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Diabetes patients adding a newcomer drug to their medications may derive cardiovascular benefits to varying degrees depending on their choice between GLP-1 agonists and SGLT-2 inhibitors, a large observational dataset suggested.

Among U.S. veterans already on metformin, sulfonylurea, or insulin treatment and without cardiovascular disease (CVD), the addition of a GLP-1 agonist, instead of a DPP-4 inhibitor, was associated with short-term reductions in major adverse cardiac events (MACE) or heart failure (HF) hospitalization (13.3 vs 17.8 events per 1,000 person-years, adjusted HR 0.82, 95% CI 0.72-0.94) upon propensity score-weighted matching.

Meanwhile, SGLT-2 inhibitors were not associated with such risk reduction in a propensity score-weighted comparison with the DPP-4 inhibitor class (12.9 vs 14.9 events per 1,000 person-years, adjusted HR 0.91, 95% CI 0.78-1.08), reported Christianne Roumie, MD, MPH, of Vanderbilt University Medical Center and Nashville VA Medical Center in Tennessee, and colleagues. Their manuscript was published in the .

"These findings are hypothesis generating, and further evaluation of these medications as part of primary CVD prevention strategy is needed," Roumie's group stressed.

The investigators cautioned that follow-up spanned just a few months, lasting 0.58 years for each new prescription for individuals included in the GLP-1 agonist-DDP-4 inhibitor paired analysis. In the comparison between SGLT-2 inhibitors and DPP-4 inhibitors, follow-up was 0.42 years versus 0.47 years, respectively. The cumulative probability of MACE or HF hospitalization at 3.5 years was 0.9% for SGLT-2 inhibitors versus 1.1% for DPP-4 inhibitors; the cumulative probability reached 1.2% for GLP-1 agonists versus 1.7% for DPP-4 inhibitors.

With such short follow-up severely limiting any head-to-head comparisons between GLP-1 agonists and SGLT-2 inhibitors, the study authors nevertheless suggested that at least the former may have a role in primary prevention in people with diabetes, regardless of heart disease history.

"Unfortunately, this observational study has serious limitations that must be considered in the interpretation of results and that preclude reliable application to clinical decision making," commented Steven Nissen, MD, of the Cleveland Clinic in Ohio.

"These drugs are long-term therapies, not short-term interventions, and comparing their effects over a few months is not clinically relevant ... Randomized controlled trials have shown benefits for both drug classes in several trials studying mixed populations of primary and secondary prevention patients," Nissen wrote in an .

Indeed, Roumie's team reported that a larger analysis including patients both with and without CVD showed both GLP-1 agonists and SGLT-2 inhibitors were associated with reduced MACE (i.e., acute myocardial infarction, stroke, or cardiovascular death) and HF hospitalizations compared with DPP-4 inhibitors.

For now, the exact mechanisms of the cardioprotection offered by these two medication classes remain unclear, Roumie and colleagues said.

GLP-1 agonists mimic the action of the hormone glucagon-like peptide 1 in stimulating the production of insulin when blood sugar levels rise; popularly, semaglutide (Ozempic, Wegovy), in particular, is also prescribed to induce weight loss outside the setting of diabetes.

SGLT-2 inhibitors, including empagliflozin (Jardiance) and dapagliflozin (Farxiga), employ a different mechanism to lower blood sugar in diabetes, namely preventing the kidneys from reabsorbing sugar. They have recently entered the mainstream for heart failure across the spectrum of ejection fraction.

To investigate the effects of these two drug classes in a large cohort without prior CVD, Roumie's group probed the records of U.S. veterans receiving care from the Veterans Health Administration (VHA), with data linkage to Medicare, Medicaid, and the National Death Index.

The cohort comprised mostly white men with a median age of 67 years. Participants had diabetes for a median 8.5 years before trying one of the new medications.

After propensity score weighting, there were over 28,000 weighted pairs of new GLP-1 agonist vs DPP-4 inhibitor users; there were over 21,000 weighted pairs of new SGLT-2 inhibitor and DPP-4 inhibitor users.

Residual confounding remained possible despite statistical adjustment of the retrospective, observational study. Moreover, the investigators warned that they had not assessed DPP-4 inhibitors, GLP-1 agonists, and SGLT-2 inhibitors as first-line therapies in diabetes.

Nissen pointed out that the study lacked much valuable data, such as records of ejection fractions and micro- or macroalbuminuria. Veterans visiting clinical centers outside the VHA -- for medical emergencies such as myocardial infarction and stroke, say -- would have also had data incompletely captured in the investigators' database, he said.

"Given the limitations described earlier, the observed differences in HRs (0.82 vs. 0.91) comparing [GLP-1 agonists] and [SGLT-2 inhibitors] with [DPP-4 inhibitors] are too small to derive reliable conclusions," Nissen warned. "Caution and skepticism are appropriate when the effects are modest."

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