The Effects of SGLT2 Inhibitors on Cardiovascular and Renal Outcomes in Diabetic Patients: A Systematic Review and Meta-Analysis

Abstract

Background: Previous meta-analyses demonstrated the benefits of sodium-glucose cotransporter 2 inhibitors (SGLT2i) primarily on patients with established atherosclerotic cardiovascular disease (ASCVD), but with questionable efficacy on patients at risk of ASCVD. Additionally, evidence of beneficial cardiorenal outcomes in patients with estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 with the CV outcomes trials remains unclear. Canagliflozin, one of the SGLT2i, has recently been studied in a large randomized controlled trial in diabetic patients with chronic kidney disease. Thus, there is a need to understand the combined outcomes on the population targeted for treatment with SGLT2i as a whole, regardless of ASCVD status. This meta-analysis will therefore assess the efficacy of SGLT2i in cardiovascular and renal outcomes in general, and in patients with eGFR under 60 mL/min/1.73 m2 in particular. Methods: We searched PubMed and Cochrane databases for randomized, placebo-controlled studies involving SGLT2i. We examined composite cardiovascular outcomes of death from cardiovascular causes, nonfatal myocardial infarctions, nonfatal stroke, and heart failure hospitalizations. Renal composite outcomes and progression of albuminuria were also analyzed. Pooled relative risks (RR) and their 95% confidence intervals (CI) were calculated using a fixed-effects model. Results: The search yielded a total of 252 articles. Four studies were ultimately included in the meta-analysis after exclusion of other irrelevant studies. The pooled RR (95% CI) for the composite cardiovascular outcome was 0.93 (0.87–0.99) with a number needed to treat (NNT) of 167 in the general study population and 0.89 (0.77–1.02) in patients with eGFR <60 mL/min/1.73 m2. The pooled RR for all-cause mortality was 0.9 (0.84–0.97) with NNT = 143. The pooled RR for death from cardiovascular causes alone was 0.89 (0.81–0.99) in the general population and 0.82 (0.62–1.07) in patients with eGFR <60 mL/min/1.73 m2. The pooled RR for heart failure hospitalizations was 0.71 (0.63–0.79) with NNT = 91. With respect to renal outcomes, the pooled RR for the composite renal outcome was 0.63 (0.56–0.71) with NNT = 67; this was true even in patients with eGFR <60 mL/min/1.73 m2 0.67 (0.59–0.76). Lastly, the pooled RR for progression of albuminuria was 0.80 (0.76–0.84). Conclusion: SGLT2i are associated with significantly lower major adverse cardiovascular events, heart failure hospitalizations, and all-cause mortality. The evidence is strongest in reducing heart failure hospitalizations. However, the evidence is weaker when it comes to the population subset with eGFR <60 mL/min/1.73 m2. SGLT2i are also associated with significantly lower adverse renal events, with these effects apparent even in the population with eGFR <60 mL/min/1.73 m2.

SGLT2 Inhibitors: Slowing of Chronic Kidney Disease Progression in Type 2 Diabetes

“…1, A2) or severely increased albuminuria (macroalbuminuria) (Fig. 1, A3), or from moderately to severely increased albuminuria [32].…”

“…It should be noted that, despite multiple interventions, 25% of those treated intensively went on to develop kidney disease, suggesting that there is scope for improvement in this area of T2DM management [26]. Published evidence from large-scale randomised trials and real-world studies supports the use of SGLT2i treatments in reducing the overall rate of kidney function decline and adverse renal risk among those with T2DM [3,[27][28][29][30][31][32][33][34]. The American Diabetes Association (ADA) and European Association for the Study of Diabetes (EASD) consensus on the management of hyperglycaemia in T2DM (Fig.…”

“…Pooled renal data from a meta-analysis examining CV and renal outcomes from SGLT2i CVOTs and the CREDENCE trial showed that canagliflozin, empagliflozin and dapagliflozin were associated with favourable outcomes with respect to renal end points versus placebo [32].…”

“…The prescribing landscape is beginning to change; canagliflozin has been granted a change of licence by the European Medicines Agency (EMA) and UK Medicines and Healthcare products Regulatory Agency (MHRA) to include use in those with eGFR \ 30 ml/min/1.73 m 2 [45]. This is in recognition of the renal outcomes demonstrated in SGLT2i CVOTs, the CRE-DENCE study and CVD-REAL 3 [3,28,[30][31][32][33][34][45][46][47][48]. Currently, canagliflozin has the most direct evidence for renal benefit in patients with DKD [3].…”

Accelerated and intensified calcific atherosclerosis and microvascular dysfunction in patients with chronic kidney disease

“…Given the cardiovascular benefits shown with the use of the newer antidiabetic agents such as the sodium glucose co transporter-2 inhibitors (SGLT2i) as well as the glucagon like peptide-1 receptor agonists (GLP-1Ras) with reduction in mortality risk, HF risk (predominantly with the SGLT2i). and reduction in MACE (predominantly with the GLP-1RAs), there may be additional options available that might expand the scope of therapies for patients with coronary microvascular dysfunction (Lo et al, 2020).…”