade in patients with type 1 diabetes did not affect the progression of diabetic nephropathy. It did, however, significantly slow diabetic retinopathy. They comment that the effect of losartan on albumin excretion was unexpected and is not currently confirmed by other studies, nevertheless, they suggest that urinary albumin should be carefully monitored when angiotensin-receptor blockers are prescribed to similar patients. They comment that this study is not comparable to earlier work, and suggest that the inclusion criteria may have selected for patients at lower intrinsic risk of nephropathy.

An accompanying editorial comments on the study and its implications.

NEJM 2009; 361: 40-51 (link to abstract); NEJM 2009; 361: 83-5 (Editorial, link to extract)

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