The literature search identified 5,809 articles (see eFigure 1 in the Supplement), of which 9 trials met the inclusion criteria [11, 20–27]. 87,143 patients were enrolled, including 34,322 for SGLT-2is and 52,821 for GLP-1 RAs. All studies presented an overall low risk of bias (see eTable 3 in the Supplement). Baseline information is shown in Table 1. Mean age across the entire sample was 63.5 years (range: 60.3–66.2), and mean BMI was 31.9 (range: 30.2–32.8), duration of diabetes ranged from 9.3 to 14.1 years. The median (interquartile range) duration of follow-up was 3.1 (1.7) years. The studies enrolled mostly men (range: 54–71%). Three studies exclusively enrolled participants with established cardiovascular disease [20, 24, 25]. The comparator was placebo in all studies. In eight trials, the primary outcome was a composite of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke, i.e., three-point MACE (3P-MACE) [11, 21–27], while one trial added hospitalization for unstable angina to these three endpoints (4P-MACE) [20]. All drugs tested in the trials have been approved by the Food and Drug Administration (FDA) as a therapeutic option for the treatment of type 2 diabetes.
Efficacy of GLP1-RA and SGLT-2i on MACE
Overall, SGLT-2 inhibitors and GLP-1 receptor agonists showed 11% [HR 0.89, (95% CI 0.83–0.96)] and 12% [HR 0.88, (95% CI 0.82–0.94)] reduction of major cardiovascular events, respectively (Fig. 1).
Six trials reported a subgroup analysis by history of cardiovascular disease [11, 21–23, 26, 27], while another three included only patients who experienced at least one cardiovascular event [20, 24, 25]. In 61,078 patients with established cardiovascular disease, GLP1-RA and SGLT-2i drugs showed a 14% reduction of MACE [GLP1-RA: 0.86 (0.79–0.94); SGLT-2i: 0.86 (0.80–0.93)]. By contrast, in 25,499 patients at high risk of cardiovascular disease, but without history of cardiovascular events, GLP1-RA and SGLT-2i seemed to have minimal or no effect on MACE [GLP1-RA: 0.95 (0.83–1.08); SGLT-2i: 1.00 (0.87–1.16)] (difference in effect between patients with vs. without a history of cardiovascular disease: p = 0.044, I2 = 75.3%) (Fig. 2)
Seven trials reported results stratified by prior heart failure [20–24, 26, 27]. SGLT-2i and GLP1-RA drugs showed a risk reduction in MACE of 10% and 14% in the subgroups of patients without prior heart failure [0.90 (0.83–0.98) and 0.86 (0.78–0.96)], and a 9% risk reduction among patients with prior heart failure (difference in effect between patients with vs. without heart failure: p = 0.652) (eFigure 2 in the Supplement).
A subgroup analysis by eGFR levels was reported in eight trials [20–27]. Compared to placebo, SGLT2i drugs showed a trend towards larger reduction in the risk of MACE among patients with CKD than among patients without CKD [0.82 (0.69–0.97) vs 0.91 (0.83-1.00)], (p = 0.322). GLP-1 RA drugs appeared to have similar reductions in the risk of MACE, independently of history of CKD (Fig. 3).
All trials reported findings stratified by HbA1c level. Five trials selected 8% as the threshold to identify patient subgroups [21, 23, 24, 26, 27]. In patients with uncontrolled diabetes (HbA1c > 8%), SGLT2i and GLP1-RA drugs reduced the risk of MACE by 16% [0.84 (0.75–0.95)] and 18% [0.82 (0.71–0.95)], respectively; while in patients with a better diabetes control (HbA1c ≤ 8%), the risk reduction was 8–9% [GLP1-RA: 0.91 (0.82-1.00); SGLT-2i: 0.92 (0.79–1.07)] (Fig. 4) (p = 0.152). Duration of diabetes did not appear to modify the effect of GLP1-RA drugs on MACE across subgroups [duration < 10 years: 0.88 (0.77–0.99); duration ≥ 10 years: 0.89 (0.83–0.95)];SGLT-2i drugs showed a 14% reduction in the risk of MACE in patients with a history of diabetes longer than ten years and had null effect on those with a shorter one [duration < 10 years: 0.86 (0.79–0.93) ; duration ≥ 10 years: 1.03 (0.94–1.13)] (eFigure 3 in the Supplement) (difference between patients with diabetes < 10 years vs. duration ≥ 10 years: p = 0.472). The effect of GLP1-RA and SGLT-2i drugs on MACE appeared to be similar in groups of patients with or without obesity (eFigure 4 in the Supplement) (difference between patients with vs. without obesity: p = 0.605). Similarly, SGLT-2i drugs showed equal risk reductions in subgroups pf patients with and without hypertension (eFigure 5 in the Supplement), for the three trials that included subgroup analyses for uncontrolled hypertension [25–27].
All included trials explored the effect of gender, race, and age on MACE [11, 20–27]. The effect of GLP1-RA and SGLT-2i drugs on MACE was similar across all these factors, though we observed a trend towards larger reductions in the risk of MACE for GLP1-RA among Asian patients [0.75 (0.60–0.92)], compared with white and black individuals [0.90 (0.82–0.98) vs 0.88 (0.64–1.20)] (difference between patients with vs. without obesity: p = 0.107) (eFigures 6–7 in the Supplement), and for SGLT-2i among individuals aged 65 years or older [0.81 (0.69–0.96)], compared to those younger [0.95 (0.85–1.07)] (difference between patients younger vs. older than 65 years old: p = 0.263) (eFigure 8 in the Supplement).