Q: Should all diabetic patients take ACE inhibitors, even
those without proteinuria?
Byron J. Hoogwerf, MD
Department of Endocrinology, Cleveland Clinic
A: Recent studies have shown that angiotensin-converting
enzyme (ACE) inhibitors can slow the progression to diabetic nephropathy in patients with
type 1 or type 2 diabetes with microalbuminuria or macroalbuminuria.
Should we extend this reasoning, and give all
patients with diabetes ACE inhibitors, even if they have no proteinuria?
I believe it is premature to recommend using ACE
inhibitors in all patients with diabetes mellitus. We do, however, have good evidence that
ACE inhibitors are beneficial in specific groups of diabetic patients, eg, those with
microalbuminuria or frank proteinuria. There is also accumulating evidence of benefit in
patients with congestive heart failure and myocardial infarction. Whether these
indications should be expanded awaits the results of further study.
Blood pressure and the kidney
A major principle to protect the kidney from the
complications of diabetes is to treat high blood pressure aggressively, no matter what
type of antihypertensive drug is used. In early studies in patients with type 1 diabetes,
Parving et al1 and Mogensen2 used antihypertensive drugs such as
diuretics, beta-blockers, and hydralazine; they demonstrated that lowering blood pressure
reduces proteinuria and slows the decline of renal function.
Current guidelines suggest that a value less than
130/85 mm Hg is a reasonable target. Whether lower blood pressures will accrue greater
benefits is not yet firmly established.
ACE inhibitors and renal disease in
diabetes
Although the primary goal in protecting the
kidney is to reduce the blood pressure, a preponderance of current evidence indicates that
ACE inhibitors protect the kidney better than other blood-pressure-lowering medications,
probably because ACE inhibitors specifically lower the intrarenal pressure.
After animal studies demonstrated a renal
protective effect of ACE inhibitors, a number of human trials followed.3,4
Lewis et al5 performed a landmark study in patients with type 1 diabetes,
albuminuria, and mildly impaired creatinine clearance—ie, patients who were just
beginning to develop renal failure. The ACE inhibitor captopril reduced the risk for a
decline in renal function compared with other antihypertensive regimens (not including
calcium channel blockers).
Additional data indicate that ACE inhibitors may
slow the progression of microalbuminuria to macroalbuminuria even in normotensive
patients.6 An increasing urine albumin excretion rate is a surrogate for
end-stage renal disease, and is the basis for the current recommendations for use of ACE
inhibitors and blood pressure regimens in diabetic patients who have microalbuminuria or
macroalbuminuria.
Enthusiasm for ACE inhibitors may be tempered by
the findings of the United Kingdom Prospective Diabetes Study (UKPDS), in which atenolol
(a beta-blocker) and captopril were equally effective in reducing the risk for albuminuria
in hypertensive type 2 diabetic subjects.7 Since proteinuria in type 2 diabetic
patients may not necessarily be related to diabetic nephropathy, other methods of managing
hypertension may be equally efficacious in protecting type 2 diabetic patients from
adverse medical outcomes—including renal disease and atherothrombotic events.
ACE inhibitors and coronary heart disease
Because angiotensin has potential adverse effects
on the heart, use of ACE inhibitors in diabetic patients may help to reduce the risk for
coronary heart disease events. In the Appropriate Blood Pressure Control in Diabetes
(ABCD) trial,8 the risk of fatal and nonfatal myocardial infarction was higher
in patients receiving a calcium channel blocker (nisoldipine) than with an ACE inhibitor
(enalapril).
Although this finding was interpreted as an
adverse effect of the calcium channel blocker, it may have been a beneficial effect of the
ACE inhibitor.
A major trial is underway to assess the effects
of ACE inhibitors in patients at high risk of atherosclerotic events. This trial, called
the HOPE (Heart Outcomes Prevention Evaluation) study, has two components: the main HOPE
study (in patients at high risk for coronary heart disease events, with or without
diabetes)9 and a substudy called MICRO-HOPE10 in diabetic patients
only. The latter should be able to demonstrate whether ACE inhibitor therapy will prevent
new-onset albuminuria as well as reduce the risk for coronary heart disease events.
Results of this study should be available in
early 2000. Positive results would lend support to the notion that high-risk type 2
diabetic patients, even those without proteinuria, might benefit from routine use of ACE
inhibitors.
Several studies with angiotensin II receptor
blockers are also underway.
References
1. Parving HH, Andersen AR, et al.
Diabetic nephropathy and arterial hypertension. The effect of antihypertensive treatment.
Diabetes 1983; 32(Suppl 2):83–87.
2. Mogensen CE. Antihypertensive
treatment inhibiting the progression of diabetic nephropathy. Act Endocrinol 1980;
238(Suppl):103–108.
3. Kasiske BL Kalil RSN, Ma JZ, Liao M,
Keane WG. Effect of antihypertensive therapy on the kidney in patients with
diabetes: a metaregression analysis. Ann Intern Med 1993; 118:129–138.
4. Salem JK, Hoogwerf BJ.
Diabetic nephropathy: strategies for preventing renal failure. Cleve Clin J Med 1996;
63:331–338.
5. Lewis IF, Hunsicker LG, Bain RP, et
al. The effect of angiotensin-converting enzyme inhibition on diabetic
nephropathy. N Engl J Med 1993; 329:1456–1462.
6. Ravid M, Savin H, et al.
Long-term stabilizing effect of angiotensin-converting enzyme inhibition on plasma
creatinine and on proteinuria in normotensive type II diabetic patients. Ann Intern Med
1993; 118:577–581.
7. UK Prospective Diabetes Study (UKPDS)
Group. Efficacy of atenolol and captopril in reducing risk of macrovascular and
microvascular complications in type 2 diabetes: UKPDS 39. BMJ 1998; 317:713–720.
8. Estacio RO, Jeffers BW, et al.
The effect of nisoldipine as compared with enalapril on cardiovascular outcomes in
patients with non–insulin-dependent diabetes and hypertension. N Engl J Med 1998;
338:645–652.
9. The HOPE Study Investigators.
The HOPE (Heart Outcomes Prevention Evaluation) Study: the design of a large, simple
randomized trial of an angiotensin-converting enzyme inhibitor (ramipril) and vitamin E in
patients at high risk of cardiovascular events. Can J Cardiol 1996; 12:127–137.
10. Gerstein HC, Bosch J, et al.
Rationale and design of a large study to evaluate the renal and cardiovascular effects of
an ACE inhibitor and vitamin E in high-risk patients with diabetes. The MICRO-HOPE Study.
Heart Outcomes Prevention Evaluation. Diabetes Care 1996: 19:1225–1228.
