The Clinical Impact of SGLT2 Inhibitors in Patients with and without Type 2 Diabetes: Systematic Review

Authors

  • Moamen Abdelfadil Ismail
  • Sally Abbas Noureldaeim Abdalla
  • Mohanad Ali
  • Yousif B. Hamdalneel
  • Ahmed Almuhanna
  • Maryam Ali Alanazi
  • Lmees Nabel Rmdan
  • Fadeek Busaleh
  • Adel Mansour Almutairi
  • Alaa Muneef Alotaibi
  • Mona Qarradi
  • Afnan Mamdouh Wafa
  • Atheer Aeysh Alonazi
  • Alhamza Younis Hamza
  • Ahmed Motawea Elsefy

DOI:

https://doi.org/10.69980/ajpr.v28i5.512

Abstract

Background: Sodium-glucose co-transporter-2 (SGLT2) inhibitors have demonstrated significant benefits in reducing cardiovascular events and delaying kidney disease progression in patients with type 2 diabetes, heart failure, or chronic kidney disease (CKD). However, their impact on non-diabetic populations remains less explored. This systematic review aimed to evaluate the effects of SGLT2 inhibitors  in patients with and without type 2 diabetes.

Methods: A comprehensive literature search was conducted using MEDLINE and Embase databases up to September 5, 2022. Randomized, double-blind, placebo-controlled trials with at least 500 participants per arm and a minimum follow-up of six months were included. Primary outcomes were kidney disease progression, acute kidney injury (AKI), and composite cardiovascular outcomes. Data were analyzed using inverse-variance weighting to derive summary relative risks (RRs) with 95% confidence intervals (CIs).

Results: The analysis included 13 trials with 90,413 participants. SGLT2 inhibitors reduced the risk of kidney disease progression by 37% (RR 0.63, 95% CI 0.58–0.69) and AKI by 23% (RR 0.77, 95% CI 0.70–0.84), with consistent benefits observed in both diabetic and non-diabetic populations. Cardiovascular death or heart failure hospitalization was reduced by 23% (RR 0.77, 95% CI 0.74–0.81). Safety outcomes included a higher risk of diabetic ketoacidosis (RR 2.12, 95% CI 1.49–3.04) and limb amputations (RR 1.15, 95% CI 1.02–1.30) in diabetic patients, but no significant risks were noted in non-diabetic individuals.

Conclusion: SGLT2 inhibitors provide significant renal and cardiovascular benefits across diverse patient populations, irrespective of diabetes type II  status. These findings support their broader use in managing CKD and heart failure, though careful monitoring for adverse effects is warranted in diabetic patients.

Author Biographies

Moamen Abdelfadil Ismail

Lecturer of Internal Medicine, Faculty of Medicine, Helwan University, Internal Medicine consultant, King Abdulaziz specialist hospital - Sakaka - Aljouf

Sally Abbas Noureldaeim Abdalla

Critical Care Clinical Pharmacist, University of Medical Science and Technology, Khartoum, Sudan

Mohanad Ali

Quality Assurance/QP, Manager Pharmaceutical Sciences, Saudi Pharmaceutical Industries & Medical Appliances Corporation (SPIMACO)

Yousif B. Hamdalneel

Department of Clinical Pharmacy and Pharmacy Practice, Faculty of Pharmacy, University of Gezira, Wad Medani, Sudan

Ahmed Almuhanna

Pharmacy

Maryam Ali Alanazi

Pharmacy

Lmees Nabel Rmdan

Pharmacy

Fadeek Busaleh

Pharmacy

Adel Mansour Almutairi

Pharmacy

Alaa Muneef Alotaibi

Pharmacy

Mona Qarradi

Pharmacy

Afnan Mamdouh Wafa

Pharmacy

Atheer Aeysh Alonazi

Specialty Pharmacy

Alhamza Younis Hamza

Pharmacy

Ahmed Motawea Elsefy

Lecture Internal Medicine Tanta University

References

1. Staplin N, Roddick AJ, Emberson J, et al. Net effects of sodium-glucose co-transporter-2 inhibition in different patient groups: a meta-analysis of large placebo-controlled randomized trials. EClinicalMedicine. 2021;41 doi: 10.1016/j.eclinm.2021.101163.

2. Zannad F, Ferreira JP, Pocock SJ, et al. SGLT2 inhibitors in patients with heart failure with reduced ejection fraction: a meta-analysis of the EMPEROR-Reduced and DAPA-HF trials. Lancet. 2020;396:819–829. doi: 10.1016/S0140-6736(20)31824-9.

3. Anker SD, Butler J, Filippatos G, et al. Empagliflozin in heart failure with a preserved ejection fraction. N Engl J Med. 2021;385:1451–1461. doi: 10.1056/NEJMoa2107038.

4. Solomon SD, McMurray JJV, Claggett B, et al. Dapagliflozin in heart failure with mildly reduced or preserved ejection fraction. N Engl J Med. 2022;387:1089–1098. doi: 10.1056/NEJMoa2206286.

5. Vaduganathan M, Docherty KF, Claggett BL, et al. SGLT-2 inhibitors in patients with heart failure: a comprehensive meta-analysis of five randomised controlled trials. Lancet. 2022;400:757–767. doi: 10.1016/S0140-6736(22)01429-5.

6. Neuen BL, Young T, Heerspink HJL, et al. SGLT2 inhibitors for the prevention of kidney failure in patients with type 2 diabetes: a systematic review and meta-analysis. Lancet Diabetes Endocrinol. 2019;7:845–854. doi: 10.1016/S2213-8587(19)30256-6.

7. Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med. 2019;380:2295–2306. doi: 10.1056/NEJMoa1811744.

8. Heerspink HJL, Stefánsson BV, Correa-Rotter R, et al. Dapagliflozin in patients with chronic kidney disease. N Engl J Med. 2020;383:1436–1446. doi: 10.1056/NEJMoa2024816.

9. Bhatt DL, Szarek M, Pitt B, et al. Sotagliflozin in patients with diabetes and chronic kidney disease. N Engl J Med. 2021;384:129–139. doi: 10.1056/NEJMoa2030186.

10. Wheeler DC, Stefánsson BV, Jongs N, et al. Effects of dapagliflozin on major adverse kidney and cardiovascular events in patients with diabetic and non-diabetic chronic kidney disease: a prespecified analysis from the DAPA-CKD trial. Lancet Diabetes Endocrinol. 2021;9:22–31. doi: 10.1016/S2213-8587(20)30369-7.

11. Packer M, Butler J, Zannad F, et al. Empagliflozin and major renal outcomes in heart failure. N Engl J Med. 2021;385:1531–1533. doi: 10.1056/NEJMc2112411.

12. Herrington WG, Wanner C, Green JB, et al. Design, recruitment, and baseline characteristics of the EMPA-KIDNEY trial. Nephrol Dial Transplant. 2022;37:1317–1329. doi: 10.1093/ndt/gfac040.

13. The EMPA-KIDNEY Collaborative Group. Empagliflozin in patients with chronic kidney disease. N Engl J Med (in press).

14. Jha V, Garcia-Garcia G, Iseki K, et al. Chronic kidney disease: global dimension and perspectives. Lancet. 2013;382:260–272. doi: 10.1016/S0140-6736(13)60687-X.

15. Levey AS, Coresh J. Chronic kidney disease. Lancet. 2012;379:165–180. doi: 10.1016/S0140-6736(11)60178-5.

16. Sterne JAC, Savović J, Page MJ, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ. 2019;366 doi: 10.1136/bmj.l4898.

17. Packer M, Anker SD, Butler J, et al. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med. 2020;383:1413–1424. doi: 10.1056/NEJMoa2022190.

18. Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019;380:347–357. doi: 10.1056/NEJMoa1812389.

19. Cherney DZI, Charbonnel B, Cosentino F, et al. Effects of ertugliflozin on kidney composite outcomes, renal function and albuminuria in patients with type 2 diabetes mellitus: an analysis from the randomised VERTIS CV trial. Diabetologia. 2021;64:1256–1267. doi: 10.1007/s00125-021-05407-5.

20. Bhatt DL, Szarek M, Steg PG, et al. Sotagliflozin in patients with diabetes and recent worsening heart failure. N Engl J Med. 2021;384:117–128. doi: 10.1056/NEJMoa2030183.

21. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377:644–657. doi: 10.1056/NEJMoa1611925.

22. Wheeler DC, Toto RD, Stefánsson BV, et al. A pre-specified analysis of the DAPA-CKD trial demonstrates the effects of dapagliflozin on major adverse kidney events in patients with IgA nephropathy. Kidney Int. 2021;100:215–224. doi: 10.1016/j.kint.2021.03.033.

23. Wheeler DC, Jongs N, Stefansson BV, et al. Safety and efficacy of dapagliflozin in patients with focal segmental glomerulosclerosis: a prespecified analysis of the dapagliflozin and prevention of adverse outcomes in chronic kidney disease (DAPA-CKD) trial. Nephrol Dial Transplant. 2022;37:1647–1656. doi: 10.1093/ndt/gfab335.

24. Early Breast Cancer Trialists' Collaborative Group . vol 1. Oxford University Press; Oxford: 1990. Treatment of early breast cancer. Vol 1. Worldwide evidence 1985–1990.

25. Deeks JJ, Higgins JPT, Altman DG, on behalf of the Cochrane Statistical Methods Group . In: Cochrane Handbook for Systematic Reviews of Interventions version 6.1. Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, Welch VA, editors. John Wiley & Sons; Chichester: 2019. Chapter 10: Analysing data and undertaking meta-analyses.

26. Perkovic V, de Zeeuw D, Mahaffey KW, et al. Canagliflozin and renal outcomes in type 2 diabetes: results from the CANVAS Program randomised clinical trials. Lancet Diabetes Endocrinol. 2018;6:691–704. doi: 10.1016/S2213-8587(18)30141-4.

27. Oshima M, Neal B, Toyama T, et al. Different eGFR decline thresholds and renal effects of canagliflozin: data from the CANVAS Program. J Am Soc Nephrol. 2020;31:2446–2456. doi: 10.1681/ASN.2019121312.

28. Mahaffey KW, Neal B, Perkovic V, et al. Canagliflozin for primary and secondary prevention of cardiovascular events: results from the CANVAS Program (Canagliflozin Cardiovascular Assessment Study) Circulation. 2018;137:323–334. doi: 10.1161/CIRCULATIONAHA.117.032038.

29. Neuen BL, Ohkuma T, Neal B, et al. Relative and absolute risk reductions in cardiovascular and kidney outcomes with canagliflozin across KDIGO risk categories: findings from the CANVAS Program. Am J Kidney Dis. 2021;77:23–34.e1. doi: 10.1053/j.ajkd.2020.06.018.

30. Cannon CP, Pratley R, Dagogo-Jack S, et al. Cardiovascular outcomes with ertugliflozin in type 2 diabetes. N Engl J Med. 2020;383:1425–1435. doi: 10.1056/NEJMoa2004967.

31. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373:2117–2128. doi: 10.1056/NEJMoa1504720.

32. Perkovic V, Koitka-Weber A, Cooper ME, et al. Choice of endpoint in kidney outcome trials: considerations from the EMPA-REG OUTCOME trial. Nephrol Dial Transplant. 2020;35:2103–2111. doi: 10.1093/ndt/gfz179.

33. Inzucchi SE, Iliev H, Pfarr E, Zinman B. Empagliflozin and assessment of lower-limb amputations in the EMPA-REG OUTCOME Trial. Diabetes Care. 2018;41:e4–e5. doi: 10.2337/dc17-1551.

34. McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med. 2019;381:1995–2008. doi: 10.1056/NEJMoa1911303.

35. Petrie MC, Verma S, Docherty KF, et al. Effect of dapagliflozin on worsening heart failure and cardiovascular death in patients with heart failure with and without diabetes. JAMA. 2020;323:1353–1368. doi: 10.1001/jama.2020.1906.

36. Anker SD, Butler J, Filippatos G, et al. Effect of empagliflozin on cardiovascular and renal outcomes in patients with heart failure by baseline diabetes status: results from the EMPEROR-Reduced Trial. Circulation. 2021;143:337–349. doi: 10.1161/CIRCULATIONAHA.120.051824.

37. Zannad F, Ferreira JP, Pocock SJ, et al. Cardiac and kidney benefits of empagliflozin in heart failure across the spectrum of kidney function: insights from EMPEROR-Reduced. Circulation. 2021;143:310–321. doi: 10.1161/CIRCULATIONAHA.120.051685.

38. Packer M, Zannad F, Butler J, et al. Influence of endpoint definitions on the effect of empagliflozin on major renal outcomes in the EMPEROR-Preserved trial. Eur J Heart Fail. 2021;23:1798–1799. doi: 10.1002/ejhf.2334.

39. Sarraju A, Li J, Cannon CP, et al. Effects of canagliflozin on cardiovascular, renal, and safety outcomes in participants with type 2 diabetes and chronic kidney disease according to history of heart failure: results from the CREDENCE trial. Am Heart J. 2021;233:141–148. doi: 10.1016/j.ahj.2020.12.008.

40. Mahaffey KW, Jardine MJ, Bompoint S, et al. Canagliflozin and cardiovascular and renal outcomes in type 2 diabetes mellitus and chronic kidney disease in primary and secondary cardiovascular prevention groups. Circulation. 2019;140:739–750. doi: 10.1161/CIRCULATIONAHA.119.042007.

41. Heerspink HJL, Cherney D, Postmus D, et al. A pre-specified analysis of the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) randomized controlled trial on the incidence of abrupt declines in kidney function. Kidney Int. 2022;101:174–184. doi: 10.1016/j.kint.2021.09.005.

42. Heerspink HJL, Sjöström CD, Jongs N, et al. Effects of dapagliflozin on mortality in patients with chronic kidney disease: a pre-specified analysis from the DAPA-CKD randomized controlled trial. Eur Heart J. 2021;42:1216–1227. doi: 10.1093/eurheartj/ehab094.

43. Wan X, Wang W, Liu J, Tong T. Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range. BMC Med Res Methodol. 2014;14:135. doi: 10.1186/1471-2288-14-135.

44. Garg SK, Henry RR, Banks P, et al. Effects of sotagliflozin added to insulin in patients with type 1 diabetes. N Engl J Med. 2017;377:2337–2348. doi: 10.1056/NEJMoa1708337.

45. Kosiborod MN, Esterline R, Furtado RHM, et al. Dapagliflozin in patients with cardiometabolic risk factors hospitalised with COVID-19 (DARE-19): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Diabetes Endocrinol. 2021;9:586–594. doi: 10.1016/S2213-8587(21)00180-7.

46. Herrington WG, Preiss D, Haynes R, et al. The potential for improving cardio-renal outcomes by sodium-glucose co-transporter-2 inhibition in people with chronic kidney disease: a rationale for the EMPA-KIDNEY study. Clin Kidney J. 2018;11:749–761. doi: 10.1093/ckj/sfy090.

47. Macha S, Mattheus M, Halabi A, Pinnetti S, Woerle HJ, Broedl UC. Pharmacokinetics, pharmacodynamics and safety of empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, in subjects with renal impairment. Diabetes Obes Metab. 2014;16:215–222. doi: 10.1111/dom.12182.

48. Levey AS, Inker LA, Matsushita K, et al. GFR decline as an end point for clinical trials in CKD: a scientific workshop sponsored by the National Kidney Foundation and the US Food and Drug Administration. Am J Kidney Dis. 2014;64:821–835. doi: 10.1053/j.ajkd.2014.07.030.

49. Levin A, Agarwal R, Herrington WG, et al. International consensus definitions of clinical trial outcomes for kidney failure: 2020. Kidney Int. 2020;98:849–859. doi: 10.1016/j.kint.2020.07.013.

50. Heerspink HJL, Weldegiorgis M, Inker LA, et al. Estimated GFR decline as a surrogate end point for kidney failure: a post hoc analysis from the Reduction of End Points in Non-Insulin-Dependent Diabetes With the Angiotensin II Antagonist Losartan (RENAAL) study and Irbesartan Diabetic Nephropathy Trial (IDNT) Am J Kidney Dis. 2014;63:244–250. doi: 10.1053/j.ajkd.2013.09.016.

51. Willis M, Nilsson A, Kellerborg K, et al. Cost-Effectiveness of canagliflozin added to standard of care for treating diabetic kidney disease (DKD) in patients with type 2 diabetes mellitus (T2DM) in England: estimates using the CREDEM-DKD model. Diabetes Ther. 2021;12:313–328. doi: 10.1007/s13300-020-00968-x.

52. Chertow GM, Vart P, Jongs N, et al. Effects of dapagliflozin in stage 4 chronic kidney disease. J Am Soc Nephrol. 2021;32:2352–2361. doi: 10.1681/ASN.2021020167.

53. Draznin B, Aroda VR, Bakris G, et al. 11. Chronic kidney disease and risk management: standards of medical care in diabetes—2022. Diabetes Care. 2022;45(suppl 1):S175–S184. doi: 10.2337/dc22-S011.

54. de Boer IH, Khunti K, Sadusky T, et al. Diabetes management in chronic kidney disease: a consensus report by the American Diabetes Association (ADA) and Kidney Disease: Improving Global Outcomes (KDIGO) Diabetes Care. 2022 doi: 10.2337/dci22-0027. published online Oct 3.

55. Kidney Disease: Improving Global Outcomes (KDIGO) Diabetes Work Group KDIGO 2020 clinical practice guideline for diabetes management in chronic kidney disease. Kidney Int. 2020;98:S1–115. doi: 10.1016/j.kint.2020.06.019.

56. National Institute for Health and Care Excellence Dapagliflozin for treating chronic kidney disease. Technology appraisal guidance [TA775] March 9, 2022. www.nice.org.uk/guidance/ta775

57. UK Kidney Association UK Kidney Association clinical practice guideline: sodium-glucose co-transporter-2 (SGLT-2) inhibition in adults with kidney disease. Oct 18, 2021. https://ukkidney.org/health-professionals/guidelines/guidelines-commentaries

58. Fox CS, Matsushita K, Woodward M, et al. Associations of kidney disease measures with mortality and end-stage renal disease in individuals with and without diabetes: a meta-analysis. Lancet. 2012;380:1662–1673. doi: 10.1016/S0140-6736(12)61350-6.

59. Levey AS, Gansevoort RT, Coresh J, et al. Change in albuminuria and GFR as end points for clinical trials in early stages of CKD: a scientific workshop sponsored by the National Kidney Foundation in collaboration with the US Food and Drug Administration and European Medicines Agency. Am J Kidney Dis. 2020;75:84–104. doi: 10.1053/j.ajkd.2019.06.009.

60. Rosenstock J, Marquard J, Laffel LM, et al. Empagliflozin as adjunctive to insulin therapy in type 1 diabetes: the EASE trials. Diabetes Care. 2018;41:2560–2569. doi: 10.2337/dc18-1749.

Downloads

Published

2025-07-18

Issue

Vol. 28 No. 5 (2025): American Journal of Psychiatric Rehabilitation

Section

Articles

License

Copyright (c) 2025 American Journal of Psychiatric Rehabilitation

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.

This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 International License permitting all use, distribution, and reproduction in any medium, provided the work is properly cited.