Medicine and Opera

I recently reviewed a paper that indicated that angiotensin blockade with an angiotensin receptor blocker (ARB) did not protect against the development of diabetic nephropathy in diabetic patients with normal renal function. Despite what that paper concluded angiotensin blockade with and an angiotensin converting enzyme (ACE) inhibitor offered protection.

Two papers in the July 7 Annals of Internal Medicine looked at the effect of ARBs in patients with renal disease. The first study included patients with high vascular risk but who did not have microalbuminuria; about a third were diabetic. In these patients the ARB telmisartan had no effect on major renal outcomes.

The second study was of normotensive diabetic patients. Candesartan (another ARB given at a maximum dose of 32 mg daily) did not prevent microalbuminuria in patients with either type 1 or type 2 diabetes. This makes three studies which indicate no salutary renal effect of ARBs.

The clinician is left wondering if ACE inhibitors are better for the kidney than ARBs or other anti-hypertensive medicines. This question may remain unresolved because ACE inhibitors are available in generic form while ARBs are still on patent. Thus there is little incentive for drug companies to fund long and expensive research projects which are not likely to help them market their product. The NIH should be encouraged to mount additional studies of ACE inhibitors on patients at great risk for serious renal disease who are at an early stage of their disease.

The best practice in the absence of such studies would be to continue to prescribe ACE inhibition in diabetic patients and other at increased renal risk and to do so early in their disease. The worst that will happen from this treatment is that blood pressure will be reduced and the retina will be protected; there is no down side. I think that ARBs should be avoided  unless the patients cannot tolerate ACE inhibition, usually because of cough and rarely because of angioedema.

If there turns out to be a different effect on clinical outcomes between the two types of angiotensin blockers the explanation for the difference will be of intense interest. One possible explanation for a difference between ACE inhibitors and ARBs is that the former decreases angiotensin levels while the latter increases them. ARBs block the AT-1 receptor. If angiotensin exerts a harmful effect mediated by a mechanism other the via the AT-1 receptor then ARBs would make things worse while ACE inhibitors would be beneficial.

I suspect when the fog lifts that ACE inhibition will be shown to have a beneficial effect on patients at high risk for progressive renal disease. But well designed research will have the final word.

The July 2 issue of the New England Journal of Medicine has an article on the prevention of diabetic nephropathy and retinopathy that will elicit much attention. It concludes “Early blockade of the renin-angiotensin system in patients with type 1 diabetes did not slow nephropathy progression but slowed the progression of retinopathy.” An accompanying editorial reached the same conclusion. This finding is surprising. Angiotensin blockade is standard treatment for patients with diabetic nephropathy at any stage and is often given to diabetic patients before they show signs of kidney disease.

I’ll just focus on the renal findings. The conclusion is misleading on two counts. The first is that the design of the study excluded patients who were most likely to benefit from angiotensin blockade and the second is that the data are, in my view, improperly interpreted.

The exclusion criteria were microalbuminuria, hypertension, and a glomerular filtration rate (GFR) of less than 90 ml/min. Thus the patients followed were at lower risk to show major progression of diabetic nephropathy than those who already had clear signs of it. But let’s ignore this and just look at the data in the study.

The primary renal endpoint of the study was a change in mesangial fractional volume (MFV). Increasing MFV is an early marker of the progression of diabetic nephropathy. The patients had renal biopsies at baseline and after 5 years of follow-up. Secondary end points included changes in microalbuminuria and GFR. The data show that “MFV between baseline and five years increased by 0.016 unit in the placebo group (p=0.004) and 0.026 unit in the losartan group (p<0.001) but did not change significantly (0.005 units) in the enalapril group.”

This is the key finding that is ignored both by the study authors and the editorialists. Angiotensin inhibition with enalapril prevented mesangial expansion. The authors try to explain away this critical observation by saying that the MFV at five years was not significantly different across the three groups. So what! Mesangial expansion did not occur in patients treated with an ACE inhibitor. These data indicate that angiotensin blockade with an ACE inhibitor but not with and angiotensin receptor blocker prevents progression of diabetic nephropathy. This important observation is thrown away. It’s also missed by the three editorial writers. Doubtless the press and many physicians will also miss it.

Progression of microalbuminuria was a secondary outcome. None of the groups had microalbuminuria (defined as 20 to 200 µg/min ) at the start of the study and none had it at the end, though it did go from 6.5 to 10.6 in the losartan group. This is statistically significant, but seems likely to be of little or no clinical significance as it’s not even close to being outside the normal range.  Yet the editorialists say “Inhibition of the renin-angiotensin system did not reduce the incidence of microalbuminuria…” They doubtless were looking at how many patients within each group developed proteinuria even though albumin excretion was not abnormal in any group.

At the end of five years 18% of the losartan group had (see figure) microalbuminuria. In the placebo group 6% had increased albumin excretion, while only 4% of the enalapril group had an increase and no patients on enalapril developed it over the last 2.5 years of the study. This again suggests a beneficial effect of ACE inhibition and a possible deleterious effect of the ARB. This makes the above statement seem a big stretch.

“The GFR decreased similarly in all three groups; by 6.6 to 8.9 ml/min (p<0.002 in all three).” But the GFR was still at least 120 ml/min. These data require an interpretation not offered in either the paper or the editorial. The blood pressure was lower in the two treatment groups. Angiotensin blockade can lower GFR at the same time it’s preserving glomerular function. I can’t be sure, but it is nevertheless possible that enalapril lowered GFR because of both a greater effect on blood pressure and a direct renoprotective effect on the glomerulus, while GFR in the placebo group fell because of disease progression. In other words, if the study were longer the GFR might have been much lower in the placebo group than in the enalapril treated patients.

What to make of this ambiguous study? I think that current treatment of patients with incipient diabetic nephropathy, regardless of whether type 1 or type 2, is best done with ACE inhibition. At the very least more study is indicated to resolve the issues I’ve discussed and which this paper leaves uncertain.