Antihypertensive agents for preventing diabetic kidney disease

Jicheng Lv; Vlado Perkovic; Celine V Foote; Maria E Craig; Jonathan C Craig; Giovanni FM Strippoli

doi:10.1002/14651858.CD004136.pub3

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Figure 1

Study flow diagram.

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Figure 2

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

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Figure 3

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

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Analysis 1.1

Comparison 1 ACEi versus placebo/no treatment, Outcome 1 Normo‐ to micro‐ or macroalbuminuria.

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Analysis 1.2

Comparison 1 ACEi versus placebo/no treatment, Outcome 2 All‐cause mortality.

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Analysis 1.3

Comparison 1 ACEi versus placebo/no treatment, Outcome 3 Doubling of SCr.

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Analysis 1.4

Comparison 1 ACEi versus placebo/no treatment, Outcome 4 ESKD.

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Analysis 1.5

Comparison 1 ACEi versus placebo/no treatment, Outcome 5 Adverse events.

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Analysis 1.6

Comparison 1 ACEi versus placebo/no treatment, Outcome 6 Blood pressure.

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Analysis 2.1

Comparison 2 ARB versus placebo/no treatment, Outcome 1 Normo‐ to micro‐ or macroalbuminuria.

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Analysis 2.2

Comparison 2 ARB versus placebo/no treatment, Outcome 2 All‐cause mortality.

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Analysis 2.3

Comparison 2 ARB versus placebo/no treatment, Outcome 3 Doubling of SCr.

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Analysis 2.4

Comparison 2 ARB versus placebo/no treatment, Outcome 4 ESKD.

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Analysis 2.5

Comparison 2 ARB versus placebo/no treatment, Outcome 5 Adverse events.

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Analysis 2.6

Comparison 2 ARB versus placebo/no treatment, Outcome 6 Blood pressure.

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Analysis 3.1

Comparison 3 ACEi versus ARB, Outcome 1 Normo‐ to micro‐ or macroalbuminuria.

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Analysis 3.2

Comparison 3 ACEi versus ARB, Outcome 2 All‐cause mortality.

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Analysis 4.1

Comparison 4 ACEi versus CCB, Outcome 1 Normo to micro or macroalbuminuria.

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Analysis 4.2

Comparison 4 ACEi versus CCB, Outcome 2 All‐cause mortality.

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Analysis 4.3

Comparison 4 ACEi versus CCB, Outcome 3 Doubling of SCr.

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Analysis 4.4

Comparison 4 ACEi versus CCB, Outcome 4 ESKD.

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Analysis 4.5

Comparison 4 ACEi versus CCB, Outcome 5 Blood pressure.

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Analysis 5.1

Comparison 5 Prevention of kidney disease: other agents, Outcome 1 ACEi + ARB versus ACEi.

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Analysis 5.2

Comparison 5 Prevention of kidney disease: other agents, Outcome 2 ACEi versus BB.

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Analysis 5.3

Comparison 5 Prevention of kidney disease: other agents, Outcome 3 ACEi + CCB versus ACEi.

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Analysis 5.4

Comparison 5 Prevention of kidney disease: other agents, Outcome 4 CCB versus placebo.

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Table 1. Guidelines on pharmacological management of hypertension in diabetic patients

Guideline	Indication	ACEi	ARB	BB	CCB	Diuretics	AB
Chobanian 2003^a USA	Hypertension	Yes	Yes	Yes	Yes	Yes	Yes
	DKD (type 1 diabetes)	Yes	Yes
	DKD (type 2 diabetes)	Yes	Yes
ADA 2010^b USA	Hypertension	Yes	Yes
	DKD (type 1 diabetes)	Yes	Yes
	DKD (type 2 diabetes)	Yes	Yes
KDOQI 2007^c USA	Hypertension
	DKD (type 1 diabetes)	Yes	Yes
	DKD (type 2 diabetes)	Yes	Yes
CDA 2008^d Canada	Hypertension^h	Yes	Yes		Yes	Yes
	DKD (type 1 diabetes)	Yes
	DKD (type 2 diabetes)	Yes	Yes^j
ESH‐ESC 2007^e Europe	Hypertensionⁱ	Yes	Yes		Yes		Yes
	DKD (type 1 diabetes)	Yes	Yes
	DKD (type 2 diabetes)	Yes	Yes
Williams 2004^f UK	Hypertension		Yes^l			Yes
	DKD (type 1 diabetes)	Yes
	DKD (type 2 diabetes)	Yes
Chadban 2010^g Australia	Hypertension
	DKD (type 1 diabetes)	Yes
	DKD (type 2 diabetes)	Yes	Yes
^a Joint National Committee on Prevention, Diagnosis and Management of Hypertension; ^b American Diabetes Association; ^c Kidney Disease Outcome Quality Initiative; ^d Canadian Diabetes Association; ^e European Society of Hypertension; ^f British Hypertension Society; ^g Caring for Australians with Renal Impairment; ^h With special consideration given to ACEi or ARB; ⁱ A blocker of the renin‐angiotensin system should be a regular component of combination treatment and the one preferred when monotherapy is sufficient; ^j Consensus for ARB use in type 1 diabetes; ^kUse calcium antagonists for hypertension when can be managed with monotherapy; use any agent for hypertension which requires combination treatment; ^lIf intolerant to other agents AB ‐ alpha‐blocker; ACEi ‐ angiotensin‐converting enzyme inhibitors; ARB ‐ angiotensin receptor blockers; BB ‐ beta‐blockers; CCB ‐ calcium channel blockers; DKD ‐ diabetic kidney disease

Table 1. Guidelines on pharmacological management of hypertension in diabetic patients

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Table 2. Subgroup analysis of ACEi and ARB for preventing diabetic kidney disease

Variables	ACEi versus placebo				ARB versus placebo				ACEi versus CCB
Variables	Subgroup	Studies	RR (95% CI)	Heterogeneity (P)	Subgroup	Studies	RR (95% CI)	Heterogeneity (P)	Subgroup	Studies	RR (95% CI)	Heterogeneity (P)
Normoalbuminuria	≥ 500	4	0.84 (0.79,0.90)	0.023	≥ 1500	4	0.86 (0.76,0.97)	0.089	≥ 300	2	0.57 (0.34,0.96)	0.756
Normoalbuminuria	< 500	4	0.36 (0.17,0.79)	0.023	< 1500	3	1.30 (0.49,3.45)	0.089	< 300	3	0.63 (0.38,1.04)	0.756
Event rate/100 person‐years	≥ 5	4	0.76 (0.54,1.07)	0.059	≥ 2.8	4	0.83 (0.73,0.94)	0.035	≥ 2.0	3	0.57 (0.39,0.82)	0.378
Event rate/100 person‐years	< 5	4	0.59 (0.41,0.85)	0.059	< 2.8	3	1.27 (0.79,2.03)	0.035	< 2.0	2	1.01 (0.30,3.43)	0.378
Duration of follow‐up (years)	≥ 4	4	0.76 (0.58,1.00)	0.126	≥ 4.8	4	1.27 (0.52,3.11)	0.062	≥ 3	3	0.60 (0.38,0.94)	0.973
Duration of follow‐up (years)	< 4	4	0.60 (0.36,1.00)	0.126	< 4.8	3	0.84 (0.74,0.94)	0.062	< 3	2	0.59 (0.34,1.04)	0.973
Diabetes mellitus^a	Type 1	4	0.54 (0.24,1.20)	0.526	Type 1	5	1.16 (0.79,1.70)	0.048	Type 1	0		Not estimated
	Type 2	3	0.67 (0.43,1.04)		Type 2	3	0.83 (0.73,0.94)		Type 2	5	0.60 (0.42, 0.85)
	mixed	1	0.71 (0.39,1.29)		Mixed	0			Mixed	0
Hypertension^b	Yes	4	0.64 (0.43,0.96)	0.740	Yes	3	0.84 (0.75,0.95)	0.127	Yes	5	0.60 (0.42, 0.85)	Not estimated
Hypertension^b	No	5	0.82 (0.73,0.92)	0.740	No	5	1.06 (0.67,1.69)	0.127	No	0		Not estimated
Systolic BP (mm Hg) (difference between treatment/control)	≤ ‐3	4	0.84 (0.79,0.90)	0.075	≤ ‐3.5	3	0.85 (0.61, 1.18)	0.259	> 0	3	0.68 (0.43,1.07)	0.420
Systolic BP (mm Hg) (difference between treatment/control)	> ‐3	3	0.41 (0.15,1.08)	0.075	> ‐3.5	3	1.21 (0.72, 2.05)	0.259	≤ 0	2	0.50 (0.29,0.87)	0.420
Diastolic BP (mm Hg) (difference between treatment/control)	≤ ‐2	4	0.68 (0.50,0.92)	0.175	≤ ‐2	3	0.94 (0.75, 1.18)	0.828	> 0	2	0.65 (0.39,1.08)	0.651
	< ‐2	4	0.61 (0.36,1.05)	0.175	< ‐2	3	1.07 (0.66, 1.73)	0.828	≤ 0	3	0.55 (0.34,0.90)	0.651
Allocation concealment	Yes	3	0.84 (0.79,0.90)	0.019	Yes	5	0.86 (0.77,0.96)	0.047	Yes	1	1.01 (0.30,3.43)	0.378
Allocation concealment	Unclear	5	0.48 (0.29,0.79)	0.019	Unclear	2	0.96 (0.07,12.80)	0.047	Unclear	4	0.57 (0.34,0.82)	0.378
Intention‐to‐treat analysis	Yes	3	0.84 (0.79,0.90)	0.019	Yes	5	0.88 (0.74,1.05)	0.741	Yes	1	0.59 (0.34,1.04)	0.973
Intention‐to‐treat analysis	Unclear/No	5	0.48 (0.29,0.79)	0.019	Unclear/No	2	1.37 (0.45,4.14)	0.741	Unclear/no	4	0.60 (0.38,0.94)	0.973
Lost to follow‐up	< 1%	4	0.71 (0.44,1.16)	0.075	< 1%	3	0.77 (0.63,0.93)	0.119	< 1%	2	0.63 (0.38,1.04)	0.580
Lost to follow‐up	≤ 1%	4	0.64 (0.48,0.86)	0.075	≤ 1%	4	0.99 (0.78,1.24)	0.119	≤ 1%	3	0.57 (0.34,0.96)	0.580
^a TRANSCEND was split as type 1 and type 2 diabetes mellitus; ^b ADVANCE was split as hypertension and normotension ACEi ‐ angiotensin‐converting enzyme inhibitors; ARB ‐ angiotensin receptor blockers; CCB ‐ calcium channel blockers

Table 2. Subgroup analysis of ACEi and ARB for preventing diabetic kidney disease

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Comparison 1. ACEi versus placebo/no treatment

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Normo‐ to micro‐ or macroalbuminuria Show forest plot	8	11906	Risk Ratio (M‐H, Random, 95% CI)	0.71 [0.56, 0.89]

2 All‐cause mortality Show forest plot	6	11350	Risk Ratio (M‐H, Random, 95% CI)	0.84 [0.73, 0.97]

3 Doubling of SCr Show forest plot	5	10749	Risk Ratio (M‐H, Random, 95% CI)	0.77 [0.39, 1.49]

4 ESKD Show forest plot	3	10504	Risk Ratio (M‐H, Random, 95% CI)	1.94 [0.66, 5.70]

5 Adverse events Show forest plot	6		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

5.1 Cough	6	11791	Risk Ratio (M‐H, Random, 95% CI)	1.84 [1.24, 2.72]
5.2 Headache	3	10504	Risk Ratio (M‐H, Random, 95% CI)	1.19 [0.47, 3.02]
5.3 Hyperkalaemia	3	2783	Risk Ratio (M‐H, Random, 95% CI)	2.98 [0.47, 18.78]
6 Blood pressure Show forest plot	2		Mean Difference (IV, Random, 95% CI)	Subtotals only

6.1 Systolic BP	2	7526	Mean Difference (IV, Random, 95% CI)	‐5.37 [‐7.12, ‐3.62]
6.2 Diastolic BP	2	7526	Mean Difference (IV, Random, 95% CI)	‐1.50 [‐1.50, ‐1.50]

Comparison 1. ACEi versus placebo/no treatment

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Comparison 2. ARB versus placebo/no treatment

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Normo‐ to micro‐ or macroalbuminuria Show forest plot	5	7653	Risk Ratio (M‐H, Random, 95% CI)	0.90 [0.68, 1.19]

2 All‐cause mortality Show forest plot	5	7653	Risk Ratio (M‐H, Random, 95% CI)	1.12 [0.88, 1.41]

3 Doubling of SCr Show forest plot	3	6217	Risk Ratio (M‐H, Random, 95% CI)	1.36 [0.64, 2.88]

4 ESKD Show forest plot	3	6217	Risk Ratio (M‐H, Random, 95% CI)	0.50 [0.09, 2.71]

5 Adverse events Show forest plot	3		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

5.1 Cough	2	1770	Risk Ratio (M‐H, Random, 95% CI)	1.01 [0.42, 2.44]
5.2 Headache	3	3191	Risk Ratio (M‐H, Random, 95% CI)	0.73 [0.52, 1.01]
5.3 Hyperkalaemia	3	3191	Risk Ratio (M‐H, Random, 95% CI)	2.30 [0.69, 7.71]
6 Blood pressure Show forest plot	2		Mean Difference (IV, Random, 95% CI)	Subtotals only

6.1 Systolic BP	2	1770	Mean Difference (IV, Random, 95% CI)	‐3.28 [‐5.29, ‐1.27]
6.2 Diastolic BP	2	1770	Mean Difference (IV, Random, 95% CI)	‐2.0 [‐2.64, ‐1.36]

Comparison 2. ARB versus placebo/no treatment

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Comparison 3. ACEi versus ARB

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Normo‐ to micro‐ or macroalbuminuria Show forest plot	2	4303	Risk Ratio (M‐H, Random, 95% CI)	0.57 [0.14, 2.23]

2 All‐cause mortality Show forest plot	2	4303	Risk Ratio (M‐H, Random, 95% CI)	1.02 [0.85, 1.22]

Comparison 3. ACEi versus ARB

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Comparison 4. ACEi versus CCB

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Normo to micro or macroalbuminuria Show forest plot	5	1253	Risk Ratio (M‐H, Random, 95% CI)	0.60 [0.42, 0.85]

2 All‐cause mortality Show forest plot	5	1519	Risk Ratio (M‐H, Random, 95% CI)	0.84 [0.26, 2.73]

3 Doubling of SCr Show forest plot	3	607	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]

4 ESKD Show forest plot	4	680	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]

5 Blood pressure Show forest plot	2		Mean Difference (IV, Random, 95% CI)	Subtotals only

5.1 Systolic BP	2	430	Mean Difference (IV, Random, 95% CI)	4.0 [1.59, 6.41]
5.2 Diastolic BP	2	430	Mean Difference (IV, Random, 95% CI)	1.22 [‐0.42, 2.85]

Comparison 4. ACEi versus CCB

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Comparison 5. Prevention of kidney disease: other agents

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 ACEi + ARB versus ACEi Show forest plot	2	4171	Risk Ratio (M‐H, Random, 95% CI)	0.88 [0.78, 1.00]

2 ACEi versus BB Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

3 ACEi + CCB versus ACEi Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

4 CCB versus placebo Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

Comparison 5. Prevention of kidney disease: other agents

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