Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • JSH2025 Systematic Review Series: Clinical Questions in the Management of Hypertension
  • Published:

Efficacy of renin-angiotensin system inhibitors, calcium channel blockers, and diuretics in hypertensive patients with diabetes: subgroup analysis based on albuminuria in a systematic review and meta-analysis

Hypertension Research volume 48, pages 1880–1890 (2025)Cite this article

Abstract

In hypertensive patients with diabetes, the effectiveness of renin-angiotensin system (RAS) inhibitors in improving mortality, cardiovascular events, and renal outcomes, compared to other antihypertensive drugs such as calcium channel blockers (CCBs) and diuretics, remains uncertain, particularly in the context of albuminuria. A comprehensive literature search was conducted using PubMed, the Cochrane Library, and the Japan Medical Abstracts Society databases up to October 2024. A meta-analysis of 12 randomized controlled trials, including 14,163 patients, was performed. RAS inhibitors showed no significant advantage over CCBs or diuretics for all-cause mortality (relative risk [RR]: 1.00, 95% confidence interval [CI]: 0.92–1.08, p = 0.98), myocardial infarction (RR: 0.64, 95% CI: 0.32–1.31, p = 0.22), stroke (RR: 1.14, 95% CI: 1.00–1.31, p = 0.05), composite cardiovascular events (RR: 0.93, 95% CI: 0.81–1.07, p = 0.45), or end-stage renal disease (RR: 0.88, 95% CI: 0.72–1.08, p = 0.21). Subgroup analyses stratified by albuminuria status revealed no significant benefits of RAS inhibitors, regardless of albuminuria presence. The findings emphasize the need for cautious interpretation due to limited sample sizes, wide confidence intervals, and low precision. These results highlight the importance of considering not only RAS inhibitors but also other antihypertensive drugs as the first-line choice for blood pressure control in diabetic patients, with careful attention to side effects and other relevant factors.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1

Similar content being viewed by others

References

  1. Marx N, Federici M, Schütt K, Müller-Wieland D, Ajjan RA, Antunes MJ, et al. 2023 ESC Guidelines for the management of cardiovascular disease in patients with diabetes. Eur Heart J. 2023;44:4043–140.

    Article  PubMed  CAS  Google Scholar 

  2. Mancia G, Schumacher H, Redon J, Verdecchia P, Schmieder R, Jennings G, et al. Blood pressure targets recommended by guidelines and incidence of cardiovascular and renal events in the Ongoing telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET). Circulation. 2011;124:1727–36.

    Article  PubMed  Google Scholar 

  3. McEvoy JW, McCarthy CP, Bruno RM, Brouwers S, Canavan MD, Ceconi C, et al. 2024 ESC Guidelines for the management of elevated blood pressure and hypertension. Eur Heart J. 2024;45:3912–4018.

    Article  PubMed  Google Scholar 

  4. Mancia G, Kreutz R, Brunström M, Burnier M, Grassi G, Januszewicz A, et al. 2023 ESH Guidelines for the management of arterial hypertension The Task Force for the management of arterial hypertension of the European Society of Hypertension: endorsed by the International Society of Hypertension (ISH) and the European Renal Association (ERA). J Hypertens. 2023;41:1874–2071.

    Article  PubMed  CAS  Google Scholar 

  5. Unger T, Borghi C, Charchar F, Khan NA, Poulter NR, Prabhakaran D, et al. 2020 International Society of Hypertension global hypertension practice guidelines. Hypertension. 2020;75:1334–57.

    Article  PubMed  CAS  Google Scholar 

  6. Whelton PK, Carey RM, Aronow WS, Casey DE Jr, Collins KJ, Dennison Himmelfarb C, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice guidelines. Hypertension. 2018;71:e13–e115.

    PubMed  CAS  Google Scholar 

  7. Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001;345:861–9.

    Article  PubMed  CAS  Google Scholar 

  8. Palmer SC, Mavridis D, Navarese E, Craig JC, Tonelli M, Salanti G, et al. Comparative efficacy and safety of blood pressure-lowering agents in adults with diabetes and kidney disease: a network meta-analysis. Lancet. 2015;385:2047–56.

    Article  PubMed  CAS  Google Scholar 

  9. Parving HH, Lehnert H, Bröchner-Mortensen J, Gomis R, Andersen S, Arner P, et al. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med. 2001;345:870–8.

    Article  PubMed  CAS  Google Scholar 

  10. Viberti G, Wheeldon NM, MicroAlbuminuria Reduction With VALsartan (MARVAL) Study Investigators. Microalbuminuria reduction with valsartan in patients with type 2 diabetes mellitus: a blood pressure-independent effect. Circulation. 2002;106:672–8.

    Article  PubMed  CAS  Google Scholar 

  11. Schmieder RE, Hilgers KF, Schlaich MP, Schmidt BM. Renin-angiotensin system and cardiovascular risk. Lancet. 2007;369:1208–19.

    Article  PubMed  CAS  Google Scholar 

  12. Cherney DZ, Zinman B, Kennedy CR, Moineddin R, Lai V, Yang S, et al. Long-term hemodynamic and molecular effects persist after discontinued renin-angiotensin system blockade in patients with type 1 diabetes mellitus. Kidney Int. 2013;84:1246–53.

    Article  PubMed  CAS  Google Scholar 

  13. Das S, Zhang E, Senapati P, Amaram V, Reddy MA, Stapleton K, et al. A novel angiotensin II-induced long noncoding RNA giver regulates oxidative stress, inflammation, and proliferation in vascular smooth muscle cells. Circ Res. 2018;123:1298–312.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Taal MW, Brenner BM. Renoprotective benefits of RAS inhibition: from ACEI to angiotensin II antagonists. Kidney Int. 2000;57:1803–17.

    Article  PubMed  CAS  Google Scholar 

  15. Kunimura A, Himuro N, Fujiyoshi A, Segawa H, Ohnishi H, Saitoh S. The effects of renin-angiotensin system inhibitors on mortality, cardiovascular events, and renal events in hypertensive patients with diabetes: a systematic review and meta-analysis of randomized controlled trials. Hypertens Res. 2019;42:669–80.

    Article  PubMed  CAS  Google Scholar 

  16. Bangalore S, Fakheri R, Toklu B, Messerli FH. Diabetes mellitus as a compelling indication for use of renin angiotensin system blockers: systematic review and meta-analysis of randomized trials. BMJ. 2016;352:i438.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Alsalemi N, Sadowski CA, Elftouh N, Louis M, Kilpatrick K, Houle SK, et al. The effect of renin-angiotensin-aldosterone system inhibitors on continuous and binary kidney outcomes in subgroups of patients with diabetes: a meta-analysis of randomized clinical trials. BMC Nephrol. 2022;23:161.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Tatti P, Pahor M, Byington RP, Di Mauro P, Guarisco R, Strollo G, et al. Outcome results of the fosinopril versus amlodipine cardiovascular Events Randomized Trial (FACET) in patients with hypertension and NIDDM. Diabetes Care. 1998;21:597–603.

    Article  PubMed  CAS  Google Scholar 

  20. Estacio RO, Jeffers BW, Hiatt WR, Biggerstaff SL, Gifford N, Schrier RW. The effect of nisoldipine as compared with enalapril on cardiovascular outcomes in patients with non-insulin-dependent diabetes and hypertension. N. Engl J Med. 1998;338:645–52.

    Article  PubMed  CAS  Google Scholar 

  21. Lindholm LH, Hansson L, Ekbom T, Dahlöf B, Lanke J, Linjer E, et al. Comparison of antihypertensive treatments in preventing cardiovascular events in elderly diabetic patients: results from the Swedish Trial in Old Patients with Hypertension-2. STOP Hypertension-2 Study Group. J Hypertens. 2000;18:1671–5.

    Article  PubMed  CAS  Google Scholar 

  22. Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001;345:851–60.

    Article  PubMed  CAS  Google Scholar 

  23. Berl T, Hunsicker LG, Lewis JB, Pfeffer MA, Porush JG, Rouleau JL, et al. Cardiovascular outcomes in the irbesartan Diabetic Nephropathy Trial of patients with type 2 diabetes and overt nephropathy. Ann Intern Med. 2003;138:542–9.

    Article  PubMed  CAS  Google Scholar 

  24. Baba S, J-MIND Study Group. Nifedipine and enalapril equally reduce the progression of nephropathy in hypertensive type 2 diabetics. Diabetes Res Clin Pract. 2001;54:191–201.

    Article  PubMed  CAS  Google Scholar 

  25. Yui Y, Sumiyoshi T, Kodama K, Hirayama A, Nonogi H, Kanmatsuse K, et al. Nifedipine retard was as effective as angiotensin converting enzyme inhibitors in preventing cardiac events in high-risk hypertensive patients with diabetes and coronary artery disease: the Japan Multicenter Investigation for cardiovascular Diseases-B (JMIC-B) subgroup analysis. Hypertens Res. 2004;27:449–56.

    Article  PubMed  CAS  Google Scholar 

  26. Marre M, Puig JG, Kokot F, Fernandez M, Jermendy G, Opie L, et al. Equivalence of indapamide SR and enalapril on microalbuminuria reduction in hypertensive patients with type 2 diabetes: the NESTOR Study. J Hypertens. 2004;22:1613–22.

    Article  PubMed  CAS  Google Scholar 

  27. Whelton PK, Barzilay J, Cushman WC, Davis BR, Iiamathi E, Kostis JB, et al. Clinical outcomes in antihypertensive treatment of type 2 diabetes, impaired fasting glucose concentration, and normoglycemia: antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Arch Intern Med. 2005;165:1401–9.

    Article  PubMed  CAS  Google Scholar 

  28. Rahman M, Pressel S, Davis BR, Nwachuku C, Wright JT Jr, Whelton PK, et al. Renal outcomes in high-risk hypertensive patients treated with an angiotensin-converting enzyme inhibitor or a calcium channel blocker vs a diuretic: a report from the antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Arch Intern Med. 2005;165:936–46.

    Article  PubMed  CAS  Google Scholar 

  29. Nakao K, Hirata M, Oba K, Yasuno S, Ueshima K, Fujimoto A, et al. Role of diabetes and obesity in outcomes of the candesartan antihypertensive survival evaluation in Japan (CASE-J) trial. Hypertens Res. 2010;33:600–6.

    Article  PubMed  CAS  Google Scholar 

  30. Fogari R, Zoppi A, Corradi L, Mugellini A, Lazzari P, Preti P, et al. Long-term effects of ramipril and nitrendipine on albuminuria in hypertensive patients with type II diabetes and impaired renal function. J Hum Hypertens. 1999;13:47–53.

    Article  PubMed  CAS  Google Scholar 

  31. Umemura S, Arima H, Arima S, Asayama K, Dohi Y, Hirooka Y, et al. The Japanese Society of Hypertension guidelines for the management of hypertension (JSH 2019). Hypertens Res. 2019;42:1235–481.

    Article  PubMed  Google Scholar 

  32. Heart Outcomes Prevention Evaluation Study Investigators. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Heart Outcomes Prevention Evaluation Study Investigators. Lancet. 2000;355:253–9.

    Article  Google Scholar 

  33. Casas JP, Chua W, Loukogeorgakis S, Vallance P, Smeeth L, Hingorani AD, et al. Effect of inhibitors of the renin-angiotensin system and other antihypertensive drugs on renal outcomes: systematic review and meta-analysis. Lancet. 2005;366:2026–33.

    Article  PubMed  CAS  Google Scholar 

  34. Wu HY, Huang JW, Lin HJ, Liao WC, Peng YS, Hung KY, et al. Comparative effectiveness of renin-angiotensin system blockers and other antihypertensive drugs in patients with diabetes: systematic review and Bayesian network meta-analysis. BMJ. 2013;347:f6008.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Saito Y, Yamamoto H, Nakajima H, Takahashi O, Komatsu Y. Incidence of and risk factors for newly diagnosed hyperkalemia after hospital discharge in non-dialysis-dependent CKD patients treated with RAS inhibitors. PLoS ONE. 2017;12:e0184402.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Strippoli GF, Craig M, Deeks JJ, Schena FP, Craig JC. Effects of angiotensin converting enzyme inhibitors and angiotensin II receptor antagonists on mortality and renal outcomes in diabetic nephropathy: systematic review. BMJ. 2004;329:828.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Acknowledgements

The authors would like to thank Editage for providing professional English language editing services.

Author information

Authors and Affiliations

  1. Division of Nephrology and Hypertension, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Japan

    Daisuke Ichikawa

  2. Center for Basic Medical Research, International University of Health and Welfare (IUHW) Narita Campus, Narita, Japan

    Wakako Kawarazaki

  3. Department of Nephrology and Hypertension, Saiseikai Yokohamashi Nanbu Hospital, Yokohama, Japan

    Sanae Saka

  4. Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan

    Tomohiko Kanaoka

  5. Department of Public Health, Sapporo Medical University School of Medicine, Sapporo, Japan

    Hirofumi Ohnishi

  6. Department of Preventive Medicine and Public Health, Faculty of Medicine, Fukuoka University, Fukuoka, Japan

    Hisatomi Arima

  7. Division of Nephrology, Department of Internal Medicine, Teikyo University, Itabashi, Japan

    Shigeru Shibata

Authors
  1. Daisuke Ichikawa
    View author publications

    Search author on:PubMed Google Scholar

  2. Wakako Kawarazaki
    View author publications

    Search author on:PubMed Google Scholar

  3. Sanae Saka
    View author publications

    Search author on:PubMed Google Scholar

  4. Tomohiko Kanaoka
    View author publications

    Search author on:PubMed Google Scholar

  5. Hirofumi Ohnishi
    View author publications

    Search author on:PubMed Google Scholar

  6. Hisatomi Arima
    View author publications

    Search author on:PubMed Google Scholar

  7. Shigeru Shibata
    View author publications

    Search author on:PubMed Google Scholar

Corresponding author

Correspondence to Daisuke Ichikawa.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ichikawa, D., Kawarazaki, W., Saka, S. et al. Efficacy of renin-angiotensin system inhibitors, calcium channel blockers, and diuretics in hypertensive patients with diabetes: subgroup analysis based on albuminuria in a systematic review and meta-analysis. Hypertens Res 48, 1880–1890 (2025). https://doi.org/10.1038/s41440-025-02146-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41440-025-02146-7

Keywords

This article is cited by

Search

Advanced search

Quick links