ACE Inhibitors or ARBs to Prevent CKD in Patients with Microalbuminuria

Jason M. Corbo; Teresa M. Breslin; Lucas G. Hill; Sarah L. Rindfuss; Joan Nashelsky

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Oct 15, 2016 Issue

FPIN's Clinical Inquiries

ACE Inhibitors or ARBs to Prevent CKD in Patients with Microalbuminuria

JASON M. CORBO, PharmD, BCPS, South Texas Veterans Health Care System, San Antonio, Texas

TERESA M. DELELLIS, PharmD, BCPS, Manchester University College of Pharmacy, Natural, and Health Sciences, Fort Wayne, Indiana

LUCAS G. HILL, PharmD, BCPS, BCACP, The University of Texas at Austin College of Pharmacy, Austin, Texas

SARAH L. RINDFUSS, PharmD, BCPS, Allegheny Health Network, West Penn Hospital Care Partner Clinic, Pittsburgh, Pennsylvania

JOAN NASHELSKY, MLS, University of Iowa Center for Human Rights, Iowa City, Iowa

Am Fam Physician. 2016 Oct 15;94(8):652-653.

Clinical Question

Does therapy with angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) prevent progression to chronic kidney disease (CKD) in normotensive patients with microalbuminuria?

Evidence-Based Answer

ACE inhibitors reduce the risk of progression to macroalbuminuria in normotensive patients with microalbuminuria and type 1 diabetes mellitus. (Strength of Recommendation [SOR]: C, based on a meta-analysis of randomized controlled trials [RCTs] with disease-oriented outcomes.) ACE inhibitors and ARBs reduce the risk of progression to macroalbuminuria in normotensive patients with microalbuminuria and type 2 diabetes. (SOR: C, based on disease-oriented evidence from small RCTs.) ACE inhibitors and ARBs do not reliably affect serum creatinine levels. Recommendations are not available for normotensive patients without diabetes who have microalbuminuria.

Evidence Summary

TYPE 1 DIABETES

A 2001 meta-analysis of 10 small RCTs (N = 698) described the effect of ACE inhibitors vs. placebo on progression to macro-albuminuria in normotensive patients with microalbuminuria and type 1 diabetes.1 Several definitions of normotension were allowed; microalbuminuria was defined as a urinary albumin excretion rate of 20 to 200 mcg per minute, whereas a rate greater than 200 mcg per minute was considered macroalbuminuria. Two-year follow-up data were available for 646 patients. Nine of the 10 trials demonstrated a significantly lower risk of progression to macroalbuminuria with ACE inhibitors compared with placebo (odds ratio [OR] = 0.38; 95% confidence interval [CI], 0.25 to 0.57). Regression to normal albuminuria occurred more often with ACE inhibitors than with placebo (OR = 3.07; 95% CI, 2.14 to 4.44). Changes in estimated creatinine clearance and glomerular filtration rate were not reported. The authors of this meta-analysis and several of the referenced studies received funding from industry.

TYPE 2 DIABETES

All studies demonstrated the benefits of therapy with ACE inhibitors and ARBs on urinary albumin excretion in patients with type 2 diabetes, but the magnitude of effect varied by comparison group. Three RCTs showed a statistically significant reduction in urinary albumin excretion in patients treated with losartan (Cozaar) or enalapril (Vasotec) over one to five years; two studies showed no difference with ramipril (Altace) or enalapril (Table 1).2–6 Only one study found a significant difference in the serum creatinine level in treated patients (significant decrease in the enalapril group).4 No study of patients with type 2 diabetes found a significant difference in blood pressure, A1C level, or body mass index between treated patients and the control group.

Enlarge Print

Table 1.

Summary of Randomized Controlled Trials of Normotensive Patients with Type 2 Diabetes Mellitus and Microalbuminuria

Study (n)	Intervention	Comparison group	Effect on 24-hour urinary albumin excretion	Effect on serum creatinine
Agha, et al., 2009 (361)2	Losartan (Cozaar), 50 mg per day	Vitamin B₁₂, 500 mcg per day	Reduction with losartan (101.9 to 47.5 mg per dL) vs. no change with vitamin B₁₂ over six months (104.7 to 103.9 mg per dL; P < .0001)	Not reported
Sano, et al., 1996 (56)3	Enalapril (Vasotec), 5 mg per day	Placebo	Reduction with enalapril (115.4 to 75.3 mg per dL; P < .001) vs. increase with placebo (93.9 to 150.0 mg per dL; no P value given) over 48 months	No difference in either group over 48 months
Ravid, et al., 1994 (94)4	Enalapril, 10 mg per day	Placebo	30% ARR for development of macroalbuminuria with enalapril vs. placebo (95% CI, 15% to 45%; NNT = 3)	Stable in enalapril group vs. 13% decrease in reciprocal creatinine in placebo group at five years (P < .05)
Vongterapak, et al., 1998 (28)5	Ramipril (Altace), 1.25 mg per day	Placebo	No change with ramipril (29.5 to 27.7 mg per dL) vs. increase with placebo (30.6 to 39.0 mg per dL; P < .05) over 12 weeks	No change in either group over 12 weeks; not statistically evaluated
Ravid, et al., 1996 (108)6	Enalapril, 10 mg per day	Placebo	42% ARR for development of macroalbuminuria with enalapril vs. placebo (95% CI, 15% to 69%; NNT = 2)	Stable in enalapril group vs. 16% decrease in reciprocal creatinine in placebo group at seven years (P < .05)

ARR = absolute risk reduction; CI = confidence interval; NNT = number needed to treat.

Information from references 2 through 6.

Table 1.

Summary of Randomized Controlled Trials of Normotensive Patients with Type 2 Diabetes Mellitus and Microalbuminuria

Study (n)	Intervention	Comparison group	Effect on 24-hour urinary albumin excretion	Effect on serum creatinine
Agha, et al., 2009 (361)2	Losartan (Cozaar), 50 mg per day	Vitamin B₁₂, 500 mcg per day	Reduction with losartan (101.9 to 47.5 mg per dL) vs. no change with vitamin B₁₂ over six months (104.7 to 103.9 mg per dL; P < .0001)	Not reported
Sano, et al., 1996 (56)3	Enalapril (Vasotec), 5 mg per day	Placebo	Reduction with enalapril (115.4 to 75.3 mg per dL; P < .001) vs. increase with placebo (93.9 to 150.0 mg per dL; no P value given) over 48 months	No difference in either group over 48 months
Ravid, et al., 1994 (94)4	Enalapril, 10 mg per day	Placebo	30% ARR for development of macroalbuminuria with enalapril vs. placebo (95% CI, 15% to 45%; NNT = 3)	Stable in enalapril group vs. 13% decrease in reciprocal creatinine in placebo group at five years (P < .05)
Vongterapak, et al., 1998 (28)5	Ramipril (Altace), 1.25 mg per day	Placebo	No change with ramipril (29.5 to 27.7 mg per dL) vs. increase with placebo (30.6 to 39.0 mg per dL; P < .05) over 12 weeks	No change in either group over 12 weeks; not statistically evaluated
Ravid, et al., 1996 (108)6	Enalapril, 10 mg per day	Placebo	42% ARR for development of macroalbuminuria with enalapril vs. placebo (95% CI, 15% to 69%; NNT = 2)	Stable in enalapril group vs. 16% decrease in reciprocal creatinine in placebo group at seven years (P < .05)

ARR = absolute risk reduction; CI = confidence interval; NNT = number needed to treat.

Information from references 2 through 6.

Recommendations from Others

The Kidney Disease: Improving Global Outcomes guideline recommends ARBs or ACE inhibitors for adults with CKD with or without diabetes who have a urinary albumin excretion rate of 30 to 300 mg per 24 hours and in whom blood pressure medications are indicated. The guideline recommends a blood pressure goal of 130/80 mm Hg or less in these patients.7 The American Diabetes Association recommends ACE inhibitors or ARBs for nonpregnant patients with diabetes and microalbuminuria, but it makes no specific recommendations for blood pressure beyond its standard goals.8 The National Kidney Foundation recommends an ACE inhibitor or ARB in normotensive patients with diabetes and an albumin level greater than 30 mg per g who are at high risk of CKD or progression.9 The National Kidney Foundation guideline does not provide recommendations for normotensive patients without diabetes.

Address correspondence to Jason M. Corbo, PharmD, BCPS, at jason. corbo@gmail.com. Reprints are not available from the authors.

Author disclosure: No relevant financial affiliations.

REFERENCES

show all references

1. ACE Inhibitors in Diabetic Nephropathy Trialist Group. Should all patients with type 1 diabetes mellitus and microalbuminuria receive angiotensin-converting enzyme inhibitors? A meta-analysis of individual patient data. Ann Intern Med. 2001;134(5):370–379....

2. Agha A, Amer W, Anwar E, Bashir K. Reduction of microalbuminuria by using losartan in normotensive patients with type 2 diabetes mellitus: a randomized controlled trial. Saudi J Kidney Dis Transpl. 2009;20(3):429–435.

3. Sano T, Hotta N, Kawamura T, et al. Effects of long-term enalapril treatment on persistent microalbuminuria in normotensive type 2 diabetic patients: results of a 4-year, prospective, randomized study. Diabet Med. 1996;13(2):120–124.

4. Ravid M, Savin H, Jutrin I, Bental T, Lang R, Lishner M. Long-term effect of ACE inhibition on development of nephropathy in diabetes mellitus type II. Kidney Int Suppl. 1994;45:S161–S164.

5. Vongterapak S, Dahlan W, Nakasatien S, et al. Impediment of the progressions of microalbuminuria and hyperlipidemia in normotensive type 2 diabetes by low-dose ramipril. J Med Assoc Thai. 1998;81(9):671–681.

6. Ravid M, Lang R, Rachmani R, Lishner M. Long-term renoprotective effect of angiotensin-converting enzyme inhibition in non-insulin-dependent diabetes mellitus. A 7-year follow-up study. Arch Intern Med. 1996;156(3):286–289.

7. Kidney Disease: Improving Global Outcomes (KDIGO) Blood Pressure Work Group. KDIGO clinical practice guideline for the management of blood pressure in chronic kidney disease. Kidney Int Suppl. 2012;2(5):337–414.

8. American Diabetes Association. Microvascular complications and foot care. Diabetes Care. 2015;38(suppl):S58–S66.

9. National Kidney Foundation. KDOQI clinical practice guideline for diabetes and CKD: 2012 update [published correction appears in Am J Kidney Dis. 2013;61(6):1049]. Am J Kidney Dis. 2012;60(5):850–886.

Clinical Inquiries provides answers to questions submitted by practicing family physicians to the Family Physicians Inquiries Network (FPIN). Members of the network select questions based on their relevance to family medicine. Answers are drawn from an approved set of evidence-based resources and undergo peer review. The strength of recommendations and the level of evidence for individual studies are rated using criteria developed by the Evidence-Based Medicine Working Group ( http://www.cebm.net/?o=1025).

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