The EMPA-OUTCOME trial involving empagliflozin (a SGLT-2 receptor inhibitor) has shown significant reductions in major adverse cardiac events (MACEs), cardiovascular mortality, and hospitalization for heart failure (HF) when administered on top of standard-of-care therapy for T2DM patients at high CV risk.
Since SGLT2 inhibitors can attenuate the high glucose-induced dysfunction of pericytes and mesangial cells, the desirable effects of SGLT2 inhibitors on HF and renal dysfunction might be explained by their direct actions on these cells in the heart and kidney microvasculature.
In a randomized trial of patients with heart failure and reduced ejection fraction, the SGLT2 inhibitor dapagliflozin markedly reduced mortality and worsening heart failure (McMurray et al., 2019).
While dipeptidyl peptidase-4 (DPP-4) inhibitors exhibited increased heart failure hospitalization in the SAVOR-TIMI 53 trial evaluating saxagliptin and in the secondary analysis of the EXAMINE trial for alogliptin, the effects of glucagon-like peptide-1 (GLP-1) analogs and sodium-glucose co-transporter-2 (SGLT2) inhibitors on CV outcomes in diabetes have largely been positive.
However, the newest antidiabetic medications, sodium-glucose cotransporter 2 (SGLT2) inhibitors, have shown to significantly reduce CV mortality and heart failure (HF) hospitalizations.
Thus, recent guidelines for type 2 diabetes suggest that among oral agents to use together with metformin, SGLT-2 inhibitors should be preferred in patients at increased cardiovascular risk, kidney disease or heart failure.
Accordingly, in this review, we summarize the key pharmacodynamic effects of SGLT2 inhibitors and the clinical evidence that support the rationale for the use of SGLT2 inhibitors in patients with HF who have T2D.
Emerging data have demonstrated that sodium-glucose cotransporter-2 (SGLT2) inhibitors prevent cardiovascular events, especially heart failure-associated endpoints.
At the present time, SGLT2 inhibitors are indicated for the treatment of type 2 diabetes; however, the results of ongoing trials in participants with heart failure but without diabetes are eagerly awaited.
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).
Recent evidence has unveiled the irrefutable data that SGLT2 inhibitors reduce CV events in patients with T2DM, with a profound effect on reductions in hospitalization for HF.
Our results demonstrate that SGLT2 inhibitors may be novel therapeutics against reduced exercise endurance capacity in HF, by improving mitochondrial fatty acid oxidation in skeletal muscle.
The SGLT-2 inhibitors have opened a new perspective for clinicians treating patients with T2D and established CV disease in light of their 'pleiotropic' effects, specifically on heart failure, while GLP-1RAs seem to present more favourable effects on atherosclerotic events.
The Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients-Removing Excess Glucose (EMPA-REG OUTCOME) study demonstrated for the first time that a glucose-lowering agent, the sodium glucose cotransporter 2 (SGLT2) inhibitor empagliflozin, could reduce major adverse cardiovascular events, cardiovascular mortality, hospitalization for heart failure, and overall mortality when given in addition to standard care in patients with T2DM at high cardiovascular risk.
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.
Furthermore, there is growing evidence to illustrate the overall safety profile of this class of agents and support the benefit-risk profile of SGLT2 inhibitors as a preferred option following metformin monotherapy failure, with respect to both kidney disease progression and heart failure outcomes.
In the only completed trial to date to assess a sodium-glucose cotransporter-2 (SGLT2) inhibitor, empagliflozin reduced the risk of composite cardiovascular endpoints, predominantly through its impact on cardiovascular mortality and heart failure hospitalization.
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.