A symposium 'Focus on diabetes in heart failure' held at the Heart Failure 2019 Congress focussed on the treatment of two global epidemics: heart failure and type 2 diabetes mellitus (T2DM). Chair of the session, Professor Petar M Seferović, discussed newer classes of glucose-lowering agents and how they may fit into the treatment of patients with these co-existing conditions.

Considering the strong interaction between T2DM and poor outcomes in heart failure, itis highly relevant that T2DM treatment does not exacerbate this association, as previously observed with thiazolidinediones. Instead, glucose-lowering medications should have a neutral effect or, preferably, reduce the risk of heart failure.

Sodium-glucose co-transporter-2 (SGLT2) inhibitors are a relatively new class that lower plasma glucose levels by inhibiting glucose reabsorption in the renal proximal tubule, without increasing hypoglycaemia, and promote weight loss by inducing glycosuria. The beneficial effects of SGLT2 inhibitors on heart failure have been recently documented in landmark cardiovascular (CV) outcome trials.

The first, EMPA-REG OUTCOME, included 7,020 T2DM patients with established CV disease (CVD) who were randomised to empagliflozin or placebo. Empagliflozin vs placebo produced a significant 14% risk reduction in major adverse CV events (MACE; non-fatal myocardial infarction, non-fatal stroke and CV mortality), with a striking 32% reduction in heart failure hospitalisation and a 38% and 32% reduction in CV mortality and all-cause mortality, respectively. In the second trial, CANVAS, 10,142 T2DM patients with established CVD (66%) or at high CV risk (34%) were randomised to canagliflozin or placebo. A similar 14% reduction in MACE was observed with canagliflozin vs placebo as well as a substantial 33% reduction in heart failure hospitalisation.

The most recent and largest trial, DECLARETIMI 58, compared dapagliflozin vs placebo in 17,160 T2DM patients, where 59% were primary-prevention patients. Dapagliflozin did not reduce the co-primary outcome of MACE vs placebo, but was superior in reducing the second co-primary outcome of CV death or heart failure hospitalisation by 17%, driven by a significant 27% reduction in heart failure hospitalisation. In a sub-analysis, dapagliflozin was found to reduce heart failure hospitalisation regardless of baseline ejection fraction, although the greatest benefit was observed among high-risk patients with reduced ejection fraction. Interestingly, lower heart failure hospitalisation rates occurred early in patients with reduced ejection fraction, but approximately 12 months later in individuals without reduced ejection fraction, suggesting possible differential underlying effects.

The putative mechanisms for CV protection with SGLT2 inhibitors remain unresolved. Early improvement in haemodynamic status (i.e. reduction in preload and afterload) in relation to a reduction of fluid overload, particularly in the interstitial compartment via SGLT2-inhibitor-induced diuresis and natriuresis, may be the most relevant mechanism. Positive influences on cardiac metabolism and mitochondrial function (i.e. reduced fatty acid metabolism and more efficient ketone body utilisation), and preservation of renal function, may also favourably impact on the risk of heart failure. Importantly, these effects also pertain to individuals without diabetes, providing a rationale for assessing the potential benefit of SGLT2 inhibitors in patients with heart failure irrespective of concomitant diabetes.

Given the evidence from large-scale CV outcome trials, the use of SGLT2 inhibitors is recommended to reduce the risk of heart failure and mortality in 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure as well as in 2016 ESC Guidelines for CVD prevention. Likewise, the most recent recommendations from European and American diabetologists’ associations position SGLT2 inhibitors as the preferred T2DM treatment in patients with, or at risk of, heart failure.

Recent trials also provide a perspective on the CV safety of other newer classes of glucose-lowering medications. Among the dipeptidyl peptidase-4 inhibitors, saxagliptin should not be used in patients with, or at risk of heart failure, while caution is advised with alogliptin. There is no evidence of adverse outcomes with linagliptin or sitagliptin. Glucagon like peptide-1 receptor agonists demonstrated a neutral effect on heart failure in CV outcome trials; however, an adverse signal in smaller trials of patients with severely reduced ejection fraction suggests further studies are warranted in advanced heart failure.”

This article is a news release from Heart failure Congress 2019.  Read the original here.