Challenging Dogma: Is It Really True That “ACE” Inhibitors Do Not Slow The Development/Progression Of Diabetic Nephropathy?

There was a very interesting article in this week’s New England Journal of Medicine. The article was written by Michael Mauer and associates and entitled “Renal and Retinal Effects of Enalapril and Losartan in Type 1 Diabetes.  Before I get into the study findings, I need to provide a bit of background information for those readers not up on treatment of diabetic nephropathy ( kidney disease).  Diabetic nephropathy is the most common cause of kidney failure in the U.S. and the most common reason for chronic kidney dialysis.  It is clear from the Diabetes Control and Complications Trial (DCCT) and other studies that the two biggest risk factors for the development and progression of diabretic nephopathy (in both type 1 and 2 diabetes) are blood glucose control and blood pressure.  A number of studies have also shown that use of a certain class of antihypertensive agents called angiotensin-converting enzyme inhibitors, or “ACE” inhibitors for short, can slow progression of diabetic nephropathy.  It is more or less established dogma that ACE inhibitors prevent progression of established diabetic nephropathy.  Even the American Diabetes Association strongly recommends treatment with ACE inbibitors in patients with diabetes who show even early signs of diabetic nephropathy (typically, leakage of small amounts of protein in the urine which is called microalbuminuria.  Many physicians treat their diabetic patients who do not show excessive microalbuminuria with ACE inhibitors on a prophylactic basis although the scientific evidence for such a treatment strategy is not well established.

The Mauer study design

Mauer and colleagues studied 285 people with type 1 diabetes at least 18 years of age with diabetes duration 2-20 years.  Patients were excluded from the study if they had hypertension or any evidence of diabetic nephropathy.  Most patients had kidney biopsies at the beginning and end of the study which lasted 5 years.  The patients were randomly assigned to one of three treatment groups: placebo, Losartan (an ACE inhibitor) or Enalopril (an ACE inhibitor.

Study results

Basically, the study showed no benefit in terms of development of elevated microalbumin levels with the ACE inhibitors; in fact, the Losartan group actually showed a statistically significant higher incidence of elevated microalbumin levels than did the placebo group.  Among the three  treatment groups, there were no differences in the extent of morphologic kidney changes over the 5-year period.  Both ACE inhibitor groups showed significantly less progression of diabetic retinopathy (65-70% less risk for progression).

So now what?

These results were, to say the least, surprising to many experts.  The question remains how to reconcile the Mauer study results with results of earlier studies and what to do with patients who are now being treated with ACE inhibitors?  In my opinion, we should not panic, but sit back and try to sort this all out.  There are some important limitations of the Mauer study that cannot be ignored.  First, only 25-40% of patients with diabetes ever develop diabetic nephropathy.  It seems clear that some patients are not prone to develop diabetic nephropathy despite having risk factors such as hypertension and poor glycemic control.  Some studies suggest there are genetic factors that either decrease or increase patient risks for the development of nephropathy in addition to the known clinical risk factors.  So, it is hard to know what to make of the fact that the placebo group showed only a 6% increase in cumulative incidence of abnormal levels of microalbuminuria.  Ideally, the study should have excluded patients who were at little or no risk for the development of nephropathy regardless of blood glucose control and blood pressure.  Of course, there was no way to do that.

Also, I wonder whether the investigators should have looked at their data with regard to patients’ levels of glycemic control?   The only A1c data in the study were baseline A1cs in the three treatment groups to show that the groups were similar at baseline in terms of glycemic control.  We already know that the level of HbA1c is a strong risk predictor for the development/progression of diabetic nephropathy.  Maybe the A1c trumps the effects of the ACE inhibitor; perhaps the ACE inhibitor is not protective unless the A1c is low?

So, for now I would recommend using an ACE inhibitor as a first line choice for treating hypertension in a patient with diabetes.  I would not, however (and never did) consider using ACE inhibitors to prevent the development of diabetic nephropathy.  I am still undecided whether to recommend an ACE inhibitor to a patient with abnormal and steadily increasing levels of microalbuminuria.  Of course, what complicates all of this are the Mauer study data on diabetic retinopathy; maybe the new dogma will be that ACE inhibitors should be used in all patients with diabetes to prevent/slow progression of diabetic retinopathy?  Most important, we should not forget the old dogma which still stands- glycemic control and blood pressure are both proven powerful risk factors for the development/progression of all diabetic complications.  If one “covers” all the risk factors for diabetic complications, there is no need to debate whether ACE inhibitors help or not.

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