A large population-based cohort study found that patients with immune-mediated inflammatory diseases and type 2 diabetes who initiated glucagon-like peptide-1 (GLP-1) receptor agonists may have had significantly lower risks of all-cause mortality and major adverse cardiovascular events (MACE) compared with those who initiated dipeptidyl peptidase-4 (DPP-4) inhibitors.

In the study, published in PLOS ONE, investigators analyzed the data of 10,855 adults in British Columbia, Canada between January 1, 2010, and December 31, 2021. The cohort included 3,570 GLP-1 receptor agonist initiators and 7,285 DPP-4 inhibitor initiators. The mean age of the patients was 60.67 years, and the most common immune-mediated inflammatory diseases were psoriatic disease (42.4%) and rheumatoid arthritis (37.5%). Weighted mean follow-up was 1.46 years for the GLP-1 receptor agonist group and 1.88 years for the DPP-4 inhibitor group.

The study included patients with rheumatoid arthritis, psoriatic disease, ankylosing spondylitis, inflammatory bowel disease, and systemic autoimmune rheumatic diseases. The investigators used administrative health data and identified patients using International Classification of Diseases, Ninth or 10th Revision (ICD-9 or ICD-10) codes, requiring at least two physician-diagnosed codes at least 2 months apart within a 2-year window for both immune-mediated inflammatory diseases and type 2 diabetes.

The primary outcome was all-cause mortality, with MACE and its components (cardiovascular death, myocardial infarction, and ischemic stroke) as secondary outcomes. Cox proportional hazard regressions with propensity score overlap weighting were used to balance baseline characteristics between the two groups.

The investigators observed a 52% relative risk reduction in all-cause mortality (hazard ratio [HR] = 0.48, 95% confidence interval [CI] = 0.31–0.75) and a 34% relative risk reduction in MACE (HR = 0.66, 95% CI = 0.50–0.88) among GLP-1 receptor agonist initiators compared with DPP-4 inhibitor initiators. This corresponded to 9 fewer deaths and 11 fewer MACE per 1,000 person-years, respectively.

Among the key findings were:

• All-cause mortality: 28 deaths in the GLP-1 receptor agonist group (8.5 per 1,000 person-years) vs 446 deaths in the DPP-4 inhibitor group (17.9 per 1,000 person-years)
• MACE: 83 events in the GLP-1 receptor agonist group (21.5 per 1,000 person-years) vs 632 events in the DPP-4 inhibitor group (32.0 per 1,000 person-years)
• Myocardial infarction: HR = 0.62 (95% CI = 0.40–0.96)
• Cardiovascular death: HR = 0.53 (95% CI = 0.20–1.40)
• Ischemic stroke: HR = 0.74 (95% CI = 0.50–1.11).

In the rheumatoid arthritis subgroup, exposure to GLP-1 receptor agonists was associated with a 55% relative risk reduction in all-cause mortality (HR = 0.45; 95% CI = 0.22–0.93) and a 61% relative risk reduction in MACE (HR = 0.39, 95% CI = 0.22–0.69). A trend toward reduced all-cause mortality was observed in the psoriatic disease subgroup, but it did not reach statistical significance (HR = 0.54, 95% CI = 0.25–1.19).

Sensitivity analyses excluding patients with prior myocardial infarction or ischemic stroke, those who discontinued therapy within 3 months of initiation, and using an intention-to-treat approach all yielded similar results, supporting the robustness of the findings. The intention-to-treat analysis, with a mean follow-up of 4.92 years for the GLP-1 receptor agonist group and 4.82 years for the DPP-4 inhibitor group, showed an HR of 0.72 (95% CI = 0.60–0.86) for all-cause mortality and 0.80 (95% CI = 0.69–0.94) for MACE.

The investigators also compared outcomes in age- and sex-matched adults without immune-mediated inflammatory diseases, finding similar risk reductions in mortality and MACE. In the per-protocol analysis for patients without the disease, the HR for all-cause mortality was 0.34 (95% CI = 0.26–0.44) and 0.70 (95% CI = 0.60–0.80) for MACE. This suggested that the cardioprotective effects of GLP-1 receptor agonists may be consistent across populations with and without immune-mediated inflammatory diseases.

To assess the specificity of the observed effects, the investigators evaluated herpes zoster reactivation as a negative control outcome, finding no significant difference between the two groups (HR = 0.96, 95% CI = 0.65–1.43).

The investigators acknowledged several limitations, including potential residual confounding and incomplete capture of comorbidities, particularly obesity. However, they noted that the E-value for all-cause mortality was 3.59, indicating that an unmeasured confounder would need to be associated with both GLP-1 receptor agonist use and all-cause mortality by a risk ratio of 3.59 to nullify the findings.

Strengths of the study included its population-based design, enhancing generalizability, and the use of multiple sensitivity analyses to support the robustness of the results.

The investigators suggested that the observed benefits of GLP-1 receptor agonists might extend beyond glycemic control, potentially leading to decreased adipokine-mediated inflammation and improved disease activity in immune-mediated inflammatory diseases. They also highlighted potential weight-independent anti-inflammatory effects of GLP-1 receptor agonists, noting that these agents can inhibit the NF-κB pathway, a key regulator of inflammatory processes.

Given these findings, the investigators called for further investigation into the effects of GLP-1 receptor agonists on disease activity in immune-mediated inflammatory diseases and whether weight loss through GLP-1 receptor agonists can improve clinical outcomes in patients with obesity and immune-mediated inflammatory diseases, independent of glycemic control.

The study's results also raised questions about current treatment guidelines for patients with both immune-mediated inflammatory diseases and type 2 diabetes. While the findings suggest potential benefits of prioritizing GLP-1 receptor agonists in this population, the investigators emphasized the need for randomized controlled trials to confirm these observational results before recommending changes to clinical practice.

Conflict of interest disclosures were not made available at time of publishing.