Are High- or Low-dose SGLT2 Inhibitors Associated With Cardiovascular and Respiratory Adverse Events? A Meta-analysis

Abstract

The association between high-dose or low-dose sodiumglucose cotransporter 2 (SGLT2) inhibitors and various cardiovascular and respiratory serious adverse events (SAE) is unclear. Our meta-analysis aimed to define the association between high-dose or low-dose SGLT2 inhibitors and 86 kinds of cardiovascular SAE and 58 kinds of respiratory SAE. We included large cardiorenal outcome trials of SGLT2 inhibitors. Meta-analysis was conducted and stratified by the dose of SGLT2 inhibitors (high dose or low dose) to synthesize risk ratio (RR) and 95% confidence interval (CI). We included 9 trials. Compared with placebo, SGLT2 inhibitors used at high dose or low dose were associated with the decreased risks of 6 kinds of cardiovascular SAE [eg, bradycardia (RR, 0.60; 95% CI, 0.41-0.89), atrial fibrillation (RR, 0.79; 95% CI, 0.69-0.92), and hypertensive emergency (RR, 0.34; 95% CI, 0.15-0.78)] and 6 kinds of respiratory SAE [eg, asthma (RR, 0.59; 95% CI, 0.37-0.93), chronic obstructive pulmonary disease (RR 0.77, 95% CI 0.62-0.96), and sleep apnea syndrome (RR 0.37, 95% CI 0.17-0.81)]. SGLT2 inhibitors used at high dose or low dose did not show significant associations with 132 other cardiopulmonary SAE. For any outcome of interest, the subgroup difference according to the dose of SGLT2 inhibitors was not significant (P subgroup . 0.05). SGLT2 inhibitors used at whether high dose or low dose are associated with the decreased risks of 12 cardiopulmonary disorders (eg, bradycardia, atrial fibrillation, hypertensive emergency, asthma, chronic obstructive pulmonary disease, and sleep apnea syndrome). These findings may suggest the potential efficacy of high-or low-dose SGLT2 inhibitors for the prevention and treatment of these cardiopulmonary disorders.

Association of adverse respiratory events with sodium-glucose cotransporter 2 inhibitors versus dipeptidyl peptidase 4 inhibitors among patients with type 2 diabetes in South Korea: a nationwide cohort study

“…To date, only a few studies have investigated respiratory events associated with SGLT2is, despite its biological plausibility [ 11 ]. The lower risk of respiratory events with SGLT2is observed in the present study is consistent with prior meta-analyses that compared adverse respiratory events using data from placebo-controlled randomized trials of SGLT2is; these meta-analyses found a 25% lower risk of overall respiratory disorders [ 21 ], a 16% lower risk of pneumonia [ 22 ], a 48–60% lower risk of acute pulmonary edema [ 22 , 23 ], a 29% lower risk of respiratory failure [ 23 ], and a 41% lower risk of asthma [ 24 ]. Another trial that compared dapagliflozin versus placebo in patients with COVID-19 also hinted at potential respiratory benefits albeit showing an inconclusive lower rate of respiratory decompensation (9.3% versus 11.2%; HR 0.85, 95% CI 0.60 to 1.20) [ 40 ]; network meta-analyses in patients with diabetes and COVID-19 also suggested respiratory benefits with SGLT2is by reporting lower COVID-19 mortality [ 41 , 42 ].…”

“…In contrast, only a small number of studies have investigated the respiratory effects of SGLT2is. Meta-analyses of randomized controlled trials showed that SGLT2is reduce the risk of adverse respiratory events versus placebo, including the risks of respiratory disorders [ 21 ], pneumonia [ 22 ], and respiratory failure [ 23 ], as well as the risk of asthma versus dipeptidyl peptidase-4 inhibitors (DPP4is) [ 24 ]. However, the respiratory effects of SGLT2is compared with other second or third-line antidiabetic drugs remain less well understood, and there is substantial uncertainty regarding the generalizability of trial findings to real-world settings [ 25 ].…”

Association of Sodium-Glucose Cotransporter 2 Inhibitor vs Dipeptidyl Peptidase-4 Inhibitor Use With Risk of Incident Obstructive Airway Disease and Exacerbation Events Among Patients With Type 2 Diabetes in Hong Kong

“…A recent meta-analysis of cardiorenal trials reported that compared with placebo, SGLT2I use was associated with a reduced risk of OAD. 19 A network meta-analysis further suggested that SGLT2I use was associated with a reduced incidence of asthma compared with dipeptidyl peptidase-4 inhibitor (DPP4I) use. 20 However, the OAD events in these trials were likely underreported, as they were extracted from reports of serious adverse events rather than being the primary end points.…”

GLP-1 receptor agonists, SGLT-2 inhibitors, and obstructive sleep apnoea: can new allies face an old enemy?

“…Two recent meta-analyses, which explored any possible adverse events after therapy with SGLT2 inhibitors, have shown that this drug class was associated with reduced risk of developing OSA [89,90]. In the first meta-analysis, which analysed data from 9 major studies (33,124 individuals in the SGLT2 inhibitor arm vs. 26,568 individuals in the placebo arm) found that the relative risk (RR) for experiencing OSA after their administration was 0.36 (p = 0.023) [89].…”

“…The second meta-analysis investigated data from 9 cardiorenal outcome studies that were stratified by 2 different doses of SGLT2 inhibitors (high or low dose); all of them had large sample sizes (ranging from 3730 to 17,160 patients). It was suggested that SGLT2 inhibitors administered either at low dose or high dose were associated with RR of 0.37 for developing OSA (95% CI: 0.17-0.81; I 2 = 0) [90]. Another meta-analysis, in which data from 9 large RCTs were analysed to evaluate the possible associations of several respiratory disorders and SGLT2 administration, suggested that SGLT2 inhibitors reduced the occurrence of OSA by 65% compared with placebo (RR = 0.35; I 2 = 0, p for treatment effect: 0.073) [91].…”