Skip main navigation

Cardiovascular Outcomes in GRADE (Glycemia Reduction Approaches in Type 2 Diabetes: A Comparative Effectiveness Study)

and the GRADE Study Research Group
Originally publishedhttps://doi.org/10.1161/CIRCULATIONAHA.123.066604Circulation. 2024;149:993–1003

    BACKGROUND:

    Cardiovascular disease is a major cause of morbidity and mortality in patients with type 2 diabetes. The effects of glucose-lowering medications on cardiovascular outcomes in individuals with type 2 diabetes and low cardiovascular risk are unclear. We investigated cardiovascular outcomes by treatment group in participants randomly assigned to insulin glargine, glimepiride, liraglutide, or sitagliptin, added to baseline metformin, in GRADE (Glycemia Reduction Approaches in Type 2 Diabetes: A Comparative Effectiveness Study).

    METHODS:

    A total of 5047 participants with a mean±SD age of 57.2±10.0 years, type 2 diabetes duration of 4.0±2.7 years, and low baseline prevalence of cardiovascular disease (myocardial infarction, 5.1%; cerebrovascular accident, 2.0%) were followed for a median of 5 years. Prespecified outcomes included between-group time-to-first event analyses of MACE-3 (composite of major adverse cardiovascular events: cardiovascular death, myocardial infarction, and stroke), MACE-4 (MACE-3+unstable angina requiring hospitalization or revascularization), MACE-5 (MACE-4+coronary revascularization), MACE-6 (MACE-5+hospitalization for heart failure), and the individual components. MACE outcomes and hospitalization for heart failure in the liraglutide-treated group were compared with the other groups combined using Cox proportional hazards models. MACE-6 was also analyzed as recurrent events using a proportional rate model to compare all treatment groups.

    RESULTS:

    We observed no statistically significant differences in the cumulative incidence of first MACE-3, MACE-4, MACE-5, or MACE-6, or their individual components, by randomized treatment group. However, when compared with the other treatment groups combined, the liraglutide-treated group had a significantly lower risk of MACE-5 (adjusted hazard ratio, 0.70 [95% CI, 0.54–0.91]; P=0.021), MACE-6 (adjusted hazard ratio, 0.70 [95% CI, 0.55–0.90]; P=0.021), and hospitalization for heart failure (adjusted hazard ratio, 0.49 [95% CI, 0.28–0.86]; P=0.022). Compared with the liraglutide group, significantly higher rates of recurrent MACE-6 events occurred in the groups treated with glimepiride (rate ratio, 1.61 [95% CI, 1.13–2.29]) or sitagliptin (rate ratio 1.75; [95% CI, 1.24–2.48]).

    CONCLUSIONS:

    This comparative effectiveness study of a contemporary cohort of adults with type 2 diabetes, largely without established cardiovascular disease, suggests that liraglutide treatment may reduce the risk of cardiovascular events in patients at relatively low risk compared with other commonly used glucose-lowering medications.

    REGISTRATION:

    URL: https://www.clinicaltrials.gov; Unique identifier: NCT01794143.

    Footnotes

    *The GRADE Research Group listing is provided in the Supplemental Appendix.

    This manuscript was sent to John J.V. McMurray, Guest Editor, for review by expert referees, editorial decision, and final disposition.

    Supplemental Material is available at https://www.ahajournals.org/doi/suppl/10.1161/CIRCULATIONAHA.123.066604.

    For Sources of Funding and Disclosures, see page 1001–1002.

    Circulation is available at www.ahajournals.org/journal/circ

    Correspondence to: Jennifer B. Green, MD, c/o The Biostatistics Center, George Washington University, 6110 Executive Blvd, Ste 750, Rockville, MD 20852. Email

    REFERENCES

    • 1. Morrish NJ, Wang SL, Stevens LK, Fuller JH, Keen H. Mortality and causes of death in the WHO Multinational Study of Vascular Disease in Diabetes.Diabetologia. 2001; 44:S14–S21. doi: 10.1007/pl00002934CrossrefMedlineGoogle Scholar
    • 2. Gregg EW, Li Y, Wang J, Burrows NR, Ali MK, Rolka D, Williams DE, Geiss L. Changes in diabetes-related complications in the United States, 1990-2010.N Engl J Med. 2014; 370:1514–1523. doi: 10.1056/NEJMoa1310799CrossrefMedlineGoogle Scholar
    • 3. Rawshani A, Rawshani A, Franzén S, Sattar N, Eliasson B, Svensson AM, Zethelius B, Miftaraj M, McGuire DK, Rosengren A, et al. Risk factors, mortality, and cardiovascular outcomes in patients with type 2 diabetes.N Engl J Med. 2018; 379:633–644. doi: 10.1056/NEJMoa1800256CrossrefMedlineGoogle Scholar
    • 4. McGuire DK, Shih WJ, Cosentino F, Charbonnel B, Cherney DZI, Dagogo-Jack S, Pratley R, Greenberg M, Wang S, Huyck S, et al. Association of SGLT2 inhibitors with cardiovascular and kidney outcomes in patients with type 2 diabetes: a meta-analysis.JAMA Cardiol. 2021; 6:148–158. doi: 10.1001/jamacardio.2020.4511CrossrefMedlineGoogle Scholar
    • 5. Palmer SC, Tendal B, Mustafa RA, Vandvik PO, Li S, Hao Q, Tunnicliffe D, Ruospo M, Natale P, Saglimbene V, et al. Sodium-glucose cotransporter protein-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists for type 2 diabetes: systematic review and network meta-analysis of randomised controlled trials.BMJ. 2021; 372:m4573. doi: 10.1136/bmj.m4573CrossrefMedlineGoogle Scholar
    • 6. Nathan DM, Buse JB, Kahn SE, Krause-Steinrauf H, Larkin ME, Staten M, Wexler D, Lachin JM; GRADE Study Research Group. Rationale and design of the Glycemia Reduction Approaches in Diabetes: a Comparative Effectiveness Study (GRADE).Diabetes Care. 2013; 36:2254–2261. doi: 10.2337/dc13-0356CrossrefMedlineGoogle Scholar
    • 7. Wexler DJ, Krause-Steinrauf H, Crandall JP, Florez HJ, Hox SH, Kuhn A, Sood A, Underkofler C, Aroda VR; GRADE Research Group. Baseline characteristics of randomized participants in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE).Diabetes Care. 2019; 42:2098–2107. doi: 10.2337/dc19-0901CrossrefMedlineGoogle Scholar
    • 8. Nathan DM, Lachin JM, Bebu I, Burch HB, Buse JB, Cherrington AL, Fortmann SP, Green JB, Kahn SE, Kirkman MS, et al; GRADE Study Research Group. Glycemia reduction in type 2 diabetes: microvascular and cardiovascular outcomes.N Engl J Med. 2022; 387:1075–1088. doi: 10.1056/NEJMoa2200436CrossrefMedlineGoogle Scholar
    • 9. Nathan DM, Lachin JM, Balasubramanyam A, Burch HB, Buse JB, Butera NM, Cohen RM, Crandall JP, Kahn SE, Krause-Steinrauf H, et al; GRADE Study Research Group. Glycemia reduction in type 2 diabetes: glycemic outcomes.N Engl J Med. 2022; 387:1063–1074. doi: 10.1056/NEJMoa2200433CrossrefMedlineGoogle Scholar
    • 10. Buse JB, Wexler DJ, Tsapas A, Rossing P, Mingrone G, Mathieu C, D’Alessio DA, Davies MJ. 2019 Update to: management of hyperglycemia in type 2 diabetes, 2018: a consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).Diabetes Care. 2020; 43:487–493. doi: 10.2337/dci19-0066CrossrefMedlineGoogle Scholar
    • 11. American Diabetes Association. Cardiovascular disease and risk management: standards of medical care in diabetes: 2019.Diabetes Care. 2019; 42:S103–S123. doi: 10.2337/dc19-S010CrossrefMedlineGoogle Scholar
    • 12. Hicks KA, Tcheng JE, Bozkurt B, Chaitman BR, Cutlip DE, Farb A, Fonarow GC, Jacobs JP, Jaff MR, Lichtman JH, et al; American College of Cardiology. 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).Circulation. 2015; 132:302–361. doi: 10.1161/CIR.0000000000000156LinkGoogle Scholar
    • 13. Hicks KA, Mahaffey KW, Mehran R, Nissen SE, Wiviott SD, Dunn B, Solomon SD, Marler JR, Teerlink JR, Farb A, et al; Standardized Data Collection for Cardiovascular Trials Initiative (SCTI). 2017 Cardiovascular and stroke endpoint definitions for clinical trials.J Am Coll Cardiol. 2018; 71:1021–1034. doi: 10.1016/j.jacc.2017.12.048CrossrefMedlineGoogle Scholar
    • 14. Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing.J R Stat Soc. 1995; 57:289–300. doi: 10.1111/j.2517-6161.1995.tb02031.xCrossrefGoogle Scholar
    • 15. Lin D, Wei L, Yang I, Ying Z. Semiparametric regression for the mean and rate functions of recurrent events.J R Stat Soc. 2000; 62:711–730.CrossrefGoogle Scholar
    • 16. Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JF, Nauck MA, Nissen SE, Pocock S, Poulter NR, Ravn LS, et al; LEADER Steering Committee. Liraglutide and cardiovascular outcomes in type 2 diabetes.N Engl J Med. 2016; 375:311–322. doi: 10.1056/NEJMoa1603827CrossrefMedlineGoogle Scholar
    • 17. Lawless JF, Nadeau C. Some simple robust methods for the analysis of recurrent events.Technometrics. 1995; 37:158–168. doi: 10.1080/00401706.1995.10484300CrossrefGoogle Scholar
    • 18. Giugliano D, Maiorino MI, Bellastella G, Esposito K. The residual cardiorenal risk in type 2 diabetes.Cardiovasc Diabetol. 2021; 20:36. doi: 10.1186/s12933-021-01229-2CrossrefMedlineGoogle Scholar
    • 19. Dunlay SM, Givertz MM, Aguilar D, Allen LA, Chan M, Desai AS, Deswal A, Vaughan Dickson V, Kosiborod MK, Lekavich CL, et al; American Heart Association Heart Failure and Transplantation Committee of the Council on Clinical Cardiology; Council on Cardiovascular and Stroke Nursing; and the Heart Failure Society of America. Type 2 diabetes mellitus and heart failure: a scientific statement from the American Heart Association and the Heart Failure Society of America: this statement does not represent an update of the 2017 ACC/AHA/HFSA heart failure guideline update.Circulation. 2019; 140:e294–e324. doi: 10.1161/CIR.0000000000000691LinkGoogle Scholar
    • 20. McAllister DA, Read SH, Kerssens J, Livingstone S, McGurnaghan S, Jhund P, Petrie J, Sattar N, Fischbacher C, Kristensen SL, et al. Incidence of hospitalization for heart failure and case-fatality among 3.25 million people with and without diabetes mellitus.Circulation. 2018; 138:2774–2786. doi: 10.1161/CIRCULATIONAHA.118.034986LinkGoogle Scholar
    • 21. US Food and Drug Administration. Diabetes mellitus: evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes; summarized in FDA Background Document for the Endocrinologic and Metabolic Drugs Advisory Committee Meeting, October 24-25, 2018.Published December 19, 2008. Accessed February 6, 2024. Chromeextension://efaidnbmnnnibpcajpcglclefindmkaj/https://www.fda.gov/media/121272/downloadGoogle Scholar
    • 22. McMurray JJV, Solomon SD, Inzucchi SE, Køber L, Kosiborod MN, Martinez FA, Ponikowski P, Sabatine MS, Anand IS, Bělohlávek J, et al; DAPA-HF Trial Committees and Investigators. Dapagliflozin in patients with heart failure and reduced ejection fraction.N Engl J Med. 2019; 381:1995–2008. doi: 10.1056/NEJMoa1911303CrossrefMedlineGoogle Scholar
    • 23. Packer M, Anker SD, Butler J, Filippatos G, Pocock SJ, Carson P, Januzzi J, Verma S, Tsutsui H, Brueckmann M, et al; EMPEROR-Reduced Trial Investigators. Cardiovascular and renal outcomes with empagliflozin in heart failure.N Engl J Med. 2020; 383:1413–1424. doi: 10.1056/NEJMoa2022190CrossrefMedlineGoogle Scholar
    • 24. Anker SD, Butler J, Filippatos G, Ferreira JP, Bocchi E, Böhm M, Brunner-La Rocca HP, Choi DJ, Chopra V, Chuquiure-Valenzuela E, et al; EMPEROR-Preserved Trial Investigators. Empagliflozin in heart failure with a preserved ejection fraction.N Engl J Med. 2021; 385:1451–1461. doi: 10.1056/NEJMoa2107038CrossrefMedlineGoogle Scholar
    • 25. Heerspink HJL, Stefánsson BV, Correa-Rotter R, Chertow GM, Greene T, Hou FF, Mann JFE, McMurray JJV, Lindberg M, Rossing P, et al; DAPA-CKD Trial Committees and Investigators. Dapagliflozin in patients with chronic kidney disease.N Engl J Med. 2020; 383:1436–1446. doi: 10.1056/NEJMoa2024816CrossrefMedlineGoogle Scholar
    • 26. Perkovic V, Jardine MJ, Neal B, Bompoint S, Heerspink HJL, Charytan DM, Edwards R, Agarwal R, Bakris G, Bull S, et al; CREDENCE Trial Investigators. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy.N Engl J Med. 2019; 380:2295–2306. doi: 10.1056/NEJMoa1811744CrossrefMedlineGoogle Scholar
    • 27. Herrington WG, Staplin N, Wanner C, Green JB, Hauske SJ, Emberson JR, Preiss D, Judge P, Mayne KJ, Ng SYA, et al; EMPA-KIDNEY Collaborative Group. Empagliflozin in patients with chronic kidney disease.N Engl J Med. 2022; doi: 10.1056/NEJMoa2204233CrossrefMedlineGoogle Scholar
    • 28. Draznin B, Aroda VR, Bakris G, Benson G, Brown FM, Freeman R, Green J, Huang E, Isaacs D, Kahan S, et al; American Diabetes Association Professional Practice Committee. Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes: 2022.Diabetes Care. 2022; 45(Suppl 1):S125–S143. doi: 10.2337/dc22-S009CrossrefMedlineGoogle Scholar
    • 29. American Diabetes Association Professional Practice Committee. Cardiovascular disease and risk management: standards of medical care in diabetes: 2022.Diabetes Care. 2022; 45(Suppl 1):S144–S174. doi: 10.2337/dc22-S010CrossrefMedlineGoogle Scholar
    • 30. Das SR, Everett BM, Birtcher KK, Brown JM, Januzzi JL, Kalyani RR, Kosiborod M, Magwire M, Morris PB, Neumiller JJ, et al. 2020 Expert consensus decision pathway on novel therapies for cardiovascular risk reduction in patients with type 2 diabetes: a report of the American College of Cardiology solution set oversight committee.J Am Coll Cardiol. 2020; 76:1117–1145. doi: 10.1016/j.jacc.2020.05.037CrossrefMedlineGoogle Scholar
    • 31. Davies MJ, Aroda VR, Collins BS, Gabbay RA, Green J, Maruthur NM, Rosas SE, Del Prato S, Mathieu C, Mingrone G, et al. Management of hyperglycemia in type 2 diabetes, 2022: a consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).Diabetes Care. 2022; 45:2753–2786. doi: 10.2337/dci22-0034CrossrefMedlineGoogle Scholar
    • 32. Gerstein HC, Bosch J, Dagenais GR, Díaz R, Jung H, Maggioni AP, Pogue J, Probstfield J, Ramachandran A, Riddle MC, et al; ORIGIN Trial Investigators. Basal insulin and cardiovascular and other outcomes in dysglycemia.N Engl J Med. 2012; 367:319–328. doi: 10.1056/NEJMoa1203858CrossrefMedlineGoogle Scholar
    • 33. Rosenstock J, Kahn SE, Johansen OE, Zinman B, Espeland MA, Woerle HJ, Pfarr E, Keller A, Mattheus M, Baanstra D, et al; CAROLINA Investigators. Effect of linagliptin vs glimepiride on major adverse cardiovascular outcomes in patients with type 2 diabetes: the CAROLINA randomized clinical trial.JAMA. 2019; 322:1155–1166. doi: 10.1001/jama.2019.13772CrossrefMedlineGoogle Scholar
    • 34. Rosenstock J, Perkovic V, Johansen OE, Cooper ME, Kahn SE, Marx N, Alexander JH, Pencina M, Toto RD, Wanner C, et al; CARMELINA Investigators. Effect of linagliptin vs placebo on major cardiovascular events in adults with type 2 diabetes and high cardiovascular and renal risk: the CARMELINA randomized clinical trial.JAMA. 2019; 321:69–79. doi: 10.1001/jama.2018.18269CrossrefMedlineGoogle Scholar
    • 35. Green JB, Bethel MA, Armstrong PW, Buse JB, Engel SS, Garg J, Josse R, Kaufman KD, Koglin J, Korn S, et al; TECOS Study Group. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes.N Engl J Med. 2015; 373:232–242. doi: 10.1056/NEJMoa1501352CrossrefMedlineGoogle Scholar
    • 36. Drucker DJ. The cardiovascular biology of glucagon-like peptide-1.Cell Metab. 2016; 24:15–30. doi: 10.1016/j.cmet.2016.06.009CrossrefMedlineGoogle Scholar

    eLetters(0)

    eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. Comments are reviewed for appropriate use of tone and language. Comments are not peer-reviewed. Acceptable comments are posted to the journal website only. Comments are not published in an issue and are not indexed in PubMed. Comments should be no longer than 500 words and will only be posted online. References are limited to 10. Authors of the article cited in the comment will be invited to reply, as appropriate.

    Comments and feedback on AHA/ASA Scientific Statements and Guidelines should be directed to the AHA/ASA Manuscript Oversight Committee via its Correspondence page.