Risk of ICU Admission and Related Mortality in Patients With Sodium-Glucose Cotransporter 2 Inhibitors and Dipeptidyl Peptidase-4 Inhibitors: A Territory-Wide Retrospective Cohort Study

Abstract

Objectives: The benefit of sodium-glucose cotransporter 2 (SGLT2) inhibitors in reducing the occurrence rate of adverse cardiac and renal outcomes in patients with type 2 diabetes has been well described in randomized trials. Whether this benefit extends to patients at the most severe end of the disease spectrum requiring admission to the ICU remains to be examined.

Design: Retrospective observational study.

Setting: Data were obtained from a territory-wide clinical registry in Hong Kong (Clinical Data Analysis and Reporting System).

Patients: All adult patients (age ≥ 18 yr) with type 2 diabetes and newly prescribed SGLT2 inhibitors or dipeptidyl peptidase-4 (DPP-4) inhibitors between January 1, 2015, and December 31, 2019.

Interventions: None.

Measurements and main results: After 1:2 propensity score matching, a total of 27,972 patients (10,308 SGLT2 inhibitors vs 17,664 DPP-4 inhibitors) were included in the final analysis. The mean age was 59 ± 11 years, and 17,416 (62.3%) were male. The median follow-up period was 2.9 years. The use of SGLT2 inhibitors was associated with decreased ICU admission (286 [2.8%] vs 645 [3.7%]; hazard ratio [HR], 0.79; 95% CI, 0.69-0.91; p = 0.001) and lower risks of all-cause mortality (315 [3.1%] vs 1,327 [7.5%]; HR, 0.44; 95% CI, 0.38-0.49; p < 0.001), compared with DPP-4 inhibitors. The severity of illness upon ICU admission by Acute Physiology and Chronic Health Evaluation IV-predicted risk of death was also lower in SGLT2 inhibitors users. Admissions and mortality due to sepsis were lower in SGLT2 inhibitor users compared with DPP-4 inhibitor users (admissions for sepsis: 45 [0.4%] vs 134 [0.8%]; p = 0.001 and mortality: 59 [0.6%] vs 414 [2.3%]; p < 0.001, respectively).

Conclusions: In patients with type 2 diabetes, SGLT2 inhibitors were independently associated with lower rates of ICU admission and all-cause mortality across various disease categories.

Figure 1.

Estimated probabilities of ICU admission stratified by sodium-glucose cotransporter 2 (SGLT2) inhibitor group and dipeptidyl peptidase-4 (DPP-4) inhibitor group. Use of SGLT2 inhibitors was associated with lower risks of critical illness requiring any ICU admission (hazard ratio [HR], 0.79; 95% CI, 0.69–0.91; p = 0.001) (A), emergent ICU admission (HR, 0.75; 95% CI, 0.64–0.89; p = 0.001) (B), and nonoperative ICU admission (HR, 0.66; 95% CI, 0.54–0.79; p < 0.001) (C) compared with use of DPP-4 inhibitors.

Figure 2.

Estimated probabilities of all-cause mortality stratified by sodium-glucose cotransporter 2 (SGLT2) inhibitor group and dipeptidyl peptidase-4 (DPP-4) inhibitor group. Use of SGLT2 inhibitors was associated with lower risks of all-cause mortality (hazard ratio [HR], 0.44; 95% CI, 0.38–0.49; p < 0.001) (A), mortality due to infectious causes (HR, 0.26; 95% CI, 0.20–0.34; p < 0.001) (B), cardiovascular mortality (HR, 0.58; 95% CI, 0.46–0.72; p < 0.001) (C), and renal mortality (HR, 0.22; 95% CI, 0.07–0.73; p = 0.014) (D) compared with use of DPP-4 inhibitors.

Figure 3.

Forest plots for subgroups analyses. The effect of sodium-glucose cotransporter 2 inhibitors (SGLT2i) on the outcomes of ICU admission and all-cause mortality was modified by estimated glomerular filtration rate (eGFR) (p for interaction < 0.001 and 0.004, respectively). Patients who were on less than two oral hypoglycemic agents and patients who were initiated on index medication before 2018 also derived greater clinical benefit. There was no effect modification in other predefined subgroups for the two co-primary outcomes—critical illness requiring any ICU admission (A) and all-cause mortality (B). DDP4i = dipeptidyl peptidase-4 inhibitor, HbA1c = hemoglobin A1c.