SGLT2 Inhibitor Use and Risk for ASCVD Events in Type 2 Diabetes

Use of sodium-glucose transport 2 (SGLT2) inhibitors is not associated with a significant decrease in the risk for acute coronary syndrome (ACS), peripheral arterial occlusive disease (PAOD), or ischemic stroke (IS) among patients with type 2 diabetes, according to a study in Cardiovascular Diabetology.

Researchers conducted a meta-analysis to assess the relationship between SGLT2 inhibitor use and atherosclerotic cardiovascular disease events in patients with type 2 diabetes.

A literature search was performed in PubMed, Embase, Cochrane Library, and ClinicalTrials.gov databases, with the last search occurring in November 2022. Eligible studies were in English, had a comprehensive documentation of outcomes, and included patients aged 18 years or older with type 2 diabetes. The control group was defined as individuals who received placebo or active therapy using oral hypoglycemic drugs.

The primary outcome was the incidence of ACS (acute myocardial infarction and/or unstable angina), PAOD, and IS.

The analysis included 43 randomized controlled trials (RCTs) with 79,504 patients who had type 2 diabetes. Of these patients, 48,568 received SGLT2 inhibitors in combination with background treatment, and 30,936 patients used placebo or oral hypoglycemic drugs. The trials were published from 2010 to 2020 and reported on canagliflozin (10 studies), dapagliflozin (15 studies), empagliflozin (15 studies), and ertugliflozin (6 studies). The median follow-up was 1.9 years.

Among 35 studies reporting ACS as an adverse event, no significant heterogeneity was observed (I²=0%, P =.82 for the Q test). The overall risk ratio (RR) was not significant (0.97; 95% CI, 0.89-1.05), and ACS was not significantly different among the 4 SGLT2 inhibitor groups and the control group.

In 20 studies including PAOD as an adverse event, no significant heterogeneity occurred (I²=0%; P =.90 for the Q test). The RR was not significant (0.98; 95% CI, 0.78-1.24). PAOD was not different among the 4 SGLT2 inhibitor groups in the subanalysis.

IS was reported as an adverse event in 23 trials, with no significant heterogeneity (I²=0%; P =.96 for the Q test). The overall RR was not significant (0.95; 95% CI, 0.79-1.14). In subgroup analysis, IS was not significantly different among the 4 SGLT2 inhibitor groups and the control group.

Cardiovascular mortality was included as an adverse event in 23 studies, with no heterogeneity (I²=32%; P =.11 for the Q test). The overall RR was significant (0.85; 95% CI, 0.77-0.93). In the subgroup analysis, canagliflozin and empagliflozin had lower RRs, and dapagliflozin and ertugliflozin did not have a benefit for cardiovascular mortality.

In 38 studies with all-cause mortality as an adverse event, no significant heterogeneity was observed (I²=0%; P =.61 for the Q test). The overall RR was significant (0.88; 95% CI, 0.82-0.94). Subgroup analysis showed that empagliflozin had a lower risk of all-cause mortality, and canagliflozin, dapagliflozin, and ertugliflozin were similar to the control group.

A limitation of this study is that baseline variations in clinical settings, age, follow-up, and disease duration could have biased the findings. Also, discrepancies may have occurred in the number of cases reported for the same disease on ClinicalTrials.gov across funding organizations, and the investigators may have underestimated the actual incidence because they used a strict disease definition to prevent multiple counting of the same patient.

“…SGLT2i [inhibitor] use was associated with a reduction in cardiovascular mortality and all-cause mortality that are consistent with previous research,” wrote the study authors. “However, contrary to notions about the cardiovascular effects of SGLT2i, people with diabetes who are treated with these drugs do not have a significantly decreased chance of developing ACS, PAOD, or IS compared to the controls.”