ACE Inhibitors vs ARBs in Hypertensive Diabetics: A systematic review of cardiovascular mortality and renal outcomes

 Corresponding author: Edwin Agbeze Copyright © 2025 Author(s) retain the copyright of this article. This article is published under the terms of the Creative Commons Attribution Liscense 4.0. ACE Inhibitors vs ARBs in Hypertensive Diabetics: A systematic review of cardiovascular mortality and renal outcomes Edwin C. Agbeze 1, *, Mariam Eniola Olatinwo 2, Martha Emmanuel Ebiale 3, Jimmy Blessing Uduak 1, Toheeb Kazeem 4, Edeh Joel Kosisochukwu 5 and Innocent Chibuike Okafor 6 1 Department of Pharmacy, University of Uyo, Akwa Ibom Nigeria. 2 Department of Pharmacy, Hacettepe University Ankara, Turkey. 3 Department of Medical Biochemistry, Cross River State University of Technology, Nigeria. 4 Department of Food Science and Technology, Federal University of Technology, Akure. 5 Department of Medical Laboratory Sciences, University of Nigeria, Nigeria. 6 Department of Histopathology, University of Uyo Teaching Hospital, Nigeria. World Journal of Advanced Research and Reviews, 2025, 27(03), 192-205 Publication history: Received on 27 July 2025; revised on 01 September 2025; accepted on 03 September 2025 Article DOI: https://doi.org/10.30574/wjarr.2025.27.3.3125 Abstract Hypertension in individuals with diabetes markedly increases the risk of cardiovascular events and renal complications, making optimal management essential. Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are widely prescribed as modulators of the renin–angiotensin–aldosterone system (RAAS). This systematic review examined their relative effectiveness in reducing cardiovascular mortality and preserving kidney function among hypertensive diabetic patients. Literature was searched across PubMed, Cochrane Library, and Scopus for randomized controlled trials and meta-analyses published within the last twenty years. Both ACEIs and ARBs were found to lower blood pressure effectively and delay the progression of diabetic nephropathy. ACEIs showed a modest advantage in lowering cardiovascular and all-cause mortality, while ARBs demonstrated comparable renal protective effects with better tolerability in patients intolerant to ACEIs. Evidence also suggests ARBs may provide greater benefit in advanced stages of chronic kidney disease, whereas ACEIs appear more advantageous in primary cardiovascular prevention. These findings emphasize the need for individualized treatment approaches, with ACEIs recommended as first-line therapy when tolerated, and ARBs as suitable alternatives. Further large-scale comparative trials are warranted to refine clinical decision-making and maximize therapeutic outcomes in this high-risk population. Keywords: Angiotensin converting Enzyme (ACE) inhibitors; Angiotensin receptor blocker; Hypertensives; Diabetics; Cardiovascular mortality; Renal Outcomes 1. Introduction Hypertension is a leading global health burden and a significant risk factor for cardiovascular morbidity and mortality [1]. The use of renin–angiotensin–aldosterone system (RAAS) inhibitors, particularly angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), has transformed the management of hypertension, diabetes, and renal complications [2,3]. Although ACEIs and ARBs act through distinct pharmacological mechanisms, both drug classes provide cardiovascular and renal protection [4,5]. However, their comparative effectiveness in hypertensive diabetic patients remains an area of clinical and research interest, especially with respect to cardiovascular mortality and renal outcomes [6,7]. World Journal of Advanced Research and Reviews, 2025, 27(03), 192-205 193 Several landmark clinical trials, meta-analyses, and real-world studies have evaluated the relative efficacy and safety of ACEIs versus ARBs [8–10]. Some evidence suggests that ACEIs may offer superior cardiovascular protection, while ARBs are generally better tolerated due to fewer adverse effects, such as cough and angioedema [11–13]. This systematic review aims to synthesize current evidence comparing ACEIs and ARBs in hypertensive diabetic populations, with a focus on cardiovascular mortality and renal outcomes. Objective To systematically review and compare the impact of ACE inhibitors versus ARBs on Cardiovascular mortality and renal outcomes in hypertensive diabetic patients. 2. Methods Figure 1 Prisma flow chart The methodological framework employed in conducting this systematic review is guided by PRISMA 2020, a systematic search of PubMed, Scopus, Web of Science, and Google Scholar was conducted to identify randomized controlled trials (RCTs), meta-analyses, and observational studies comparing ACEIs and ARBs in hypertensive diabetic patients. Studies World Journal of Advanced Research and Reviews, 2025, 27(03), 192-205 194 published between 2000 and 2025 were included. Outcomes accessed were cardiovascular mortality, major adverse cardiovascular events (MACE), and renal end point such as electrolyte glomerular filtration rate (eGFR) decline, albuminuria, and progression to end stage renal disease (ESRD). Table 1 PICO Framework Population (P) Adults with both hypertension and diabetes mellitus Intervention (I) ACE inhibitors Comparison (C): ARBs Outcomes (O) Cardiovascular mortality, major adverse cardiovascular events (MACE), renal outcomes (e.g., eGFR decline, proteinuria, ESRD) The methodology also includes the development of a research question using the PICO framework, eligibility criteria for study selection, the search strategy applied through Google Scholar, procedures for screening and selection, data extraction methods, and the tools used for assessing the quality and risk of bias in the included studies. 2.1. Eligibility Criteria The following inclusion and exclusion criteria were used to determine study eligibility: Table 2 Inclusion and exclusion criteria Inclusion Criteria Exclusion Criteria Studies involving adults diagnosed with both hypertension and diabetes Studies not involving adults diagnosed with both hypertension and diabetes Comparative studies evaluating ACE inhibitors vs ARBs Studies not involving a direct comparison of ACE inhibitors and ARBs Studies reporting cardiovascular mortality and/or renal outcomes (e.g., eGFR, ESRD, albuminuria) Studies not reporting cardiovascular mortality and/or renal outcomes (e.g., eGFR, ESRD, albuminuria) Peer-reviewed articles published Unreviewed articles published Articles written in English Articles written in other languages World Journal of Advanced Research and Reviews, 2025, 27(03), 192-205 195 3. Results Table 3 Summary of included articles S N STUDY YEA R AUTHO R COUNTRY/RE GION DESIGN/ SAMPLE SIZE POPULATI ON INTERVENTION/COMP ARATOR CARDIOVASC ULAR OUTCOME RENAL OUTCOME KEY FINDINGS 1 Renin inhibitors vs ARBs for Primary Hypertensi on 202 5 Wang GM, Li LJ, Fan L, Xu M, Tang WL, Wright JM China and Canada Systemati c review of 11 RCTs; N=6780 Adults with mild primary hypertensi on (age 52– 59, no CV disease) Aliskiren vs ARBs (losartan, valsartan, irbesartan, telmisartan); duration 4 weeks–9 months No significant difference in mortality, no MI/stroke data No ESRD data Little/no difference in outcomes; short duration studies; need for larger, longer-term RCTs 2 Use of ACEi/ARBs , SGLT2 inhibitors and MRAs Can Help Us Reach the Therapeuti c Ceiling in CKD 202 4 Pantelis Sarafidis Greece Narrative review; reference s major trials CKD patients, T2D, albuminuri a, hypertensi on ACEI, ARBs, SGLT2i (empagliflozin, dapagliflozin), MRA (finerenone) vs placebo/standard care SGLT2i ↓ CV and all-cause death; ACEI/ARB show no CV benefit in CKD ACEI/ARB ↓ eGFR decline; SGLT2i ↓ to <0.5 mL/min/1.73m² /year; Finerenone beneficial in T2D + CKD ACEi/ARB foundationa l; SGLT2i/MR A additive benefit; avoid dual RAS blockade due to safety 3 Diabetic Nephropat hy-Based Hypertensi on Treatment 202 3 F. Josse Pasca Pradana, Syahrul Tuba Indonesia Mini review; reference s various trials T2D with diabetic nephropat hy and CKD ACEI, ARB, low vs high dose; dual ACEi+ARB ACEI ↓ CV risk (BPindependent); ARBs less benefit Combo ↓ proteinuria more; no ESRD benefit; risks: hyperkalemia, AKI ACEi preferred for CV/renal outcomes; combo more potent but riskier; not recommend ed routinely World Journal of Advanced Research and Reviews, 2025, 27(03), 192-205 196 4 Chronic Kidney Disease and the Future of Multimoda l Therapy 202 5 Michael Leonard and Sarah Gome United States Narrative review (not a clinical trial) Reference s multiple largescale clinical trials and metaanalyses No original sample size reported Population s referenced across cited studies typically include: Adults with chronic kidney disease (CKD), especially those with type 2 diabetes (T2D) or hypertensi on Common characteris tics: middleaged to elderly, varied sex, often comorbid with cardiovasc ular disease and metabolic disorders The article reviews several therapeutic approaches, including: SGLT2 inhibitors (e.g., empagliflozin, dapagliflozin) Finerenone (nonsteroidal mineralocorticoid receptor antagonist) ACE inhibitors (e.g., enalapril, ramipril) ARBs (e.g., losartan, irbesartan) GLP-1 receptor agonists as emerging adjuncts Combination therapies are emphasized; no fixed dose or duration provided, as the review summarizes various trial protocols. SGLT2 inhibitors reduce risk of major adverse cardiovascular events (MACE), cardiovascular death, and hospitalization for heart failure Finerenone shown to reduce heart failure hospitalization s and improve CV mortality in patients with CKD and T2D No new independent trials are conducted in this article; it cites outcomes from trials like EMPA-REG, CREDENCE, and FIDELIODKD SGLT2 inhibitors slow decline in eGFR, reduce albuminuria, and delay progression to ESRD Finerenone further reduces progression of CKD when added to standard care in patients with T2D Combination therapies appear to yield additive renal benefits The future of CKD therapy lies in multimodal treatment, combining RAS blockers (ACEi/ARBs ), SGLT2 inhibitors, and MRAs like finerenone Monotherap y is no longer sufficient to address the complex pathophysio logy of CKD with T2D or hypertensio n Emphasis on individualiz ed, riskbased treatment plans to maximize cardio-renal protection World Journal of Advanced Research and Reviews, 2025, 27(03), 192-205 197 Future research should focus on sequencing and optimizing combination s for diverse patient profiles 5 Comparati ve Renal Effects of Angiotensi n Receptor Neprilysin Inhibitors and SGLT2 Inhibitors: A Network Metaanalysis 202 3 S. A. Luk, et al. Multinational (metaanalysis) Network metaanalysis; multiple RCTs pooled Adults with CKD, T2DM, or HF; varied demograph ics ARNIs, SGLT2i vs RAAS blockers (ACEI/ARBs); dose and duration varied No significant difference in MACE; slight edge with SGLT2i in HF patients Both drug classes significantly reduced albuminuria and delayed eGFR decline; SGLT2i superior in slowing progression to ESRD SGLT2 inhibitors show stronger renal protection, ARNIs competitive but evidence more limited 6 The Combinati on of Beta‑Block ers and ACE Inhibitors Across the Spectrum of Heart Failure 202 3 Anker et al. Global (analysis from major HF trials) Post hoc pooled analysis; >10,000 patients HF patients including diabetics, varied age and comorbidit ies ACE inhibitors + betablockers vs monotherapy Combination therapy reduced CV death, hospitalisation for HF, and allcause mortality Not primary endpoint; slight increase in renal adverse events but outweighed by CV benefits ACEi + betablockers have synergistic benefit in HF; tolerability must be monitored 7 The pivotal role of ACE inhibitors and ARBs in 202 2 Elliott W.J., et al. USA/ International Review of RCTs and guidelines Hypertensi ve patients, including T2DM and CKD ACEI vs ARB vs placebo; dose varied ACE inhibitors reduce MI, stroke, CV death; ARBs Both reduce albuminuria, delay ESRD; ACEI possibly stronger in ACEi preferred first-line in most unless intolerant; World Journal of Advanced Research and Reviews, 2025, 27(03), 192-205 198 hypertensi on and cardiovasc ular and renal protection population s similar but fewer data microalbuminuri a ARBs effective alternative 8 Chronic Kidney Disease and Risk Manageme nt: Standards of Care in Diabetes 202 3 Nuha A. ElSayed et al. (ADA) United States Clinical guideline based on multiple RCTs and populatio n studies Adults with T1DM or T2DM and CKD (or at risk) ACEI or ARBs vs placebo or standard care; SGLT2i and MRAs included RAAS inhibitors and SGLT2i reduce CV mortality and HF hospitalization ; GLP-1 RAs reduce ASCVD risk ACEI/ARBs reduce albuminuria and ESRD risk; enhanced effect with SGLT2i and MRAs RAAS blockade remains foundationa l; SGLT2i and MRAs provide additive benefit; combination ACEi+ARB discouraged 9 The Associatio n Between Dual RAAS Inhibition and Risk for Adverse Kidney Outcomes in People with Diabetes 202 2 Yamada, Y. et al. Japan Retrospec tive cohort analysis; over 5,000 patients Adults with diabetes; various comorbidit ies including hypertensi on and CKD stages 1–4 Dual RAAS inhibition (ACEI + ARB) vs. monotherapy Not the primary focus; limited mention eGFR decline, incidence of ESRD, doubling of serum creatinine Dual RAAS blockade was associated with a higher risk of renal adverse outcomes (e.g., acute kidney injury, eGFR decline), especially in those with baseline CKD. Supports current guidelines that World Journal of Advanced Research and Reviews, 2025, 27(03), 192-205 199 discourage dual therapy due to safety risks. 1 0 Beyond Blood Glucose and Blood Pressure Control in Type 2 Diabetes: Alternative Manageme nt Strategies to Prevent CKD 202 3 Wright, W.L., Urquhar t, S., and Brunton, S. United States Narrative Review Patients with Type 2 diabetes, especially those with or at risk of CKD Focuses on use of ACEI/ARBs, SGLT2 inhibitors, and nonsteroidal MRAs (like finerenone) Reduction in CV mortality, heart failure hospitalization in trials involving SGLT2 inhibitors and finerenone Slowed progression of CKD, reduced albuminuria, decreased eGFR decline Emphasizes integrated managemen t using newer agents alongside RAAS inhibitors. ACE inhibitors and ARBs remain foundationa l but should be combined with SGLT2 inhibitors or finerenone for optimal cardiorenal outcomes. 1 1 Change in Albuminur ia as a Surrogate Endpoint for Cardiovasc ular and Renal Outcomes: A Metaanalysis of 202 3 Palmer, S.C. et al. Multinational (authors from Australia, UK, Canada) Metaanalysis of 41 randomiz ed trials (n > 30,000) Adults with CKD, T2DM, or hypertensi on; many with albuminuri a Various agents including ACE inhibitors, ARBs, SGLT2 inhibitors, MRAs vs placebo or standard care Albuminuria reduction linked with reduced risk of CV events Strong correlation between reduced albuminuria and slower CKD progression Change in albuminuria is a valid surrogate marker for both renal and cardiovascul ar outcomes, supporting its use in early-phase World Journal of Advanced Research and Reviews, 2025, 27(03), 192-205 200 41 Randomise d Trials clinical trials and decisionmaking in high-risk populations. 1 2 Novel Diabetic Nephropat hy-Based Hypertensi on Treatment for Type-2 Diabetes Mellitus 202 3 Imamur a, T. et al. Japan Narrative review and treatment framewor k proposal T2DM patients with hypertensi ve nephropat hy; various CKD stages ACE inhibitors, ARBs, SGLT2 inhibitors, calcium channel blockers, mineralocorticoid receptor antagonists (e.g., esaxerenone) Improved BP control and reduced CV complications through multidrug strategies Slowed progression of nephropathy with early RAAS inhibition and newer agents Advocates a stage-based and individualiz ed hypertensio n strategy using RAAS inhibitors early, and then incorporatin g SGLT2i and MRAs for optimal renal and cardiovascul ar protection in T2DM. 1 3 RiskDirected Manageme nt of Diabetic Kidney Disease 202 2 Packha m, D.K. and de Boer, I.H. Australia and United States Narrative review and perspectiv e article Patients with diabetic kidney disease (DKD); focus on stratified risk Focus on ACEI, ARBs, SGLT2 inhibitors, MRAs; recommends personalized, risk-based approaches SGLT2 inhibitors and MRAs (like finerenone) reduce CV events; ACEi/ARBs foundational Combined approach slows eGFR decline and reduces progression to ESRD DKD managemen t should be personalize d based on albuminuria and eGFR; RAAS inhibitors remain standard, but newer agents