Comparative Effectiveness of Second-line Antihyperglycemic Agents for Cardiovascular Outcomes: A Large-scale, Multinational, Federated Analysis of the LEGEND-T2DM Study
ABSTRACT Background SGLT2 inhibitors (SGLT2is) and GLP-1 receptor agonists (GLP1-RAs) reduce major adverse cardiovascular events (MACE) in patients with type 2 diabetes mellitus (T2DM). However, their effectiveness relative to each other and other second-line antihyperglycemic agents is unknown, without any major ongoing head-to-head trials.Methods Across the LEGEND-T2DM network, we included ten federated international data sources, spanning 1992-2021. We identified 1,492,855 patients with T2DM and established cardiovascular disease (CVD) on metformin monotherapy who initiated one of four second-line agents (SGLT2is, GLP1-RAs, dipeptidyl peptidase 4 inhibitor [DPP4is], sulfonylureas [SUs]). We used large-scale propensity score models to conduct an active comparator, target trial emulation for pairwise comparisons. After evaluating empirical equipoise and population generalizability, we fit on-treatment Cox proportional hazard models for 3-point MACE (myocardial infarction, stroke, death) and 4-point MACE (3-point MACE + heart failure hospitalization) risk, and combined hazard ratio (HR) estimates in a random-effects meta-analysis.Findings Across cohorts, 16·4%, 8·3%, 27·7%, and 47·6% of individuals with T2DM initiated SGLT2is, GLP1-RAs, DPP4is, and SUs, respectively. Over 5·2 million patient-years of follow-up and 489 million patient-days of time at-risk, there were 25,982 3-point MACE and 41,447 4-point MACE events. SGLT2is and GLP1-RAs were associated with a lower risk for 3-point MACE compared with DPP4is (HR 0·89 [95% CI, 0·79-1·00] and 0·83 [0·70-0·98]), and SUs (HR 0·76 [0·65-0·89] and 0·71 [0·59-0·86]). DPP4is were associated with a lower 3-point MACE risk versus SUs (HR 0·87 [0·79-0·95]). The pattern was consistent for 4-point MACE for the comparisons above. There were no significant differences between SGLT2is and GLP1-RAs for 3-point or 4-point MACE (HR 1·06 [0·96-1·17] and 1·05 [0·97-1·13]).Interpretation In patients with T2DM and established CVD, we found comparable cardiovascular risk reduction with SGLT2is and GLP1-RAs, with both agents more effective than DPP4is, which in turn were more effective than SUs. These findings suggest that the use of GLP1-RAs and SGLT2is should be prioritized as second-line agents in those with established CVD.Funding National Institutes of Health, United States Department of Veterans Affairs.
Medienart: |
Preprint |
---|
Erscheinungsjahr: |
2024 |
---|---|
Erschienen: |
2024 |
Enthalten in: |
bioRxiv.org - (2024) vom: 10. Feb. Zur Gesamtaufnahme - year:2024 |
---|
Sprache: |
Englisch |
---|
Beteiligte Personen: |
Khera, Rohan [VerfasserIn] |
---|
Links: |
Volltext [kostenfrei] |
---|
Themen: |
---|
doi: |
10.1101/2024.02.05.24302354 |
---|
funding: |
|
---|---|
Förderinstitution / Projekttitel: |
|
PPN (Katalog-ID): |
XBI042450969 |
---|
LEADER | 01000caa a22002652 4500 | ||
---|---|---|---|
001 | XBI042450969 | ||
003 | DE-627 | ||
005 | 20240211090427.0 | ||
007 | cr uuu---uuuuu | ||
008 | 240209s2024 xx |||||o 00| ||eng c | ||
024 | 7 | |a 10.1101/2024.02.05.24302354 |2 doi | |
035 | |a (DE-627)XBI042450969 | ||
035 | |a (biorXiv)10.1101/2024.02.05.24302354 | ||
040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
041 | |a eng | ||
100 | 1 | |a Khera, Rohan |e verfasserin |0 (orcid)0000-0001-9467-6199 |4 aut | |
245 | 1 | 0 | |a Comparative Effectiveness of Second-line Antihyperglycemic Agents for Cardiovascular Outcomes: A Large-scale, Multinational, Federated Analysis of the LEGEND-T2DM Study |
264 | 1 | |c 2024 | |
336 | |a Text |b txt |2 rdacontent | ||
337 | |a Computermedien |b c |2 rdamedia | ||
338 | |a Online-Ressource |b cr |2 rdacarrier | ||
520 | |a ABSTRACT Background SGLT2 inhibitors (SGLT2is) and GLP-1 receptor agonists (GLP1-RAs) reduce major adverse cardiovascular events (MACE) in patients with type 2 diabetes mellitus (T2DM). However, their effectiveness relative to each other and other second-line antihyperglycemic agents is unknown, without any major ongoing head-to-head trials.Methods Across the LEGEND-T2DM network, we included ten federated international data sources, spanning 1992-2021. We identified 1,492,855 patients with T2DM and established cardiovascular disease (CVD) on metformin monotherapy who initiated one of four second-line agents (SGLT2is, GLP1-RAs, dipeptidyl peptidase 4 inhibitor [DPP4is], sulfonylureas [SUs]). We used large-scale propensity score models to conduct an active comparator, target trial emulation for pairwise comparisons. After evaluating empirical equipoise and population generalizability, we fit on-treatment Cox proportional hazard models for 3-point MACE (myocardial infarction, stroke, death) and 4-point MACE (3-point MACE + heart failure hospitalization) risk, and combined hazard ratio (HR) estimates in a random-effects meta-analysis.Findings Across cohorts, 16·4%, 8·3%, 27·7%, and 47·6% of individuals with T2DM initiated SGLT2is, GLP1-RAs, DPP4is, and SUs, respectively. Over 5·2 million patient-years of follow-up and 489 million patient-days of time at-risk, there were 25,982 3-point MACE and 41,447 4-point MACE events. SGLT2is and GLP1-RAs were associated with a lower risk for 3-point MACE compared with DPP4is (HR 0·89 [95% CI, 0·79-1·00] and 0·83 [0·70-0·98]), and SUs (HR 0·76 [0·65-0·89] and 0·71 [0·59-0·86]). DPP4is were associated with a lower 3-point MACE risk versus SUs (HR 0·87 [0·79-0·95]). The pattern was consistent for 4-point MACE for the comparisons above. There were no significant differences between SGLT2is and GLP1-RAs for 3-point or 4-point MACE (HR 1·06 [0·96-1·17] and 1·05 [0·97-1·13]).Interpretation In patients with T2DM and established CVD, we found comparable cardiovascular risk reduction with SGLT2is and GLP1-RAs, with both agents more effective than DPP4is, which in turn were more effective than SUs. These findings suggest that the use of GLP1-RAs and SGLT2is should be prioritized as second-line agents in those with established CVD.Funding National Institutes of Health, United States Department of Veterans Affairs | ||
650 | 4 | |a Biology |7 (dpeaa)DE-84 | |
650 | 4 | |a 570 |7 (dpeaa)DE-84 | |
700 | 1 | |a Aminorroaya, Arya |4 aut | |
700 | 1 | |a Dhingra, Lovedeep Singh |0 (orcid)0000-0002-5664-4126 |4 aut | |
700 | 1 | |a Thangaraj, Phyllis M |4 aut | |
700 | 1 | |a Camargos, Aline Pedroso |4 aut | |
700 | 1 | |a Bu, Fan |4 aut | |
700 | 1 | |a Ding, Xiyu |4 aut | |
700 | 1 | |a Nishimura, Akihiko |4 aut | |
700 | 1 | |a Anand, Tara V |4 aut | |
700 | 1 | |a Arshad, Faaizah |4 aut | |
700 | 1 | |a Blacketer, Clair |4 aut | |
700 | 1 | |a Chai, Yi |4 aut | |
700 | 1 | |a Chattopadhyay, Shounak |4 aut | |
700 | 1 | |a Cook, Michael |4 aut | |
700 | 1 | |a Dorr, David A |0 (orcid)0000-0003-2318-7261 |4 aut | |
700 | 1 | |a Duarte-Salles, Talita |0 (orcid)0000-0002-8274-0357 |4 aut | |
700 | 1 | |a DuVall, Scott L |0 (orcid)0000-0002-4898-3865 |4 aut | |
700 | 1 | |a Falconer, Thomas |4 aut | |
700 | 1 | |a French, Tina E |4 aut | |
700 | 1 | |a Hanchrow, Elizabeth E |4 aut | |
700 | 1 | |a Kaur, Guneet |4 aut | |
700 | 1 | |a Lau, Wallis CY |0 (orcid)0000-0003-2320-0470 |4 aut | |
700 | 1 | |a Li, Jing |4 aut | |
700 | 1 | |a Li, Kelly |4 aut | |
700 | 1 | |a Liu, Yuntian |4 aut | |
700 | 1 | |a Lu, Yuan |0 (orcid)0000-0001-5264-2169 |4 aut | |
700 | 1 | |a Man, Kenneth KC |0 (orcid)0000-0001-8645-1942 |4 aut | |
700 | 1 | |a Matheny, Michael E |4 aut | |
700 | 1 | |a Mathioudakis, Nestoras |4 aut | |
700 | 1 | |a McLeggon, Jody-Ann |4 aut | |
700 | 1 | |a McLemore, Michael F |4 aut | |
700 | 1 | |a Minty, Evan |4 aut | |
700 | 1 | |a Morales, Daniel R |4 aut | |
700 | 1 | |a Nagy, Paul |4 aut | |
700 | 1 | |a Ostropolets, Anna |4 aut | |
700 | 1 | |a Pistillo, Andrea |4 aut | |
700 | 1 | |a Phan, Thanh-Phuc |4 aut | |
700 | 1 | |a Pratt, Nicole |4 aut | |
700 | 1 | |a Reyes, Carlen |4 aut | |
700 | 1 | |a Richter, Lauren |4 aut | |
700 | 1 | |a Ross, Joseph |0 (orcid)0000-0002-9218-3320 |4 aut | |
700 | 1 | |a Ruan, Elise |4 aut | |
700 | 1 | |a Seager, Sarah L |4 aut | |
700 | 1 | |a Simon, Katherine R |4 aut | |
700 | 1 | |a Viernes, Benjamin |4 aut | |
700 | 1 | |a Yang, Jianxiao |4 aut | |
700 | 1 | |a Yin, Can |4 aut | |
700 | 1 | |a You, Seng Chan |4 aut | |
700 | 1 | |a Zhou, Jin J |4 aut | |
700 | 1 | |a Ryan, Patrick B |4 aut | |
700 | 1 | |a Schuemie, Martijn J |4 aut | |
700 | 1 | |a Krumholz, Harlan M |0 (orcid)0000-0003-2046-127X |4 aut | |
700 | 1 | |a Hripcsak, George |4 aut | |
700 | 1 | |a Suchard, Marc A |0 (orcid)0000-0001-9818-479X |4 aut | |
773 | 0 | 8 | |i Enthalten in |t bioRxiv.org |g (2024) vom: 10. Feb. |
773 | 1 | 8 | |g year:2024 |g day:10 |g month:02 |
856 | 4 | 0 | |u http://dx.doi.org/10.1101/2024.02.05.24302354 |z kostenfrei |3 Volltext |
912 | |a GBV_XBI | ||
951 | |a AR | ||
952 | |j 2024 |b 10 |c 02 |