How does empagliflozin perform in older type 2 diabetics compared to liraglutide and sitagliptin in terms of HHF and MACE risks?
Last fall, a study was published in JAMA Network Open, focusing on older patients with type 2 diabetes mellitus (DM2), examining the cardiovascular risk impact when treated with empagliflozin, liraglutide, or sitagliptin. Currently, there is limited evidence comparing the effectiveness of various glucose-lowering agents intended for second-line treatment in DM2 patients undergoing routine care, who have a broad spectrum of cardiorenal risks.
Antidiabetics and cardiovascular risk reduction
Expert societies recommend two classes of glucose-lowering agents for their cardioprotective effects: sodium-glucose cotransporter 2 inhibitors (SGLT2i, also known as gliflozins) and glucagon-like peptide 1 receptor agonists (GLP-1RA). The implementation of these guidelines in routine practice remains a challenge mainly because the cardiovascular (CV) benefit of these drugs may not be uniform across patient subgroups.
The protective effects of SGLT2i and GLP-1RA concerning major adverse cardiovascular events (MACE – myocardial infarction, stroke, or CV death) were more pronounced in patients with pre-existing atherosclerotic cardiovascular disease (ASCVD) or heart failure (HF), whereas their influence on heart failure hospitalization (HHF) was consistent regardless of baseline cardiovascular status. According to available clinical trial data, age is also a potential modifier of CV effects of SGLT2i and GLP-1RA – for example, SGLT2i empagliflozin shows a greater effect on reducing CV death and MACE risk in patients older than 65 years. Cardioprotective benefits and reduced MACE risk were reported for liraglutide, the first GLP-1RA, particularly in patients older than 75 years.
The presented study aimed to evaluate the association of empagliflozin use with CV outcomes compared to liraglutide, as the most frequently used GLP-1RA, and sitagliptin, the most commonly used dipeptidyl peptidase-4 (DPP-4) inhibitor with proven neutral CV effect. The CV benefit was assessed overall and in subgroups by age, sex, and the presence of ASCVD, HF, and chronic kidney disease (CKD).
Study cohort
This retrospective cohort study involved effectiveness comparisons based on data from the US national health insurance system Medicare from August 1, 2014, to September 30, 2018, with follow-up from medication initiation to therapy change, death, or a gap in Medicare enrollment exceeding 30 days. Analysis took place from October 1, 2021, to April 30, 2022. Patients older than 65 years with DM2 were included.
Cohort 1 consisted of 45,788 patients (22,894 propensity score-matched pairs) who initiated treatment with empagliflozin or liraglutide. The median age in this cohort was 71.9 years, 51.1% were women, and 83.1% were white. Cohort 2 included 45,624 patients (22,812 pairs) with a median age of 72.1 years (46.9% women, 82.9% white) who started empagliflozin or sitagliptin.
The primary outcome measures were composite modified MACE (including MI, ischemic or hemorrhagic stroke, and all-cause mortality) and heart failure as the primary cause of hospitalization. Secondary outcome measures included individual components of the modified MACE and HF as a cause of hospitalization.
Results
Patients in Cohort 1 treated with empagliflozin had a similar risk regarding the modified MACE (hazard ratio [HR] 0.90; 95% confidence interval [CI] 0.79–1.03) and reduced HHF risk (HR 0.66; 95% CI 0.52–0.82) compared to those who initiated liraglutide therapy. Across subgroups, empagliflozin was associated with a lower risk of modified MACE in patients with a history of ASCVD (HR 0.83) and HF (HR 0.77). Potential heterogeneity of estimates by sex was observed (men vs. women: HR 0.85 vs. 1.16; p = 0.02 for homogeneity). The reduction in HHF risk was observed across most subgroups.
Compared to sitagliptin, empagliflozin was associated with reduced MACE risk (HR 0.68; 95% CI 0.60–0.77) and HHF (HR 0.45; 95% CI 0.36–0.56), consistently across all subgroups. The absolute benefits of empagliflozin compared to sitagliptin were greater in patients with a history of ASCVD, HF, or CKD.
Summary and discussion
In this study focusing on older adults, empagliflozin was associated with a lower risk of hospitalization for heart failure compared to liraglutide and sitagliptin, similar effects on the modified MACE compared to liraglutide, lower risk concerning the modified MACE compared to sitagliptin, and greater absolute benefits in patients with existing cardiorenal disease.
These findings suggest that, concerning the risk of hospitalization due to heart failure, older patients with type 2 diabetes may benefit more from empagliflozin than from liraglutide or sitagliptin, while for MACE risk, empagliflozin might be more suitable than liraglutide in patients with a history of cardiovascular disease and than sitagliptin across all patient subgroups.
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Source: Htoo P. T., Tesfaye H., Schneeweiss S. et al. Comparative effectiveness of empagliflozin vs liraglutide or sitagliptin in older adults with diverse patient characteristics. JAMA Netw Open 2022 Oct; 5 (10): e2237606, doi: 10.1001/jamanetworkopen.2022.37606.
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