Effects of SGLT2 Inhibitors on Atherosclerosis: Lessons from Cardiovascular Clinical Outcomes in Type 2 Diabetic Patients and Basic Researches

Atherosclerosis-caused cardiovascular diseases (CVD) are the leading cause of mortality in type 2 diabetes mellitus (T2DM). Sodium-glucose cotransporter 2 (SGLT2) inhibitors are effective oral drugs for the treatment of T2DM patients. Multiple pre-clinical and clinical studies have indicated that SGLT2 inhibitors not only reduce blood glucose but also confer benefits with regard to body weight, insulin resistance, lipid profiles and blood pressure. Recently, some cardiovascular outcome trials have demonstrated the safety and cardiovascular benefits of SGLT2 inhibitors beyond glycemic control. The SGLT2 inhibitors empagliflozin, canagliflozin, dapagliflozin and ertugliflozin reduce the rates of major adverse cardiovascular events and of hospitalization for heart failure in T2DM patients regardless of CVD. The potential mechanisms of SGLT2 inhibitors on cardioprotection may be involved in improving the function of vascular endothelial cells, suppressing oxidative stress, inhibiting inflammation and regulating autophagy, which further protect from the progression of atherosclerosis. Here, we summarized the pre-clinical and clinical evidence of SGLT2 inhibitors on cardioprotection and discussed the potential molecular mechanisms of SGLT2 inhibitors in preventing the pathogenesis of atherosclerosis and CVD.

Comparative Cardio-Renal Outcomes of Type 2 Diabetes Patients Administered Glucagon-Like Peptide-1 Receptor Agonists: A Network Meta-Analysis

Background: Cardio-renal profiles are available from cardiovascular outcome trials of glucagon-like peptide-1 receptor agonists (GLP-1 RAs).Methods: A comprehensive systematic review of Embase, Medline, Web of Knowledge, and CENTRAL databases was conducted. Randomized controlled cardiovascular outcome trials of type 2 diabetes mellitus (T2DM) patients administered GLP-1 RAs were included. The following primary outcomes were examined: cardiovascular death, major adverse cardiovascular events (MACE), myocardial infarction, stroke, mortality, heart failure, hypoglycemia, pancreatitis, and thyroid carcinoma. Secondary outcomes included: composite kidney outcome, worsening kidney function, macroalbuminuria, and retinopathy.Results: Seven trials involving 56,004 patients and eight interventions were identified. Albiglutide was associated with fewer MACE and myocardial infarction events compared with lixisenatide. Lixisenatide was related to a greater number of stroke events and cardiovascular deaths compared to once-weekly semaglutide and oral semaglutide, respectively. Improved mortality was associated with oral semaglutide compared with once-weekly semaglutide, albiglutide, dulaglutide, exenatide, or lixisenatide. Risks of heart failure, thyroid carcinoma, and pancreatitis were similar among all the treatments. Weighting of the nine primary outcomes identified oral semaglutide as first among the eight treatments examined. Among three of the secondary outcomes, once-weekly semaglutide ranked first. Better composite kidney outcome was observed with once-weekly semaglutide than with dulaglutide or exenatide; once-weekly semaglutide improved macroalbuminuria compared with exenatide or lixisenatide; and albiglutide, exenatide, and placebo was associated with fewer cases of retinopathy compared with once-weekly semaglutide. Meanwhile, kidney function was less likely to worsen with dulaglutide than with lixisenatide or placebo.Conclusion: Semaglutide should be considered when GLP-1 RAs are indicated for T2DM patients.

Series: Cardiovascular outcome trials for diabetes drugs Canagliflozin and the CANVAS Program, dapagliflozin and DECLARE-TIMI 58, ertugliflozin and VERTIS CV

EMPA-REG OUTCOME was a landmark trial with the sodium-glucose co-transporter-2 (SGLT2) inhibitor empagliflozin, which demonstrated significant reductions in major adverse cardiovascular events (MACE, a composite of cardiovascular death, non-fatal myocardial infarction and non-fatal stroke) driven by reductions in cardiovascular deaths and accompanied by an early reduction in hospitalisation for heart failure. This was followed by cardiovascular outcome trials with canagliflozin, dapagliflozin and ertugliflozin. The CANVAS Program was an integrated analysis of the CANVAS and CANVAS-R trials with canagliflozin. It demonstrated a significant reduction in MACE, but not in any of the components, and there was an unexpected increase in amputations and fractures with canagliflozin. The DECLARE-TIMI 58 trial with dapagliflozin had two co-primary endpoints. A composite endpoint of cardiovascular death or hospitalisation for heart failure was significantly reduced, but there was no significant difference in MACE comparing dapagliflozin with placebo. Analysis of patients with a prior myocardial infarction, however, demonstrated significant reductions in MACE. The VERTIS CV trial with ertugliflozin was disappointing as there was no difference in MACE comparing ertugliflozin and placebo. In all four trials a reduction in hospitalisation for heart failure was observed in patients with type 2 diabetes, regardless of whether they had existing atherosclerotic cardiovascular disease or increased cardiovascular risk. Pre-specified renal outcomes were reduced with empagliflozin, canagliflozin and dapagliflozin, and these drugs are now commonly used in the management of people with type 2 diabetes. It is hard to envisage an ongoing role for ertugliflozin in routine clinical management as the evidence for its cardiovascular benefit is not convincing.

SGLT-2 inhibitors and cardiorenal outcomes in patients with or without type 2 diabetes: a meta-analysis of 11 CVOTs

Background It has been suggested that sodium–glucose cotransporter 2 (SGLT-2) inhibitors reduce the cardiorenal risk in patients with type 2 diabetes (T2D). The purpose of this study is to provide an update of all large cardiovascular outcome trials (CVOTs) with SGLT-2 inhibitors to assess their cardiorenal efficacy in patients with and without T2D. Methods An electronic search up to 30 September 2021 was conducted in PubMed, EMBASE, the Cochrane Database of Systematic Reviews, and ClinicalTrials.gov. to determine eligible trials. We included CVOTs comparing any SGLT-2 inhibitor with placebo, reporting desired cardiovascular or renal outcomes and with a follow-up duration of at least 6 months. Results Eleven CVOTs, with data from five SGLT-2 inhibitors (empagliflozin, canagliflozin, dapagliflozin, ertugliflozin and sotagliflozin) and 77,541 participants, were included. In the overall analysis, the risk of the composite CV mortality or hospitalization for heart failure (HF) was reduced by 23% (HR = 0.77, 95% CI 0.73–0.82, P < 0.001) compared with placebo, with not significant heterogeneity (I2 = 26%, P = 0.20), and irrespective of the presence of T2D (P for interaction = 0.81) and age (> 65 vs ≤ 65 years, P for interaction = 0.78). The risk of CV mortality, total mortality and hospitalization for HF was significantly reduced by 16%, 13%, and 32%, respectively; similarly, the risk of the composite renal outcome was reduced by 35% (HR = 0.65, 95% CI 0.56–0.75), with moderate heterogeneity (I2 = 32%). In the analysis of 6 CVOTs reporting the data, the risk of major cardiovascular events (MACE) was reduced by 12%, with low heterogeneity (I2 = 21.2%, P = 0.19) and irrespective of the presence of established CV disease at baseline (P for interaction = 0.46). Conclusions Therapy with SGLT-2 inhibitors in patients with cardiometabolic and renal diseases results in a sustained to moderate reduction of the composite CV death or hospitalization for HF, robust reduction of HF and renal outcomes, moderate reduction of CV mortality, total mortality and MACE.

58 Effects of sodium–glucose co-transporter 2 (SGLT2) inhibitors on major cardiovascular events in Type 2 diabetic patients: a meta-analysis of randomized controlled trials

Aims Sodium–glucose co-transporter-2 inhibitors (SGLT2i) reduce cardiovascular (CV) events in diabetic patients, with a consistent effect on heart failure (HF) related outcomes. However, the effects on ischaemic CV events appear less certain, in particular in patients with history of HF. The aim of this meta-analysis is to investigate CV benefit of SGLT2i and to assess the effects in patients with and without established atherosclerotic cardiovascular disease (ASCVD), with and without HF, and with estimated glomerular filtration rate &lt; or ≥ 60 mL/min. Methods We searched PubMed, Embase, Cochrane, ISI Web of Science, SCOPUS, and clinicaltrial.gov databases. We performed a systematic review and meta-analysis of randomized, placebo-controlled, cardiovascular outcome trials (CVOT) of SGLT2i in diabetic patients, assessing the effects of SGLT2i on 3-point MACE [CV death, non-fatal myocardial infarction (MI), non-fatal stroke] and composite of HF hospitalization or CV death. Results Of 205 articles, 7 CVOTs were included in the meta-analysis. Compared to placebo, SGLT2i significantly reduced by 10% the risk of 3-point MACE (HR 0.90; P = 0.025) (Figure panel A) and the risk of CV death or HF hospitalization by 24% (HR 0.76; P &lt; 0.001) (Figure panel B). SGLT2i significantly reduced HF hospitalization by 30% (HR 0.70; P &lt; 0.001), with consistent effects in all subgroups analysed, CV death by 17% (HR 0.83; P = 0.035) and all-cause mortality by 18% (HR 0.82; P = 0.024). No significant effects were observed on MI and stroke. Conclusions SGLT2i significantly reduce CV outcome in diabetic patients. SGLT2i remarkably and consistently reduce HF hospitalization, in patients with and without HF at baseline and independently on the presence of ASCVD.

Call for action in ANCA-associated vasculitis and lupus nephritis: promises and challenges of SGLT-2 inhibitors

Sodium–glucose cotransporter- 2 inhibitors (SGLT- 2i) have recently been demonstrated to exert profound cardio- and nephroprotection in large cardiovascular outcome trials. They reduce progression of chronic kidney disease (CKD) including albuminuria and improve outcomes in heart failure patients with and without type 2 diabetes on top of angiotensin-blocking agents. These benefits translate into improved mortality in cardiorenal risk patients. While the detailed molecular mechanisms underlying these surprising clinical outcomes are not fully understood, their antidiabetic properties are not causative. Rather reduction of glomerular hyperfiltration and tubuloprotection are involved as root cause mechanisms of their clinical effects. Finally, their side effect profile is advantageous especially in non-diabetic patients also reducing the risk of acute kidney injury. Among the independent risk factors for excess mortality, CKD is still one of the strongest predictors of a poor prognosis in patients with both ANCA- associated vasculitis (AAV) and lupus nephritis (LN). Since patients with autoimmune disease were excluded from all recent large renal outcome trials with SGLT-2i and given their strong nephroprotective potential, we herein advocate to study this unique class of disease-modifying therapies when it comes to kidney and cardiovascular health in patients with AAV and LN.

Improvement of glycemic control and reduction of major cardiovascular events in 18 cardiovascular outcome trials: an updated meta-regression

Background Besides providing reassurance about cardiovascular (CV) safety of newer diabetes drugs, cardiovascular outcome trials (CVOTs) have also shown encouraging benefits on some CV endpoints. The contribution of the better glycemic control in the reduction of major cardiovascular events (MACE) remains an open question. The aim of this study is to evaluate the associations between the reduction of HbA1c and risk of MACE, MACE components, hospitalization for heart failure (HF) and all-cause death in CVOTs. Methods An electronic search up to July 2021 was conducted to determine eligible trials. Systematic review identified eighteen CVOTs reporting prespecified CV outcomes. Pooled summary estimates and 95% confidence intervals (CI) were calculated according to the random effects model using the Paule-Mandel method; restricted maximum likelihood estimators were used to estimate model parameters in the metaregression. Results The eighteen CVOTs evaluated 161,156 patients and included four trials with dipeptidyl-peptidase-4 inhibitors (DPP-4i), eight trials with glucagon-like peptide-1 receptor agonists (GLP-1RA) and six trials with sodium-glucose cotransporter-2 inhibitors (SGLT-2i). Random-effects model meta-analysis showed an association between treatment and risk of MACE (hazard ratio [HR] 0.90; 95% CI 0.86, 0.94, P < 0.001), with significant heterogeneity between studies (I2 = 45.2%, Q statistic P = 0.040). In meta-regression, there was an association between the reduction in HbA1c at the end of the trial and the HR reduction for MACE (beta = − 0.298, P = 0.007), with significant heterogeneity (I2 = 40%, Q statistic P = 0.04); this association was totally driven by the risk reduction of non-fatal stroke, which explained 100% of between-study variance (beta = − 0.531, R2 = 100%), without heterogeneity (I2 = 24%, Q statistic P = 0.206). There was no association between the reduction in HbA1c and the HR for heart failure or all-cause death. Conclusions The reduction of HbA1c in eighteen CVOTs was significantly associated with reduction of non-fatal stroke, explaining all (R2 = 100%) of the between-study variance. While the contribution of glucose lowering in some CV benefits of newer agents does not influence their indications for the patient with type 2 diabetes, it may hopefully facilitate their use.