Diabetic Nephropathy: How 'Playing an ACE' Can Reduce Your Patient's Risk

ERIC A. ORZECK, MD
Baylor College of Medicine

It is often said that the United States does not provide health care, only sickness care. With few exceptions-such as weight control, reduction of alcohol intake, and smoking cessation-physicians seldom intervene to prevent disease. For persons with diabetes mellitus, however, a compelling case for preventive care can be made-particularly as it relates to the use of medications to prevent nephropathy.

In 1992, the yearly cost for the care of patients with diabetes was estimated at $45 billion; a slightly greater additional amount was spent on mdireef costs, including missed work, disability and death. The almost $100 billion spent on these patients represented 15% of all US health care expenditures.¹ Moreover, persons with diabetes constitute the largest percentage ( ver 25%) of those who start renal dialysis each year.

Here I review the evidence that supports he use of angiotensin-conveiling enzyme (ACE) inhibitors and angiotensin H receptor blockers to prevent and manage diabetic nephropathy. I will begin by reviewing the risk factors for renal disease in diabetes. I will also provide suggested regimens for these agents, as well as a few eats about potential adverse effects.

RISK FACTORS FOR NEPHROPATHY

Microalbuminuria. The appearance of microalbuminuria (albumin in amounts too small to be detected with routine proteinuria screening) indicates that frank proteinuria will develop, usually within 10 years, with further progression to renal failure and end-stage renal disease (Figure).² Microalbuminuria is also related to cardiovascular morbidity and mortality in patients with type 2 diabetes.³

In their overview of the literature, Dinneen and Gerstein³ reviewed 11 cohort studies. Five of the studies used spot urinary albumin ranges of 15 to 300 mg/L, while six used timed samples of excretion greater than 10.5 pg/mm. Even after adjusting for other cardiovascular risk factors, microalbuminuria was associated with an overall odds ratio of 2.5 for death and 2 for cardiovascular morbidity or mortality.

Hypertension. This is another risk factor for nephropathy in diabetic patients. However, even when blood pressure is reduced to normal (defined as 130/85 mm Hg or lower), mlcroalbuminuria can still progress to frank nephropathy.⁴

PROTECTING RENAL FUNCTION

Hemoglobin A_1C reduction. The oft-quoted Diabetes Control and Complications Trial (DCCI), which studied type 1 diabetes, showed that lowering hemoglobin A_1C levels by almost two percentage points reduces the development of nephropathy in primary prevention by 44% and lowers the progression of renal disease in secondary intervention by 56%.⁵ Similar improvements were seen in the other complications related to mlcrovascular disease, such as retinopathy and neuropathy.

While these results seem to settle any questions about complications in patients with type 1 diabetes (who represent 10% of all diabetic patients), what about the 9O% with type 2 diabetes? Recently, Vijan and colleagues⁶ demonstrated that not only will a decrease in hemoglobin A1C levels reduce the lifetime risk of end-stage renal disease, but the earlier the intervention, the greater the decrease in the risk of nephropathy.

Drug therapy. Treating hypertension and maintaining appropriate glucose control remain important however, ACE inhibitors have an effeet more protective of renal function than that accorded by blood pressure control alpne.⁷ The prototype medication originally studied was captopril, but there is now evidence that other ACE inhibitors have the same protective effect-as does the newer class of agents that affect renal function, the angiotensin II receptor blockers. The progression of microalbuminuria is reduced even in normotensive patients with diabetes.⁸

Furthermore, a meta-analysis of 10 studies involving a total of 1,594 patients revealed the same beneficial effects of ACE inhibitors on renal function in patients without diabetes, compared with other antihypertensive agents.⁸ ACE inhibitors substantially delay the onset of renal disease by 30% without increasing mortality. This effect was independent of baseline renal function, which allows for the use of ACE inhibitors throughout the entire spectrum of renal disease. Because of their greater renal spedficity, the angiotensin H receptor blockers may prove to be the drugs of choice, if additional studies bear out preliminary information about their effectiveness.

In addition to lowering systemic blood pressure (if needed), ACE inhibitors and angiotensin H receptor blockers lower proteinuria by improving glomerular permeability and decrease the formation of proteins that further reduce glomerular function.^9,10 These agents have a vascular effect as well. Angiotensin II constricts the efferent flow from the kidney, and this increases the glomerular capillary pressure. By stopping asoconstriction,, the opening of the efferent artery decreases the glomerular capillary pressure, improves the glomerular filtration rate, and thus improves overall renal function.

Figure - In persons with diabetes, the appearance of microalbumiruria indicates that frank proteinuria will develop, usually within 10 years, with further progression to renal failure and end-stage renal disease. Adapted from DeFronzo RA. Diabetes Mellitus: Management and Cornplications. 1985 ¹³

SUGGESTED STRATEGY

For persons with type 1 or type 2 diabetes, begin a program of tight glycemic control and then institute an ACE inhibitor or an angiotensiri H receptor blocker as prophylactic therapy, even if there is no evidence of renal dysfunction (See table below). In patients with overt nephropathy (either increased microalbuminuria or frank proteinuria in patients with type 1 diabetes), use an ACE inhibitor or an angiotensin II receptor blocker to slow the progression to end-stage renal disease. The use of these agents in patients with type 2 disease (including those with overt nephropathy if they are not volume-depleted and the serum creatinine level is 3 mg/dL or less) is also strongly recommended, especially if they have hypertension.

A FEW CAVEATS

Never use ACE inhibitors or angiotensin H receptor blockers in pregnant women. Also, remember that patients who take ACE inhibitors or angiotensin II receptor blockers may have adverse reactions, such as:

• Cough, which occurs in 10% to 20% of patients taking ACE inhibitors (but rarely in those taking angiotensin II receptor blockers).

• Angioedema, especially in African-Americans; however, this adverse effect is extremely rare in patients taking angiotensin II receptor blockers. ¹¹

Although angioedema can occur as early as the first day of medication use, it may not be seen until 1 or more years later and is not as prevalent as ACE inhibitor-related cough. Start therapy with a short-acting ACE inhibitor (such as captopril, 25 mg tid), and switch 2 to 4 weeks later to a longer-acting daily dose of an ACE inhibitor or an angiotensin II receptor blocker if no problems have appeared.

References

1. Rubin, R, Altman, W, Mendelson D. Health care expenditures for people with diabetes mellitus, 1992. J Clin Endocrinol Metab. 1994;78:809A-809F.

2. Orzeck EA. How best to detect microalbuminuria in diabetic patients? Consultant. 1997;37:2541.

3. Dineen S, Gerstein H. The association of microalbuminuria and mortality in non-insulin dependent diabetes mellitus. Arch Intern Med. 1997; 157:1413-1418.

4. Stein P, Black H. Drug treatment of hypertension in patients with diabetes mellitus. Diabetes Care. 1991;14:425-428.

5. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993; 329:977-986.

6. Vijan S, Hofer T, Hayward R. Estimated benefits of glycemic control in microvascular complications in Type 2 diabetes. Ann Intern Med. 1997;127:788-795.

7. Lewis E, Hunsicker L, Bain R, et al. The effect of angiotensin converting enzyme inhibition on diabetic neuropathy. N Engl J Med. 1993;329:1456-1462.

8. Giatras I, Lau J, Levey A. Effect of angiotensin converting enzyme inhibitors on the progression of nondiabetic renal disease: a meta-analysis of randomized trials. Ann Intern Med 1997:127:337-345.

9. Viberti G. Mogensen C, Groop L, et al. Effect of captopril on progression to clinical proteinuria in patients with insulin dependent diabetes mellitus ajd microalbuminuria. JAMA 1994;271:275-279

10. Gansevoort R, Zeeuw D, deJohn P. Is the antiproteinuric effect of ACE inhibition mediated by interference in the renin-angiotensin system? Int Soc Nephrol. 1994; 45:861-867.

11. USP DI®: Drug information for the Health Care Professional. 18th ed. Rockville, Md: United States Pharmacopeial Convention: 1998; 1:1895.

12. Consensus Development conference on the diagnosis and management of nephropathy in patients with diabetes mellitus. Diabetes Care. 1994;17:1357-1361.

13. DeFronzo RA. Diabetes and the kidney: an update. In: Olefsky JM, Sherwin RS, eds. Diabetes Mellitus: Management and Complications. New York: Churchill Livingstone; 1985:169.

This article appeared in the August 1998 issue of Consultants: Consultations in Primary Care Vol 38. Issue 8 pp. 1980-1982.