T2D: Risk of CV and all-cause mortality lower with SGLT2 vs DPP-4 inhibitors

A real-world propensity score-matched study in Hong Kong finds that, compared with use of dipeptidyl peptidase-4 (DPP-4) inhibitors, use of sodium-glucose cotransporter 2 (SGLT2) inhibitors in type 2 diabetes (T2D) patients is associated with lower risk of incident atrial fibrillation (AF), stroke/transient ischaemic attack (TIA), and cardiovascular (CV) and all-cause mortality.

“Diabetes mellitus increases the risk of AF, which is a known risk factor for ischaemic stroke, the likelihood of which is increased 2.5-fold among diabetic patients,” wrote the researchers. [Lancet 2010;375:2215-2222; J Am Coll Cardiol 2019;74:1107-1115; Front Physiol 2018;9:835] “Given that the potential protective effects of novel antidiabetic agents are increasingly becoming the focus of research, our study aimed to evaluate the risk of ischaemic stroke, AF, CV and all-cause mortality between SGLT2 and DPP-4 inhibitor users in Hong Kong.”

The retrospective, territory-wide cohort study included 61,233 T2D patients (median age, 62.7 years; male, 55.4 percent), of whom 35.5 percent were SGLT2 inhibitor users and 64.5 percent were DPP-4 users. Over a median follow-up duration of 2,030 days, 2,496 patients (4.1 percent) developed new-onset AF, 2,179 patients (3.6 percent) developed stroke/TIA, and 6,607 patients (10.8 percent) died from any cause, of which 1,963 (3.2 percent) died from CV diseases. [Cardiovasc Drugs Ther 2022;doi:10.1007/s10557-022-07319-x]

After adjusting for past comorbidities and significant demographic, co-medication, and biomarker differences, SGLT2 vs DPP-4 inhibitor users showed lower risks of new-onset AF (hazard ratio [HR], 0.68; 95 percent confidence interval [CI], 0.56 to 0.83; p=0.0001), stroke (HR, 0.64; 95 percent CI, 0.53 to 0.79; p<0.0001), all-cause mortality (HR, 0.44; 95 percent CI, 0.37 to 0.51, p<0.0001) and CV mortality (HR, 0.39; 95 percent CI, 0.27 to 0.56, p<0.0001). “Propensity score, cause-specific and sub-distribution hazard models, and competing risk and sensitivity analyses confirmed the association between SGLT2 inhibitor use and lower risks of incident AF, stroke/TIA, CV mortality, and all-cause mortality compared with DPP-4 inhibitor use,” highlighted the researchers.

Animal studies have demonstrated that SGLT2 inhibitors can prevent atrial remodelling, which is an important pathogenic mechanism of AF. [Cardiovasc Diabetol 2019;18:165] In T2D patients, the protective effects of SGLT2 inhibitors are likely mediated through weight loss, diuretic effect, decreased blood pressure, and better glucose and lipid profile. [Postgrad Med J 2017;93:373-375] “It remains unclear whether the CV outcomes are similar across individual SGLT2 inhibitors, particularly when large-scale randomized controlled trials comparing different agents against placebo yielded different results, which was also demonstrated in the present study when individual SGLT2 inhibitors were analyzed,” noted the researchers.

Of patients receiving SGLT2 inhibitors, 59.1 percent had been on dapagliflozin, 23.0 percent on canagliflozin, 21.2 percent on empagliflozin, and 11.6 percent on ertugliflozin throughout the study (January 2015 to December 2020). Due to changes in medication, some patients were exposed to more than one SGLT2 inhibitor. Exposure to both empagliflozin and canagliflozin (n=1,596) was the most common, followed by canagliflozin and ertugliflozin (n=646), dapagliflozin and empagliflozin (n=575) and others.

“The greater protective effects of SGLT2 inhibitors against AF and stroke suggest that patients at risk of the two conditions should be prescribed an SGLT2 inhibitors instead of a DPP-4 inhibitor as part of the individualized management plan for patients with T2D,” concluded the researchers.