Gliflozins and Heart Failure

“Gliflozins”, or sodium-glucose co-transporter 2 (SGLT2) inhibitors, are the newest class of oral anti-diabetic medications. Dapagliflozin was the first agent in this class to be approved for use in diabetes in 2012 (by both the European Medicines Agency and the Therapeutic Goods Administration), with empagliflozin and ertugliflozin being approved later – in 2014 and 2018 respectively. Gliflozins exert their therapeutic effect by inhibiting the sodium-glucose co-transporter 2 in the nephron, thus reducing the reabsorption of glucose. They are approved to treat type 2 diabetes mellitus (T2DM).

T2DM is a known risk factor for heart failure (HF), particularly those with longstanding diabetes, poor glycaemic control, insulin treatment or microvascular complications such as nephropathy.

In 2015 a randomised, double-blind, placebo-controlled clinical trial was initiated to investigate the cardiovascular outcomes of diabetic patients treated with empagliflozin. The trial followed 7,020 patients across 42 countries and measured a composite of death from cardiovascular causes as well as nonfatal myocardial infarction (MI) and stroke. The empagliflozin group was found to have a significantly lower incidence of primary outcomes (10.5% vs 12.1%) as well as all-cause mortality (HR, 0.68; 95% CI, 0.57 to 0.82, P<0.001) and heart failure (HR, 0.65; 95% CI, 0.50 to 0.85; P=0.002). Although this trial was designed merely to show the cardiovascular safety of gliflozins, these surprising results were in fact the first incidence of a glucose-lowering agent showing clear superiority to placebo when measuring primary CVD (cardiovascular disease) endpoints.

If these results were not remarkable enough, the latency in improved clinical outcomes is surprisingly short, indicating that a reduction in blood-glucose level (BGL) is unlikely to be implicated. The median treatment period was only 2.6 years with a difference in primary outcome becoming evident approximately three months after initiating empagliflozin. In contrast, “Even when a formal multifactorial intervention is undertaken, such as in the Intensified Multifactorial Intervention in Patients With Type 2 Diabetes and Microalbuminuria (STENO-2) trial (ie, renin-angiotensin system blockers, aspirin, and lipid-lowering agents), cardiovascular protection is not observed for several years”.

It is also interesting to note that the treatment arm of the trial did not experience a reduction in ischemic events (MI/stroke), implying that perhaps the 35% reduction in hospitalisations due to HF may be a decisive factor. A paper published in February 2020 in BBA – Molecular Basis for Disease by researchers from a German university hospital reviewed current hypotheses on the mechanisms by which gliflozins may be of benefit in HF. Whilst the mechanism(s) is/are not fully understood, the researchers suggest it is likely to be pleiotropic (affecting genes that code for multiple phenotypes), possibly involving metabolism and electromechanical coupling in the myocardium.

In March 2020 the American College of Cardiology published results of a trial investigating the protective effect of dapagliflozin in patients with HF. This was a randomised placebo-controlled trial with 4,744 participants with a mean age of 66 years. Similar to the empagliflozin trial, this study found that dapagliflozin reduced cardiovascular deaths and HF events compared to placebo. These results were independent of diabetes status (T1DM patients were excluded), age, background health or other medications.

Finally, the CANVAS trial – investigating canagliflozin (not marketed in Australia) – and a further meta-analysis of all three trials, added further weight to the class-effect of gliflozins reducing the risk of hospitalisations due to HF in patients with and without established atherosclerotic CVD. The meta-analysis found the reduced hospitalisation for HF and CVD mortality rate to be 23% and to have an even greater protective effect in those with reduced eGFR (estimated glomerular filtration rate). Conversely, the risk reduction for major adverse cardiovascular events was found to be only modest (11%), and this was largely observed in those with established atherosclerotic CVD (ASCVD). However, the more recent CREDENCE trial, looking at canagliflozin in those with albuminuric chronic kidney disease (CKD), provided more robust evidence of the potential benefits of gliflozins with atherothrombotic events – major adverse cardiovascular events (MACE) HR = 0.8 (0.67-0.95)⁵.

Upon reanalysis of the data from DECLARE-TIMI 58, researchers found similar benefits for ASCVD patients taking dapagliflozin – MACE HR 0.84 (95% CI, 0.72-0.99) – but only in patients with prior MI. The effect of reduced ejection fraction was also re-analysed from this data, showing increased benefits of dapagliflozin in those with reduced ejection fraction. The following table summarises the differences.

Table 1. (Adapted from Verma S, et al.)

(CV Death = deaths from cardiovascular disease, rEF = reduced ejection fraction)

It would, therefore, appear that SGLT2-inhibitors (gliflozins) are rapidly emerging as a novel treatment for heart failure, including heart failure with preserved left ventricular ejection fraction.