SGLT-2 Inhibitors, GLP-1 Agonists Linked to Lower Mortality Than DPP-4 Inhibitors

Sean L. Zheng, BM BCh, MA

While several drug classes have proven efficacious in improving glycemic control in patients with type 2 diabetes (T2D), sodium-glucose cotransporter 2 (SGLT-2) inhibitors and glucagon-like peptide 1 (GLP-1) agonists have been associated with lower mortality compared to dipeptidyl peptidase 4 (DPP-4) inhibitors.

In a meta-analysis of 236 clinical trials including 176,310 participants with T2D, Sean L. Zheng, BM BCh, MA, MRCP, of the Department of Endocrinology at Imperial College Healthcare NHS Foundation Trust, in London, UK, and colleagues explored comparisons of SGLT-2 inhibitors, GLP-1 agonists, and DPP-4 inhibitors against each other or placebo. All trials included had a follow-up period of at least 12 weeks.

“The SGLT-2 inhibitors were associated with additional cardiovascular benefits for heart failure events compared with incretin-based therapies and control groups and for [myocardial infarction] events compared with control groups,” Zheng and colleagues wrote. “Of the 3 classes tested, SGLT-2 inhibition may be preferred over the incretin-based therapies based on their association with lower mortality and their favorable adverse event profile.”

In a recent real-world analysis of SGLT-2 inhibitors that was presented at ACC.18, the findings echoed that assumption, suggesting “that the cardiovascular effects of SGLT-2 inhibitors may extend across patient ethnic and racial backgrounds, geographic regions, as well as the CV risk continuum,” Mikhail Kosiborod, MD, a cardiologist and clinical researcher at St. Luke’s Mid America Heart Institute, and a professor of medicine at the University of Kansas-Missouri-Kansas City, said.

The findings revealed that the SGLT-2 inhibitors (absolute risk difference [aRD], −1.0%; hazard ratio [HR], 0.80; 95% credible interval [CrI], 0.71 to 0.89) and GLP-1 agonists (aRD, −0.6%; HR, 0.88; 95% CrI, 0.81 to 0.94) were associated with significantly lower all-cause mortality than the control groups, while DPP-4 inhibitors were not significantly associated with lower all-cause mortality (aRD, 0.1%; HR, 1.02; 95% CrI, 0.94 to 1.11) than were the control groups.

Additionally, SGLT-2 inhibitors (aRD, −0.9%; HR, 0.78; 95% CrI, 0.68 to 0.90) and GLP-1 agonists (aRD, −0.5%; HR, 0.86; 95% CrI, 0.77 to 0.96) were associated with lower mortality than DPP-4 inhibitors.

In regard to cardiovascular mortality, SGLT-2 inhibitors had an aRD of −0.8% (HR, 0.79; 95% CrI, 0.69 to 0.91) and GLP-1 agonists had an aRD of −0.5% (HR, 0.85; 95% CrI, 0.77 to 0.94) when compared to control groups. Rates of heart failure events were lower with SGLT-2 inhibitors (aRD, −1.1%; HR, 0.62; 95% CrI, 0.54 to 0.72), as well as rates of myocardial infarction (aRD, −0.6%; HR, 0.86; 95% CrI, 0.77 to 0.97) compared to placebo or other controls.

GLP-1 agonists were associated with a higher risk of adverse events leading to withdrawal from clinical trials than SGLT-2 inhibitors (aRD, 5.8%; HR, 1.80; 95% CrI, 1.44 to 2.25) and DPP-4 inhibitors (aRD, 3.1%; HR, 1.93; 95% CrI, 1.59 to 2.35).

Zheng and colleagues wrote that “Compared with control groups, the use of SGLT-2 inhibitors was associated with absolute risk reductions (RRs) in all-cause and cardiovascular mortality of 1% and 0.8%, respectively. For the same outcomes, GLP-1 agonists had more modest absolute RRs of 0.6% and 0.5%, respectively. Given that absolute RR depends on the baseline risk, it is probable that these estimates are greater in higher-risk populations, with a [correspondingly] lower number needed to treat and better cost-effectiveness. The magnitudes of these absolute RRs using SGLT-2 inhibitors and GLP-1 agonists are important in the context of established standards of care in diabetes. For example, the associated absolute RR in mortality has been shown to be 0.5% for lowering blood pressure21 and 0.9% for lowering low-density lipoprotein cholesterol (per mmol/L reduction).”

The authors reported 5 limitations: the availability and quality of data was variable, the participant characteristics that may have affected the relative efficacy of interventions are similar across the groups, the clinical efficacy and safety was evaluated by drug class rather than by individual drug type, short trial follow-up duration and low event rates limited the evaluation of the 3 agents in patients with low cardiovascular risk, and the meta-analysis did not address the effect of treatments on HbA1c and glycemic control.

The study, “Comparison of Type 2 Diabetes Treatments in Improving Survival,” was published in JAMA.