Table.

 Studies of Prevention of Microalbuminuria in Patients With Type 2 Diabetes and Hypertension

Study	Population	Design	Endpoint(s)	Mean Baseline BP (mm Hg)	Between‐Group Difference in Mean BP Change (mm Hg)	Outcome(s)	Investigators’ Interpretation	Comments
ADVANCE 28	11,140 patients with type 2 diabetes plus a history of CVD or ≥1 other cardiovascular risk factor. 26% had microalbuminuria at baseline.	RCT of fixed combination of perindopril/indapamide or matching placebo in addition to current therapy. Follow‐up: mean of 4.3 y.	Primary: composites of major macrovascular and microvascular events (death from CVD, nonfatal stroke or nonfatal MI, and new or worsening renal or diabetic eye disease). New or worsening nephropathy and development of microalbuminuria were secondary outcomes.	145/81	Mean reduction of 5.6/2.2 vs placebo.	Relative risk of major macrovascular or microvascular event reduced by 9% vs placebo (P=.04). Significant 21% reduction in all renal events (95% CI, 15%–27%; P<.0001), driven by reduced risks for developing microalbuminuria and macroalbuminuria (both P<.003).	BP‐lowering treatment with perindopril‐indapamide administered routinely to individuals with type 2 diabetes provides important renoprotection, even among those with initial BP <120/70 mm Hg. Unable to identify a BP threshold below which renal benefit is lost.	Selection bias: patients intolerant of perindopril/indapamide withdrawn before randomization. Difference in outcome may be attributable to indapamide rather than the combination. Unknown whether ”normotensive” patients and those developing microalbuminuria were already on RAS blockers, although likely (recommended by current management guidelines). Between‐group differences in glycemic control may have influenced results.
HOPE and MICROHOPE substudy 38	3654 high‐risk patients, aged ≥55 y with type 2 diabetes but no clinical proteinuria. However >30% of patients in each treatment arm had baseline microalbuminuria.	Double‐blind RCT of ramipril vs placebo. ITT analysis.	Primary: composite of MI, stroke, or death from cardiovascular causes. Overt nephropathy was the main outcome in the substudy.	139/79	−1.92/−3.3 in the ramipril group vs +0.55/−2.3 in the placebo group.	Study stopped 6 months early because of consistent benefit of ramipril vs placebo. Ramipril lowered risk of the primary outcome by 25% (95% CI, 12–36, P=.0004) (even after adjustment for BP changes), MI by 22% (95% CI, 6–36), stroke by 33% (95% CI, 10–50), cardiovascular death by 37% (95% CI, 21–51), total mortality by 24% (95% CI, 8–37), revascularization by 17% (95% CI, 2–30), and overt nephropathy by 24% (95% CI, 3–40, P=.027). In patients without baseline microalbuminuria, the risk of new‐onset microalbuminuria was reduced, but not significantly, by 9% [–4 to 20], P=.17.	Ramipril significantly lowered the risk of major cardiovascular outcomes and overt nephropathy in a broad range of high‐risk patients with diabetes.	No target BP. No significant reduction of new‐onset microalbuminuria. Ambulatory BP lower in the ramipril group than placebo group.
BENEDICT 37	1204 patients with type 2 diabetes and normal urinary albumin excretion.	≥3 y randomized treatment with trandolapril plus verapamil SR, trandolapril alone or verapamil alone. Target HbA1c: <7.0%. Target BP: ≤120/80 mm Hg or ≤130/80 mm Hg in separate publications.	Primary: development of persistent microalbuminuria.	∼151/87	12/7, 12/6, 10/5, and 9/4, respectively in trandolapril + verapamil, trandolapril, verapamil, and placebo groups.	Reached in 5.7% of patients receiving trandolapril plus verapamil, 6% receiving trandolapril, 11.9% receiving verapamil, and 10% receiving placebo.	Optimal BP was achieved in these normoalbuminuric patients with type 2 diabetes. Onset of microalbuminuria was significantly delayed with verapamil SR plus trandolapril compared with placebo (P=.01), and with trandolapril alone vs placebo. The delay in onset of microalbuminuria with verapamil SR plus trandolapril and trandolapril alone exceeded expectations based on changes in BP alone.	Atypical diabetic population: mean HbA1c 5.8%. Mean on‐study BP was 140/80+ mm Hg. Half the patients received SNS blockers, which are known to reduce albuminuria. Thus BENEDICT did NOT show that controlling BP to a low level can prevent microalbuminuria in typical diabetic patients.
DIRECT 39	1905 patients, aged 37–75 y, with type 2 diabetes who were normoalbuminuric and either normotensive or receiving antihypertensive therapy.	3 related RCTs to examine effect of candesartan vs placebo on retinopathy in type 1 and type 2 diabetes. Median follow‐up of 4.7 y. Patients who developed microalbuminuria were prescribed open‐label ACE inhibitor therapy.	Primary: incidence of new microalbuminuria in the pooled study population. Secondary: rate of change of albuminuria in the pooled study population.	123/74.5 (139/79.5 for those on antihypertensive therapy)	−4.3/−2.5 and −2.9/−1.3 vs placebo in patients receiving or not receiving antihypertensive therapy at baseline, respectively (P<.005).	Primary and secondary outcomes did not differ importantly between candesartan and placebo groups. The adjusted rate of change of UAER was lower with candesartan: (by 10% and 6.8%, respectively, in the normotensive patients and those receiving antihypertensive therapy at baseline.	Candesartan had no effect on incidence of microalbuminuria over 4.7 y in a study sample of normoalbuminuric and normotensive patients with type 1 diabetes and normoalbuminuric patients with type 2 diabetes with or without treated hypertension. The adjusted rate of change in UAER, although lower with candesartan, was modest, and its clinical significance is uncertain.	Patients at low risk for microalbuminuria. Studies powered for retinopathy not renal endpoints. Nonsignificant difference between groups might have become significant had study continued for a further 2 y. No information about effect on BP or renal and cardiovascular events in subgroup of patients on dual RAS blockade with candesartan and open‐label ACE inhibitor therapy.
ROADMAP (ongoing) 40 , 41	4449 patients with type 2 diabetes and confirmed normoalbuminuria and ≥1 additional cardiovascular risk factor.	Double‐blind, randomized RCT of olmesartan vs placebo in addition to standard antihypertensive therapy (excluding RAS inhibitors) to achieve a BP target ≤130/80 mm Hg. Expected duration: median of 5 y.	Primary: occurrence of microalbuminuria. Secondary: include cumulative incidence of cardiovascular and renal disease mortality and morbidity.	141/84	Not available; study continues. At 1 year, 61% of total study population had achieved BP goal.	Not available; study continues.	Not applicable.	Avoids many of the shortcomings of previous studies, eg: almost all patients are RAS blocker‐naive; defined target BP; excellent BP control: target achieved by majority of patients at 1 year; ABPM substudy to assess effects on 24‐hour blood pressure profile.
TRANSCEND 42	5926 subjects with CVD or diabetes with end organ damage intolerant to ACE inhibitors. At baseline 36% and 76%, respectively, had diabetes or hypertension, and 10% had microalbuminuria.	RCT vs placebo. Median follow‐up of 56 months.	Primary renal outcome was first occurrence of dialysis, renal transplantation, doubling of serum creatinine, or death. Secondary outcome was composite of dialysis of doubling of serum creatinine. Other renal outcomes included changes in eGFR and UAER, progression of proteinuria, development of new microalbuminuria.	141/82	−4.0/−2.2 for telmisartan vs placebo.	No important difference in the composite renal outcome with telmisartan (58 patients [1.96%]) vs placebo (46 patients [1.55%]) (hazard ratio, 1.29 [95% CI, 0.87 –1.89]; P=0.20). Among the telmisartan and placebo groups, 7 and 10 patients had dialysis and 56 and 36 patients had doubling of serum creatinine, respectively (hazard ratio, 1.59 [CI, 1.04–2.41]; P=.031). Albuminuria increased less with telmisartan than with placebo (32% [CI, 23%–41%] vs 63% [CI, 52%–76%]; P<.001). Declines in eGFR were greater with telmisartan than placebo (mean change in eGFR, −3.2 mL/min per 1.73 m2 (SD, 18.3) vs –0.26 mL/min per 1.73 m2 (SD, 18.0); P<.001).	ARBs offer no renal benefit in ACE‐intolerant subjects at high vascular risk but without macroalbuminuria. Although telmisartan reduced proteinuria, the implications of this reduction as a surrogate marker for progression of renal disease are uncertain in patients with relatively stable eGFR.	At baseline, all patients had CVD and a minority (10%) had microalbuminuria, despite previous treatment with RAS blocker. Results therefore difficult to interpret.
RASS 43	285 normotensive individuals with type 1 diabetes and normoalbuminuria.	RCT of losartan, enalapril, or placebo. 5‐year follow‐up.	Primary: change in fraction of glomerular volume occupied by mesangium in kidney‐biopsy specimens. Retinopathy: progression on retinopathy severity scale of ≥2 steps.	120/71	−4.0/0.0 for losartan vs placebo; −2.0/−2.0 for enalapril vs placebo.	No significant difference in changes in mesangial fractional volume per glomerulus between enalapril, losartan, and placebo groups. 5‐year cumulative incidence of microalbuminuria was 6% in placebo group, 4% with enalapril (P=.96, log‐rank test), and 17% with losartan (P=.01, log‐rank test). Odds of retinopathy progression reduced by 65% with enalapril vs placebo and by 70% with losartan vs placebo, independently of BP changes.	Early blockade of the RAS in patients with type 1 diabetes slowed progression of retinopathy but NOT of nephropathy. Blockade of RAS for primary prevention of diabetic nephropathy in type 1 diabetes is not supported by the present evidence.	Carefully conducted study in patients with BP truly in the normal range.

Abbreviations: ABPM, ambulatory blood pressure monitoring; ACE, angiotensin‐converting enzyme; ADVANCE, Action in Diabetes and Vascular Disease: Preterax and Diamicron‐MR Controlled Evaluation; ARB, angiotensin receptor blocker; BP, blood pressure; BENEDICT, Bergamo Nephrologic Diabetes Complications Trial; CI, confidence interval; CVD, cardiovascular disease; DIRECT, Diabetic Retinopathy Candesartan Trials; eGFR, estimated glomerular filtration rate; HbA1c, glycated hemoglobin; HOPE, Heart Outcomes Prevention Evaluation study; ITT, intention‐to‐treat; MI, myocardial infarction; MICRO‐HOPE, Microalbuminuria, Cardiovascular, and Renal Outcomes in the HOPE substudy; RAS, renin‐angiotensin system; RASS, Renin Angiotensin System Study; RCT, randomized controlled trial; ROADMAP, Randomized Olmesartan and Diabetes Microalbuminuria Prevention study; SD, standard deviation; TRANSCEND, Telmisartan Randomised Assessment Study in ACE Intolerant Subjects With Cardiovascular Disease; UAER, urinary albumin excretion rate.