SGLT2 inhibitors, GLP-1 agonists associated with lower mortality compared to DPP-4 inhibitors, analysis finds

Glucagon-like peptide-1 (GLP-1) agonists were associated with a higher risk of adverse events than sodium-glucose cotransporter-2 (SGLT2) inhibitors or dipeptidyl peptidase 4 (DPP-4) inhibitors, according to the meta-analysis.


Use of sodium-glucose cotransporter-2 (SGLT2) inhibitors or glucagon-like peptide-1 (GLP-1) agonists was significantly associated with lower all-cause mortality compared with dipeptidyl peptidase 4 (DPP-4) inhibitors, a meta-analysis found.

To compare the effects of the three drug classes on mortality and cardiovascular end points in patients with type 2 diabetes, researchers analyzed 236 randomized clinical trials with 176,310 participants and at least 12 weeks of follow-up. Results appeared in the April 17 JAMA.

Compared to control groups receiving placebo or no treatment, all-cause mortality was lower in patients on SGLT2 inhibitors (absolute risk difference [RD], −1.0%; hazard ratio [HR], 0.80; 95% credible interval [CrI], 0.71 to 0.89) and GLP-1 agonists (absolute RD, −0.6%; HR, 0.88; 95% CrI, 0.81 to 0.94). This was also true when the drugs were compared with DPP-4 inhibitors (absolute RD for SGLT2 inhibitors, −0.9%; HR, 0.78 [95% CrI, 0.68 to 0.90]; absolute RD for GLP-1 agonists, −0.5%; HR, 0.86 [95% CrI, 0.77 to 0.96]). DPP-4 inhibitors did not significantly lower all-cause mortality compared to controls (absolute RD, 0.1%; HR, 1.02 [95% CrI, 0.94 to 1.11]).

Cardiovascular mortality was also reduced with SGLT2 inhibitors (absolute RD, −0.8%; HR, 0.79 [95% CrI, 0.69 to 0.91]) and GLP-1 agonists (absolute RD, −0.5%; HR, 0.85 [95% CrI, 0.77 to 0.94]) compared to control groups. SGLT2 inhibitors were significantly associated with lower rates of heart failure events (absolute RD, −1.1%; HR, 0.62 [95% CrI, 0.54 to 0.72]) and myocardial infarction (absolute RD, −0.6%; HR, 0.86 [95% CrI, 0.77 to 0.97]) compared to control groups.

GLP-1 agonists were associated with a higher risk of adverse events leading to trial withdrawal when compared to SGLT2 inhibitors (absolute RD, 5.8%; HR, 1.80 [95% CrI, 1.44 to 2.25]) and DPP-4 inhibitors (absolute RD, 3.1%; HR, 1.93 [95% CrI, 1.59 to 2.35]). No drug class was associated with reduction in all stroke compared with controls, but GLP-1 agonists were associated with reduction in nonfatal stroke (HR, 0.87 [95% CrI, 0.76 to 0.99]; absolute RD, −0.3% [95% CrI, −0.5% to −0.02%]). All drug classes increased hypoglycemia compared to controls (HR for DPP-4 inhibitors, 1.29; HR for GLP-1 agonists, 1.44; HR for SGLT2 inhibitors, 1.24).

“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,” the authors wrote. “It will be important to test these 3 classes against and in addition to metformin monotherapy for cardiovascular outcomes to better determine treatment algorithms.”