Cardiovascular Risks With SGLT2 Inhibitors in Clinical Practice Among Patients With Type 2 Diabetes

Abstract

Importance: Cardiovascular disease (CVD) can be recurrent during type 2 diabetes (T2D) progression in this aging population. The effectiveness of sodium-glucose cotransporter 2 inhibitor (SGLT2i) therapy on total (ie, first and subsequent) CVD among patients with T2D in clinical practice remains uncertain.

Objective: To analyze the comparative association of SGLT2i vs dipeptidyl peptidase 4 inhibitor (DPP4i) therapy with total CVD among patients with T2D in clinical practice.

Design, setting, and participants: This retrospective cohort study used electronic medical records at the National Cheng Kung University Hospital, a leading medical center in Taiwan, from 2015 through 2021. Adult patients with T2D who initiated first use of the study drugs from 2016 through 2019, with up to 6 years of follow-up, were identified.

Main outcomes and measures: The primary outcomes included total composite CVD events and individual CVD subtypes (ie, atrial fibrillation, coronary heart disease, heart failure, stroke, myocardial infarction, and transient ischemic attack). A shared frailty model analysis was used to assess the association of treatment with repeat CVD events. Data from patients at high risk for CVD recurrence were further analyzed. Data were analyzed from September 1, 2022, to December 31, 2023.

Results: Overall, 8384 patients with T2D were identified (mean [SD] age, 63.7 [12.4] years; 4645 [55.4%] male). A total of 1632 propensity score-matched pairs of SGLT2i (mean [SD] age, 57.8 [12.0] years; 673 [41.2%] female and 959 [58.8%] male) and DPP4i (mean [SD] age, 58.2 [12.9] years; 655 [40.1%] female and 977 [59.9%] male) users were included. SGLT2i was associated with reduced total CVD risk vs DPP4i therapy (hazard ratio [HR], 0.82 [95% CI, 0.69-0.98]) but not the first CVD event (with the use of SGLT2i therapy were more prominent for patients at high risk of CVD (ie, HR, 0.70 [95% CI, 0.62-0.80] for individuals with estimated glomerular filtration rate lower than 60 mL/min/1.73 m2; HR, 0.70 [95% CI, 0.64-0.78]; for individuals having any diabetes-related complications; and HR, 0.72 [95% CI, 0.65-0.80] for individuals with a history of CVD) compared with the overall cohort. Among patients at high risk of CVD, greater reduced total CVD burden associated with SGLT2i therapy was observed for women vs men (eg, HR, 0.59 [95% CI, 0.49-0.72] in the subgroup with CVD history).

Conclusions and relevance: In this cohort study of patients with T2D, the use of SGLT2is vs DPP4is was associated with reduced total cardiovascular burden, suggesting that long-term use of this therapy may optimize treatment benefit among patients with chronic CVD. The SGLT2i-associated benefit among patients with high risk of CVD encourages the prioritization of SGLT2i use for these vulnerable individuals.

Figure 1.. Absolute Standardized Mean Differences of Baseline Characteristics Between SGLT2i and DPP4i Groups Before and After Propensity Score Matching in the Overall Study Cohort

Baseline characteristics were measured in the year before and at the index date (ie, the date of newly stable SGLT2i or DPP4i use in the study period). History of any cardiovascular disease (CVD) was determined from inpatient, outpatient, or emergency department medical records. A standardized mean difference greater than 0.1 indicates a significant between-group difference in the patient baseline characteristic. aDCSI indicates adapted Diabetes Complications Severity Index; AMI, acute myocardial infarction; CHD, coronary heart disease; DPP4is, dipeptidyl peptidase 4 inhibitors; GLA, glucose-lowering agent; GLP-1RA, glucagon-like peptide-1 receptor agonist; HbA_1c, glycated hemoglobin; HDL, high-density lipoprotein; LDL, low-density lipoprotein; RAAS, renin-angiotensin-aldosterone system; SGLT2is, sodium-glucose cotransporter 2 inhibitors; TIA, transient ischemic attack; and TZD, thiazolidinedione.

Figure 2.. Distribution of Total Cardiovascular Disease (CVD) Events by Number of Events During Study Follow-Up for the Overall Cohort and 3 Subgroups

Percentages were calculated as the number of CVD events in each category divided by the total number of CVD events in each treatment group during the follow-up period. aDCSI represents adapted Diabetes Complications Severity Index; DPP4is, dipeptidyl peptidase 4 inhibitors; eGFR, estimated glomerular filtration rate; HR, hazard ratio; and SGLT2is, sodium-glucose cotransporter 2 inhibitors.

Figure 3.. Risk for Time to First Cardiovascular Disease (CVD) Event (Using Cox Proportional Hazards Model Analysis) and Total CVD Events (Using Shared Frailty Model Analysis) Associated With SGLT2i vs DPP4i Use in Overall Patient Cohort (N = 1632)

DPP4is represents dipeptidyl peptidase 4 inhibitors: SGLT2is, sodium-glucose cotransporter 2 inhibitors. ^aEvents are the first or repeat CVD events, and rates (%) were calculated as the total number of events divided by the total number of patients in each treatment group. ^bComposite CVD included atrial fibrillation, coronary heart disease, heart failure, hemorrhagic stroke, ischemic stroke, myocardial infarction, and transient ischemic attack. ^cSince no recurrent transient ischemic attacks occurred in the study follow-up period, the analysis for this event was not performed.

Figure 4.. HRs for the Interaction of Treatment Exposure With Patient Baseline Characteristics in the Overall Cohort and Patient Subgroups

GLA (glucose-lowering agent) includes acarbose, glucagon-like peptide-1 receptor agonists, insulin, meglitinides, metformin, sulfonylureas, and thiazolidinedione. aDCSI indicates adapted Diabetes Complications Severity Index; CVD, cardiovascular disease; DPP4is, dipeptidyl peptidase 4 inhibitors; eGFR, estimated glomerular filtration rate; HR, hazard ratio; and SGLT2is, sodium-glucose cotransporter 2 inhibitors. ^aEvents included the first and repeat CVD events. ^bHistory of any CVD was determined from inpatient, outpatient, and emergency department medical records.