Table 1.
Summary of included clinical trials and patient characteristics
| Trial | Follow-up (years) | No of patients | Mean age (years) | Female (%) | Type of diabetes | Level of albuminuria* | Treatment | Change in MAP (mm Hg) | Outcomes | ||
|---|---|---|---|---|---|---|---|---|---|---|---|
| All cause mortality | End stage renal disease | Doubling of serum creatinine | |||||||||
| Parving et al 1989 | 1.0 | 32 | 30.9 | 28.1 | 1 | Macro | ACE inhibitor; placebo | –2.6; 5.7 | 1/15; 1/17 | 1/15; 3/17 | 2/15; 3/17 |
| Bauer et al 1992 | 1.5 | 33 | 50.0 | 27.3 | Mixed | Macro | ACE inhibitor; placebo | –0.7; 0.01 | 1/18; 0/15 | 1/18; 0/15 | — |
| Björck et al 1992 | 2.2 | 40 | — | — | 1 | Macro | ACE inhibitor; β blocker | –12.0; –6.0 | 0/22; 0/18 | 2/22; 2/18 | — |
| Chan et al 1992 | 1.0 | 102 | 58.1 | 59.8 | 2 | Mixed | ACE inhibitor; CCB | –22.0; –21.0 | 1/50; 0/52 | — | — |
| Chase et al 1993 | 2.0 | 16 | 20.8 | 25.0 | 1 | Micro | ACE inhibitor; placebo | 3.3; 1.0 | 0/7; 0/9 | — | — |
| Hallab et al 1993 | 1.0 | 25 | 37.6 | 44.0 | 1 | Micro | ACE inhibitor; diuretic | 8.0; 5.0 | 0/13; 0/12 | — | — |
| Lewis et al 1993 | 3.0 | 409 | 34.5 | 47.2 | 1 | Macro | ACE inhibitor; placebo | –6.0; –4.0 | 8/207; 14/202 | 20/207; 31/202 | 25/207; 43/202 |
| O’Donnell et al 1993 | 1.0 | 32 | 48.7 | 28.1 | Mixed | Micro | ACE inhibitor; placebo | –3.7; –1.3 | 0/15; 0/17 | — | — |
| Ravid et al 1993 | 5.0 | 108 | 44.1 | 61.1 | 2 | Micro | ACE inhibitor; placebo | 1.0; 5.0 | 0/56; 0/52 | 0/56; 0/52 | 2/56; 12/52 |
| Bakris et al 1994 | 1.5 | 15 | 26.6 | 53.3 | 1 | Micro | ACE inhibitor; placebo | –10.0; 0 | 0/8; 0/7 | — | — |
| Capek et al 1994 | 1.0 | 20 | 63.6 | 65.0 | 2 | Micro | ACE inhibitor; placebo | –3.0; 1.7 | 0/10; 0/10 | 0/10; 0/10 | 0/10; 0/10 |
| Elving et al 1994 | 2.0 | 30 | 38.0 | 23.3 | 1 | Macro | ACE inhibitor; β blocker | –10.0; –4.0 | 0/15; 0/15 | — | — |
| Sano et al 1994 | 4.0 | 52 | 64.0 | — | 2 | Micro | ACE inhibitor; placebo | 0.3; –2.6 | 1/26; 0/26 | — | — |
| Laffel et al 1995 | 2.0 | 143 | 32.7 | 49.7 | 1 | Micro | ACE inhibitor; placebo | –8.7; 2.0 | 1/70; 0/73 | — | — |
| Bakris et al 1996 | 6.0 | 52 | 62.1 | 50.0 | 2 | Macro | ACE inhibitor; CCB; β blocker | –16.0; –18.0; –15.0 | 1/18; 1/18; 4/16 | — | 1/18; 2/18; 5/16 |
| Viberti et al 1996 | 2.0 | 235 | 32.2 | 47.7 | 1 | Micro | ACE inhibitor; placebo | –3.3; 1.0 | 1/116; 1/119 | — | — |
| Nielsen et al 1997 | 3.5 | 43 | 60.5 | 44.2 | 2 | Macro | ACE inhibitor; β blocker | –11.7; –10.0 | 1/21; 5/22 | 1/21; 1/22 | — |
| ABCD 1998 | 5.0 | 470 | 57.5 | 32.6 | 2 | Micro and macro | ACE inhibitor; CCB | — | 13/235; 17/235 | — | — |
| Bakris et al 1998 | 1.0 | 44 | 59.7 | 43.2 | 2 | Macro | ACE inhibitor+CCB; ACE inhibitor; CCB | –26.0; –21.0; –25.3 | 0/16; 0/14; 0/14 | — | — |
| Crepaldi et al 1998 | 3.0 | 92 | 37.1 | 31.5 | 1 | Micro | ACE inhibitor; CCB; placebo | –9.0; –4.0; –5.7 | 0/32; 0/26; 0/34 | — | — |
| FACET 1998 | 3.5 | 380 | 63.1 | 40.5 | 2 | Normo and micro | ACE inhibitor; CCB | –9.71; –11.7 | 4/189; 5/191 | — | — |
| Garg et al 1998 | 1.0 | 11 | 25.4 | 72.7 | 1 | Micro | ACE inhibitor; placebo | –7.9; –1.6 | 0/7; 0/4 | — | — |
| Nankervis et al 1998 | 3.0 | 40 | 46.0 | 20.0 | Mixed | Micro | ACE inhibitor; placebo | –3.0; 2.3 | 0/20; 3/20 | — | — |
| Ravid et al 1998 | 6.0 | 194 | 55.0 | 61.3 | 2 | Normo | ACE inhibitor; placebo | 1.8; 5.9 | 3/97; 2/97 | — | — |
| Cordonnier et al 1999 | 2.0 | 22 | 47.0 | 18.2 | 2 | Micro and macro | ACE inhibitor; placebo | –5.0; –1.0 | 0/11; 0/11 | — | — |
| Fogari et al 1999 | 2.0 | 107 | 56.3 | 0.0 | 2 | Macro | ACE inhibitor; CCB | –14.2; –12.4 | — | 1/54; 1/53 | — |
| Mathiesen et al 1999 | 4.0 | 44 | 28.9 | 50.0 | 1 | Micro | ACE inhibitor; placebo | –5.3; –0.7 | 0/21; 0/23 | — | — |
| Muirhead et al 1999 | 1.1 | 122 | 56.0 | 27.0 | 2 | Micro | ACE inhibitor; ARB; placebo | –1.7; –2.3; 0.03 | 0/29; 0/62; 0/31 | — | — |
| ATLANTIS 2000 | 2.0 | 134 | 40.0 | 29.1 | 1 | Micro | ACE inhibitor; placebo | –2.3; 3.3 | 5/88; 0/46 | — | — |
| Lacourcière et al 2000 | 1.0 | 103 | 58.5 | 19.4 | 2 | Micro and macro | ACE inhibitor; ARB | –11.3; –11.9 | 0/51; 0/52 | — | — |
| Tarnow 2000 | 4.0 | 52 | 38.1 | 38.5 | 1 | Macro | ACE inhibitor; CCB | –8.0; –2.0 | 0/25; 3/27 | 2/25; 3/27 | — |
| Bojestig et al 2001 | 2.0 | 55 | 39.7 | 25.5 | 1 | Micro | ACE inhibitor; placebo | 2.0; 2.7 | 0/37; 0/18 | — | — |
| Deerochanawong et al 2001 | 1.0 | 60 | 56.1 | 70.0 | 2 | Micro | ACE inhibitor; CCB | –0.4; –2.7 | 0/30; 0/30 | — | — |
| ESPRIT 2001 | 3.0 | 54 | 38.0 | 37.0 | 1 | Micro and macro | ACE inhibitor; CCB; placebo | 3.7; 2.3; 3.3 | 0/18; 0/18; 0/18 | — | — |
| IDNT 2001 | 2.5 | 1715 | 58.9 | 33.5 | 2 | Macro | ARB; CCB; placebo | –13.3; –12.7; –9.3 | 87/579; 83/567; 93/569 | 82/579; 104/567; 101/569 | 98/579; 144/567; 135/569 |
| IRMA–2 2001 | 2.0 | 590 | 58.0 | 31.5 | 2 | Micro | ARB; placebo | –8.7; –7.7 | 3/389; 1/201 | 0/389; 0/201 | 0/389; 0/201 |
| Jerums 2001 | 2.0 | 42 | 30.8 | 59.5 | 1 | Micro | ACE inhibitor; CCB; placebo | –7.7; –3.7; 2.7 | 0/17; 1/13; 0/12 | — | — |
| Kopf et al 2001 | 1.0 | 46 | 52.1 | 32.6 | Mixed | Micro | ACE inhibitor; CCB | –13.5; –17.7 | 0/23; 0/23 | — | — |
| Kventy et al 2001 | 3.0 | 89 | 45.0 | 43.8 | 1 | Normo | ACE inhibitor; placebo | 4.0; 0 | 0/43; 0/46 | — | — |
| RENAAL 2001 | 3.4 | 1513 | 60.0 | 36.8 | 2 | Macro | ARB; placebo | –9.6; –9.2 | 158/751; 155/762 | 147/751; 194/762 | 162/751; 198/762 |
| Fogari et al 2002 | 4.0 | 309 | 62.5 | 43.4 | 2 | Micro | ACE inhibitor+CCB; ACE inhibitor; CCB | –21.0; –13.6; –15.2 | 2/104; 3/102; 4/103 | — | — |
| JAPAN-IDDM 2002 | 1.5 | 79 | 33.5 | 64.6 | 1 | Micro and macro | ACE inhibitor; placebo | 1.3; 3.3 | 0/52; 0/27 | 0/52; 0/27 | 2/52; 2/27 |
| BENEDICT 2004 | 3.0 | 1204 | 62.3 | 47.3 | 2 | Normo | ACE inhibitor+CCB; ACE inhibitor; CCB; placebo | –8.3; –7.6; –6.4; –6.1 | 2/300; 4/301; 2/303; 5/300 | — | — |
| DETAIL 2004 | 5.0 | 250 | 60.6 | 27.2 | 2 | Mixed | ACE inhibitor; ARB | –4.1; –6.5 | 6/130; 6/120 | 0/130; 0/120 | — |
| DIABHYCAR 2004 | 3.0 | 4912 | 65.1 | 30.1 | 2 | Micro and macro | ACE inhibitor; placebo | –2.4; –2.0 | 334/2443; 324/2469 | 11/2443; 12/2469 | 48/2443; 60/2469 |
| NESTOR 2004 | 1.0 | 569 | 59.2 | 35.5 | 2 | Micro | ACE inhibitor; diuretic | –15.0; –16.6 | 1/286; 2/283 | — | — |
| Ko et al 2005 | 1.0 | 42 | 61.0 | 59.5 | 2 | Mixed | ACE inhibitor; ARB | –3.3; –3.0 | 0/20; 0/22 | — | — |
| Rizzoni et al 2005 | 1.0 | 15 | 58.0 | 26.7 | 2 | Normo and micro | ACE inhibitor; ARB | –15.5; –7.9 | 0/7; 0/8 | — | — |
| Schram et al 2005 | 1.0 | 70 | 61.7 | 38.6 | 2 | Normo and micro | ACE inhibitor; ARB; diuretic | –14.3; –14.7; –14.0 | 0/22; 0/24; 0/24 | — | — |
| ABCD-2V 2006 | 1.9 | 129 | 56.1 | 32.6 | 2 | Normo and micro | ARB; placebo | –8.7; –3.3 | 1/66; 0/63 | — | — |
| Katayama et al 2006 | 1.0 | 87 | 66.5 | 48.3 | 2 | Normo and micro | ARB+CCB; ARB | –2.7; –1.3 | 0/46; 0/41 | — | — |
| Tong et al 2006 | 2.0 | 38 | 65.8 | 34.2 | 2 | Micro and macro | ACE inhibitor; placebo | –2.7; –4.0 | 0/18; 0/20 | 0/18; 0/20 | 4/18; 5/20 |
| ADVANCE 2007 | 4.3 | 11140 | — | — | 2 | Mixed | ACE inhibitor+diuretic; placebo | –8.3; –7.0 | 408/5569; 471/5571 | 25/5569; 21/5571 | 55/5569; 45/5571 |
| DIRECT-Prevent 1 2008 | 4.0 | 1421 | 29.7 | 43.3 | 1 | Normo | ARB; placebo | — | 7/711; 5/710 | — | — |
| DIRECT-Protect 1 2008 | 4.0 | 1905 | 33.5 | 42.7 | 1 | Normo | ARB; placebo | — | 7/951; 8/954 | — | — |
| DIRECT-Protect 2 2008 | 4.0 | 1905 | 56.8 | 50.2 | 2 | Normo | ARB; placebo | — | 37/951; 35/954 | — | — |
| GUARD 2008 | 1.0 | 332 | 57.7 | 34.6 | 2 | Mixed | ACE inhibitor+CCB; ACE inhibitor+diuretic | –15.5; –12.9 | 1/166; 2/166 | — | — |
| Perrin et al 2008 | 5.0 | 13 | 23.5 | 53.8 | 1 | Normo | ARB; placebo | –3.7; 8.7 | 0/7; 0/6 | — | — |
| Kohlmann et al 2009 | 1.0 | 110 | 62.7 | 43.6 | 2 | Micro | ACE inhibitor+CCB; ARB+diuretic | –17.1; –16.0 | 0/54; 0/56 | — | — |
| Mehdi et al 2009 | 1.0 | 80 | 51.1 | 52.5 | Mixed | Macro | ACE inhibitor; ACE inhibitor+diuretic; ACE inhibitor+ARB | –5.0; 1.7; –4.7 | 0/27; 0/27; 1/26 | — | — |
| MITEC 2009 | 3.0 | 209 | 59.7 | 36.4 | 2 | Mixed | ARB; CCB | –17.7; –19.0 | 0/100; 0/109 | — | — |
| RASS 2009 | 5.0 | 285 | 29.7 | 53.7 | 1 | Normo | ACE inhibitor; ARB; placebo | –5.7; –4.3; –2.0 | 1/94; 1/96; 1/95 | 0/94; 0/96; 0/95 | — |
| ROADMAP 2011 | 3.2 | 4447 | 57.7 | 53.9 | 2 | Normo | ARB; placebo | –8.2; –5.0 | 26/2232; 15/2215 | 0/2232; 0/2215 | 23/2232; 23/2215 |
ABCD=Appropriate Blood Pressure Control in Diabetes; ABCD-2V=The Appropriate Blood Pressure Control in Diabetes Part 2 with Valsartan; ADVANCE=Action in Diabetes and Vascular disease: preterAx and diamicroN-MR Controlled Evaluation; ATLANTIS=Ace-Inhibitor Trial to Lower Albuminuria in Normotensive Insulin-Dependent Subjects; BENEDICT=Bergamo Nephrologic Diabetes Complications Trial; DETAIL=Diabetics Exposed to Telmisartan and Enalapril; DIABHYCAR=Noninsulin-Dependent Diabetes, Hypertension, Microalbuminuria, Proteinuria, Cardiovascular Events, and Ramipril; DIRECT=DIabetic REtinopathy Candesartan Trials; ESPRIT=European Study for the Prevention of Renal Disease in Type 1 Diabetes; FACET=Fosinopril versus Amlodipine Cardiovascular Events Trial; GUARD=Gauging Albuminuria Reduction With Lotrel in Diabetic Patients With Hypertension; IDNT=Irbesartan Diabetic Nephropathy Trial; IRMA-2=Irbesartan Microalbuminuria II; JAPAN-IDDM=Japanese trial of ACE inhibitors on renal protection against nephropathy in IDDMs; MITEC=Media Intima Thickness Evaluation with Candesartan cilexetil; NESTOR=Natrilix SR versus Enalapril Study in hypertensive Type 2 diabetics with MicrOalbuminuRia; RASS=Renin-Angiotensin System Study; RENAAL=Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan; ROADMAP=Randomised Olmesartan and Diabetes Microalbuminuria Prevention.
ACE=angiotensin converting enzyme; ARB=angiotensin receptor blocker; CCB=calcium channel blocker; MAP=mean arterial pressure.
See panel for full trial names. See supplementary file for references of included trials in meta-analysis.
Outcomes are shown as ratio of event number to total patient number.
*Normoalbuminuria is defined as urine albumin excretion rate below 20 μg/min, microalbuminuria as urine albumin excretion rate between 20 μg/min and 200 μg/min, and macroalbuminuria as urine albumin excretion rate above 200 μg/min.