Summary | The future of SGLT2i in HF: Managing patients without T2DM?
In his presentation prof. Voors addressed three major questions after the first study results with SGLT2i thus far: 1) Can we now routinely recommend SGLT2i in T2DM patients with concomitant HF? 2) Will SGLT2i work in HF patients without T2DM as well? 3) Which SGLT2i trials are ongoing?
He showed a slide with details of three major CV outcome trials (CVOTs) testing SGLT2i: EMPA-REG OUTCOME, the CANVAS Program and DECLARE-TIMI-58. There is great consistency in the design of the trials (all including T2DM patients with established CVD or CV risk factors). Results also showed great consistency, with ~15-25% reduction in primary endpoints. For a HF cardiologist, the most interesting finding is the reduction of ~35% in HF hospitalization.
However, before SGLT2i can be used in HF patients, there are a few things to consider and caveats to address said Voors. In these trials, the proportion of patients with a history of HF was low: ~10%. In addition, HF in these patients was not well-established; type of HF and NT-proBNP levels were unknown in many patients. Furthermore, HF hospitalizations were often not adjudicated. This makes it difficult to translate data of T2DM patients with high CV risk to a real-world HF population.
Originally, SGLT2i were designed as glucose-lowering drugs, but now the question is relevant whether these agents will also work in patients without T2DM. There are many potential mechanisms how SGLT2i might be beneficial for the heart and give benefit in HF patients. The most important effect of SGLT2i for HF patients is the diuretic effect, which is related to glucose excretion. In non-diabetics, there is less glucose to be excreted, and thus also less sodium. Therefore, in theory, the natriuretic and diuretic effects of SGLT2i should be reduced when glucose levels are lower. But it is unsure whether this holds true in practice. He showed the results of a pooled analysis of 11 phase 3 trials in T2DM patients randomized to placebo or dapagliflozin . In patients with lower eGFR, the reduction in HbA1c was smaller. However, effects on decongestion were independent of eGFR level. The authors of this study concluded that the effects of dapagliflozin are partly mediated by non-glucosuric effects. Although the EASD/ADA already recommends to use SGLT2i in patients with HF and impaired renal function, Voors said it might not be prime time yet and we have to wait for study results to arrive.
Voors next gave an overview of ongoing HF trials with SGLT2i. DAPA-HF will enroll >4000 patients with HFrEF, randomized to dapagliflozin or placebo, irrespective of diabetes status, with HF hospitalization or CV death as primary outcome. The EMPEROR program examines the effect of empagliflozin across the full spectrum of HF, with separate trials enrolling HFrEF and HFpEF patients. The DELIVER trial will enroll ~4500 HFpEF patients in which the effect of dapagliflozin will be evaluated and the SOLOIST trial examines the combined effect of SGLT1 and SGLT2 inhibitors in HF patients across the whole LVEF range and patients will be randomized during worsening HF. In addition, the EMPERIAL Preserved and Reduced trials will examine the effect of empagliflozin on exercise capacity in HF patients. He ended by presenting the study design details of the EMPA-RESPONSE, a first acute HF RCT, examining the effect of empagliflozin in 80 patients.
This is a summary of the presentation given by prof. Adriaan Voors, during the PACE symposium entitled 'Heart Failure, diabetes and SGLT2i: Time to change practice?', held during ESC HF in Athens, Greece on May 25, 2019.