Comparative Effectiveness of Second-Line Antihyperglycemic Agents for Cardiovascular Outcomes
Rohan KheraArya AminorroayaLovedeep Singh DhingraPhyllis ThangarajAline Pedroso CamargosFan BuXiyu DingAkihiko NishimuraTara V. AnandFaaizah ArshadClair BlacketerYi ChaiShounak ChattopadhyayMichael B. CookDavid A. DorrTalita Duarte‐SallesScott L. DuVallThomas FalconerTina FrenchElizabeth E HanchrowGuneet KaurWallis C. Y. LauJing LiKelly LiYuntian LiuYuan LuKenneth K. C. ManMichael E. MathenyNestoras MathioudakisJody‐Ann McLeggonMichael F McLemoreEvan MintyDaniel R. MoralesPaul NagyAnna OstropoletsAndrea PistilloNicole PrattCarlen ReyesLauren RichterJoseph S. RossElise RuanSarah SeagerKatherine SimonBenjamin ViernesJianxiao YangCan YinSeng Chan YouJin ZhouPatrick B. RyanMartijn J. SchuemieHarlan M. KrumholzGeorge HripcsakMarc A. Suchard
Why the study?
Do SGLT2 inhibitors and GLP1 receptor agonists improve cardiovascular outcomes compared to DPP4 inhibitors and sulfonylureas as second-line agents in patients with T2DM and CVD?
Key Points
- To compare the cardiovascular effectiveness of SGLT2 inhibitors, GLP-1 receptor agonists, DPP-4 inhibitors, and sulfonylureas as second-line antihyperglycemic treatments in patients with type 2 diabetes and cardiovascular disease.
- Included 1,492,855 patients with type 2 diabetes and cardiovascular disease across ten international data sources from the LEGEND-T2DM network (1992–2021) initiating second-line therapy after metformin monotherapy.
- Conducted an active comparator target trial emulation using large-scale propensity score modeling and on-treatment Cox proportional hazards models pooled via random-effects meta-analysis.
- Across 5.2 million patient-years of follow-up (25,982 3-point MACE and 41,447 4-point MACE events), SGLT2is and GLP1-RAs showed no significant difference for 3-point MACE (HR 1.06 [95% CI, 0.96–1.17]) or 4-point MACE (HR 1.05 [95% CI, 0.97–1.13]).
- Both SGLT2is and GLP1-RAs showed lower 3-point MACE risk than DPP4is (HR 0.89 [95% CI, 0.79–1.00] and HR 0.83 [95% CI, 0.70–0.98]) and sulfonylureas (HR 0.76 [95% CI, 0.65–0.89] and HR 0.72 [95% CI, 0.58–0.88]).
- DPP-4 inhibitors were associated with a lower risk of 3-point MACE compared with sulfonylureas (HR 0.87 [95% CI, 0.79–0.95]), with consistent findings observed across all comparisons for 4-point MACE.
Study Design
Type
Cohort (n=1,492,855)
Multicenter
Yes
Structured PICO
Do SGLT2 inhibitors and GLP1 receptor agonists improve cardiovascular outcomes compared to DPP4 inhibitors and sulfonylureas as second-line agents in patients with T2DM and CVD?
P
Population
1,492,855 patients with type 2 diabetes and cardiovascular disease on metformin monotherapy initiating a second-line agent, followed over 5.2 million patient-years.
E
Exposure
Initiation of SGLT2 inhibitors (SGLT2is) or GLP1 receptor agonists (GLP1-RAs) as second-line antihyperglycemic agents.
C
Comparator
Active comparators including dipeptidyl peptidase-4 inhibitors (DPP4is) and sulfonylureas (SUs) as second-line agents.
O
Outcome
3-point MACE (myocardial infarction, stroke, death) and 4-point MACE (3-point MACE + heart failure hospitalization).composite
Main Result
Hazard Ratio: 0.89 (95% CI 0.79–1)
Key expert perspectives
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“The older generation drugs do seem to be inferior on cardiovascular risk reduction. I think that's an important key takeaway while we make these decisions in practice, especially among those who have high risk, whether continued use of some of the old drugs is appropriate.”
Implication
SGLT2 inhibitors and GLP1 receptor agonists provide comparable cardiovascular risk reduction and are superior to DPP4 inhibitors and sulfonylureas as second-line agents in patients with T2DM and CVD.
Abstract
Background: Sodium-glucose co-transporter-2 inhibitors (SGLT2is) and glucagon-like peptide-1 receptor agonist (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. Objectives: To compare the cardiovascular effectiveness of SGLT2is, GLP1-RAs, dipeptidyl peptidase-4 inhibitors (DPP4is), and sulfonylureas (SUs) as second-line antihyperglycemic agents in T2DM. 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 cardiovascular disease (CVD) on metformin monotherapy who initiated one of four second-line agents (SGLT2is, GLP1-RAs, DPP4is, or 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 using random-effects meta-analysis. Results: 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 3-point MACE risk than 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 0.72 [0.58–0.88]). 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]). Conclusions: In patients with T2DM and 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.
Discussion
No takes yet. Share an insight, caveat, or question.
Cite This Study
Khera et al. (2024) conducted a cohort in Type 2 diabetes mellitus and cardiovascular disease (n=1,492,855). SGLT2 inhibitors and GLP-1 receptor agonists vs. DPP-4 inhibitors and sulfonylureas was evaluated on 3-point MACE (myocardial infarction, stroke, death) (HR 0.89, 95% CI 0.79-1.00).