Effect of Renin Angiotensin-System Inhibitors on Reduction of Microalbuminuria in Normotensive Patients with Diabetes: A Systematic Review and Meta-Analysis

Introduction

Elevated urinary protein excretion may serve as an early clinical indicator of kidney injury in people with diabetes,^1,2, which necessitates therapeutic intervention.³ According to the Kidney Disease: Improving Global Outcomes (KDIGO)-2022 guidelines, albuminuria is categorized based on the urine albumin-to-creatinine ratio (UACR) as follows: A1 (normal to mildly increased, <30 mg/g), A2 (moderately increased, 30–299 mg/g; formerly microalbuminuria), and A3 (severely increased, ≥300 mg/g; formerly macroalbuminuria).⁴ While albuminuria thresholds aid in risk stratification, the risk of diabetic nephropathy (DN) increases progressively with any albumin excretion above 30 mg/g, particularly when levels rise over time.⁵ Remission of moderately increased albuminuria was linked to shorter duration of the condition, better glycemic control (HbA1c <7%), lower systolic blood pressure (<129 mmHg), and angiotensin converting enzyme inhibitors / angiotensin II receptor blockers (ACEi/ARBs) use. At the 8-year follow-up, remission or a ≥50% reduction in albumin excretion was associated with significantly lower risk of death and hospitalization from kidney and cardiovascular events (adjusted risk 0.41), as well as a slower decline in glomerular filtration rate (GFR).^6-8 A slower decline in GFR indicates kidney protection, which is associated with remission of moderately increased albuminuria, especially when achieved through antihypertensive treatment and good glycemic control.⁹ Only 18% of patients with T2DM and moderately increased albuminuria experienced regression to normal albumin levels, indicating a relatively low rate of improvement.¹⁰

So far, there is no evidence that renin–angiotensin–aldosterone system inhibitors or other interventions prevent the onset of diabetic kidney disease in individuals without hypertension or albuminuria. Accordingly, the ADA recommends against the routine use of these medications solely to prevent the development of diabetic kidney disease limiting their use as the preferred first-line therapy for managing BP in individuals with diabetes, hypertension, eGFR < 60 mL/min/1.73 m², and a UACR ≥300 mg/g.^11-14 Although ACEi/ARBs are commonly prescribed for individuals with moderately increased albuminuria (UACR of 30–299 mg/g) even in the absence of hypertension, outcome trials have not been conducted to assess whether these agents improve renal outcomes in this context. The ADA 2024 standards of care cite two long-term double-blinded trials on ACEi and ARBs that demonstrated no renoprotective effect of either drug class in individuals with T1DM or T2DM who were normotensive, with or without moderately increased albuminuria.^15-18 Therefore, we decided to pool the data from older trials that enrolled normotensive patients (blood pressure <140/90 mmHg) with moderately increased albuminuria who were treated with either an ACEi or an ARB, to evaluate whether sufficient evidence exists to support the use of these agents in normotensive individuals.

Methodology

The review followed PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) guidelines.¹⁹ The present study was registered with the International Prospective Register of Systematic Reviews, Centre for Reviews and Dissemination (PROSPERO) CRD42024571295.

We conducted comprehensive literature searches in PubMed, the Cochrane Library, Embase, and ClinicalTrials.gov, using the PICOS framework.. The text words for searching included ‘‘normotensive, proteinuria, albuminuria, moderately increased albuminuria, angiotensin receptor-blockers, ARB, angiotensin-converting enzyme inhibitor, ACEi,” and the names of currently available ARB or ACEi (losartan, valsartan, irbesartan, candesartan, telmisartan, eprosartan, olmesartan, imidapril, enalapril, lisinopril, captopril, cilazapril, ramipril, perindopril, and fosinopril).’’ Meanwhile, we also checked the reference lists of review articles, meta-analyses, and original studies to cover more eligible trials. The systematic search was updated through a peer-review process until 28^th February 2025. The search was limited to full-text publications in English.

Data extraction was conducted independently by three reviewers (RK.P, M.G, VR.N, and B.S) using a predefined data sheet. Discrepancies in extracted data were discussed and resolved by a fourth reviewer (R.K). The screening process included initial title and abstract review, followed by full-text assessment. Conflicts were addressed through discussion and repetition of screening steps. Each study underwent independent critical appraisal by two reviewers (B.S and M.G), with disagreements resolved by additional reviewers (R.K, S.M, and VR.N). Case reports, basic research, news articles, non-medical papers, letters, comments, conference abstracts, unpublished manuscripts (preprints), and duplicate publications were excluded.

This review included randomized controlled trials (RCTs) of ACEi/ARB in the reduction of moderately increased albuminuria in normotensive patients with diabetes with a comparator of placebo for ≥3 months. The PICOS for our review was as follows: (i) Population- Normotensive patients with diabetes (T1DM/T2DM) (BP: < 140/90 mm of Hg), with moderately increased albuminuria; (ii) Intervention- Use of angiotensin-receptor-blockers (ARB), angiotensin-converting enzyme inhibitor (ACEi), and the names of currently available ARB or ACEi (losartan, valsartan, irbesartan, candesartan, telmisartan, eprosartan, olmesartan, imidapril, enalapril, lisinopril, captopril, cilazapril, ramipril, perindopril, and fosinopril) for > 3 months; (iii) Comparator- Placebo; (iv) Outcomes- Reduction of urinary albumin excretion, urinary protein excretion and proteinuria and improvement of GFR (mL/min/m2); and (v) Study design- randomized controlled trials (RCTs).

RCTs that included ACEI or ARB use in normotensive patients with diabetes (T1DM or T2DM); 18-75-year-old patients with moderately increased albuminuria (UAE 30-299 mg/day) were included. Studies of diabetic hypertensives with renal impairment (eGFR < 30 mL/min/m²) and those not from RCTs, including case reports, case series, animal studies, or quantitative research, were excluded.

The Cochrane Risk of Bias Assessment Tool (RevMan 5.4) was applied to assess each of the 13 included RCTs. The first three researchers independently assessed the literature for quality and subsequently concorded to ensure consistent results. Selection bias, performance bias, detection bias, attrition bias, reporting bias, and other biases, such as design-specific risks of bias, baseline imbalance, blocked randomization in unblinded trials, were assessed with the Cochrane risk of bias tool. Any discrepancies were resolved by discussion with other authors. The overall risk of bias for each study was reported as low, unclear, and high risk.²⁰

Results

We filtered 1408 studies, of which 13 RCTs^22-34 involving 1374 participants were finally selected for the present analysis. Details of the study selection process are shown in Figure 1, and Table 1 provides a summary of the baseline characteristics of the included RCTs. In the RCTs, most of the follow-up time was ≥12 weeks. The mean age of the enrolled patients varied from 24 to 69.4 years.

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Figure 1:

PRISMA flow chart outlining literature search.

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Effect on moderately increased albuminuria

ACEIs or ARBs in patients with diabetes

As depicted in Figure 2, 13 RCTs reported the albumin levels, and the forest plot showed a significant reduction of albuminuria with ACE/ARBs (-59.64% [-71.96, -47.32]; I2=91%, p <0.00001) compared to placebo in normotensive diabetics.

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Figure 2:

Effect of ACEIs or ARBs in the reduction of moderately increased albuminuria (A2) in diabetics.

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ACEIs or ARBs in patients with type-1 diabetes

In T1DM [Figure 3], seven RCTs examined the albumin levels, and the forest plot showed a significant reduction of albuminuria with ACE/ARBs (-64.78% [-81.56, -47.99]; I2=73%, p<0.001) compared to placebo.

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Figure 3:

Effect of ACEIs or ARBs in the reduction of moderately increased albuminuria (A2) in T1DM patients.

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ACEIs or ARBs in patients with type-2 diabetes

In T2DM [Figure 4], 9 RCTs examined the albumin levels, and the forest plot showed a significant reduction of albuminuria with ACE/ARBs (-60.09% [-80.93, -39.25]; I2=92%, p <0.0001) compared to placebo. Stratified analyses by diabetes type demonstrated a significant reduction in moderately increased albuminuria with ACEi/ARB treatment in both T1DM (MD –64.78, 95% CI –81.56 to –47.99) and T2DM (MD –60.09, 95% CI –80.93 to –39.25). However, the test for subgroup differences was not significant (χ² = 0.12, p = 0.73) [Figure 5].

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Figure 4:

Effect of ACEIs or ARBs in the reduction of moderately increased albuminuria (A2) in T2DM patients.

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Figure 5:

Subgroup analysis of the reduction of moderately increased albuminuria (A2) among patients with T2DM and T1DM.

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Duration of use of ACEIs or ARBs (< 1year, 1-3 years and > 3 years)

Supplementary Figure 1 shows the reduction of albuminuria based on duration of usage (< 1, 1-3, and > 3 years) of ACEIs/ARBs. The duration of use was significantly associated with a reduction in moderately increased albuminuria (p < 0.05), amounting to -35.3 mg/g, -58.74 mg/g, and -117.61 mg/g, respectively. Furthermore, the subgroup difference was also statistically significant between the three groups (p<0.005). The meta-regression with mean duration was also assessed, and it was established that the efficacy of ACE/ARB therapy in reducing microalbuminuria is positively correlated with treatment duration, with the most pronounced and significantly superior benefit observed in studies evaluating treatment periods >3 years (Supplementary Table 1).

Supplementary Figure 1

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Supplementary Table 1

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Risk of developing macroalbuminuria (A3)

Out of 13 RCTs, 4 of ACE inhibitors reported that the patients progressed from micro to severely increased albuminuria. The percentage of patients progressing from micro- to severely increased albuminuria was 6.9% in ACE users and 22.5% in the placebo group, respectively. The significant risk reduction was noticed in the ACE group (p<0.0001) (Supplementary Figure 2).

Supplementary Figure 2

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Discussion

This systematic review and meta-analysis provide evidence that ACEi and ARB reduce albuminuria in normotensive patients with diabetes compared to placebo. The pooled analysis of 13 RCTs, which includes both T1DM & T2DM, demonstrated a notable reduction in urinary albumin excretion (WMD: −59.64 mg/g; 95% CI: −71.96 to −47.32 mg/g; p < 0.00001), with consistent benefit across diabetes types. Though the subgroup analyses of our results showed slightly greater reduction in albuminuria among patients with T1DM (−64.78 mg/g) compared to T2DM (−60.09 mg/g), suggesting the potential for broad clinical applicability across diabetes subtypes. The significant heterogeneity observed (I² > 70%) may reflect differences in treatment duration, baseline renal function, or albuminuria quantification methods across studies. A key strength of this review is the demonstration of a time-dependent effect of ACE/ARB. Patients treated for more than three years experienced a marked reduction in albuminuria (−117.61 mg/g) compared to those treated for shorter durations, indicating that long-term RAS inhibition may confer increasing renal protection over time. This observation is consistent with previous long-term cohort findings, where regression of albuminuria was associated with improved renal outcomes and reduced cardiovascular events.^34-36

Moreover, a significant protective effect against progression to severely increased albuminuria (A3) was noted. Only 6.9% of patients in the ACEi group progressed from moderately (A2)- to severely increased albuminuria (A3), compared to 22.5 mg/g in the placebo group (p < 0.0001), reinforcing the importance of early pharmacologic intervention even in normotensive patients. This aligns with prior studies suggesting that albuminuria is an early modifiable marker of diabetic kidney disease and a predictor of renal and cardiovascular morbidity.³⁷ Albuminuria reduction is clinically significant, as it correlates with improved renal and cardiovascular outcomes, reducing the risk of kidney failure and mortality. A large meta-analysis by Coresh et al. (2019) found that every 30% reduction in albuminuria corresponded to a 23% lower risk of kidney failure and 12% lower cardiovascular risk. Thus, the albuminuria reduction seen with ACEi/ARB therapy is clinically relevant, indicating durable renoprotective and cardiovascular benefits.⁵ Thus, the findings in this meta-analysis are consistent with the KDIGO 2022 recommendations than the ADA, with the latter favoring ACEi/ARB use in this study population.⁴ However, it is important to note that our analysis targeted a distinct patient subgroup: normotensive diabetics with established moderately increased albuminuria. The beneficial effects observed in our analysis suggest that the presence of albuminuria, rather than elevated blood pressure alone, should guide therapeutic use of RAS inhibitors. In our study, treatment with ACEIs/ARBs significantly improves or preserves (4.34 mL/min/1.73 m²) GFR in patients with diabetes (p = 0.03). The range of GFR in our study is wide, with the included studies showing the hyperfiltration phase of diabetic nephropathy. ACEi/ARBs are generally associated with a reduction in GFR initially. However, with continued usage, these agents are renoprotective and preserve or improve GFR.^38,39 This may explain the marginal improvement in GFR and may be a subtle pointer towards the use of these drugs for renoprotection in this subset of patients with diabetes with moderately increased albuminuria. Despite these important insights, several limitations must be acknowledged. High heterogeneity across studies, potentially due to variable baseline characteristics, duration of therapy, and differing diagnostic thresholds for albuminuria, may affect the generalizability of our findings. Additionally, most included RCTs were not powered for hard renal endpoints such as ESKD or mortality, and long-term data remain limited. Furthermore, although publication bias was not evident on funnel plot analysis, the exclusion of non-English and unpublished trials could contribute to selective reporting.

To conclude, in normotensive patients with diabetes and moderately increased albuminuria, ACEi/ARBs significantly reduce albuminuria, an effect that is suggestive of renoprotection and delay in progression. However, more confirmatory trials with hard endpoints are needed.