Compare SGLT2I versus non-SGLT2I users in type-2 diabetic mellitus patients on GLP-1 receptor agonist: A population-based and machine learning causal inference analysis

Background Both sodium-glucose cotransporter-2 (SGLT2) inhibitors and GLP-1 receptor agonists (GLP1a) demonstrated benefits against cardiovascular diseases in type 2 diabetes (T2D). However, the effects of SGLT2I amongst patients already on GLP1a users remain unknown. Objective This real-world study compared the risks of cardiovascular diseases with and without exposure to SGLT2I amongst GLP1a users. Methods This was a retrospective population-based cohort study of patients with type-2 diabetes mellitus (T2DM) on GLP1a between 1st January 2015 and 31st December 2020 using a territory-wide registry from Hong Kong. The primary outcomes were new-onset myocardial infarction, atrial fibrillation, heart failure, and stroke/transient ischaemic attack (TIA). The secondary outcome was all-cause mortality. Propensity score matching (1:2 ratio) using the nearest neighbour search was performed. Multivariable Cox regression was used to identify significant associations. The machine learning causal inference analysis was used to estimate the treatment effect. Results This cohort included 2526 T2DM patients on GLP1a (median age: 52.5 years old [SD: 10.9]; 57.34 % males). The SGLT2I users and non-SGLT2I users consisted of 1968 patients and 558 patients, respectively. After matching, non-SGLT2I users were associated with high risks of myocardial infarction (Hazard ratio [HR]: 2.91; 95% Confidence Interval [CI]: 1.30-6.59) and heart failure (HR: 2.49; 95% CI: 1.22-5.08) compared to non-SGLT2I users after adjusting for demographics, comorbidities, medications, renal function, and glycaemic tests. However, non-SGLT2I users were not associated with the risks of atrial fibrillation (HR: 1.52; 95% CI: 0.65-3.53) and stroke/TIA (HR: 1.72; 95% CI: 0.70-4.24). The results remained consistent in the competing risk and the sensitivity analyses. Conclusions SGLT2I non-users was associated with higher risks of myocardial infarction and heart failure when compared to SGLT2I users after adjustments amongst T2DM patients on GLP1a. The result remained consistent in the machine learning causal inference analysis. ![Figure][1] ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement The authors received no funding for the research, authorship, and/or publication of this article. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study was approved by the Institutional Review Board of the University of Hong Kong/Hospital Authority Hong Kong West Cluster (HKU/HA HKWC IRB) (UW-20-250), and New Territories East Cluster-Chinese University of Hong Kong (NTEC-UCHK) Clinical Research Ethnics Committee (2018.309, 2018.643) and complied with the Declaration of Helsinki. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data are not available, as the data custodians (the Hospital Authority and the Department of Health of Hong Kong SAR) have not given permission for sharing due to patient confidentiality and privacy concerns. Local academic institutions, government departments, or nongovernmental organizations may apply for the access to data through the Hospital Authority's data sharing portal (https://www3.ha.org.hk/data). [1]: pending:yes