Angiotensin‐converting‐enzyme inhibitors and angiotensin receptor blockers for preventing the progression of diabetic kidney disease

Patrizia Natale; Suetonia C Palmer; Sankar D Navaneethan; Jonathan C Craig; Giovanni FM Strippoli

doi:10.1002/14651858.CD006257.pub2

. 2024 Apr 29;2024(4):CD006257. doi: 10.1002/14651858.CD006257.pub2

Angiotensin‐converting‐enzyme inhibitors and angiotensin receptor blockers for preventing the progression of diabetic kidney disease

Patrizia Natale ^1,^2,³, Suetonia C Palmer ⁴, Sankar D Navaneethan ⁵, Jonathan C Craig ^6,⁷, Giovanni FM Strippoli ^1,^3,^6,^✉

Editor: Cochrane Kidney and Transplant Group

PMCID: PMC11057222 PMID: 38682786

Abstract

Background

Guidelines suggest that adults with diabetes and kidney disease receive treatment with angiotensin‐converting‐enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB). This is an update of a Cochrane review published in 2006.

Objectives

We compared the efficacy and safety of ACEi and ARB therapy (either as monotherapy or in combination) on cardiovascular and kidney outcomes in adults with diabetes and kidney disease.

Search methods

We searched the Cochrane Kidney and Transplants Register of Studies to 17 March 2024 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Registry Platform (ICTRP) Search Portal, and ClinicalTrials.gov.

Selection criteria

We included studies evaluating ACEi or ARB alone or in combination, compared to each other, placebo or no treatment in people with diabetes and kidney disease.

Data collection and analysis

Two authors independently assessed the risk of bias and extracted data. Summary estimates of effect were obtained using a random‐effects model, and results were expressed as risk ratios (RR) and their 95% confidence intervals (CI) for dichotomous outcomes and mean difference (MD) or standardised mean difference (SMD) and 95% CI for continuous outcomes. Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.

Main results

One hundred and nine studies (28,341 randomised participants) were eligible for inclusion. Overall, the risk of bias was high.

Compared to placebo or no treatment, ACEi may make little or no difference to all‐cause death (24 studies, 7413 participants: RR 0.91, 95% CI 0.73 to 1.15; I² = 23%; low certainty) and with similar withdrawals from treatment (7 studies, 5306 participants: RR 1.03, 95% CI 0.90 to 1.19; I² = 0%; low certainty). ACEi may prevent kidney failure (8 studies, 6643 participants: RR 0.61, 95% CI 0.39 to 0.94; I² = 0%; low certainty).

Compared to placebo or no treatment, ARB may make little or no difference to all‐cause death (11 studies, 4260 participants: RR 0.99, 95% CI 0.85 to 1.16; I² = 0%; low certainty). ARB have uncertain effects on withdrawal from treatment (3 studies, 721 participants: RR 0.85, 95% CI 0.58 to 1.26; I² = 2%; low certainty) and cardiovascular death (6 studies, 878 participants: RR 3.36, 95% CI 0.93 to 12.07; low certainty). ARB may prevent kidney failure (3 studies, 3227 participants: RR 0.82, 95% CI 0.72 to 0.94; I² = 0%; low certainty), doubling of serum creatinine (SCr) (4 studies, 3280 participants: RR 0.84, 95% CI 0.72 to 0.97; I² = 32%; low certainty), and the progression from microalbuminuria to macroalbuminuria (5 studies, 815 participants: RR 0.44, 95% CI 0.23 to 0.85; I² = 74%; low certainty).

Compared to ACEi, ARB had uncertain effects on all‐cause death (15 studies, 1739 participants: RR 1.13, 95% CI 0.68 to 1.88; I² = 0%; low certainty), withdrawal from treatment (6 studies, 612 participants: RR 0.91, 95% CI 0.65 to 1.28; I² = 0%; low certainty), cardiovascular death (13 studies, 1606 participants: RR 1.15, 95% CI 0.45 to 2.98; I² = 0%; low certainty), kidney failure (3 studies, 837 participants: RR 0.56, 95% CI 0.29 to 1.07; I² = 0%; low certainty), and doubling of SCr (2 studies, 767 participants: RR 0.88, 95% CI 0.52 to 1.48; I² = 0%; low certainty).

Compared to ACEi plus ARB, ACEi alone has uncertain effects on all‐cause death (6 studies, 1166 participants: RR 1.08, 95% CI 0.49 to 2.40; I² = 20%; low certainty), withdrawal from treatment (2 studies, 172 participants: RR 0.78, 95% CI 0.33 to 1.86; I² = 0%; low certainty), cardiovascular death (4 studies, 994 participants: RR 3.02, 95% CI 0.61 to 14.85; low certainty), kidney failure (3 studies, 880 participants: RR 1.36, 95% CI 0.79 to 2.32; I² = 0%; low certainty), and doubling of SCr (2 studies, 813 participants: RR 1.14, 95% CI 0.70 to 1.85; I² = 0%; low certainty).

Compared to ACEi plus ARB, ARB alone has uncertain effects on all‐cause death (7 studies, 2607 participants: RR 1.02, 95% CI 0.76 to 1.37; I² = 0%; low certainty), withdrawn from treatment (3 studies, 1615 participants: RR 0.81, 95% CI 0.53 to 1.24; I² = 0%; low certainty), cardiovascular death (4 studies, 992 participants: RR 3.03, 95% CI 0.62 to 14.93; low certainty), kidney failure (4 studies, 2321 participants: RR 1.15, 95% CI 0.67 to 1.95; I² = 29%; low certainty), and doubling of SCr (3 studies, 2252 participants: RR 1.18, 95% CI 0.85 to 1.64; I² = 0%; low certainty).

Comparative effects of different ACEi or ARB and low‐dose versus high‐dose ARB were rarely evaluated. No study compared different doses of ACEi.

Adverse events of ACEi and ARB were rarely reported.

Authors' conclusions

ACEi or ARB may make little or no difference to all‐cause and cardiovascular death compared to placebo or no treatment in people with diabetes and kidney disease but may prevent kidney failure. ARB may prevent the doubling of SCr and the progression from microalbuminuria to macroalbuminuria compared with a placebo or no treatment. Despite the international guidelines suggesting not combining ACEi and ARB treatment, the effects of ACEi or ARB monotherapy compared to dual therapy have not been adequately assessed. The limited data availability and the low quality of the included studies prevented the assessment of the benefits and harms of ACEi or ARB in people with diabetes and kidney disease. Low and very low certainty evidence indicates that it is possible that further studies might provide different results.

Keywords: Humans; Angiotensin Receptor Antagonists; Angiotensin Receptor Antagonists/therapeutic use; Angiotensin-Converting Enzyme Inhibitors; Angiotensin-Converting Enzyme Inhibitors/therapeutic use; Bias; Cause of Death; Diabetes Mellitus, Type 2; Diabetes Mellitus, Type 2/complications; Diabetes Mellitus, Type 2/drug therapy; Diabetic Nephropathies; Diabetic Nephropathies/prevention & control; Disease Progression; Drug Therapy, Combination; Randomized Controlled Trials as Topic

Plain language summary

Angiotensin‐converting‐enzyme inhibitors and angiotensin receptor blockers for preventing the progression of diabetic kidney disease

Key messages

‐ Angiotensin‐converting‐enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB) may reduce kidney failure in people with diabetes and kidney disease.

‐ We are not sure whether ACEi, ARB or various combinations or doses prevent death or heart disease in people with diabetes and kidney disease.

Why treat people with diabetes who have chronic kidney disease?

Kidney disease is experienced by about one‐quarter to one‐half of people who have diabetes, usually 20 to 25 years after the onset of diabetes. Approximately one‐third of those who have diabetes with kidney disease will progress to kidney failure and require treatment with dialysis or kidney transplantation. Blood pressure‐lowering treatments prevent heart disease and enable patients to avoid or delay the need for dialysis or kidney transplantation. Two drug classes ‐ ACEi and ARB ‐ have been considered particularly effective at improving the health and well‐being of people with diabetes. We examine whether these drugs prevent kidney failure, death and heart complications in people who have diabetes and kidney disease.

What did we want to find out?

We wanted to find out if ACEi, ARB or combinations of treatment prevented the progression of kidney disease in adults with diabetes and kidney disease.

What did we do?

We searched for all trials that assessed the benefits and harms of randomly allocated ACEi, ARB, or various combinations for people with diabetes and chronic kidney disease. We compared and summarised the trials' results and rated our confidence in the information based on factors such as trial methods and sizes.

What did we find?

We found 109 studies involving 28,341 adults. ACEi and ARB may prevent kidney failure in people with diabetes and kidney disease. ACEi, ARB, or various combinations had uncertain effects on death or heart disease in people with diabetes and kidney disease.

What are the limitations of the evidence?

The small number of studies (per comparison) and the small size of the studies were limitations in this review. Not all the studies provided data about the outcomes we were interested in. We are unsure about the results.

How up‐to‐date is the evidence?

The evidence is up‐to‐date as of March 2024.

Summary of findings

Summary of findings 1. Angiotensin‐converting‐enzyme inhibitors versus placebo or no treatment for people with diabetes and kidney disease.

ACEi versus placebo or no treatment for people with diabetes and kidney disease
Patient or population: people with diabetes and kidney disease Settings: multinational (Australia, Austria, Canada, Chile, Denmark, France, Japan, India, Israel, Italy, Sweden, The Netherlands, UK, USA and other countries not specified, including Europe and North Africa) Intervention: ACEi Comparison: placebo or no treatment
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No. of participants (RCTs)	Quality of the evidence (GRADE)	Comment
	Assumed risk	Corresponding risk
	Placebo or no treatment	ACEi
All‐cause death Median follow‐up 2 years	125 per 1000	11 fewer per 1000 (34 fewer to 19 more)	RR 0.91 (0.73 to 1.15)	7413 (24)	⊕⊕⊝⊝ low^1,2	ACEi may make little or no difference to all cause death compared to placebo or no treatment in people with diabetes and kidney disease
Cardiovascular death Median follow‐up 2 years	49 per 1000	16 fewer per 1000 (43 fewer to 126 more)	RR 0.67 (0.13 to 3.57)	5625 (17)	⊕⊝⊝⊝ very low^1,2,3	It is very uncertain whether ACEi makes any difference to cardiovascular death compared to placebo or no treatment people with diabetes and kidney disease
Doubling of SCr Median follow‐up 3.8 years	43 per 1000	13 fewer per 1000 (23 fewer to 0)	RR 0.69 (0.47 to 1.01)	6702 (8)	⊕⊝⊝⊝ very low^1,2,3	It is very uncertain whether ACEi makes any difference to doubling of SCr compared to placebo or no treatment people with diabetes and kidney disease
Fatal or nonfatal stroke Median follow‐up 7 years	47 per 1000	1 more per 1000 (9 fewer to 15 more)	RR 1.02 (0.80 to 1.31)	4944 (2)	⊕⊕⊝⊝ low^1,2	ACEi may make little or no difference to fatal or nonfatal stroke compared to placebo or no treatment people with diabetes and kidney disease
Fatal or nonfatal myocardial infarction Median follow‐up 3 years	31 per 1000	6 fewer per 1000 (13 fewer to 3 more)	RR 0.79 (0.57 to 1.09)	5100 (3)	⊕⊕⊝⊝ low^2,4	ACEi may make little or no difference to fatal or nonfatal myocardial infarction compared to placebo or no treatment people with diabetes and kidney disease
Micro‐ to macroalbuminuria Median follow‐up 2 years	225 per 1000	128 fewer per 1000 (162 fewer to 81 fewer)	RR 0.43 (0.28 to 0.64)	2282 (19)	⊕⊝⊝⊝ very low^2,3,5	It is very uncertain whether ACEi makes any difference to progression from micro‐ to macroalbuminuria compared to placebo or no treatment people with diabetes and kidney disease
Micro‐ to normoalbuminuria Median follow‐up 2 years	104 per 1000	209 more per 1000 (89 more to 404 more)	RR 3.01 (1.86 to 4.88)	1959 (17)	⊕⊝⊝⊝ very low^2,3,5	It is very uncertain whether ACEi makes any difference to regression from micro‐ to normoalbuminuria compared to placebo or no treatment people with diabetes and kidney disease
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). ACEi: Angiotensin‐converting‐enzyme inhibitors; CI: Confidence interval; RR: Risk ratio; SCr: Serum creatinine
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.

ARB versus placebo or no treatment for people with diabetes and kidney disease
Patient or population: people with diabetes and kidney disease Settings: multinational (Canada, China, Hong Kong, Japan, Thailand, USA and other countries unspecified from Asia and Europe) Intervention: ARB Comparison: placebo or no treatment
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No. of participants (RCTs)	Quality of the evidence (GRADE)	Comment
	Assumed risk	Corresponding risk
	Placebo or no treatment	ARB
All‐cause death Median follow‐up 1 year	136 per 1000	1 fewer per 1000 (20 fewer to 22 more)	RR 0.99 (0.85 to 1.16)	4260 (11)	⊕⊕⊝⊝ low^1,2	ARB may make little or no difference to all‐cause death compared to placebo or no treatment in people with diabetes and kidney disease
Cardiovascular death Median follow‐up 1 year	7 per 1000	17 more per 1000 (0 to 78 more)	RR 3.36 (0.93 to 12.07)	878 (6)	⊕⊕⊝⊝ low^1,2	ARB have uncertain effects on cardiovascular death compared to placebo or no treatment in people with diabetes and kidney disease
Doubling of SCr Median follow‐up 3 years	282 per 1000	45 fewer per 1000 (79 fewer to 8 fewer)	RR 0.84 (0.72 to 0.97)	3280 (4)	⊕⊕⊝⊝ low^3,4	ARB may prevent doubling of SCr compared to placebo or no treatment in people with diabetes and kidney disease
Fatal or nonfatal stroke Median follow‐up 2.8 years	39 per 1000	9 fewer per 1000 (26 fewer to 30 more)	RR 0.76 (0.32 to 1.77)	619 (2)	⊕⊕⊝⊝ low^2,3	ARB have uncertain effects on fatal or nonfatal stroke compared to placebo or no treatment in people with diabetes and kidney disease
Fatal or nonfatal myocardial infarction Median follow‐up 2.8 years	23 per 1000	13 fewer per 1000 (20 fewer to 15 more)	RR 0.43 (0.11 to 1.65)	619 (2)	⊕⊕⊝⊝ low^2,3	ARB have uncertain effects on fatal or nonfatal myocardial infarction compared to placebo or no treatment in people with diabetes and kidney disease
Micro‐ to macroalbuminuria Median follow‐up 1.8 years	425 per 1000	238 fewer per 1000 (327 fewer to 64 fewer)	RR 0.44 (0.23 to 0.85)	815 (5)	⊕⊕⊝⊝ low^1,5	ARB may prevent progression from micro‐ to macroalbuminuria compared to placebo or no treatment in people with diabetes and kidney disease
Micro‐ to normoalbuminuria Median follow‐up 2 years	41 per 1000	188 more per 1000 (6 fewer to 1468 more)	RR 5.58 (0.85 to 36.81)	671 (4)	⊕⊝⊝⊝ very low^1,2,5	It is very uncertain whether ARB makes any difference to regression from micro‐ to normoalbuminuria compared to placebo or no treatment in people with diabetes and kidney disease
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). ARB: Angiotensin receptor blockers; CI: Confidence interval; RR: Risk ratio; SCr: Serum creatinine
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate Very low quality: We are very uncertain about the estimate

ARB versus ACEi for people with diabetes and kidney disease
Patient or population: people with diabetes and kidney disease Settings: multinational (northern Europe, Canada, Hong Kong, Japan, India, Italy, Slovenia, Spain, Thailand, The Netherlands, Turkey) Intervention: ARB Comparison: ACEi
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No. of participants (RCTs)	Quality of the evidence (GRADE)	Comment
	Assumed risk	Corresponding risk
	ACEi	ARB
All‐cause death Median follow‐up 1 year	31 per 1000	4 more per 1000 (10 fewer to 28 more)	RR 1.13 (0.68 to 1.88)	1739 (15)	⊕⊕⊝⊝ low^1,2	ARB have uncertain effects on all‐cause death compared to ACEi in people with diabetes and kidney disease
Cardiovascular death Median follow‐up 1 year	10 per 1000	2 more per 1000 (6 fewer to 20 more)	RR 1.15 (0.45 to 2.98)	1606 (13)	⊕⊕⊝⊝ low^1,2	ARB have uncertain effects on cardiovascular death compared to ACEi in people with diabetes and kidney disease
Doubling of SCr Median follow‐up 2.7 years	72 per 1000	9 fewer per 1000 (35 fewer to 35 more)	RR 0.88 (0.52 to 1.48)	767 (2)	⊕⊕⊝⊝ low^2,3	ARB have uncertain effects on doubling of SCr compared to ACEi in people with diabetes and kidney disease
Fatal or nonfatal stroke Median follow‐up 2.8 years	19 per 1000	1 fewer per 1000 (12 fewer to 24 more)	RR 0.92 (0.38 to 2.24)	1146 (5)	⊕⊕⊝⊝ low^1,2	ARB have uncertain effects on fatal or nonfatal stroke compared to ACEi in people with diabetes and kidney disease
Fatal or nonfatal myocardial infarction Median follow‐up 2.7 years	23 per 1000	6 more per 1000 (9 fewer to 35 more)	RR 1.25 (0.62 to 2.50)	1209 (6)	⊕⊕⊝⊝ low^1,2	ARB have uncertain effects on fatal or nonfatal myocardial infarction compared to ACEi in people with diabetes and kidney disease
Micro‐ to macroalbuminuria Median follow‐up 1 year	103 per 1000	3 fewer per 1000 (34 fewer to 43 more)	RR 0.97 (0.67 to 1.42)	965 (4	⊕⊕⊝⊝ low^1,2	ARB have uncertain effects on progression from micro‐ to microalbuminuria compared to ACEi in people with diabetes and kidney disease
Micro‐ to normoalbuminuria Median follow‐up 1 year	695 per 1000	28 fewer per 1000 (139 fewer to 111 more)	RR 0.96 (0.62 to 1.48)	216 (4)	⊕⊕⊝⊝ low ^2,4	ARB have uncertain effects on regression from micro‐ to normoalbuminuria compared to ACEi in people with diabetes and kidney disease
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). ACEi: Angiotensin‐converting‐enzyme inhibitors; ARB: Angiotensin receptor blockers; CI: Confidence interval; RR: Risk ratio; SCr: Serum creatinine
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate Very low quality: We are very uncertain about the estimate

Duel therapy (ACEi plus ARB) versus placebo or no treatment for people with diabetes and kidney disease
Patient or population: people with diabetes and kidney disease Settings: Japan Intervention: duel therapy (ACEi plus ARB) Comparison: placebo or no treatment
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No, of participants (RCTs)	Quality of the evidence (GRADE)	Comment
	Assumed risk	Corresponding risk
	Placebo or no treatment	ACEi + ARB
All‐cause death¹ Follow‐up 1.8 years	No events	No events	‐‐	90 (1)	⊕⊕⊝⊝ low^2,3	Studies were not designed to measure effects of dual therapy compared to placebo to no treatment on all‐cause death in people with diabetes and kidney disease
Cardiovascular death⁴ Follow‐up 1.8 years	No events	No events	‐‐	90 (1)	⊕⊕⊝⊝ low^2,3	Studies were not designed to measure effects of dual therapy compared to placebo to no treatment on cardiovascular death in people with diabetes and kidney disease
Doubling of SCr	Not reported	Not reported	‐‐	‐‐	‐‐	No studies reported this outcome
Fatal or nonfatal stroke	Not reported	Not reported	‐‐	‐‐	‐‐	No studies reported this outcome
Fatal or nonfatal myocardial infarction	Not reported	Not reported	‐‐	‐‐	‐‐	No studies reported this outcome
Micro‐ to macroalbuminuria⁵ Follow‐up 1.8 years	800 per 1000	720 fewer per 1000 (760 fewer to 608 fewer)	RR0.10 (0.05 to 0.24)	82 (1)	⊕⊕⊝⊝ low^2,3	Studies were not designed to measure effects of dual therapy compared to placebo or no treatment on progression from micro‐ to macroalbuminuria in people with diabetes and kidney disease
Micro‐ to normoalbuminuria⁶ Follow‐up 1.8 years	No events	17/72**	RR 5.27 (0.34 to 81.57)	82 (1)	⊕⊕⊝⊝ verylow^2,7	Studies were not designed to measure effects of dual therapy compared to placebo or no treatment on regression from micro‐ to normoalbuminuria in people with diabetes and kidney disease
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Events rate derived from the raw data. A 'per thousand' rate is non‐informative in view of the scarcity of evidence and zero events in the control group. ACEi: Angiotensin‐converting‐enzyme inhibitors; ARB: Angiotensin receptor blockers; CI: Confidence interval; RR: Risk ratio; SCr:** Serum creatinine
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.

ACEi alone versus ACEi plus ARB for people with diabetes and kidney disease
Patient or population: people with diabetes and kidney disease Settings: Italy, Japan, Slovenia, Spain, Turkey Intervention: ACEi alone Comparison: ACEi plus ARB
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No. of participants (RCTs)	Quality of the evidence (GRADE)	Comment
	Assumed risk	Corresponding risk
	ACEi + ARB	ACEi
All‐cause death Median follow‐up 1.8 years	34 per 1000	3 more per 1000 (17 fewer to 48 more)	RR 1.08 (0.49 to 2.40)	1166 (6)	⊕⊕⊝⊝ low^1,2	ACEi alone has uncertain effects on all‐cause death compared to ACEi plus ARB in people with diabetes and kidney disease
Cardiovascular death Median follow‐up 1 year	4 per 1000	8 more per 1000 (2 fewer to 55 more)	RR 3.02 (0.61 to 14.85)	994 (4)	⊕⊕⊝⊝ low^1,2	ACEi alone has uncertain effects on cardiovascular death compared to ACEi plus ARB in people with diabetes and kidney disease
Doubling of SCr Median follow‐up 2.7 years	75 per 1000	11 more per 1000 (22 fewer to 64 more)	RR 1.14 (0.70 to 1.85)	813 (2)	⊕⊕⊝⊝ low^2,3	ACEi alone has uncertain effects on doubling of SCr compared to ACEi plus ARB in people with diabetes and kidney disease
Fatal or nonfatal stroke Median follow‐up 4.5 years	18 per 1000	5 fewer per 1000 (14 fewer to 22 more)	RR 0.72 (0.23 to 2.24)	775 (2)	⊕⊕⊝⊝ low^2,3	ACEi alone has uncertain effects on fatal or nonfatal stroke compared to ACEi plus ARB in people with diabetes and kidney disease
Fatal or nonfatal myocardial infarction Median follow‐up 3.6 years	33 per 1000	18 fewer per 1000 (27 fewer to 4 more)	RR 0.44 (0.17 to 1.12)	880 (3)	⊕⊕⊝⊝ low^2,3	ACEi alone has uncertain effects on fatal or nonfatal myocardial infarction compared to ACEi plus ARB in people with diabetes and kidney disease
Micro‐ to macroalbuminuria Median follow‐up 1.2 years	88 per 1000	22 more per 1000 (29 fewer to 116 more)	RR 1.25 (0.67 to 2.32)	958 (3)	⊕⊝⊝⊝ very low^1,2,4	It is very uncertain whether ACEi alone makes any difference to progression from micro‐ to macroalbuminuria compared to ACEi plus ARB in people with diabetes and kidney disease
Micro‐ to normoalbuminuria Median follow‐up 1 year	333 per 1000	27 more per 1000 (87 fewer to190 more)	RR 1.08 (0.74 to 1.57)	145 (3)	⊕⊕⊝⊝ low^1,5	ACEi alone has uncertain effects on regression from micro‐ to normoalbuminuria compared to ACEi plus ARB in people with diabetes and kidney disease
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). ACEi: Angiotensin‐converting‐enzyme inhibitors; ARB: Angiotensin receptor blockers; CI: Confidence interval; RR: Risk ratio; SCr: Serum creatinine
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.

ARB alone versus ACEi plus ARB for people with diabetes and kidney disease
Patient or population: people with diabetes and kidney disease Settings: Italy, Japan, Slovenia, Spain, Turkey, USA Intervention: ARB alone Comparison: ACEi plus ARB
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No. of participants (RCTs)	Quality of the evidence (GRADE)	Comment
	Assumed risk	Corresponding risk
	ACEi + ARB	ARB
All‐cause death Median follow‐up 2 years	62 per 1000	1 more per 1000 (15 fewer to 23 more)	RR 1.02 (0.76 to 1.37)	2607 (7)	⊕⊕⊝⊝ low^1,2	ARB alone has uncertain effects on all‐cause death compared to ACEi plus ARB in people with diabetes and kidney disease
Cardiovascular death Median follow‐up 1 year	4 per 1000	8 more per 1000 (1 fewer to 56 more)	RR 3.03 (0.62 to 14.93)	992 (4)	⊕⊕⊝⊝ low^1,2	ARB alone has uncertain effects on cardiovascular death compared to ACEi plus ARB in people with diabetes and kidney disease
Doubling of SCr Median follow‐up 2.5 years	59 per 1000	11 more per 1000 (9 fewer to 38 more)	RR 1.18 (0.85 to 1.64)	2252 (3)	⊕⊕⊝⊝ low^2,3	ARB alone has uncertain effects on doubling of SCr compared to ACEi plus ARB in people with diabetes and kidney disease
Fatal or nonfatal stroke Median follow‐up 3.4 years	23 per 1000	5 fewer per 1000 (15 fewer to 15 more)	RR 0.76 (0.35 to 1.65)	2223 (3)	⊕⊕⊝⊝ low^2,3	ARB alone has uncertain effects on fatal or nonfatal stroke compared to ACEi plus ARB in people with diabetes and kidney disease
Fatal or nonfatal myocardial infarction Median follow‐up 2.7 years	57 per 1000	17 fewer per 1000 (29 fewer to 1 more)	RR 0.70 (0.49 to 1.01)	2321 (4)	⊕⊕⊝⊝ low^2,3	ARB alone has uncertain effects on fatal or nonfatal myocardial infarction compared to ACEi plus ARB in people with diabetes and kidney disease
Micro‐ to macroalbuminuria Median follow‐up 1.8 years	51 per 1000	4 more per 1000 (12 fewer to 25 more)	RR 1.07 (0.77 to 1.49)	2410 (4)	⊕⊕⊝⊝ low^1,2	ARB alone has uncertain effects on progression from micro‐ to macroalbuminuria compared to ACEi plus ARB in people with diabetes and kidney disease
Micro‐ to normoalbuminuria Median follow‐up 1 year	333 per 1000	13 more per 1000 (87 fewer to 150 more)	RR 1.04 (0.74 to 1.45)	151 (3)	⊕⊕⊝⊝ low^1,2	ARB alone has uncertain effects on regression from micro‐ to normoalbuminuria compared to ACEi plus ARB in people with diabetes and kidney disease
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). ACEi: Angiotensin‐converting‐enzyme inhibitors; ARB: Angiotensin receptor blockers; CI: Confidence interval; RR: Risk ratio; SCr: Serum creatinine
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.

ACEi versus another ACEi for people with diabetes and kidney disease
Patient or population: people with diabetes and kidney disease Settings: Hong‐Kong, Italy, Taiwan Intervention: ACEi Comparison: another ACEi
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No. of participants (RCTs)	Quality of the evidence (GRADE)	Comment
	Assumed risk	Corresponding risk
	Another ACEi	ACEi
All‐cause death¹ Median follow‐up 0.5 years	No events	No events	‐‐	269 (3)	⊕⊕⊝⊝ low^2,3	Studies were not designed to measure effects of ACEi compared to another ACEi on all‐cause death in people with diabetes and kidney disease
Cardiovascular death⁴ Median follow‐up 0.5 years	No events	No events	‐‐	269 (3)	⊕⊕⊝⊝ low^2,3	Studies were not designed to measure effects of ACEi compared to another ACEi on cardiovascular death in people with diabetes and kidney disease
Doubling of SCr	Not reported	Not reported	‐‐	‐‐	‐‐	No studies reported this outcome
Fatal or nonfatal stroke	Not reported	Not reported	‐‐	‐‐	‐‐	No studies reported this outcome
Fatal or nonfatal myocardial infarction	Not reported	Not reported	‐‐	‐‐	‐‐	No studies reported this outcome
Micro‐ to macroalbuminuria	Not reported	Not reported	‐‐	‐‐	‐‐	No studies reported this outcome
Micro‐ to normoalbuminuria	Not reported	Not reported	‐‐	‐‐	‐‐	No studies reported this outcome
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). ACEi: Angiotensin‐converting‐enzyme inhibitors; CI: Confidence interval; RR: Risk ratio; SCr: Serum creatinine
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.

ARB versus another ARB for people with diabetes and kidney disease
Patient or population: people with diabetes and kidney disease Settings: multinational (Argentina, Australia, Brazil, Canada, Mexico, New Zealand, South Korea, Taiwan, Thailand, USA, Japan, Europe, Asia, and South Africa) Intervention: ARB Comparison: another ARB
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No. of participants (RCTs)	Quality of the evidence (GRADE)	Comment
	Assumed risk	Corresponding risk
	Another ARB	ARB
All‐cause death Median follow‐up 1 year	21 per 1000	9 fewer per 1000 (20 fewer to 125 more)	RR 0.58 (0.05 to 7.08)	2041 (5)	⊕⊝⊝⊝ very low^1,2,3	It is very uncertain whether ARB makes any difference to all‐cause death compared to another ARB in people with diabetes and kidney disease
Cardiovascular death Median follow‐up 1 year	9 per 1000	3 more per 1000 (5 fewer to 25 more)	RR 1.34 (0.47 to 3.82)	1360 (4)	⊕⊕⊝⊝ low^1,2	ARB have uncertain effects on cardiovascular death compared to another ARB in people with diabetes and kidney disease
Doubling of SCr⁴ Follow‐up 1 year	7 per 1000	0 per 1000 (6 fewer to 28 more)	RR 1.00 (0.20 to 4.94)	857 (1)	⊕⊕⊝⊝ low^2,5	Studies were not designed to measure effects of ARB compared to another ARB on doubling of serum creatinine in people with diabetes and kidney disease
Fatal or nonfatal stroke⁶ Follow‐up 1 year	12 per 1000	15 more per 1000 (3 fewer to 64 more)	RR 2.21 (0.77 to 6.29)	857 (1)	⊕⊕⊝⊝ low^2,5	Studies were not designed to measure effects of ARB compared to another ARB on fatal or nonfatal stroke in people with diabetes and kidney disease
Fatal or nonfatal myocardial infarction⁷ Follow‐up 1 year	26 per 1000	17 fewer per 1000 (23 fewer to 4 more)	RR 0.36 (0.12 to 1.14)	857 (1)	⊕⊕⊝⊝ low^2,5	Studies were not designed to measure effects of ARB compared to another ARB on fatal or nonfatal myocardial infarction in people with diabetes and kidney disease
Micro‐ to macroalbuminuria 8 Follow‐up 1 year	90 per 1000	31 more per 1000 (12 fewer to 96 more)	RR 1.34 (0.87 to 2.07)	716 (1)	⊕⊕⊝⊝ low 2,5	Studies were not designed to measure effects of ARB compared to another ARB on progression from micro‐ to macroalbuminuria in people with diabetes and kidney disease
Micro‐ to normoalbuminuria⁹ Follow‐up 1 year	11 per 1000	0 per 1000 (8 fewer to 32 more)	RR 0.98 (0.25 to 3.88)	716 (1)	⊕⊕⊝⊝ low^2,5	Studies were not designed to measure effects of ARB compared to another ARB on regression from micro‐ to normoalbuminuria in people with diabetes and kidney disease
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). ARB: Angiotensin receptor blockers; CI: Confidence interval; RR: Risk ratio; SCr: Serum creatinine
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.

Low‐dose ARB versus high‐dose ARB for people with diabetes and kidney disease
Patient or population: people with diabetes and kidney disease Settings: Canada Intervention: low‐dose ARB Comparison: high‐dose ARB
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No. of participants (RCTs)	Quality of the evidence (GRADE)	Comment
	Assumed risk	Corresponding risk
	High‐dose ARB	Low‐dose ARB
All‐cause death¹	No events	No events	‐‐	156 (2)	⊕⊕⊝⊝ low^2,3	Studies were not designed to measure effects of low‐dose ARB compared to high‐dose ARB on all‐cause death in people with diabetes and kidney disease
Cardiovascular death⁴ Follow‐up 0.6 years	No events	No events	‐‐	156 (2)	⊕⊕⊝⊝ low^2,3	Studies were not designed to measure effects of low‐dose ARB compared to high‐dose ARB on cardiovascular death in in people with diabetes and kidney disease
Doubling of SCr	Not reported	Not reported	‐‐	‐‐	‐‐	No studies reported this outcome
Fatal or nonfatal stroke	Not reported	Not reported	‐‐	‐‐	‐‐	No studies reported this outcome
Fatal or nonfatal myocardial infarction	Not reported	Not reported	‐‐	‐‐	‐‐	No studies reported this outcome
Micro‐ to macroalbuminuria	Not reported	Not reported	‐‐	‐‐	‐‐	No studies reported this outcome
Micro‐ to normoalbuminuria	Not reported	Not reported	‐‐	‐‐	‐‐	No studies reported this outcome
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). ARB: Angiotensin receptor blockers; CI: Confidence interval; RR: Risk ratio; SCr: Serum creatinine
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.

Low‐dose ARB plus spironolactone versus high‐dose ARB plus spironolactone for people with diabetes and kidney disease
Patient or population: people with diabetes and kidney disease Settings: single centre Intervention: low‐dose ARB plus spironolactone Comparison: high‐dose ARB plus spironolactone
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No. of participants (RCTs)	Quality of the evidence (GRADE)	Comment
	Assumed risk	Corresponding risk
	High‐dose ARB + spironolactone	Low‐dose ARB + spironolactone
All‐cause death	Not reported	Not reported	‐‐	‐‐	‐‐	No studies reported this outcome
Cardiovascular death	Not reported	Not reported	‐‐	‐‐	‐‐	No studies reported this outcome
Doubling of SCr	Not reported	Not reported	‐‐	‐‐	‐‐	No studies reported this outcome
Fatal or nonfatal stroke	Not reported	Not reported	‐‐	‐‐	‐‐	No studies reported this outcome
Fatal or nonfatal myocardial infarction	Not reported	Not reported	‐‐	‐‐	‐‐	No studies reported this outcome
Micro‐ to macroalbuminuria	Not reported	Not reported	‐‐	‐‐	‐‐	No studies reported this outcome
Micro‐ to normoalbuminuria	Not reported	Not reported	‐‐	‐‐	‐‐	No studies reported this outcome
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). ARB: Angiotensin receptor blockers; CI: Confidence interval; SCr: Serum creatinine
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.

Date	Event	Description
24 April 2024	New search has been performed	Risk of bias, GRADE assessment incorporated
24 April 2024	New citation required but conclusions have not changed	82 new studies included, no change to conclusions
23 February 2014	Amended	Protocol updated for review update and inclusion of network meta‐analysis. Changed terminology of angiotensin II receptor antagonists (AIIRA) to angiotensin receptor blockers (ARB)
23 February 2014	Amended	Added author (Suetonia Palmer)
26 November 2013	Amended	Search strategies updated
18 March 2010	Amended	Contact details updated.
13 May 2009	Amended	Contact details updated.
26 August 2008	Amended	Converted to new review format.

Database	Search terms
CENTRAL	MeSH descriptor: [Angiotensin‐Converting Enzyme Inhibitors] explode all trees MeSH descriptor: [Angiotensin Receptor Antagonists] explode all trees losartan:ti,ab,kw (Word variations have been searched) irbesartan:ti,ab,kw (Word variations have been searched) candesartan:ti,ab,kw (Word variations have been searched) eprosartan:ti,ab,kw (Word variations have been searched) valsartan:ti,ab,kw (Word variations have been searched) olmesartan:ti,ab,kw (Word variations have been searched) telmisartan:ti,ab,kw (Word variations have been searched) captopril:ti,ab,kw (Word variations have been searched) enalapril:ti,ab,kw (Word variations have been searched) fosinopril:ti,ab,kw (Word variations have been searched) lisinopril:ti,ab,kw (Word variations have been searched) perindopril:ti,ab,kw (Word variations have been searched) {or #1‐#14} MeSH descriptor: [Diabetic Nephropathies] this term only diabetic nephropath:ti,ab,kw (Word variations have been searched) diabetic kidney or diabetic renal*:ti,ab,kw (Word variations have been searched) MeSH descriptor: [Albuminuria] this term only MeSH descriptor: [Proteinuria] this term only proteinuria or albuminuria or microalbuminuria or macroalbuminuria:ti,ab,kw (Word variations have been searched) {or #16‐#21} {and #15, #22}
MEDLINE	exp Angiotensin‐Converting Enzyme Inhibitors/ exp Angiotensin II Type 1 Receptor Blockers/ losartan.tw. irbesartan.tw. candesartan.tw. eprosartan.tw. valsartan.tw. olmesartan.tw. telmisartan.tw. captopril.tw. enalapril.tw. fosinopril.tw. lisinopril.tw. perindopril.tw. ramipril.tw. or/1‐15 Diabetic Nephropathies/ diabetic nephropath$.tw. (diabetic kidney$ or diabetic renal$).tw. Albuminuria/ Proteinuria/ (proteinuria$ or albuminuria$ or microalbuminuria$ or macroalbuminuria).tw. or/17‐22 and/16,23
EMBASE	exp dipeptidyl carboxypeptidase inhibitor/ exp angiotensin receptor antagonist/ or/1‐2 diabetic nephropathy/ diabetic nephropath$.tw. (diabetic kidney$ or diabetic renal$).tw. exp albuminuria/ (proteinuria$ or albuminuria$ or microalbuminuria$ or macroalbuminuria).tw. or/4‐8 and/3,9

Potential source of bias	Assessment criteria
Random sequence generation Selection bias (biased allocation to interventions) due to inadequate generation of a randomised sequence	Low risk of bias: Random number table; computer random number generator; coin tossing; shuffling cards or envelopes; throwing dice; drawing of lots; minimization (minimization may be implemented without a random element, and this is considered to be equivalent to being random).
	High risk of bias: Sequence generated by odd or even date of birth; date (or day) of admission; sequence generated by hospital or clinic record number; allocation by judgement of the clinician; by preference of the participant; based on the results of a laboratory test or a series of tests; by availability of the intervention.
	Unclear: Insufficient information about the sequence generation process to permit judgement.
Allocation concealment Selection bias (biased allocation to interventions) due to inadequate concealment of allocations prior to assignment	Low risk of bias: Randomisation method described that would not allow investigator/participant to know or influence intervention group before eligible participant entered in the study (e.g. central allocation, including telephone, web‐based, and pharmacy‐controlled, randomisation; sequentially numbered drug containers of identical appearance; sequentially numbered, opaque, sealed envelopes).
	High risk of bias: Using an open random allocation schedule (e.g. a list of random numbers); assignment envelopes were used without appropriate safeguards (e.g. if envelopes were unsealed or non‐opaque or not sequentially numbered); alternation or rotation; date of birth; case record number; any other explicitly unconcealed procedure.
	Unclear: Randomisation stated but no information on method used is available.
Blinding of participants and personnel Performance bias due to knowledge of the allocated interventions by participants and personnel during the study	Low risk of bias: No blinding or incomplete blinding, but the review authors judge that the outcome is not likely to be influenced by lack of blinding; blinding of participants and key study personnel ensured, and unlikely that the blinding could have been broken.
	High risk of bias: No blinding or incomplete blinding, and the outcome is likely to be influenced by lack of blinding; blinding of key study participants and personnel attempted, but likely that the blinding could have been broken, and the outcome is likely to be influenced by lack of blinding.
	Unclear: Insufficient information to permit judgement
Blinding of outcome assessment Detection bias due to knowledge of the allocated interventions by outcome assessors.	Low risk of bias: No blinding of outcome assessment, but the review authors judge that the outcome measurement is not likely to be influenced by lack of blinding; blinding of outcome assessment ensured, and unlikely that the blinding could have been broken.
	High risk of bias: No blinding of outcome assessment, and the outcome measurement is likely to be influenced by lack of blinding; blinding of outcome assessment, but likely that the blinding could have been broken, and the outcome measurement is likely to be influenced by lack of blinding.
	Unclear: Insufficient information to permit judgement
Incomplete outcome data Attrition bias due to amount, nature or handling of incomplete outcome data.	Low risk of bias: No missing outcome data; reasons for missing outcome data unlikely to be related to true outcome (for survival data, censoring unlikely to be introducing bias); missing outcome data balanced in numbers across intervention groups, with similar reasons for missing data across groups; for dichotomous outcome data, the proportion of missing outcomes compared with observed event risk not enough to have a clinically relevant impact on the intervention effect estimate; for continuous outcome data, plausible effect size (difference in means or standardized difference in means) among missing outcomes not enough to have a clinically relevant impact on observed effect size; missing data have been imputed using appropriate methods.
	High risk of bias: Reason for missing outcome data likely to be related to true outcome, with either imbalance in numbers or reasons for missing data across intervention groups; for dichotomous outcome data, the proportion of missing outcomes compared with observed event risk enough to induce clinically relevant bias in intervention effect estimate; for continuous outcome data, plausible effect size (difference in means or standardized difference in means) among missing outcomes enough to induce clinically relevant bias in observed effect size; ‘as‐treated’ analysis done with substantial departure of the intervention received from that assigned at randomisation; potentially inappropriate application of simple imputation.
	Unclear: Insufficient information to permit judgement
Selective reporting Reporting bias due to selective outcome reporting	Low risk of bias: The study protocol is available and all of the study’s pre‐specified (primary and secondary) outcomes that are of interest in the review have been reported in the pre‐specified way; the study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were pre‐specified (convincing text of this nature may be uncommon).
	High risk of bias: Not all of the study’s pre‐specified primary outcomes have been reported; one or more primary outcomes is reported using measurements, analysis methods or subsets of the data (e.g. subscales) that were not pre‐specified; one or more reported primary outcomes were not pre‐specified (unless clear justification for their reporting is provided, such as an unexpected adverse effect); one or more outcomes of interest in the review are reported incompletely so that they cannot be entered in a meta‐analysis; the study report fails to include results for a key outcome that would be expected to have been reported for such a study.
	Unclear: Insufficient information to permit judgement
Other bias Bias due to problems not covered elsewhere in the table	Low risk of bias: The study appears to be free of other sources of bias.
	High risk of bias: Had a potential source of bias related to the specific study design used; stopped early due to some data‐dependent process (including a formal‐stopping rule); had extreme baseline imbalance; has been claimed to have been fraudulent; had some other problem.
	Unclear: Insufficient information to assess whether an important risk of bias exists; insufficient rationale or evidence that an identified problem will introduce bias.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 Death: any cause	24	7413	Risk Ratio (M‐H, Random, 95% CI)	0.91 [0.73, 1.15]
1.2 Withdrawn	7	5306	Risk Ratio (M‐H, Random, 95% CI)	1.03 [0.90, 1.19]
1.3 Cardiovascular death	17	5625	Risk Ratio (M‐H, Random, 95% CI)	0.67 [0.13, 3.57]
1.4 Kidney failure	8	6643	Risk Ratio (M‐H, Random, 95% CI)	0.61 [0.39, 0.94]
1.5 Fatal or nonfatal myocardial infarction	3	5100	Risk Ratio (M‐H, Random, 95% CI)	0.79 [0.57, 1.09]
1.6 Fatal or nonfatal stroke	2	4944	Risk Ratio (M‐H, Random, 95% CI)	1.02 [0.80, 1.31]
1.7 Doubling of serum creatinine	8	6702	Risk Ratio (M‐H, Random, 95% CI)	0.69 [0.47, 1.01]
1.8 Reduction in GFR	3	116	Risk Ratio (M‐H, Random, 95% CI)	0.91 [0.55, 1.51]
1.9 Change in GFR [mL/min/1.73 m²]	3	88	Mean Difference (IV, Random, 95% CI)	0.20 [‐0.50, 0.90]
1.10 GFR (at end of treatment) [mL/min/1.73 m²]	7	188	Mean Difference (IV, Random, 95% CI)	‐1.41 [‐8.79, 5.97]
1.11 Micro‐ to macroalbuminuria	19	2282	Risk Ratio (M‐H, Random, 95% CI)	0.43 [0.28, 0.64]
1.12 Micro‐ to normoalbuminuria	17	1959	Risk Ratio (M‐H, Random, 95% CI)	3.01 [1.86, 4.88]
1.13 Hyperkalaemia	4	1289	Risk Ratio (M‐H, Random, 95% CI)	0.82 [0.48, 1.40]
1.14 Cough	10	6615	Risk Ratio (M‐H, Random, 95% CI)	3.26 [2.30, 4.60]
1.15 Headache	5	6244	Risk Ratio (M‐H, Random, 95% CI)	0.84 [0.34, 2.12]
1.16 Impotence	5	1528	Risk Ratio (M‐H, Random, 95% CI)	1.02 [0.26, 3.91]
1.17 Dizziness	1	58	Risk Ratio (M‐H, Random, 95% CI)	3.00 [0.33, 27.18]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
2.1 Death: any cause	11	4260	Risk Ratio (M‐H, Random, 95% CI)	0.99 [0.85, 1.16]
2.2 Withdrawn	3	721	Risk Ratio (M‐H, Random, 95% CI)	0.85 [0.58, 1.26]
2.3 Cardiovascular death	6	878	Risk Ratio (M‐H, Random, 95% CI)	3.36 [0.93, 12.07]
2.4 Kidney failure	3	3227	Risk Ratio (M‐H, Random, 95% CI)	0.82 [0.72, 0.94]
2.5 Fatal and nonfatal myocardial infarction	2	619	Risk Ratio (M‐H, Random, 95% CI)	0.43 [0.11, 1.65]
2.6 Fatal or nonfatal stroke	2	619	Risk Ratio (M‐H, Random, 95% CI)	0.76 [0.32, 1.77]
2.7 Doubling of serum creatinine	4	3280	Risk Ratio (M‐H, Random, 95% CI)	0.84 [0.72, 0.97]
2.8 Reduction in GFR	2	171	Risk Ratio (M‐H, Random, 95% CI)	0.25 [0.03, 2.14]
2.9 GFR (at end of treatment) [mL/min/1.73 m²]	1	80	Mean Difference (IV, Random, 95% CI)	‐11.57 [‐21.73, ‐1.41]
2.10 Micro‐ to macroalbuminuria	5	815	Risk Ratio (M‐H, Random, 95% CI)	0.44 [0.23, 0.85]
2.11 Micro‐ to normoalbuminuria	4	671	Risk Ratio (M‐H, Random, 95% CI)	5.58 [0.85, 36.81]
2.12 Hyperkalaemia	4	1299	Risk Ratio (M‐H, Random, 95% CI)	5.29 [1.89, 14.85]
2.13 Cough	3	784	Risk Ratio (M‐H, Random, 95% CI)	2.81 [2.13, 3.71]
2.14 Headache	1	91	Risk Ratio (M‐H, Random, 95% CI)	0.47 [0.03, 7.22]
2.15 Dizziness	1	91	Risk Ratio (M‐H, Random, 95% CI)	0.16 [0.01, 3.78]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
3.1 Death: any cause	15	1739	Risk Ratio (M‐H, Random, 95% CI)	1.13 [0.68, 1.88]
3.2 Withdrawn: any cause	6	612	Risk Ratio (M‐H, Random, 95% CI)	0.91 [0.65, 1.28]
3.3 Cardiovascular death	13	1606	Risk Ratio (M‐H, Random, 95% CI)	1.15 [0.45, 2.98]
3.4 Kidney failure	3	837	Risk Ratio (M‐H, Random, 95% CI)	0.56 [0.29, 1.07]
3.5 Fatal or nonfatal myocardial infarction	6	1209	Risk Ratio (M‐H, Random, 95% CI)	1.25 [0.62, 2.50]
3.6 Fatal or nonfatal stroke	5	1146	Risk Ratio (M‐H, Random, 95% CI)	0.92 [0.38, 2.24]
3.7 Doubling of serum creatinine	2	767	Risk Ratio (M‐H, Random, 95% CI)	0.88 [0.52, 1.48]
3.8 Reduction in GFR	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
3.9 Micro‐ to macroalbuminuria	4	965	Risk Ratio (M‐H, Random, 95% CI)	0.97 [0.67, 1.42]
3.10 Micro‐ to normoalbuminuria	4	216	Risk Ratio (M‐H, Random, 95% CI)	0.96 [0.80, 1.16]
3.11 Hyperkalaemia	5	891	Risk Ratio (M‐H, Random, 95% CI)	1.08 [0.71, 1.64]
3.12 Cough	4	868	Risk Ratio (M‐H, Random, 95% CI)	0.21 [0.08, 0.54]
3.13 Headache	1	91	Risk Ratio (M‐H, Random, 95% CI)	1.43 [0.06, 34.04]
3.14 Impotence	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
3.15 Dizziness	2	115	Risk Ratio (M‐H, Random, 95% CI)	0.07 [0.00, 1.28]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
4.1 Death: any cause	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
4.2 Cardiovascular death	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
4.3 Micro‐ to macroalbuminuria	1	82	Risk Ratio (M‐H, Random, 95% CI)	0.10 [0.05, 0.24]
4.4 Micro‐ to normoalbuminuria	1	82	Risk Ratio (M‐H, Random, 95% CI)	5.27 [0.34, 81.57]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
5.1 Death: any cause	7	3773	Risk Ratio (M‐H, Random, 95% CI)	1.02 [0.78, 1.33]
5.1.1 ACEi	6	1166	Risk Ratio (M‐H, Random, 95% CI)	1.08 [0.49, 2.40]
5.1.2 ARB	7	2607	Risk Ratio (M‐H, Random, 95% CI)	1.02 [0.76, 1.37]
5.2 Withdrawn: any cause	3	1787	Risk Ratio (M‐H, Random, 95% CI)	0.80 [0.55, 1.18]
5.2.1 ACEi	2	172	Risk Ratio (M‐H, Random, 95% CI)	0.78 [0.33, 1.86]
5.2.2 ARB	3	1615	Risk Ratio (M‐H, Random, 95% CI)	0.81 [0.53, 1.24]
5.3 Cardiovascular death	4	1986	Risk Ratio (M‐H, Random, 95% CI)	3.03 [0.98, 9.34]
5.3.1 ACEi	4	994	Risk Ratio (M‐H, Random, 95% CI)	3.02 [0.61, 14.85]
5.3.2 ARB	4	992	Risk Ratio (M‐H, Random, 95% CI)	3.03 [0.62, 14.93]
5.4 Kidney failure	4	3201	Risk Ratio (M‐H, Random, 95% CI)	1.30 [0.95, 1.77]
5.4.1 ACEi	3	880	Risk Ratio (M‐H, Random, 95% CI)	1.36 [0.79, 2.32]
5.4.2 ARB	4	2321	Risk Ratio (M‐H, Random, 95% CI)	1.15 [0.67, 1.95]
5.5 Fatal or nonfatal myocardial infarction	4	3201	Risk Ratio (M‐H, Random, 95% CI)	0.66 [0.47, 0.93]
5.5.1 ACEi	3	880	Risk Ratio (M‐H, Random, 95% CI)	0.44 [0.17, 1.12]
5.5.2 ARB	4	2321	Risk Ratio (M‐H, Random, 95% CI)	0.70 [0.49, 1.01]
5.6 Fatal or nonfatal stroke	3	2998	Risk Ratio (M‐H, Random, 95% CI)	0.81 [0.48, 1.38]
5.6.1 ACEi	2	775	Risk Ratio (M‐H, Random, 95% CI)	0.72 [0.23, 2.24]
5.6.2 ARB	3	2223	Risk Ratio (M‐H, Random, 95% CI)	0.76 [0.35, 1.65]
5.7 Doubling of serum creatinine	3	3065	Risk Ratio (M‐H, Random, 95% CI)	1.17 [0.89, 1.53]
5.7.1 ACEi	2	813	Risk Ratio (M‐H, Random, 95% CI)	1.14 [0.70, 1.85]
5.7.2 ARB	3	2252	Risk Ratio (M‐H, Random, 95% CI)	1.18 [0.85, 1.64]
5.8 Reduction in GFR	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
5.8.1 ARB	1	1448	Risk Ratio (M‐H, Random, 95% CI)	1.32 [0.96, 1.82]
5.9 Micro‐ to macroalbuminuria	4	3368	Risk Ratio (M‐H, Random, 95% CI)	1.10 [0.85, 1.41]
5.9.1 ACEi	3	958	Risk Ratio (M‐H, Random, 95% CI)	1.25 [0.67, 2.32]
5.9.2 ARB	4	2410	Risk Ratio (M‐H, Random, 95% CI)	1.07 [0.77, 1.49]
5.10 Micro‐ to normoalbuminuria	3	296	Risk Ratio (M‐H, Random, 95% CI)	1.07 [0.85, 1.35]
5.10.1 ACEi	3	145	Risk Ratio (M‐H, Random, 95% CI)	1.08 [0.74, 1.57]
5.10.2 ARB	3	151	Risk Ratio (M‐H, Random, 95% CI)	1.04 [0.74, 1.45]
5.11 Hyperkalaemia	5	3241	Risk Ratio (M‐H, Random, 95% CI)	0.85 [0.60, 1.20]
5.11.1 ACEi	4	900	Risk Ratio (M‐H, Random, 95% CI)	1.01 [0.71, 1.44]
5.11.2 ARB	5	2341	Risk Ratio (M‐H, Random, 95% CI)	0.79 [0.46, 1.37]
5.12 Cough	2	1458	Risk Ratio (M‐H, Random, 95% CI)	0.66 [0.04, 9.72]
5.12.1 ACEi	2	730	Risk Ratio (M‐H, Random, 95% CI)	2.15 [0.89, 5.22]
5.12.2 ARB	2	728	Risk Ratio (M‐H, Random, 95% CI)	0.14 [0.02, 1.17]
5.13 Impotence	1	136	Risk Ratio (M‐H, Random, 95% CI)	0.31 [0.03, 2.95]
5.13.1 ACEi	1	67	Risk Ratio (M‐H, Random, 95% CI)	0.32 [0.01, 7.68]
5.13.2 ARB	1	69	Risk Ratio (M‐H, Random, 95% CI)	0.31 [0.01, 7.27]
5.14 Dizziness	1	44	Risk Ratio (M‐H, Random, 95% CI)	Not estimable
5.14.1 ACEi	1	22	Risk Ratio (M‐H, Random, 95% CI)	Not estimable
5.14.2 ARB	1	22	Risk Ratio (M‐H, Random, 95% CI)	Not estimable

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
6.1 Death: any cause	3	269	Risk Ratio (M‐H, Random, 95% CI)	Not estimable
6.2 Withdrawn	2	194	Risk Ratio (M‐H, Random, 95% CI)	0.87 [0.28, 2.76]
6.3 Cardiovascular death	3	269	Risk Ratio (M‐H, Random, 95% CI)	Not estimable
6.4 Hypekalaemia	1	16	Risk Ratio (M‐H, Random, 95% CI)	3.75 [0.18, 80.19]
6.5 Cough	1	176	Risk Ratio (M‐H, Random, 95% CI)	0.21 [0.07, 0.59]
6.6 Headache	1	176	Risk Ratio (M‐H, Random, 95% CI)	1.00 [0.21, 4.82]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
7.1 Death: any cause	5	2041	Risk Ratio (M‐H, Random, 95% CI)	0.58 [0.05, 7.08]
7.2 Cardiovascular death	4	1360	Risk Ratio (M‐H, Random, 95% CI)	1.34 [0.47, 3.82]
7.3 Kidney failure	1	857	Risk Ratio (M‐H, Random, 95% CI)	0.88 [0.32, 2.40]
7.4 Fatal or nonfatal myocardial infarction	1	857	Risk Ratio (M‐H, Random, 95% CI)	0.36 [0.12, 1.14]
7.5 Fatal or nonfatal stroke	1	857	Risk Ratio (M‐H, Random, 95% CI)	2.21 [0.77, 6.29]
7.6 Doubling of serum creatinine	1	857	Risk Ratio (M‐H, Random, 95% CI)	1.00 [0.20, 4.94]
7.7 GFR (at end of treatment) [mL/min/1.7 3m²]	1	716	Mean Difference (IV, Random, 95% CI)	‐0.70 [‐4.00, 2.60]
7.8 Macro‐to microalbuminuria	1	716	Risk Ratio (M‐H, Random, 95% CI)	1.34 [0.87, 2.07]
7.9 Macro‐to normoalbuminuria	1	716	Risk Ratio (M‐H, Random, 95% CI)	0.98 [0.25, 3.88]
7.10 Hyperkalaemia	2	1065	Risk Ratio (M‐H, Random, 95% CI)	1.10 [0.27, 4.50]
7.11 Dizziness	1	349	Risk Ratio (M‐H, Random, 95% CI)	10.81 [0.60, 194.08]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
8.1 Death: any cause	2	156	Risk Ratio (M‐H, Random, 95% CI)	Not estimable
8.2 Withdrawn: any cause	1	11	Risk Ratio (M‐H, Random, 95% CI)	0.45 [0.03, 7.39]
8.3 Cardiovascular death	2	156	Risk Ratio (M‐H, Random, 95% CI)	Not estimable
8.4 Change in GFR [mL/min/1.73 m²]	1	105	Mean Difference (IV, Random, 95% CI)	0.30 [‐1.76, 2.36]
8.5 Hyperkalaemia	3	422	Risk Ratio (M‐H, Random, 95% CI)	1.11 [0.18, 6.69]
8.6 Headache	1	306	Risk Ratio (M‐H, Random, 95% CI)	0.58 [0.27, 1.25]
8.7 Dizziness	1	306	Risk Ratio (M‐H, Random, 95% CI)	0.44 [0.17, 1.10]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
9.1 Change in GFR [mL/min/1.73 m²]	1	101	Mean Difference (IV, Random, 95% CI)	2.30 [‐0.00, 4.60]
9.2 Hyperkalaemia	1	101	Risk Ratio (M‐H, Random, 95% CI)	0.16 [0.02, 1.26]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
10.1 Type of diabetes	12	5427	Risk Ratio (M‐H, Random, 95% CI)	0.67 [0.13, 3.57]
10.1.1 Type I	7	296	Risk Ratio (M‐H, Random, 95% CI)	0.14 [0.01, 2.60]
10.1.2 Type II	5	5131	Risk Ratio (M‐H, Random, 95% CI)	1.07 [0.85, 1.35]
10.2 Presence of hypertension	12	5361	Risk Ratio (M‐H, Random, 95% CI)	1.07 [0.85, 1.35]
10.2.1 Patients with hypertension	1	50	Risk Ratio (M‐H, Random, 95% CI)	Not estimable
10.2.2 Patients without hypertension	11	5311	Risk Ratio (M‐H, Random, 95% CI)	1.07 [0.85, 1.35]
10.3 Microalbuminuria versus macroalbuminuria	15	677	Risk Ratio (M‐H, Random, 95% CI)	0.14 [0.01, 2.60]
10.3.1 Microalbuminuria	14	657	Risk Ratio (M‐H, Random, 95% CI)	0.14 [0.01, 2.60]
10.3.2 Macroalbuminuria	1	20	Risk Ratio (M‐H, Random, 95% CI)	Not estimable

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
11.1 Type of diabetes	16	2219	Risk Ratio (M‐H, Random, 95% CI)	0.40 [0.26, 0.61]
11.1.1 Type I	10	753	Risk Ratio (M‐H, Random, 95% CI)	0.42 [0.28, 0.64]
11.1.2 Type II	6	1466	Risk Ratio (M‐H, Random, 95% CI)	0.32 [0.14, 0.75]
11.2 Presence of hypertension	17	1079	Risk Ratio (M‐H, Random, 95% CI)	0.35 [0.25, 0.49]
11.2.1 Patients with hypertension	2	117	Risk Ratio (M‐H, Random, 95% CI)	0.23 [0.12, 0.45]
11.2.2 Patients without hypertension	15	962	Risk Ratio (M‐H, Random, 95% CI)	0.40 [0.27, 0.59]
11.3 Microalbuminuria versus macroalbuminuria	18	2207	Risk Ratio (M‐H, Random, 95% CI)	0.43 [0.28, 0.66]
11.3.1 Microalbuminuria	16	1918	Risk Ratio (M‐H, Random, 95% CI)	0.44 [0.26, 0.72]
11.3.2 Macroalbuminuria	2	289	Risk Ratio (M‐H, Random, 95% CI)	0.36 [0.19, 0.68]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
12.1 Type of diabetes	15	1912	Risk Ratio (M‐H, Random, 95% CI)	2.99 [1.75, 5.11]
12.1.1 Type I	11	600	Risk Ratio (M‐H, Random, 95% CI)	3.66 [2.27, 5.90]
12.1.2 Type II	4	1312	Risk Ratio (M‐H, Random, 95% CI)	1.86 [0.52, 6.64]
12.2 Presence of hypertension	15	756	Risk Ratio (M‐H, Random, 95% CI)	3.44 [2.26, 5.23]
12.2.1 Patients with hypertension	2	117	Risk Ratio (M‐H, Random, 95% CI)	4.79 [0.63, 36.44]
12.2.2 Patients without hypertension	13	639	Risk Ratio (M‐H, Random, 95% CI)	3.38 [2.20, 5.20]
12.3 Microalbuminuria versus macroalbuminuria	16	1884	Risk Ratio (M‐H, Random, 95% CI)	2.89 [1.74, 4.82]
12.3.1 Microalbuminuria	15	1820	Risk Ratio (M‐H, Random, 95% CI)	2.84 [1.68, 4.78]
12.3.2 Macroalbuminuria	1	64	Risk Ratio (M‐H, Random, 95% CI)	6.13 [0.39, 96.97]

PERMALINK

Angiotensin‐converting‐enzyme inhibitors and angiotensin receptor blockers for preventing the progression of diabetic kidney disease

Patrizia Natale

Suetonia C Palmer

Sankar D Navaneethan

Jonathan C Craig

Giovanni FM Strippoli

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Summary of findings

Summary of findings 1. Angiotensin‐converting‐enzyme inhibitors versus placebo or no treatment for people with diabetes and kidney disease.

Summary of findings 2. Angiotensin receptor blockers versus placebo or no treatment for people with diabetes and kidney disease.

Summary of findings 3. Angiotensin receptor blockers versus angiotensin‐converting‐enzyme inhibitors for people with diabetes and kidney disease.

Summary of findings 4. Dual therapy (angiotensin‐converting‐enzyme inhibitors plus angiotensin receptor blockers) versus placebo or no treatment for people with diabetes and kidney disease.

Summary of findings 5. Angiotensin‐converting‐enzyme inhibitors (ACEi) alone versus ACEi plus angiotensin receptor blockers for people with diabetes and kidney disease.

Summary of findings 6. Angiotensin receptor blockers (ARB) alone versus angiotensin‐converting‐enzyme inhibitors plus ARB for people with diabetes and kidney disease.

Summary of findings 7. Angiotensin‐converting‐enzyme inhibitors (ACEi) versus another ACEi for people with diabetes and kidney disease.

Summary of findings 8. Angiotensin receptor blocker (ARB) versus another ARB for people with diabetes and kidney disease.

Summary of findings 9. Low‐dose angiotensin receptor blockers (ARB) versus high‐dose ARB for people with diabetes and kidney disease.

Summary of findings 10. Low‐dose angiotensin receptor blockers (ARB) plus spironolactone versus high‐dose ARB plus spironolactone for people with diabetes and kidney disease.

Background

Description of the condition

Description of the intervention

How the intervention might work

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Interventions of direct interest

Types of outcome measures

Primary outcomes

Primary efficacy outcome

Primary safety outcome

Secondary outcomes

Secondary efficacy outcomes

Secondary safety outcomes

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Selection of studies

Data extraction and management

Outcome data

Data on potential effect modifiers

Other data

Assessment of risk of bias in included studies

Measures of treatment effect

Cluster‐randomised studies

Cross‐over studies

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

Summary of findings and assessment of the certainty of the evidence

Results

Description of studies

Results of the search

1.

Included studies

Study design, setting and characteristics

Study participants

Interventions

ACEi versus placebo or no treatment

ARB versus placebo or no treatment

ARB versus ACEi

ACEi plus ARB versus placebo or no treatment

ACEi or ARB alone versus ACEi plus ARB

ACEi versus ACEi plus ARB

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
13.1 Micro‐ to macroalbuminuria	3	232	Risk Ratio (M‐H, Random, 95% CI)	0.47 [0.21, 1.05]
13.2 Micro‐ to normoalbuminuria	3	232	Risk Ratio (M‐H, Random, 95% CI)	4.21 [1.94, 9.14]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
14.1 Cardiovascular death	2	35	Risk Ratio (M‐H, Random, 95% CI)	Not estimable
14.2 Micro‐ to macroalbuminuria	3	261	Risk Ratio (M‐H, Random, 95% CI)	0.87 [0.20, 3.92]
14.3 Micro‐ to normoalbuminuria	2	36	Risk Ratio (M‐H, Random, 95% CI)	6.04 [0.77, 47.71]

*Study characteristics*
Methods	Study design Parallel RCT Country: USA Setting: multicentre (recruited from a variety of sites and followed up at Time frame (recruitment): March 1991 to December 1992 Follow‐up period: 5 to 7 years
Participants	Study characteristics Inclusion criteria: 40 to 74 years, type 2 DM; BP exceeding 180/105 mm Hg; likely to complete 5 to 7 years of study; willing to participate after a complete discussion of the study and who have signed the consent form; unlikely to move from Denver area within the next 5 years Exclusion criteria: pregnant or lactating female or childbearing potential not using reliable contraception; potential pregnancy during the study; allergies to dihydropyridines or ACEi; recent or current substance abusers; state of mental or physical competence inadequate to comply with the study; second to third‐degree uncorrected heart block; MI or CVA within the previous 6 months or CAB surgery within the previous 3 months; unstable angina pectoris within the previous 6 months; CHF (NYHA III or IV); treatment with ACEi or CCB; accelerated/malignant hypertension (current the previous 5 years); current severe PVD manifested by gangrene or imminent amputation; Imminent or recent aortic dissection and/or previous mesenteric infarction; HD or PD and/or SCr > 3 mg/dL; bilateral renal artery stenosis or renal artery stenosis in a solitary functioning kidney; organ transplant recipients; significant hyperkalaemia (3 or more measurements > 6 mEq/L); progressive nephropathic diseases other than diabetic nephropathy; severe liver disease; history of malignancies or active cancer; DBP < 80 mm Hg off antihypertensive agents; isolated systolic hypertension (SBP mean > 160 mm Hg and DBP mean < 90 mm Hg off all antihypertensive agents) Baseline characteristics Number Intervention group: hypertensive group (237); normtensive group (237) Control group: hypertensive group (233); normotensive group (243) Mean age ± SEM (years) Intervention group: hypertensive group (57.5 ± 0.5); normtensive group (58.5 ± 0.6) Control group: hypertensive group (57.2 ± 0.5); normotensive group (59.1 ± 0.5) Sex (males) Intervention group: hypertensive group (67%); normtensive group (53%) Control group: hypertensive group (68%); normotensive group (56%)
Interventions	Intervention group Enalapril (intensive BP control) DBP target 75 mm Hg, 5 mg/d titrated to 10, 20 and then 40 mg/d as initial medication plus placebo Control group Nisoldipine (moderate BP control) DBP target 80 to 89 mm Hg Co‐interventions (non‐randomised antihypertensive drug) If the study intervention alone did not achieve the target BP, then open‐labelled antihypertensive medication was added in a step‐wise manner. Additional antihypertensive agents were added at the discretion of the medical director but did not include a CCB or ACEi
Outcomes	Reported outcomes GFR UAE: microalbuminuria (20 to 200 mg/min); and overt proteinuria (> 200 mg/min) CrCl BP Retinopathy Neuropathy CVE Laboratory measurements Left ventricular hypertrophy Cardiac death, cerebrovascular death, MI, CHF, coronary artery disease without MI (documented by angiogram), CVA, atherosclerotic complications (aortic dissection, atherosclerotic arterial aneurysm, and mesenteric ischemias or infarction), angina and serious ventricular arrhythmias
Notes	Additional information This study was supported by Bayer Pharmaceutical Company and 1998, the National Institute of Diabetes, Digestive, and Kidney Disease Patients were also randomised to enalapril vs nisoldipine, but these data were not reported in this review
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Methods for generating the random sequence were not reported in sufficient detail to assess risk. However, there was no imbalance in patients' baseline characteristics
Allocation concealment (selection bias)	Unclear risk	Methods to conceal allocation were not reported in sufficient detail to perform adjudication
Blinding of participants and personnel (performance bias) All outcomes	High risk	A single‐blind study was considered as high risk of bias
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "An Endpoint Committee blinded to randomisation assignment will ascertain the diagnosis of myocardial infarction, cerebrovascular accident, congestive heart failure and sudden death based on all available pertinent information." Comment: outcomes were principally laboratory measures and were at low risk of detection bias regardless of whether blinding of investigators or outcome assessors occurred. For subjective outcomes the endpoint committee was blinded
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Not reported in sufficient detail to permit adjudication
Selective reporting (reporting bias)	High risk	Clinically‐relevant outcomes that would be expected for this type of intervention were not reported
Other bias	Unclear risk	Similar participant baseline characteristics and cointerventions. It was not clear if funder could influence data analysis and study reporting or interpretation

*Study characteristics*
Methods	Study design Parallel add‐on study Country: Japan Setting: hospital Time frame: March 2002 to April 2003 Follow‐up period: 12 months
Participants	Study characteristics Inclusion criteria: type‐2 diabetic patients; 30 to 70 years; overt nephropathy with albuminuria > 30 mg/day; BP >130/80 mm Hg even after being treated with an ACEi or the combination of an ACEi and conventional Exclusion criteria: DBP > 120 mm Hg; HbA1c > 9%; SCr > 3.0 mg/dL; severe hepatic dysfunction Baseline characteristics Number: losartan + ACEi group (14); ACEi+ACEi group (20) Mea age ± SD (years): losartan + ACEi group (59.5 ± 6.5); ACEi +ACEi group (59.8 ± 6.7) Sex (M/F): losartan + ACEi group (11/3); ACEi + ACEi group (11/9)
Interventions	Losartan + ACEi group Losartan 25 to 50 mg/d, followed by titration every 3 months until their BP < 130/80 mm Hg ACEi (followed by titration every 3 months until their BP < 130/80 mm Hg) Enalapril: mean dose 4 mg/d Lisinopril: mean dose 5 mg/d Temocapril: mean dose 4 mg/d Imidapril: mean dose 5 mg/d ACEi + ACEi group Enalapril: mean dose 6.1 mg/d Imidapril: mean dose 8 mg/d Delapril: mean dose 15 mg/d Co‐interventions (non‐randomised antihypertensive drug) Amlodipine, barnedipine, benidipine, efonidipine and antidiabetic drugs
Outcomes	Reported outcomes BP UAE Laboratory parameters (including SCr, HbA1c and blood glucose) Serious adverse events
Notes	Additional information Funding source: not reported
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Methods for generating the random sequence were not reported in sufficient detail to assess risk. However, there was no imbalance in patients' baseline characteristics
Allocation concealment (selection bias)	Unclear risk	Quote: "We carried out randomisation using envelopes." Comment: Methods to conceal allocation were not reported in sufficient detail to perform adjudication
Blinding of participants and personnel (performance bias) All outcomes	High risk	Not reported. Participants and investigators were unlikely to be blinded to treatment allocation due to physical differences in the interventions
Blinding of outcome assessment (detection bias) All outcomes	High risk	Outcomes were principally laboratory measures and were at low risk of detection bias regardless of whether blinding of investigators or outcome assessors occurred. However, some outcomes (adverse events) could be influenced by knowledge of treatment assignment
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Not reported in sufficient detail to perform adjudication
Selective reporting (reporting bias)	High risk	Clinically‐relevant outcomes that would be expected for this type of intervention were not reported
Other bias	Low risk	Similar participants baseline characteristics. Funder was not reported. No other apparent sources of bias

*Study characteristics*
Methods	Study design Parallel RCT Country: India Setting: university Time frame: not reported Follow‐up period: 5 years
Participants	Study characteristics Inclusion criteria: 43 to 55 years; known duration of diabetes < 15 years; no history and clinical or laboratory evidence of non‐diabetic renal, systemic, cardiac or hepatic diseases; BMI < 27 kg/m²; normal BP values on 2 consecutive examinations (SBP ≤140 mm Hg; DBP ≤ 90 mm Hg); GFR > 90 mL/min; AER 20 to 200 µg/min on 2 consecutive visits without evidence of UTI Exclusion criteria: not reported Baseline characteristics Number (randomised/analysed): total (120/103); enalapril group (52); control group (51) Mean age ± SD (years): enalapril group (49.8 ± 3.0); control group (50.3 ± 2.1) Sex (M/F): enalapril group (30/22); control group (30/21)
Interventions	Enalapril group 10 mg/d Control group Moderate treatment Co‐interventions (non‐randomised antihypertensive drug) Not reported
Outcomes	Outcomes reported AER GFR BP Fasting plasma glucose and HbA1c Creatinine
Notes	Additional information Grant from the Department of Science and Technology, government of India
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Methods for generating the random sequence were not reported in sufficient detail to assess risk. However, there was no imbalance in patients' baseline characteristics
Allocation concealment (selection bias)	Unclear risk	Methods to conceal allocation were not reported in sufficient detail to perform adjudication
Blinding of participants and personnel (performance bias) All outcomes	High risk	A single‐blind study was considered as high risk of bias
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Outcomes were principally laboratory measures and were at low risk of detection bias regardless of whether blinding of investigators or outcome assessors occurred
Incomplete outcome data (attrition bias) All outcomes	High risk	103/120 participants completed the study
Selective reporting (reporting bias)	High risk	Clinically‐relevant outcomes that would be expected for this type of intervention were not reported
Other bias	Low risk	Similar participants baseline characteristics. Funder was unlikely to influence data analysis and study reporting or interpretation. No other apparent sources of bias

*Study characteristics*
Methods	Study design Parallel RCT Country: multinational Setting: multicentre (49 sites) Time frame (screened): January 1989 to December 1990 Follow‐up period: 36 months
Participants	Study characteristics Inclusion criteria: SCr 1.5 to 4.0 mg/dL; CrCl 30 to 60 mL/min with variations < 30% in at least 3 measurements of CrCl during a 3‐month screening period and < 15% during a subsequent 2‐week single‐blind placebo period Exclusion criteria: treatment with a corticosteroid, NSAIDs or immunosuppressive drugs; AER > 10 g/24 h and serum albumin < 25g/L (each measured at least 3 times, and twice during the screening period); renovascular hypertension; malignant hypertension or a MI or CVA in the 6 months preceding the study; CHF (NYHA III ‐ IV); DM type 1; elevated serum aminotransferase concentration; collagen disease; obstructive uropathy; cancer; chronic cough; history of allergy to an ACEi; drug or alcohol abuse; pregnancy Baseline characteristics Number: benazepril group (300); control group (283) Mean age ± SD (years): benazepril group (51 ± 13); control group (51 ± 12) Sex (M/F) (total): benazepril group (220/80); control group (201/82)
Interventions	Benazepril group 10 mg/d Control group Placebo Co‐interventions (non‐randomised antihypertensive drug) Not reported
Outcomes	Outcomes reported Doubling of the baseline SCr concentration or the need for dialysis BP All‐cause death Cardiovascular death Adverse events Cardiovascular events
Notes	Additional information Supported by a grant from Ciba–Geigy
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Methods for generating the random sequence were not reported in sufficient detail to assess risk. Participants' baseline characteristics and co‐interventions were not reported (possible imbalance in randomisation not clearly reported)
Allocation concealment (selection bias)	Unclear risk	Methods to conceal allocation were not reported in sufficient detail to perform adjudication
Blinding of participants and personnel (performance bias) All outcomes	Low risk	A double‐blind study was considered as low risk of bias
Blinding of outcome assessment (detection bias) All outcomes	High risk	Outcomes were principally laboratory measures and were at low risk of detection bias regardless of whether blinding of investigators or outcome assessors occurred. However, some outcomes (adverse events) could be influenced by knowledge of treatment assignment
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Not reported in sufficient detail to perform adjudication
Selective reporting (reporting bias)	High risk	Clinically‐relevant outcomes that would be expected for this type of intervention were not reported
Other bias	High risk	Participant baseline characteristics and co‐interventions were not reported (only for 21 participants of our interest). It was not clear if funder could influence data analysis and study reporting or interpretation

*Study characteristics*
Methods	Study design 4‐arm parallel RCT Country: Japan Setting: multicentre (2 sites) Time frame: not reported Follow‐up period: 12 months
Participants	Study characteristics Inclusion criteria: 60 to < 85 years; causal BP measured at the outpatient clinic of 140/90 mm Hg or higher was diagnosed as hypertension; undergoing diet and exercise therapy; early nephropathy defined as 30 to 299 mg/d 24‐h UAE Exclusion criteria: not reported Baseline characteristics Number: telmisartan group (20); valsartan group (20); candesartan group (20); losartan group (20) Mean age ± SD (years): telmisartan group (74.3 ± 4.4); valsartan group (73.6 ± 5.0); candesartan group (73.3 ± 5.5); losartan group ( 72.6 ± 4.7) Sex (M/F): telmisartan group (10/10); valsartan group (10/10); candesartan group (10/10); losartan group (10/10)
Interventions	Telmisartan group Mean dose 48.0 ± 16.4 mg/d Valsartan group Mean dose 116.0 ± 40.8 mg/d Candesartan group Mean dose 10.2 ± 2.0 mg/d Losartan group Mean dose 71.3 ± 21.9 mg/d Co‐interventions (non‐randomised antihypertensive drug) Not reported
Outcomes	Outcomes reported BP SCr, CrCl and urinary albumin level HbA1c Adverse events
Notes	Additional information Funding: not reported
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Methods for generating the random sequence were not reported in sufficient detail to assess risk. However, there was no imbalance in patients' baseline characteristics
Allocation concealment (selection bias)	Unclear risk	Methods to conceal allocation were not reported in sufficient detail to perform adjudication
Blinding of participants and personnel (performance bias) All outcomes	High risk	Not reported. Participants and investigators were unlikely to be blinded to treatment allocation due to physical differences in the interventions
Blinding of outcome assessment (detection bias) All outcomes	High risk	Outcomes were principally laboratory measures and were at low risk of detection bias regardless of whether blinding of investigators or outcome assessors occurred. However, some outcomes (adverse events) could be influenced by knowledge of treatment assignment
Incomplete outcome data (attrition bias) All outcomes	Low risk	All participants completed the study
Selective reporting (reporting bias)	High risk	Clinically‐relevant outcomes that would be expected for this type of intervention were not reported
Other bias	Low risk	Similar participants baseline characteristics. Funder was not reported. No other apparent sources of bias

*Study characteristics*
Methods	Study design Parallel RCT Country: UK Setting: multicentre (28 sites) Time frame: not reported Follow‐up period: 24 months
Participants	Study characteristics Inclusion criteria: DM type 1; microalbuminuria 20 to 200 µg/min in 2 of 3 collections; untreated BP < 150/90 mm Hg for patients < 50 years and < 165/90 mm Hg for patients 50 to 65 years Exclusion criteria: pregnant or lactating; women of child‐bearing potential and not using adequate contraception; concomitant therapy for hypertension; treatment on or more NSAIDs; history of drug or alcohol abuse; other known renal diseases or raised CrCl > 120 μmol/L; liver function twice that of normal on repeat testing; iodine sensitivity Baseline characteristics Number (randomised/analysed): ramipril group 1 (47/44); ramipril group 2 (45/44); control group (48/46) Mean age ± SD (years): ramipril group 1 (44 ± 11); ramipril group 2 (40 ± 13); control group (40 ± 12) Sex (M/F): ramipril group 1 (44/3); ramipril group 2 (44/1); control group (46/2)
Interventions	Ramipril group 1 25 mg/d Ramipril group 2 5 mg/d Control group Placebo Co‐interventions (non‐randomised antihypertensive drug) Not reported
Outcomes	Outcomes reported AER BP GFR Creatinine Adverse events HbA1c
Notes	Additional information This study was sponsored by Hoechst Marion Roussel (Aventis) who provided £500 per year per patient to support research costs
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Methods for generation of the random sequence were not reported in sufficient detail to assess risk. However, there was no imbalance in patients baseline characteristics
Allocation concealment (selection bias)	Low risk	Quote from Wang 2018: "Assignments were placed in sealed, sequenced, opaque envelopes, which study coordinators opened at time of enrolment to assign participants to ACTH treatment or no relapse‐preventing treatment." Comment: Allocation concealment is considered as adequate
Blinding of participants and personnel (performance bias) All outcomes	Low risk	A double‐blind study was considered as low risk of bias
Blinding of outcome assessment (detection bias) All outcomes	High risk	Outcomes were principally laboratory measures and were at low risk of detection bias regardless of whether blinding of investigators or outcome assessors occurred. However, some outcomes (adverse events) could be influenced by knowledge of treatment assignment
Incomplete outcome data (attrition bias) All outcomes	Low risk	134/140 participants were reported in the analysis
Selective reporting (reporting bias)	High risk	Clinically‐relevant outcomes that would be expected for this type of intervention were not reported
Other bias	Unclear risk	Similar participants baseline characteristics. It was not clear if funder could influence data analysis and study reporting or interpretation

*Study characteristics*
Methods	Study design Parallel RCT Country: Turkey Setting: not reported Time frame: not reported Follow‐up period: 12 months
Participants	Study characteristics Inclusion criteria: normotensive patients with type 2 DM and microalbuminuria Exclusion criteria: type 1 DM; secondary diabetes; chronic hepatic failure; CHF; CKD; hypertension (history of taking antihypertensive pills or BP < 130/85 mm Hg); chronic complications of diabetes; malignancy; UTI; smoking history; HbA1c > 7% Baseline characteristics Number (randomised/analysed): total (34/26): lisinopril group (9); losartan group (9); lisinopril + losartan group (8) Mean age ± SD (years): lisinopril group (55 ± 8.9); losartan group (55.1 ± 9.2); lisinopril + losartan group (55.1 ± 9.6) Sex (M/F): lisinopril group (4/5); losartan group (4/5); lisinopril + losartan group (3/5)
Interventions	Lisinopril group 10 mg/d Losartan group 50 mg/d Lisinopril + Losartan group 10 mg/d + 50 mg/d Co‐interventions (non‐randomised antihypertensive drug) Eight patients were only given a diet, 10 were given a diet and oral hypoglycaemic agents, and 8 were given a diet and insulin treatment for diabetes management ‐ no drugs for hypertension were reported
Outcomes	Outcomes reported AER BMI BP 24 h UAER HbA1c and fasting and postprandial plasma glucose values Potassium, blood urea nitrogen, creatinine Liver function tests Adverse events
Notes	Additional information Four patients were lost to follow‐up, 2 had adverse reactions to drugs, and 2 had newly diagnosed hypertension that necessitated a change in the treatment protocol ‐ groups not reported Funding: not reported
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Methods for generating the random sequence were not reported in sufficient detail to assess risk. However, there was no imbalance in patients' baseline characteristics
Allocation concealment (selection bias)	Unclear risk	Methods to conceal allocation were not reported in sufficient detail to perform adjudication
Blinding of participants and personnel (performance bias) All outcomes	High risk	Not reported. Participants and investigators were unlikely to be blinded to treatment allocation due to physical differences in the interventions
Blinding of outcome assessment (detection bias) All outcomes	High risk	Outcomes were principally laboratory measures and were at low risk of detection bias regardless of whether blinding of investigators or outcome assessors occurred. However, some outcomes (adverse events) could be influenced by knowledge of treatment assignment
Incomplete outcome data (attrition bias) All outcomes	High risk	26/34 participants completed the study
Selective reporting (reporting bias)	High risk	Clinically‐relevant outcomes that would be expected for this type of intervention were not reported
Other bias	Low risk	Similar participant baseline characteristics and co‐interventions. Funder was not reported. No other apparent sources of bias

*Study characteristics*
Methods	Study design Parallel RCT Country: Columbia Setting: not reported Time frame: not reported Follow‐up period: 18 months
Participants	Study characteristics Inclusion criteria: clinical diabetic nephropathy defined as the presence of persistent proteinuria > 500 mg/24 h before drug randomisation; history of either type I or type II DM; no clinical or laboratory evidence of primary kidney disease; CrCl > 20 mL/min/1.73 m²; clinical evidence of additional diabetic target organ damage (diabetic retinopathy and/or peripheral neuropathy); persistent DBP < 90 mm Hg or either drug therapy or on conventional antihypertensive drug excluding ACEi and CCB Exclusion criteria: HbA1c consistently > 12%; non‐compliance with drug therapy; history of hyperkalaemia or baseline serum potassium > 5.2 mmol/L; decompensated CHF; unstable angina pectoris or history of MI within 6 months of entering the protocol; cerebrovascular disease within 12 months of entering the protocol; females with the potential to become pregnant; history of hypersensitivity reaction to ACEi peptide‐like drugs; evidence of clinically important bladder dysfunction, negating the ability to replicate renal clearance determination Baseline characteristics Number (randomised/analysed): total (42/33); enalapril group (18); control group (15) Median age, IQR (years): enalapril group (44.1, 26 to 66); control group (57.0, 47 to 70) Sex (M/F): enalapril group (11/7); control group (13/2)
Interventions	Enalapril group 5 to 40 mg/d Control group Placebo Co‐interventions (non‐randomised antihypertensive drug) Make no change in dietary protein and sodium intake Specific antihypertensive drugs were reported, including atenolol, prazosin, hydrochlorothiazide, metolazone, minoxidil, furosemide, maxzide, hydralazine, propanolol
Outcomes	Outcomes reported GFR BP All‐cause death (sudden death) Adverse events Protein excretion Creatinine Laboratory parameters
Notes	Additional information Supported by the Missouri Kidney Program, and by Merck, Sharp & Dohme Research Laboratories
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Methods for generating the random sequence were not reported in sufficient detail to assess risk. However, there was no imbalance in patients' baseline characteristics
Allocation concealment (selection bias)	Unclear risk	Methods to conceal allocation were not reported in sufficient detail to perform adjudication
Blinding of participants and personnel (performance bias) All outcomes	Low risk	A double‐blind study was considered as low risk of bias
Blinding of outcome assessment (detection bias) All outcomes	High risk	Outcomes were principally laboratory measures and were at low risk of detection bias regardless of whether blinding of investigators or outcome assessors occurred. However, some outcomes (adverse events) could be influenced by knowledge of treatment assignment
Incomplete outcome data (attrition bias) All outcomes	High risk	24/33 participants completed the study
Selective reporting (reporting bias)	High risk	Clinically‐relevant outcomes that would be expected for this type of intervention were not reported
Other bias	Unclear risk	Similar participants baseline characteristics and co‐interventions. It was not clear if funder could influence data analysis and study reporting or interpretation