Blood pressure-lowering effects of SGLT2 inhibitors and GLP-1 receptor agonists for preventing of cardiovascular events and death in type 2 diabetes: a systematic review and meta-analysis

Abstract

Aims: To investigate the lowering BP effects of sodium glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide 1 receptor agonists (GLP-1 RAs) on the risk of major cardiovascular event stratified by glucose-lowering drugs, baseline BP, glycated hemoglobin (HbA_1c), and history of cardiovascular disease in patients with type 2 diabetes.

Methods: We performed a systematic review of the MEDLINE and EMBASE databases search up to December 31, 2022, (PROSPERO, CRD42023400899) to identify all large-scale cardiovascular outcomes (CVO) trials of SGLT2i and GLP-1 RAs in which more than 1,000 patient-years of follow-up in each randomized group. Outcomes included all-cause mortality, major adverse cardiovascular event (MACE) and its component (cardiovascular death, myocardial infarction [MI], and stroke), heart failure, and renal failure. A random-effects meta-analyses were used to pool the estimates.

Results: Eighteen CVOTs (ten for SGLT2i and eight for GLP-1 RAs) with 127,606 patients with type 2 diabetes were included. Over 2.5 years median follow-up, the average reduction of systolic BP was 2.2 mmHg (mean difference [MD] - 2.2; 95% CI - 2.7 to - 1.7) with more important reduction (P_interaction = 0.001) with SGLT2 inhibitors (- 2.9; - 3.4 to - 2.5) than with GLP-1 RAs (- 1.4; - 1.8 to - 1). With SGLT2i, every 5-mmHg reduction in systolic BP was associated with a significantly lower risk of mortality (hazard ratio[HR], 0.77; 95% CI 0.65-0.90), MACE (HR 0.81 [0.74-0.89]), cardiovascular death (HR 0.72 [0.59-0.88]), MI (HR 0.82 [0.71-0.95]), heart failure (HR 0.49 [0.42-0.57]), and renal failure (HR 0.46 [0.38-0.55]), while the association was not significant for stroke (HR 0.91 [0.69-1.19]). The corresponding effects for every 5-mmHg reduction in SBP with GLP-1 RAs were 0.65 (0.51-0.84) for all-cause mortality, 0.65 (0.56-0.76) for MACE, 0.62 (0.45-0.85) for CV death, 0.71 (0.52-0.76) for MI, 0.49 (0.35-0.69) for stroke, and 0.49 (0.35-0.66) for renal failure, while the association was not significant for heart failure (HR 0.82 [0.63-1.08]).

Conclusion: In patients with type 2 diabetes, the hypotensive effects of SGLT2i and GLP-1 RAs were significantly associated with a reduction in mortality and cardiorenal events. These findings suggest that the lowering BP effect could be seen as an additive indicator of cardiovascular protection by SGLT2i and GLP-1 RAs drugs.

Keywords: Blood pressure; CVOTs; GLP-1 RAs; MACE; Meta-analysis; SGLT2i.