News from the American Heart Association: More on Sodium–Glucose Co-Transporter 2 Inhibitors, Diabetes and Heart Failure

More data on novel antihyperglycaemic agents, especially regarding their effects on new-onset and hospitalization for heart failure (HF), were presented at the 2018 American Heart Association (AHA) Scientific Sessions in Chicago, USA, 10–12 November 2018. Taking into account its paramount clinical importance, this hot topic is rightfully fully in focus of both cardiologists and diabetologists. Even more importantly, the results of recent clinical trials of the sodium–glucose co-transporter 2 (SGLT2) inhibitor class of antihyperglycaemic agents, suggest that this class of agents may be especially beneficial in reducing the risk of HF. The most recent of these trials was DECLARE–TIMI 58, which was presented at the AHA and simultaneously published in the New England Journal of Medicine.1 DECLARE–TIMI 58 was a double-blind, placebo-controlled trial that randomized 17 160 patients with type 2 diabetes mellitus (T2DM) and established atherosclerotic cardiovascular (CV) disease, or multiple risk factors, to dapagliflozin (10 mg/day) or placebo. The median follow-up was 4.2 years. Initially, this trial was designed with a primary safety outcome of major adverse cardiovascular events (MACE). However, following the results of the EMPA-REG OUTCOME trial,2 where empagliflozin demonstrated a greater benefit in CV death and HF hospitalization than was seen for MACE, the protocol of DECLARE–TIMI 58 was amended to include two primary efficacy outcomes, both MACE and that of CV death or HF hospitalization. In DECLARE–TIMI 58 the primary safety endpoint was met, revealing non-inferiority of dapagliflozin to placebo with respect to MACE. In addition, there was a lower rate of CV death or hospitalization for HF, compared to placebo [4.9% vs. 5.8%; hazard ratio (HR) 0.83; 95% confidence interval (CI) 0.73–0.95; P = 0.005]. This was mainly driven by the reduction of HF hospitalization (HR 0.73; 95% CI 0.61–0.88), with no effect on CV death (HR 0.98; 95% CI 0.82–1.17). The reduction of HF hospitalization was evident both in patients with or without a history of HF. However, the primary efficacy endpoint of MACE was not reduced by dapagliflozin. Given that SGLT2 inhibitors also act as diuretic agents, the plausible hypothesis may be that dapagliflozin, by decreasing fluid overload, improves congestion and leads to fewer admissions for HF, with no other evidence of beneficial outcomes. Furthermore, dapagliflozin was associated with a significantly lower risk for renal events (4.3% vs. 5.6%; HR 0.76). From a safety perspective, there was an increase of diabetic keto-acidosis (27 vs. 12) and genital infections (76 vs. 9), but not hypoglycaemic events, nor amputations (associated with canagliflozin). Overall, there were fewer serious adverse events with dapagliflozin. The position of SGLT2 inhibitors in the treatment of T2DM, with or without HF, differs significantly among various guidelines. In the 2016 European Society of Cardiology (ESC) guidelines on HF,3 empagliflozin was recommended based on having been shown to improve CV outcomes, including the reduction of all-cause mortality and HF hospitalizations in patients with T2DM. Other antihyperglycaemic agents have not been shown convincingly to reduce the risk of CV events and may even increase the risk of HF. In the 2017 American College of Cardiology/American Heart Association/Heart Failure Society of America (ACC/AHA/HFSA) focused update of the 2013 ACC/AHA guideline for the management of HF, SGLT2 inhibitors were not mentioned.4 In the 2018 guidelines for the prevention, detection and management of HF in Australia,5 SGLT2 inhibitors are recommended in patients with T2DM associated with CV disease and poor glycaemic control (on top of metformin), to decrease the risk of CV events and HF hospitalization. Recently, in the 2019 American Diabetes Association Standards of Medical Care in Diabetes,6 SGLT2 inhibitors are recommended for the first time as a treatment of choice in patients with T2DM and HF, as well as in those with chronic kidney disease. The Heart Failure Association (HFA) of the ESC, both in its position papers and journal, has recently focused on the interplay between HF, diabetes and the choice of antihyperglycaemic therapy7-15. There is a wealth of data on the CV effects of novel antihyperglycaemic agents, as summarized elsewhere.16 During the past 10 years, nine CV outcome trials investigating SGLT2 inhibitors, enrolling 62 378 patients, have been initiated. Three of them (DECLARE–TIMI 58, EMPA-REG OUTCOME, and CANVAS Program) have been completed,1, 2, 17 while six will be reported within the next 2–3 years. However, it remains unclear whether HF prevention is a class effect of SGLT2 inhibitors, or the effect of specific drug(s) within this class. In the EMPA-REG OUTCOME trial,2 empagliflozin reduced the risk of 3-point MACE in 7020 patients (HR 0.86, 95% CI 0.74–0.99; P = 0.04). The empagliflozin use was also associated with significantly lower rates of CV death (3.7% vs. 5.9% in the placebo group; 38% relative risk reduction), hospitalization for HF (2.7% vs. 4.1%; 35% relative risk reduction), and death from any cause (5.7% vs. 8.3%; 32% relative risk reduction). Similarly to DECLARE–TIMI 58, the CANVAS Trial Program (CANagliflozin cardioVascular Assessment Study, CANVAS, and the CANagliflozin cardioVascular Assessment Study-Renal, CANVAS-R) has a positive non-inferiority outcome.17 The rate of the primary MACE (death from CV causes, non-fatal myocardial infarction, or non-fatal stroke) outcome was lower with canagliflozin compared to placebo (HR 0.86, 95% CI 0.75–0.97, P < 0.001 for non-inferiority; P = 0.02 for superiority). Canagliflozin also reduced the risk of HF-related hospitalizations (HR 0.67, 95% CI 0.52–0.87), similar to dapagliflozin and empagliflozin. However, there was no significant reduction in all-cause mortality (HR 0.87, 95% CI 0.74–1.01) or CV death (HR 0.87, 95% CI 0.72–1.06). Similarly to DECLARE–TIMI 58, canagliflozin improved renal endpoints (renal replacement therapy, or death from renal causes: HR 0.60, 95% CI 0.47–0.77). However, canagliflozin use was associated with an increased risk of amputation (6.3 vs. 3.4 participants per 1000 patient-years; HR 1.97, 95% CI 1.41–2.75). The clear similarity for all three SGLT2 inhibitor trials to date is a significant reduction in HF hospitalization events, suggesting the existence of a class effect. Possibly, SGLT2 inhibitors may affect the similar pathophysiological mechanisms and have a related mode of action. However, they have very different effects on all-cause and CV mortality. Therefore, the question of class effect remains unclear for these outcomes.