Am Fam Physician. 2016 Oct 15;94(8):652-653.
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?
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.
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.
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)
Sano, et al., 1996 (56)3
Enalapril (Vasotec), 5 mg per day
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
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
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
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REFERENCESshow 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.
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