Exploring the mortality and cardiovascular outcomes with SGLT-2 inhibitors in patients with T2DM at dialysis commencement: a health global federated network analysis

Abstract

Background: Sodium-glucose cotransporter 2 inhibitors (SGLT-2is) have demonstrated associations with lowering cardiovascular outcomes in patients with type 2 diabetes mellitus (T2DM). However, the impact of SGLT-2is on individuals at dialysis commencement remains unclear. The aim of this real-world study is to study the association between SGLT-2is and outcomes in patients with T2DM at dialysis commencement.

Methods: This is a retrospective cohort study of electronic health records (EHRs) of patients with T2DM from TriNetX Research Network database between January 1, 2012, and January 1, 2024. New-users using intention to treatment design was employed and propensity score matching was utilized to select the cohort. Clinical outcomes included major adverse cardiac events (MACE) and all-cause mortality. Safety outcomes using ICD-10 codes, ketoacidosis, urinary tract infection (UTI) or genital infection, dehydration, bone fracture, below-knee amputation, hypoglycemia, and achieving dialysis-free status at 90 days and 90-day readmission.

Results: Of 49,762 patients with T2DM who initiated dialysis for evaluation, a mere 1.57% of patients utilized SGLT-2is within 3 months after dialysis. 771 SGLT-2i users (age 63.3 ± 12.3 years, male 65.1%) were matched with 771 non-users (age 63.1 ± 12.9 years, male 65.8%). After a median follow-up of 2.0 (IQR 0.3-3.9) years, SGLT-2i users were associated with a lower risk of MACE (adjusted Hazard Ratio [aHR] = 0.52, p value < 0.001), all-cause mortality (aHR = 0.49, p < 0.001). SGLT-2i users were more likely to become dialysis-free 90 days after the index date (aHR = 0.49, p < 0.001). No significant differences were observed in the incidence of ketoacidosis, UTI or genital infection, hypoglycemia, dehydration, bone fractures, below-knee amputations, or 90-day readmissions.

Conclusions: Our findings indicated a lower incidence of all-cause mortality and MACE after long-term follow-up, along with a higher likelihood of achieving dialysis-free status at 90 days in SGLT-2i users. Importantly, they underscored the potential cardiovascular protection and safety of SGLT-2is use in T2DM patients at the onset of dialysis.

Keywords: Dialysis initiation; Major adverse cardiovascular events; Propensity score matching; Sodium-glucose cotransporter 2 inhibitors; Type 2 diabetes mellitus.

Fig. 1

Enrollment algorithm for patients. BMI body mass index, T2DM type 2 diabetes mellitus, PSM propensity score matching, SBP systolic blood pressure, SGLT-2is sodium–glucose cotransporter 2 inhibitors

Fig. 2

Comparison of the pre-specified outcomes of patients treated with SGLT-2is versus those non-users after prosperity score matching. The forest plots illustrated the adjusted HRs of all-cause mortality, MACE, and other secondary outcomes for SGLT-2i users versus non-users after propensity score matching. The plots present both the adjusted HRs and their 95% confidence intervals (CIs), represented as error bars. The vertical line denotes an aHR of 1.00, with lower limits of the 95% CIs exceeding 1.00 indicating a statistically significant increased risk. aHR adjust hazard ratio, 3p-MACE 3-piont major adverse cardiac event, MACE major adverse cardiac event, PS propensity score, UTI urinary tract infection

Fig. 3

Kaplan-Meier curves of the pre-specified long-term outcome. The blue curve represents individuals who are SGLT-2i users, while the purple curve represents those who are SGLT-2i non-users. Shaded areas indicate 95% CIs. (A) All-cause mortality (log-rank P < 0. 001). (B) MACE (log-rank P < 0. 001). MACE major adverse cardiac event, SGLT-2is sodium–glucose cotransporter 2 inhibitors

Fig. 4

Subgroup analysis. The forest plots illustrated the adjusted HRs of all-cause mortality and MACE for SGLT-2is users versus non-users across various subgroups. The plots present both the adjusted HRs and their 95% confidence intervals (CIs), represented as error bars. The vertical line denotes an aHR of 1.00, with lower limits of the 95% CIs exceeding 1.00 indicating a statistically significant increased risk. Advanced CKD defined as baseline kidney function less than eGFR 15 ml/min/1.73². ACEi angiotensin converting enzyme inhibitors, ARB angiotensin receptor blockers, BMI body mass index, CI confidence interval, CKD chronic kidney disease, CVD cardiovascular diseases, eGFR estimated, glomerular filtration rate, HbA1c Glycated Hemoglobin, aHR adjusted hazard ratio, MACE major adverse cardiac event, SGLT-2i sodium–glucose cotransporter 2 inhibitor