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

the GRADE Study Research Group

doi:10.1161/CIRCULATIONAHA.123.066604

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

the GRADE Study Research Group

Research output: Contribution to journal › Article › peer-review

3 Scopus citations

Abstract

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.

Original language	English
Pages (from-to)	993-1003
Number of pages	11
Journal	Circulation
Volume	149
Issue number	13
DOIs	https://doi.org/10.1161/CIRCULATIONAHA.123.066604
State	Published - Mar 26 2024

Keywords

cardiovascular diseases
diabetes mellitus
glucose
liraglutide

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10.1161/CIRCULATIONAHA.123.066604

Cite this

@article{220cdcbfbd8448f29bf981088f9e7905,

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

abstract = "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.",

keywords = "cardiovascular diseases, diabetes mellitus, glucose, liraglutide",

author = "{the GRADE Study Research Group} and Green, {Jennifer B.} and Everett, {Brendan M.} and Alokananda Ghosh and Naji Younes and Heidi Krause-Steinrauf and Joshua Barzilay and Cyrus Desouza and Inzucchi, {Silvio E.} and Yashashwi Pokharel and David Schade and Alexandra Scrymgeour and Tan, {Meng H.} and Utzschneider, {Kristina M.} and Sunder Mudaliar and Crandall, {J. P.} and McKee, {M. D.} and S. Behringer-Massera and J. Brown-Friday and E. Xhori and K. Ballentine-Cargill and S. Duran and H. Estrella and {Gonzalez De La Torre}, S. and J. Lukin and Phillips, {L. S.} and E. Burgess and D. Olson and M. Rhee and P. Wilson and Raines, {T. S.} and J. Boers and J. Costello and M. Maher-Albertelli and R. Mungara and L. Savoye and White, {C. A.} and C. Gullett and L. Holloway and F. Morehead and S. Person and M. Sibymon and S. Tanukonda and C. Adams and A. Ross and A. Balasubramanyam and R. Gaba and {Gonzalez Hattery}, E. and A. Ideozu and J. Jimenez and G. Montes and C. Wright and P. Hollander and E. Roe and A. Jackson and A. Smiley and P. Burt and L. Estrada and K. Chionh and F. Ismail-Beigi and C. Falck-Ytter and {Sayyed Kassem}, L. and A. Sood and M. Tiktin and T. Kulow and C. Newman and Stancil, {K. A.} and B. Cramer and J. Iacoboni and Kononets, {M. V.} and C. Sanders and L. Tucker and A. Werner and A. Maxwell and G. McPhee and C. Patel and L. Colosimo and A. Krol and R. Goland and J. Pring and L. Alfano and P. Kringas and C. Hausheer and J. Tejada and K. Gumpel and A. Kirpitch and H. Schneier and H. Abouassi and R. Chatterjee and Feinglos, {M. N.} and {English Jones}, J. and Khan, {S. A.} and Kimpel, {J. B.} and Zimmer, {R. P.} and M. Furst and Satterwhite, {B. M.} and Thacker, {C. R.} and {Evans Kreider}, K. and Mariash, {C. N.} and Mather, {K. J.} and Ismail, {H. M.} and A. Lteif and M. Mullen and T. Hamilton and N. Patel and G. Riera and M. Jackson and V. Pirics and D. Aguillar and D. Howard and S. Hurt and R. Bergenstal and A. Carlson and T. Martens and M. Johnson and R. Hill and J. Hyatt and C. Jensen and M. Madden and D. Martin and H. Willis and W. Konerza and S. Yang and K. Kleeberger and R. Passi and S. Fortmann and M. Herson and K. Mularski and H. Glauber and J. Prihoda and B. Ash and C. Carlson and Ramey, {P. A.} and E. Schield and B. Torgrimson-Ojerio and K. Arnold and B. Kauffman and E. Panos and S. Sahnow and K. Bays and K. Berame and J. Cook and D. Ghioni and J. Gluth and K. Schell and J. Criscola and C. Friason and S. Jones and S. Nazarov and N. Rassouli and R. Puttnam and B. Ojoawo and R. Nelson and M. Curtis and B. Hollis and C. Sanders-Jones and K. Stokes and Z. El-Haqq and A. Kolli and T. Tran and D. Wexler and Larkin, {M. E.} and J. Meigs and B. Chambers and A. Dushkin and G. Rocchio and M. Yepes and B. Steiner and H. Dulin and M. Cayford and K. Chu and A. Demanbey and M. Hillard and K. Martin and N. Thangthaeng and L. Gurry and R. Kochis and E. Raymond and V. Ripley and C. Stevens and J. Park and V. Aroda and A. Ghazi and M. Magee and A. Ressing and A. Loveland and M. Hamm and M. Hurtado and A. Kuhn and J. Leger and L. Manandhar and F. Mwicigi and O. Sanchez and T. Young and R. Garg and V. Lagari-Libhaber and Florez, {H. J.} and Valencia, {W. M.} and J. Marks and McGill, {J. B.} and M. Salam",

year = "2024",

month = mar,

day = "26",

doi = "10.1161/CIRCULATIONAHA.123.066604",

language = "English",

volume = "149",

pages = "993--1003",

journal = "Circulation",

issn = "0009-7322",

number = "13",

}

TY - JOUR

T1 - Cardiovascular Outcomes in GRADE (Glycemia Reduction Approaches in Type 2 Diabetes: A Comparative Effectiveness Study)

AU - the GRADE Study Research Group

AU - Green, Jennifer B.

AU - Everett, Brendan M.

AU - Ghosh, Alokananda

AU - Younes, Naji

AU - Krause-Steinrauf, Heidi

AU - Barzilay, Joshua

AU - Desouza, Cyrus

AU - Inzucchi, Silvio E.

AU - Pokharel, Yashashwi

AU - Schade, David

AU - Scrymgeour, Alexandra

AU - Tan, Meng H.

AU - Utzschneider, Kristina M.

AU - Mudaliar, Sunder

AU - Crandall, J. P.

AU - McKee, M. D.

AU - Behringer-Massera, S.

AU - Brown-Friday, J.

AU - Xhori, E.

AU - Ballentine-Cargill, K.

AU - Duran, S.

AU - Estrella, H.

AU - Gonzalez De La Torre, S.

AU - Lukin, J.

AU - Phillips, L. S.

AU - Burgess, E.

AU - Olson, D.

AU - Rhee, M.

AU - Wilson, P.

AU - Raines, T. S.

AU - Boers, J.

AU - Costello, J.

AU - Maher-Albertelli, M.

AU - Mungara, R.

AU - Savoye, L.

AU - White, C. A.

AU - Gullett, C.

AU - Holloway, L.

AU - Morehead, F.

AU - Person, S.

AU - Sibymon, M.

AU - Tanukonda, S.

AU - Adams, C.

AU - Ross, A.

AU - Balasubramanyam, A.

AU - Gaba, R.

AU - Gonzalez Hattery, E.

AU - Ideozu, A.

AU - Jimenez, J.

AU - Montes, G.

AU - Wright, C.

AU - Hollander, P.

AU - Roe, E.

AU - Jackson, A.

AU - Smiley, A.

AU - Burt, P.

AU - Estrada, L.

AU - Chionh, K.

AU - Ismail-Beigi, F.

AU - Falck-Ytter, C.

AU - Sayyed Kassem, L.

AU - Sood, A.

AU - Tiktin, M.

AU - Kulow, T.

AU - Newman, C.

AU - Stancil, K. A.

AU - Cramer, B.

AU - Iacoboni, J.

AU - Kononets, M. V.

AU - Sanders, C.

AU - Tucker, L.

AU - Werner, A.

AU - Maxwell, A.

AU - McPhee, G.

AU - Patel, C.

AU - Colosimo, L.

AU - Krol, A.

AU - Goland, R.

AU - Pring, J.

AU - Alfano, L.

AU - Kringas, P.

AU - Hausheer, C.

AU - Tejada, J.

AU - Gumpel, K.

AU - Kirpitch, A.

AU - Schneier, H.

AU - Abouassi, H.

AU - Chatterjee, R.

AU - Feinglos, M. N.

AU - English Jones, J.

AU - Khan, S. A.

AU - Kimpel, J. B.

AU - Zimmer, R. P.

AU - Furst, M.

AU - Satterwhite, B. M.

AU - Thacker, C. R.

AU - Evans Kreider, K.

AU - Mariash, C. N.

AU - Mather, K. J.

AU - Ismail, H. M.

AU - Lteif, A.

AU - Mullen, M.

AU - Hamilton, T.

AU - Patel, N.

AU - Riera, G.

AU - Jackson, M.

AU - Pirics, V.

AU - Aguillar, D.

AU - Howard, D.

AU - Hurt, S.

AU - Bergenstal, R.

AU - Carlson, A.

AU - Martens, T.

AU - Johnson, M.

AU - Hill, R.

AU - Hyatt, J.

AU - Jensen, C.

AU - Madden, M.

AU - Martin, D.

AU - Willis, H.

AU - Konerza, W.

AU - Yang, S.

AU - Kleeberger, K.

AU - Passi, R.

AU - Fortmann, S.

AU - Herson, M.

AU - Mularski, K.

AU - Glauber, H.

AU - Prihoda, J.

AU - Ash, B.

AU - Carlson, C.

AU - Ramey, P. A.

AU - Schield, E.

AU - Torgrimson-Ojerio, B.

AU - Arnold, K.

AU - Kauffman, B.

AU - Panos, E.

AU - Sahnow, S.

AU - Bays, K.

AU - Berame, K.

AU - Cook, J.

AU - Ghioni, D.

AU - Gluth, J.

AU - Schell, K.

AU - Criscola, J.

AU - Friason, C.

AU - Jones, S.

AU - Nazarov, S.

AU - Rassouli, N.

AU - Puttnam, R.

AU - Ojoawo, B.

AU - Nelson, R.

AU - Curtis, M.

AU - Hollis, B.

AU - Sanders-Jones, C.

AU - Stokes, K.

AU - El-Haqq, Z.

AU - Kolli, A.

AU - Tran, T.

AU - Wexler, D.

AU - Larkin, M. E.

AU - Meigs, J.

AU - Chambers, B.

AU - Dushkin, A.

AU - Rocchio, G.

AU - Yepes, M.

AU - Steiner, B.

AU - Dulin, H.

AU - Cayford, M.

AU - Chu, K.

AU - Demanbey, A.

AU - Hillard, M.

AU - Martin, K.

AU - Thangthaeng, N.

AU - Gurry, L.

AU - Kochis, R.

AU - Raymond, E.

AU - Ripley, V.

AU - Stevens, C.

AU - Park, J.

AU - Aroda, V.

AU - Ghazi, A.

AU - Magee, M.

AU - Ressing, A.

AU - Loveland, A.

AU - Hamm, M.

AU - Hurtado, M.

AU - Kuhn, A.

AU - Leger, J.

AU - Manandhar, L.

AU - Mwicigi, F.

AU - Sanchez, O.

AU - Young, T.

AU - Garg, R.

AU - Lagari-Libhaber, V.

AU - Florez, H. J.

AU - Valencia, W. M.

AU - Marks, J.

AU - McGill, J. B.

AU - Salam, M.

PY - 2024/3/26

Y1 - 2024/3/26

N2 - 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.

AB - 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.

KW - cardiovascular diseases

KW - diabetes mellitus

KW - glucose

KW - liraglutide

UR - http://www.scopus.com/inward/record.url?scp=85188689180&partnerID=8YFLogxK

U2 - 10.1161/CIRCULATIONAHA.123.066604

DO - 10.1161/CIRCULATIONAHA.123.066604

M3 - Article

C2 - 38344820

AN - SCOPUS:85188689180

SN - 0009-7322

VL - 149

SP - 993

EP - 1003

JO - Circulation

JF - Circulation

IS - 13

ER -

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

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Keywords

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