Overall, during the study period, 29,634 new users of GLP-1 RA, 25,141 new users of SGLT-2i and 228,274 new users of other AHAs were identified (baseline patients characteristics before matching are reported in Supplementary material). The median follow-up time for GLP-1 RA, SGLT-2i and other AHAs, was 4.0 ± 2.7, 1.7 ± 1.0 and 5.2 ± 2.8 years in Lombardy, and 3.5 ± 2.7, 1.7 ± 0.9 and 5.3 ± 2.8 years in Apulia, respectively.
After PSM, the Lombardy study cohort included 18,716 pairs for the GLP-1 RA group and 11,683 pairs for the SGLT-2i group, while the Apulia study cohort comprised 9,772 and 6,046 for the GLP-1 RA and SGLT-2i groups, respectively (Table 1, A and B). After matching, the variables included in the PMS were well-balanced (all standardized differences were < 0.1). In general, in both regions, subjects newly prescribed a GLP-1 RA or a SGLT-2i had similar comorbidities as controls, although patients initiating SGLT-2i were more likely to have CV disease in comparison with new users of other AHAs. In the GLP-1 RA and SGLT-2i groups, 4.0–7.0% and 12–16% of patients had established cerebrovascular and CV diseases, respectively, in both Lombardy and Apulia regions (Table 1, A and B).
Patients belonging to the GLP-1 RA or SGLT-2i groups presented with slightly higher rates of background anti-hyperglycemic treatment and received slightly more antihypertensive and lipid-lowering medications as compared to the other AHAs cohort (Table 1, A and 1B).
Differences between the GLP-1 RA and SGLT-2i groups in both regions were observed in mean age (67–68 years in SGLT-2i group versus 64–65 years in GLP-1 RA group), history of diabetes (a higher percentage of subjects in the SGLT-2i group had a duration of T2DM ≥ 10 years compared to the GLP-1 RA group), and previous prescription of insulin (34% in SGLT-2i group versus 29% in GLP-1 RA group).
Risks of death and clinical outcomes in propensity score-adjusted populations by treatment status for Lombardy and Apulia regions are reported in Fig. 1, A and B, and Fig. 2, A and B.
In the Lombardy cohort, initiation of GLP-1 RA was associated with a lower risk of death (HR 0.61, 95% CI 0.56–0.65), cerebrovascular disease (HR 0.70, 95% CI 0.63–0.79), ischemic stroke (HR 0.72, 95% CI 0.60–0.87), peripheral vascular disease (HR 0.72, 95% CI 0.64–0.82), and lower limb complications (HR 0.67, 95% CI 0.56–0.81) in comparison with the other AHAs group. In the Apulia cohort, subjects who received GLP-1 RA also exhibited a lower risk of death (HR 0.63, 95% CI 0.55–0.71), peripheral vascular disease (HR 0.80, 95% CI 0.67–0.98), and lower limb complications (HR 0.69, 95% CI 0.51–0.93) with respect to those treated with other AHAs.
In the Lombardy cohort, initiation of SGLT-2i was associated with a lower risk of death (HR 0.47, 95% CI 0.40–0.54), cerebrovascular disease (HR 0.75, 95% CI 0.61–0.91), and heart failure (HR 0.56, 95% CI 0.46–0.70) in comparison with the other AHAs group. Similar results were obtained in the Apulia cohort with reductions of risks of death (HR 0.43, 95% CI 0.32–0.57), cerebrovascular disease (HR 0.72, 95% CI 0.54–0.96), and heart failure (HR 0.57, 95% CI 0.42–0.77) compared with the other AHAs group.
When results from the two cohorts were pooled, a small but significant reduction in the risk of hospitalization for heart failure (HR 0.89, 95% CI 0.82–0.97) with GLP-1 RA compared with other AHAs was also apparent (Fig. 1S Supplementary Material).
During follow-up, the rate of serious adverse events was quite low in each region. In general, fractures were documented more frequently; however, the rate of this event was slightly lower in the SGLT-2i group (around 1%) than in the GLP-1 RA and AHAs groups (2.5%) (Table 2).
Results of the preplanned sensitivity analysis comparing GLP-1 RA or SGLT-2i with DPP-4i for each region are reported in the Supplementary material, showing baseline characteristics of matched and unmatched populations as well as risks for all considered outcomes. After PSM, the population of the two cohorts were well-matched for multiple clinical variables (all standardized differences were < 0.1, except for renal disease and heart failure in some of the comparisons; Supplementary Material). In comparison with subjects who received DPP-4i, those initiating GLP-1 RA showed statistically significant risk reductions for death, cerebrovascular disease, peripheral vascular disease, lower limb complications (Lombardy cohort, Table S9), and death and lower limb complications (Apulia cohort, Table S11), while those initiating SGLT-2i had risk reductions for death, cerebrovascular disease and heart failure (Lombardy cohort, Table S10), and death and heart failure (Apulia cohort, Table S12). These results were similar to those observed in comparison with other AHAs.