Effectiveness and safety of GLP-1 receptor agonists versus SGLT-2 inhibitors in type 2 diabetes: an Italian cohort study

Abstract

Background GLP-1 receptor agonists (GLP-1 RA) and SGLT-2 inhibitors (SGLT-2i) have shown to reduce the risk of major adverse cardiovascular events (MACE), death and worsening nephropathy when added to standard of care. However, these two dug classes differ in efficacy and safety. We compared the effectiveness and safety profile of GLP-1 RA and SGLT-2i in a large and unselected cohort of patients with type 2 diabetes resident in Lombardy from 2015 to 2020. Methods Using linkable administrative health databases, we included patients aged 50 years and older initiating GLP-1 RA or SGLT-2i. Clinical events were: death, hospital admission for myocardial infarction (MI), stroke, heart failure (HF), and renal disease as individual and composite outcomes (MACE-3: all cause-death, non-fatal MI, non-fatal stroke; MACE-4: MACE-3 plus unstable angina). Outcomes were evaluated separately in subjects with and without previous cardiovascular (CV) diseases. Treatments were compared using Cox proportional hazards regression model after Propensity Score Matching (PSM) in both intention-to-treat (ITT) and per protocol (PP) analyses. Serious adverse events were also evaluated. Results The analysis comprised 20,762 patients per cohort. The ITT analysis showed a significant risk reduction for non-fatal MI (HR 0.77; CI 95% 0.66–0.90), MACE-3 (HR 0.91; CI 95% 0.84–0.98), and MACE-4 (HR 0.92; CI 95% 0.86–0.99) in GLP-1RA compared with SGLT-2i users, while no difference was reported in the incidence of HF hospitalization and stroke between the two cohorts. Similar benefits were found in the subgroup of patients without previous CV diseases only. PP analysis largely confirmed the main results. The incidence of serious adverse events was low in both cohorts (< 1%). Conclusions GLP-1RA showed to be equally safe and more effective than SGLT-2i in reducing the risk of MACE-3, MACE-4 and MI. This study adds to the growing body of real-world evidence addressing the specific clinical properties of GLP-1RA and SGLT-2i in everyday practice to tailor treatment to the individual patient.

Substantially different findings concerning the cardiovascular and cerebrovascular effectiveness of GLP1RAs vs. SGLT2is

“…Baviera et al's study ( 1 ) showed that in T2D patients without previous cardiovascular disease (CVD) GLP1RAs vs. SGLT2is were associated with lower risks of MACE-3 [HR (95% CI): 0.87 (0.80, 0.96)], MACE-4 [HR (95% CI): 0.90 (0.83, 0.98)], and ACM [HR (95% CI): 0.88 (0.79, 0.98)]; and similar risk of HHF [HR (95% CI): 1.03 (0.87, 1.23)]. On the contrary, Lin et al's network meta-analysis ( 8 ) showed that in T2D patients without previous CVD SGLT2is vs. GLP1RAs had similar risk of MACE [HR (95% CI): 0.93 (0.73, 1.19)].…”

“…Taken together, GLP1RAs vs. SGLT2is can reduce more stroke events (GLP1RAs: 17% reduction; SGLT2is: cannot reduce stroke), and SGLT2is vs. GLP1RAs can reduce more HHF events (SGLT2is: 31% reduction; GLP1RAs: 11% reduction). However, Baviera et al's study ( 1 ) showed no difference between GLP1RAs and SGLT2is in the risks of stroke and HHF.…”

“…Taken together, GLP1RAs and SGLT2is can confer similar reductions in the risks of MI (both: 10% reduction), MACE (GLP1RAs: 14% reduction; SGLT2is: 12% reduction), and ACM (GLP1RAs: 12% reduction; SGLT2is: 13% reduction). However, Baviera et al's study ( 1 ) showed the obvious superiority of GLP1RAs over SGLT2is in reducing the risks of MI, MACE-3, MACE-4, and ACM.…”

“…On the contrary, GLP1RAs vs. SGLT2is had the similar risks of hospitalization for heart failure (HHF) [HR (95% CI): 1.03, (0.89, 1.15)] and stroke [HR (95% CI): 0.96 (0.75, 1.21)]. Moreover, the intention-to-treat analysis in Baviera et al's study ( 1 ) suggested that GLP1RAs were significantly associated with the reduced risk of ACM [HR (95% CI): 0.90 (0.82, 0.99)] compared with SGLT2is. However, these findings are substantially different with previous evidences deriving from randomized controlled trials (RCTs) as well as those deriving from cohort studies.…”

“…Baviera et al conducted a cohort study ( 1 ) which mainly focused on the effectiveness of glucagon-like peptide 1 receptor agonists (GLP1RAs) vs. sodium-glucose cotransporter 2 inhibitors (SGLT2is) on cardiovascular and cerebrovascular endpoints in patients with type 2 diabetes (T2D). Accordingly, the authors produced their main findings: compared with SGLT2is, GLP1RAs showed significant reductions in the risks of myocardial infarction (MI) [hazard ratio (HR) and 95% confidence interval (CI): 0.77 (0.66, 0.90)], major adverse cardiovascular events-3 [MACE-3: a composite of MI, stroke, or all-cause mortality (ACM)] [HR (95% CI): 0.91 (0.84, 0.98)], and MACE-4 (a composite of MACE-3 or unstable angina) [HR (95% CI): 0.92 (0.86, 0.99)].…”