Diabetes Metab J.  2025 Mar;49(2):225-234. 10.4093/dmj.2024.0238.

Study Design and Protocol for a Randomized Controlled Trial of Enavogliflozin to Evaluate Cardiorenal Outcomes in Type 2 Diabetes (ENVELOP)

• Kim NH
• Lim S
• Jeong IK
• Rhee EJ
• Moon JS
• Ryu OH
• Kwon HS
• Won JC
• Kim SS
• Kim SY
• Ku BJ
• Jin HY
• Kim SG
• Cha BS
• on Behalf of Investigators of ENVELOP Study

• KMID: 2565346
• DOI: http://doi.org/10.4093/dmj.2024.0238

Abstract

Background
The novel sodium-glucose cotransporter-2 (SGLT2) inhibitor enavogliflozin effectively lowers glycosylated hemoglobin levels and body weights without the increased risk of serious adverse events; however, the long-term clinical benefits of enavogliflozin in terms of cardiovascular and renal outcomes have not been investigated.
Methods
This study is an investigator-initiated, multicenter, randomized, pragmatic, open-label, active-controlled, non-inferiority trial. Eligible participants are adults (aged ≥19 years) with type 2 diabetes mellitus (T2DM) who have a history of, or are at risk of, cardiovascular disease. A total of 2,862 participants will be randomly assigned to receive either enavogliflozin or other SGLT2 inhibitors with proven cardiorenal benefits, such as dapagliflozin or empagliflozin. The primary endpoint is the time to the first occurrence of a composite of major adverse cardiovascular or renal events (Clinical Research Information Service registration number: KCT0009243).
Conclusion
This trial will determine whether enavogliflozin is non-inferior to dapagliflozin or empagliflozin in terms of cardiorenal outcomes in patients with T2DM and cardiovascular risk factors. This study will elucidate the role of enavogliflozin in preventing vascular complications in patients with T2DM.

Keyword

Cardiovascular diseases; Diabetes mellitus, type 2; Enavogliflozin; Kidney diseases; Randomized controlled trial; Sodium-glucose transporter 2 inhibitors

Figure

• 

  Fig. 1. Overall study scheme. T2DM, type 2 diabetes mellitus; HbA1c, glycosylated hemoglobin; CVD, cardiovascular disease; CV, cardiovascular; AE, adverse event.

• 

Reference

1. International Diabetes Federation. IDF Diabetes Atlas 2021. 10th ed. Brussels: IDF;2021.

2. Cho NH, Shaw JE, Karuranga S, Huang Y, da Rocha Fernandes JD, Ohlrogge AW, et al. IDF Diabetes Atlas: global estimates of diabetes prevalence for 2017 and projections for 2045. Diabetes Res Clin Pract. 2018; 138:271–81.

3. Bae JH, Han KD, Ko SH, Yang YS, Choi JH, Choi KM, et al. Diabetes fact sheet in Korea 2021. Diabetes Metab J. 2022; 46:417–26.

4. Abdul-Ghani MA, Norton L, Defronzo RA. Role of sodium-glucose cotransporter 2 (SGLT 2) inhibitors in the treatment of type 2 diabetes. Endocr Rev. 2011; 32:515–31.

5. Zelniker TA, Wiviott SD, Raz I, Im K, Goodrich EL, Bonaca MP, et al. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet. 2019; 393:31–9.

6. American Diabetes Association Professional Practice Committee. 9. Pharmacologic approaches to glycemic treatment: standards of care in diabetes-2024. Diabetes Care. 2024; 47(Suppl 1):S158–78.

7. Choi JH, Lee KA, Moon JH, Chon S, Kim DJ, Kim HJ, et al. 2023 Clinical practice guidelines for diabetes mellitus of the Korean Diabetes Association. Diabetes Metab J. 2023; 47:575–94.

8. Choi MK, Nam SJ, Ji HY, Park MJ, Choi JS, Song IS. Comparative pharmacokinetics and pharmacodynamics of a novel sodium-glucose cotransporter 2 inhibitor, DWP16001, with dapagliflozin and ipragliflozin. Pharmaceutics. 2020; 12:268.

9. Kwak SH, Han KA, Kim KS, Yu JM, Kim E, Won JC, et al. Efficacy and safety of enavogliflozin, a novel SGLT2 inhibitor, in Korean people with type 2 diabetes: a 24-week, multicentre, randomized, double-blind, placebo-controlled, phase III trial. Diabetes Obes Metab. 2023; 25:1865–73.

10. Kim KS, Han KA, Kim TN, Park CY, Park JH, Kim SY, et al. Efficacy and safety of enavogliflozin versus dapagliflozin added to metformin plus gemigliptin treatment in patients with type 2 diabetes: a double-blind, randomized, comparator-active study: ENHANCE-D study. Diabetes Metab. 2023; 49:101440.

11. Han KA, Kim YH, Kim DM, Lee BW, Chon S, Sohn TS, et al. Efficacy and safety of enavogliflozin versus dapagliflozin as add-on to metformin in patients with type 2 diabetes mellitus: a 24-week, double-blind, randomized trial. Diabetes Metab J. 2023; 47:796–807.

12. Ford I, Norrie J. Pragmatic trials. N Engl J Med. 2016; 375:454–63.

13. Thygesen K, Alpert JS, Jaffe AS, Simoons ML, Chaitman BR, White HD, et al. Third universal definition of myocardial infarction. Nat Rev Cardiol. 2012; 9:620–33.

14. Hicks KA, Tcheng JE, Bozkurt B, Chaitman BR, Cutlip DE, Farb A, et al. 2014 ACC/AHA key data elements and definitions for cardiovascular endpoint events in clinical trials: a report of the American College of Cardiology/American Heart Association task force on clinical data standards (writing committee to develop cardiovascular endpoints data standards). J Am Coll Cardiol. 2015; 66:403–69.

15. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015; 373:2117–28.

16. Wiviott SD, Raz I, Bonaca MP, Mosenzon O, Kato ET, Cahn A, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019; 380:347–57.

17. Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017; 377:644–57.

18. List JF, Whaley JM. Glucose dynamics and mechanistic implications of SGLT2 inhibitors in animals and humans. Kidney Int Suppl. 2011; 120:S20–7.

19. Vallon V, Thomson SC. Targeting renal glucose reabsorption to treat hyperglycaemia: the pleiotropic effects of SGLT2 inhibition. Diabetologia. 2017; 60:215–25.

20. DeFronzo RA, Norton L, Abdul-Ghani M. Renal, metabolic and cardiovascular considerations of SGLT2 inhibition. Nat Rev Nephrol. 2017; 13:11–26.

21. Davies MJ, Drexel H, Jornayvaz FR, Pataky Z, Seferovic PM, Wanner C. Cardiovascular outcomes trials: a paradigm shift in the current management of type 2 diabetes. Cardiovasc Diabetol. 2022; 21:144.

22. Heerspink HJ, Stefansson BV, Correa-Rotter R, Chertow GM, Greene T, Hou FF, et al. Dapagliflozin in patients with chronic kidney disease. N Engl J Med. 2020; 383:1436–46.

23. The EMPA-KIDNEY Collaborative Group, Herrington WG, Staplin N, Wanner C, Green JB, Hauske SJ, et al. Empagliflozin in patients with chronic kidney disease. N Engl J Med. 2023; 388:117–27.

24. McMurray JJ, Solomon SD, Inzucchi SE, Kober L, Kosiborod MN, Martinez FA, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med. 2019; 381:1995–2008.

25. Solomon SD, McMurray JJ, Claggett B, de Boer RA, DeMets D, Hernandez AF, et al. Dapagliflozin in heart failure with mildly reduced or preserved ejection fraction. N Engl J Med. 2022; 387:1089–98.

26. Packer M, Anker SD, Butler J, Filippatos G, Pocock SJ, Carson P, et al. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med. 2020; 383:1413–24.

27. Anker SD, Butler J, Filippatos G, Ferreira JP, Bocchi E, Bohm M, et al. Empagliflozin in heart failure with a preserved ejection fraction. N Engl J Med. 2021; 385:1451–61.

28. Isaji M. SGLT2 inhibitors: molecular design and potential differences in effect. Kidney Int Suppl. 2011; 120:S14–9.

29. Ma RC, Chan JC. Type 2 diabetes in East Asians: similarities and differences with populations in Europe and the United States. Ann N Y Acad Sci. 2013; 1281:64–91.

30. Thomas MC, Brownlee M, Susztak K, Sharma K, Jandeleit-Dahm KA, Zoungas S, et al. Diabetic kidney disease. Nat Rev Dis Primers. 2015; 1:15018.

31. Wang V, Vilme H, Maciejewski ML, Boulware LE. The economic burden of chronic kidney disease and end-stage renal disease. Semin Nephrol. 2016; 36:319–30.

32. Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med. 2004; 351:1296–305.