A study of 1.25 million patients with type 2 diabetes has found individual GLP-1RA and SGLT2i treatments show largely comparable cardiovascular benefits, both within and across drug classes.

The analysis, published in JACC, included adults on metformin who began second-line therapy with one of six GLP-1RAs (albiglutide, dulaglutide, exenatide, liraglutide, lixisenatide, semaglutide) or one of four SGLT2is (canagliflozin, dapagliflozin, empagliflozin, ertugliflozin) [link here].

It tracked the incidence of major adverse cardiac events using 10 US and international health record databases, finding:

• There were no clinically meaningful differences in MACE between individual agents, for example –
• Semaglutide and empagliflozin had comparable risks for 3-point MACE (HR 1.05) and 4-point MACE (HR 0.95),
• These findings were consistent for a patients with existing cardiovascular disease.

The authors noted a lack of comparison studies putting individual diabetes therapies head-to-head. American Diabetes Association guidelines continue to recommend SGLT2is and GLP-1RAs interchangeably, avoiding guidance on specific agents within each class.

“Our study helped fill this evidence gap by a large-scale, multisite analysis of real-world health databases,” wrote lead author, Professor of biomathematics at UCLA, Dr Marc Suchard, and colleagues.

“Our findings suggest interchangeability in cardiovascular effectiveness, while largely supporting similar between-class cardiovascular benefits reported in network meta-analyses of major RCTs.”

Previous trials have found the two drug classes both deliver cardio-protective benefits, though GLP-1RAs have been previously been associated with greater weight reduction and HbA1c control, while SGLT2is have shown renal and heart failure benefits [link here].

This study showed a small difference in the risk of hospitalisation for heart failure between semaglutide and dapagliflozin, which led to a small difference in 4-point MACE incidence favouring semaglutide (HR 0.83).

Dr Marc Suchard

However, the authors noted this finding should be interpreted cautiously, given it goes against existing RCT evidence of SGLT2is delivering stronger heart failure benefits.

“Our HHF outcome definition combined hospitalisation and emergency room visits with HF as these 2 visit contexts often get mixed coding in observational data sources; this practical compromise could have introduced differential outcome misclassification error,” they said.

Agent-level safety profiles were yet to be investigated, particularly around adverse events reported in other trials.

This included “higher rates of genitourinary infections and diabetic ketoacidosis for SGLT2is [and] higher risks of gastrointestinal adverse events and gallbladder diseases for GLP-1RAs,” the research team said.

The data analysed only followed patients through to 2022, meaning newer agents like tirzepatide were excluded from the study. The paper did not consider outcomes for patients on combination therapies.

Despite this, the authors said their findings reinforced the “cross-drug flexibility” seen in current clinical guidelines for patients with T2D.

“Clinical decisions should be guided by other relevant factors as well, such as safety, drug availability, patient adherence, and persistence,” they concluded.