Previous trials of SGLT-2 inhibitors showed reductions in cardiovascular (CV) events, including CV death and hospitalization for heart failure, and ischemic events in patients with atherosclerotic cardiovascular disease (ASCVD).
Trial sequential analysis provided firm evidence of a 20% reduction in major adverse cardiac events, all-cause mortality, and hospitalization for heart failure with SGLT2 inhibitors, but evidence remains inconclusive for cardiovascular mortality.
Current evidence suggests that SGLT-2 inhibitors are more effective than either GLP-1 agonists or DPP-4 inhibitors for reducing the risk of hospitalization for HF in type 2 diabetes mellitus.
This review focusses on the effects of SGLT2 inhibitors on the kidney and renal outcome: it briefly outlines renal glucose handling in diabetes and its role in glomerular hyperfiltration and renal hypoxia; describes how SGLT2 inhibitors induce an early, reversible reduction in glomerular filtration rate (GFR) and preserve GFR in the long-term in patients with T2DM; discusses whether the enhanced active transport in the renal outer medulla (OM) in response to SGLT2 inhibition is friend or foe; proposes how the blood pressure lowering and heart failure protective effect of SGLT2 inhibitors can be preserved in chronic kidney disease (CKD) despite attenuated antihyperglycemic effects; and examines whether SGLT2 inhibition enhances the incidence or severity of acute kidney injury (AKI).
Recently, large placebo-controlled outcome trials have shown that sodium-glucose co-transporter-2 (SGLT-2) inhibitors reduce the risk of CV disease (including CV death and hospitalization for heart failure) in people with type 2 diabetes who are at high risk of atherosclerotic disease, and these effects were largely independent of improvements in hyperglycaemia, BP and body weight.
Patients randomly assigned to SGLT2 had lower risks of major cardiovascular events (RR 0.85, 95%CI 0.77-0.93), heart failure (RR 0.67, 95%CI 0.55-0.80), all-cause death (RR 0.79, 95%CI 0.70-0.88) and serious decline in kidney function (RR 0.59, 0.49-0.71).
Furthermore, newer clinical trials are currently ongoing to investigate whether SGLT2 inhibitors exhibit beneficial effects for HF, both in the presence and absence of T2D.
This may help provide important clues into the mechanism of benefit of SGLT2 inhibitors in clinical trials and provide a translational framework for the ongoing large studies of SGLT2 inhibitors in the treatment of heart failure.
SGLT-2 inhibitors were significantly associated with lower rates of HF events (absolute RD, -1.1%; HR, 0.62 [95% CrI, 0.54 to 0.72]) and MI (absolute RD, -0.6%; HR, 0.86 [95% CrI, 0.77 to 0.97]) than were the control groups.
Ongoing clinical trials with SGLT2 inhibitors in heart failure are positioned to confirm or refute the hypothesis that these drugs may favourably influence the course of obesity-related HFpEF by their ability to attenuate the secretion and actions of leptin.
This review will summarize key findings of the impact of glucose-lowering agents on CV safety and HF-associated outcomes, present available data on the underlying mechanisms for the benefits of the SGLT2 inhibitors on HF, and discuss strategies to improve outcomes in patients with DM and high CV risk.
Comparative effectiveness of canagliflozin, SGLT2 inhibitors and non-SGLT2 inhibitors on the risk of hospitalization for heart failure and amputation in patients with type 2 diabetes mellitus: A real-world meta-analysis of 4 observational databases (OBSERVE-4D).
However, perhaps the most important finding has been that sodium/glucose cotransporter 2 (SGLT2; also known as SLC5A2) inhibitors reduce heart failure hospitalizations and, in the case of empagliflozin, markedly reduce the rate of cardiovascular death.
Use of SGLT2 inhibitors in specific groups (e.g. those with nocturnal hypertension, diabetes, and high salt sensitivity) could help reduce the risk of heart failure and cardiovascular mortality.
Specifically, improvement of overall CV outcomes was likely driven by reduction in HF-related events in trials investigating SGLT2 inhibitors, and by reduction in atherosclerotic events in those investigating GLP-1RAs.
The remarkable reduction in cardiovascular (CV) mortality (38%), major CV events (14%), hospitalization for heart failure (35%), and death from any cause (32%) observed over a period of 2.6 years in patients with T2D and high CV risk in the EMPA-REG OUTCOME trial involving the SGLT2 inhibitor empagliflozin (Empa) have raised the possibility that potential novel, more specific mechanisms of SGLT2 inhibition synergize with the known modest systemic improvements, such as glycemic, body weight, diuresis, and blood pressure control.
In the EMPA-REG OUTCOME trial, SGLT2 inhibition with empagliflozin reduced the primary outcome of major adverse cardiovascular events (MACE), while also reducing mortality, hospitalization for heart failure, and progression of diabetic kidney disease.
Pooled results show that SGLT2 inhibitors, when compared to placebo, significantly reduce all-cause mortality (OR 0.79, 95% CI 0.70-0.89; P < 0.001), major adverse cardiac events (OR 0.8, 95% CI 0.76-0.92; P < 0.001), non-fatal myocardial infarction (OR 0.85, 95% CI 0.73-0.98; P = 0.03) and heart failure/hospitalisation for heart failure (OR 0.67, 95% CI 0.59-0.76; P < 0.001) in patients with type 2 diabetes mellitus.
Recently, the EMPA-REG OUTCOME trial revealed that empagliflozin, an inhibitor of the sodium-glucose cotransporter 2 (SGLT2), substantially reduced the risk of hospitalization for heart failure, death from cardiovascular causes, and all-cause mortality in patients with type 2 diabetes mellitus at high cardiovascular risk.