Patients (n=4744) with New York Heart Association (NYHA) class II-IV HFrEF were randomised to either dapagliflozin (10mg once daily) or placebo, in addition to standard therapy. The primary endpoint was a composite of worsening HF (hospitalisation or an urgent visit resulting in intravenous therapy for HF) or CV death.²

Over a median of 18.2 months, the primary outcome occurred in 16.3% of patients in the dapagliflozin group and in 21.2% of patients in the placebo group (hazard ratio [HR], 0.74, 95% confidence interval [CI], 0.65 to 0.85, P<0.001). A first worsening HF event occurred in 10% in the dapagliflozin group and in 13.7% in the placebo group (HR, 0.70, 95% CI, 0.59 to 0.83, P<0.001).²

Death from CV causes occurred in 9.6% in the dapagliflozin group and in 11.5% of patients in the placebo group (HR, 0.82, 95% CI, 0.69 to 0.98 P<0.001), 11.6% and 13.9%, respectively, died from any cause (HR, 0.83, 95% CI, 0.71 to 0.97, P<0.001). Findings in patients with diabetes were similar independent of diabetes status.²

More recently Jhund et al (2023) conducted a prespecified analysis of the Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure (DELIVER) trial.³

In the DELIVER trial, dapagliflozin reduced the risk of time to first worsening HF event or CV death in patients (n=6263) with mildly reduced HF (HFmrEF) or preserved HF (HFpEF), which was defined as HF with NYHA class II-IV and an EF >40%. Jhund et al evaluated the effect of dapagliflozin on total (eg first and recurrent) HF events and CV death in the DELIVER cohort.³

The researchers also conducted several subgroup analyses to test for heterogeneity in the effect of dapagliflozin, including left ventricular EF. In the DELIVER trial, patients were randomised to dapagliflozin (10mg once daily) or placebo.³

They reported that 16.8% of HF events and CV deaths occurred in the placebo group compared with 13% in the dapagliflozin group. Patients with more HF events had features of more severe HF, such as higher N-terminal pro-B-type natriuretic peptide level, worse kidney function, more prior HF hospitalisations, and longer duration of HF, although EF was similar to those with no HF events. In the Lin, Wei, Yang, and Ying model, the rate ratio for total HF events and CV death for dapagliflozin compared with placebo was 0.77 (95% CI, 0.67-0.89, P<.001) compared with an HR of 0.82 (95% CI, 0.73-0.92, P<.001) in a traditional time to first event analysis. In the joint frailty model, the rate ratio was 0.72 (95% CI, 0.65-0.81, P<.001) for total HF events and 0.87 (95% CI, 0.72-1.05, P=.14) for CV death. The results were similar for total HF hospitalisations (without urgent HF visits) and CV and in all subgroups, including those defined by EF.³

The team concluded that in patients with HFmrEF or HFpEF, dapagliflozin reduced the risk of total HF events, including both first-time and repeated events. This benefit was observed across different subgroups and EF ranges. The characteristics associated with multiple HF events in these patients were similar to those seen in patients with HFrEF. The reduction in HF event burden with dapagliflozin was consistent regardless of the analysis method used, and the results aligned with previous trials of SGLT2i in HFmrEF and HFpEF patients.³

How do SGLT2i exert their cardioprotective benefit?

Joshi et al explain that SGLT2i work by blocking the SGLT2 protein in the kidney, which is responsible for reabsorbing glucose from the urine back into the bloodstream. By inhibiting this protein, SGLT2i increase glucose excretion in the urine, leading to reduced blood glucose levels.⁴

The primary mechanism by which SGLT2i exert their CV effects is not yet fully understood, but several potential pathways have been identified and some theories have been put forward. One theory is that these drugs have diuretic and antihypertensive effects. They cause increased urination and sodium excretion, leading to reduced blood volume and potentially lowered blood pressure.⁴

SGLT2i also have effects on glucose metabolism, potentially improving the efficiency of cardiac energy utilisation and reducing oxidative stress. Weight loss and improved glycaemic control have also been proposed as mechanisms for the CV benefits of SGLT2i. These agents lead to weight loss, particularly in patients living with diabetes, due to increased lipid mobilisation.⁴

Another mechanism that has been explored is the increase in haematocrit (the proportion of blood occupied by red blood cells) associated with SGLT2i. This increase may contribute to improved CV outcomes, although similar increases in haematocrit have not always resulted in mortality benefits, noted Joshi et al.⁴

Potential novel mechanisms of benefit include the direct cardiac effects of SGLT2i, where these agents could impact cardiac remodelling and hypertrophy, which may contribute to their CV benefits.⁴

Another intriguing aspect that has been explored is the effect of SGLT2i on cardiac energetics. SGLT2i may shift cardiac metabolism towards using more efficient ketone bodies for energy production, improving myocardial efficiency.⁴

Furthermore, write Joshi et al, SGLT2i may affect ionic homeostasis in the heart, particularly related to calcium handling and may influence calcium levels in cardiac cells, potentially improving contractile function, contributing to their cardioprotective effects.⁴

Autophagy, the process of cellular ‘clean-up’ and recycling, has been proposed as another mechanism. SGLT2i may induce autophagy due to their effects on nutrient depletion, leading to benefits in HF where dysfunctional mitochondria contribute to oxidative stress and inflammation.⁴

Lastly, SGLT2i may affect the balance of leptin and adiponectin (hormones produced by fat cells), which are involved in energy regulation and CV health.⁴

 Can SGLT2i be used for primary and secondary prevention of CV diseases?

Eminent American cardiologist Prof Eugene Braunwald, describes  SGLT2i as the statins of the 21^st century and argues that flozins can be used for risk-based primary prevention of HF.¹

However, He et al (2023) conducted a meta-analysis and showed that SGLT2i can be used for both primary and secondary CV prevention. Their analysis included 11 studies and 34 058 cases. They found that SGLT2i significantly reduced major adverse CV events (MACE) in patients with prior MI (odd ration [OR] 0.83), no prior MI (OR 0.82), prior coronary atherosclerotic disease (CAD, OR 0.82) and no prior CAD (OR 0.82) compared with placebo.⁵

In addition, SGLT2i significantly reduced HF hospitalisation in patients with prior MI (OR 0.69), no prior MI (OR 0.63), prior CAD (OR 0.65) and no prior CAD (OR 0.65) compared with placebo. SGLT2i reduced CV mortality and all-cause mortality events. MI (OR 0.79), renal damage (OR 0.73), all-cause hospitalisation (OR 0.89), and systolic as well as diastolic blood pressure were all significantly reduced in patients receiving SGLT2i.⁵

Conclusion

SGLT2i have transcended their initial role in glycaemic control to emerge as powerful cardioprotective agents. Their multifaceted mechanisms of action, spanning diuresis and glucose control to direct cardiac effects and altered metabolic pathways, offer new avenues for improving patient outcomes in HF and beyond. As research continues to unveil the intricate workings of SGLT2 inhibitors, these agents hold the potential to reshape the landscape of CV therapeutics, providing hope for a brighter future for patients with a wide range of CV diseases.

References

1. Braunwald E. SGLT2 inhibitors: the statins of the 21st century. European Heart Journal, 2022.
2. McMurray JJV, Solomon SD, Inzucchi SE, et al.Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med, 2019.
3. Jhund PS, Claggett BL, Talebi A, et al. Effect of Dapagliflozin on Total Heart Failure Events in Patients With Heart Failure With Mildly Reduced or Preserved Ejection Fraction: A Prespecified Analysis of the DELIVER Trial. JAMA Cardiol, 2023.
4. Joshi SS, Singh T, Newby DE, et al. Sodium-glucose co-transporter 2 inhibitor therapy: mechanisms of action in heart failure. Heart, 2021.
5. He G, Yang G, Huang X, et al. SGLT2 inhibitors for prevention of primary and secondary cardiovascular outcomes: A meta-analysis of randomized controlled trials. Heart and Lung, 2023