Comprehensive Analysis of Adverse Events Associated With SGLT2is: A Meta-Analysis Involving Nine Large Randomized Trials.

Recently, Lin and colleagues assessed the safety of sodium-glucose cotransporter 2 inhibitors (SGLT2is) by a meta-analysis [1], in which the authors assessed 16 kinds of adverse events (AE) reported in the published articles based on 10 randomized controlled trials. We conducted a further meta-analysis and targeted the association between use of SGLT2is and occurrences of various kinds of serious AE published in the Clinical Trials website (clinicaltrials.gov). Our meta-analysis revealed that use of SGLT2is was not significantly associated with occurrences of 980 kinds of serious AE but was significantly associated with lower risks of 29 kinds of serious AE, especially including several important respiratory diseases (e.g., asthma, chronic obstructive pulmonary disease, sleep apnoea syndrome, and pneumonia). These findings may cause more studies to evaluate the possibilities of gliflozins being used for prevention of these specific diseases.

Gliflozins for the prevention of stroke in diabetes and cardiorenal diseases: A meta-analysis of cardiovascular outcome trials.

BACKGROUND: Individual randomized trials are not powered to assess the relationship between use of sodium-glucose transporter 2 inhibitors and risk of stroke. We sought to explore this issue by a meta-analysis incorporating relevant trials including several latest trials. METHODS: Cardiovascular outcome trials of gliflozins were included. Primary outcome was stroke, while secondary outcome was major adverse cardiovascular events (MACE), which was a composite of stroke, myocardial infarction, or cardiovascular death. Meta-analysis was conducted stratified by with/without chronic kidney disease (CKD), with/without heart failure (HF), and with/without atherosclerotic cardiovascular disease (ASCVD), and stratified by different gliflozins. RESULTS: We included 9 trials in this meta-analysis. Compared with placebo, gliflozins significantly lowered stroke (hazard ratio [HR] 0.68, 95% confidence interval [CI] 0.55-0.84) and MACE (HR 0.77, 95% CI 0.69-0.86) in type 2 diabetes (T2D) patients with CKD, but did not significantly affect stroke (HR 1.00, 95% CI 0.86-1.16) and MACE (HR 0.94, 95% CI 0.86-1.02) in T2D patients without CKD. Gliflozins had no significant effects on the stroke risk (HR 0.94, 95% CI 0.82-1.07) in T2D patients regardless of HF status (Psubgroup = .684) and ASCVD status (Psubgroup = .915), but significantly lowered MACE (HR 0.89, 95% CI 0.83-0.96) in T2D patients regardless of HF status (Psubgroup = .428) and ASCVD status (Psubgroup = .423). Canagliflozin (HR 0.84, 95% CI 0.69-1.01) showed the trend of a reduction in the stroke risk versus placebo, and sotagliflozin (HR 0.73, 95% CI 0.54-0.98) significantly lowered the stroke risk; whereas the other 3 gliflozins did not significantly affect that risk. Ertugliflozin (HR 0.97, 95% CI 0.85-1.11) had no significant effects on the MACE risk, whereas the other 4 gliflozins significantly lowered that risk. CONCLUSIONS: Gliflozins, especially canagliflozin and sotagliflozin, should be recommended in T2D patients with CKD to prevent stroke. Most gliflozins lower the risk of MACE in T2D patients regardless of HF status and ASCVD status, whereas ertugliflozin is not observed to lower that risk.

Effects of SGLT2 inhibitors on cardiovascular death and all-cause death in patients with type 2 diabetes and chronic kidney disease: an updated meta-analysis including the SCORED trial.

BACKGROUND: The effects of sodium-glucose transporter 2 (SGLT2) inhibitors on cardiovascular death (CV death) and all-cause death (AC death) in patients with type 2 diabetes (T2D) and chronic kidney disease (CKD) are currently under intensive investigation. We intended to conduct an updated meta-analysis including the SCORED trial to evaluate the effects of SGLT2 inhibitors on death and cardiorenal events in this vulnerable population. METHODS: Cardiorenal outcome trials of SGLT2 inhibitors were included. Primary outcomes were CV death and AC death, while secondary outcomes were hospitalization for heart failure (HHF), myocardial infarction (MI), CKD progression, cardiovascular death or hospitalization for heart failure (CV death or HHF), major adverse cardiovascular events (MACE), and stroke. Meta-analysis was conducted for each outcome. RESULTS: Eight trials were included for meta-analysis. Compared with placebo, SGLT2 inhibitors significantly lowered the risk of CV death (HR = 0.86, 95% CI = 0.75-0.98), AC death (HR = 0.87, 95% CI = 0.79-0.96), HHF (HR = 0.64, 95% CI = 0.56-0.74), MI (HR = 0.76, 95% CI = 0.65-0.89), CKD progression (HR = 0.62, 95% CI = 0.54-0.72), and CV death or HHF (HR = 0.73, 95% CI = 0.67-0.80). No heterogeneity existed in the above meta-analyses (all I2 values = 0%), whereas moderate heterogeneity existed in the meta-analyses for MACE and stroke (I2 = 31.6% and 44.5%, respectively). CONCLUSIONS: Our findings suggest that SGLT2 inhibitors versus placebo significantly lower death, heart failure, renal failure, and MI events in patients with T2D and CKD. Head-to-head trials are needed to examine the possible differences in the effects of various gliflozins on MACE and stroke.

Meta-Analysis on the Safety and Cardiorenal Efficacy of SGLT2 Inhibitors in Patients Without T2DM.

The cardiorenal benefits of sodium-glucose cotransporter 2 (SGLT2) inhibitors in patients with type 2 diabetes mellitus (T2DM) are established, whereas those in patients without T2DM are not established. We sought to assess the cardiorenal efficacy and safety of SGLT2 inhibitors in non-T2DM patients by performing a meta-analysis based on the subgroup data of non-T2DM patients from relevant secondary analysis articles in which subgroup analyses were done according to the status of diabetes. Compared to placebo, SGLT2 inhibitors significantly reduced heart failure hospitalization [risk ratio (RR) 0.70, 95% confidence interval (CI) 0.59-0.83] and kidney-specific composite outcome (RR 0.55, 95% CI 0.40-0.75) and increased Kansas City Cardiomyopathy Questionnaire total score by 1.15 (95% CI 1.05-1.25) in patients without T2DM with heart failure (HF) or chronic kidney disease (CKD), whereas gliflozins did not significantly affect cardiovascular death, all-cause mortality, volume depletion, fracture, and amputation in this vulnerable population. There was no event of major hypoglycemia or diabetic ketoacidosis observed in the non-T2DM subgroup in included trials. These findings will further prompt gliflozins to be used for the prevention of HF and renal failure events and for the improvement of life quality in patients without T2DM with HF or CKD.

Impact of time factor and patient characteristics on the efficacy of PCI vs CABG for left main coronary disease: A meta-analysis.

BACKGROUND: The impact of time factor and patient characteristics on the efficacy of percutaneous coronary intervention (PCI) with drug-eluting stents vs. coronary-artery bypass grafting (CABG) for left main coronary disease is unclear. METHODS: We searched PubMed and Embase for related trials. Two outcomes of interest were major adverse cardiac or cerebrovascular events (MACCE, defined as a composite of all-cause mortality, myocardial infarction, stroke, or unplanned revascularization) and a composite of all-cause mortality, myocardial infarction, or stroke. We conducted random-effects meta-analysis stratified by follow-up duration and 7 factors of interest related to patient characteristics. Random-effects meta-regression was performed to calculate P values for trend and those for subgroup differences. RESULTS: We included 11 articles from 5 trials. Compared with CABG, PCI increased MACCE at the end of 3-year (hazard ratio [HR] 1.21, 95% confidence interval [CI] 1.04-1.40, I2 = 0) and 5-year (HR 1.33, 95% CI 1.20-1.48, I2 = 0) follow-up, but did not increase all-cause mortality, myocardial infarction, or stroke. The logarithm of HR of PCI vs CABG for MACCE increased as follow-up duration increased (ß = 0.057, P = .025). PCI vs CABG consistently increased 5-year MACCE across various subgroups defined by 7 factors of interest (Psubgroup ranged from .156 to .830). CONCLUSIONS: The long-term benefit of CABG vs PCI on MACCE in patients with left main coronary disease is consistent across patients with different clinical characteristics. The relative benefit of CABG on MACCE is driven by that of CABG on unplanned revascularization, and becomes greater as time goes on.

Use of SGLT2 inhibitors and occurrence of noninfectious respiratory disorders: a meta-analysis of large randomized trials of SGLT2 inhibitors.

PURPOSE: The impact of use of sodium-glucose transporter 2 (SGLT2) inhibitors on occurrence of various kinds of respiratory disorders has not been established. We aimed at evaluating the relationship between use of SGLT2 inhibitors and occurrence of 9 kinds of noninfectious respiratory disorders. METHODS: Large randomized controlled trials (RCTs) of SGLT2 inhibitors were included in this study. We conducted fixed-effects meta-analysis to synthesize risk ratios (RRs) and 95% confidence intervals (CIs). We did subgroup analysis respectively stratified by type of underlying diseases and type of SGLT2 inhibitors. RESULTS: Nine Large RCTs were included for analysis. Compared with placebo, SGLT2 inhibitors significantly reduced the occurrence of overall respiratory disorders (RR 0.75, 95% CI 0.62-0.91), acute pulmonary oedema (RR 0.51, 95% CI 0.29-0.88), asthma (RR 0.57, 95% CI 0.33-0.995), and sleep apnoea syndrome (RR 0.35, 95% CI 0.12-0.99). SGLT2 inhibitors showed the reduced trends in the risks of chronic obstructive pulmonary disease (COPD) (RR 0.79, 95% CI 0.61-1.02; P = 0.073) and pulmonary hypertension (RR 0.43, 95% CI 0.16-1.17; P = 0.098). SGLT2 inhibitors had no significant effects on three other respiratory disorders. These effects exhibited by SGLT2 inhibitors were consistent across different underlying diseases (Psubgroup ≥0.209) and different SGLT2 inhibitors (Psubgroup ≥0.192). CONCLUSIONS: SGLT2 inhibitors can significantly reduce the occurrence of acute pulmonary oedema, asthma, and sleep apnoea syndrome; and produce the reduced trends in the risks of COPD and pulmonary hypertension. These findings will prompt further investigation on SGLT2 inhibitors for primary and secondary prevention of various respiratory disorders.