Empagliflozin proven to improve clinical outcomes in real world practice across a broad spectrum of cardiovascular risk

 

Subsequent to the mandate by the US Food and Drug Administration (FDA) that all new glucose-lowering agents should be tested for cardiovascular safety, results from large randomised controlled clinical trials (RCT) have changed the treatment approach to type 2 diabetes.1,2   Merely improving glycaemic control is no longer enough. The most recent 2018 treatment recommendations from the American Diabetes Association are that, after considering drug specific and patient factors, treatment for people with atherosclerotic cardiovascular disease (ASCVD) should begin with lifestyle management and metformin and subsequently incorporate an agent proven to reduce major adverse cardiovascular events and/or cardiovascular mortality.

Most studies have shown largely neutral effects on cardiovascular outcomes.1,2  However, a relatively new class of glucose-lowering agents, the sodium-glucose co-transporter 2 (SGLT-2) inhibitors, has been shown to confer significant benefits in terms of cardiovascular outcomes in patients with type 2 diabetes.3-5   Large RCTs including a total of more than 34 000 patients demonstrated that this class of treatment significantly reduces both incidence of cardiovascular events and progression of renal disease.3-6   In particular the three agents in this class (empagliflozin, canagliflozin and dapagliflozin) were all associated with a significant 27-35% reduction in the rate of hospitalisation for heart failure.3-5  

However, only one of these agents, empagliflozin, has been shown to significantly reduce the incidence of cardiovascular death.3-5   The EMPA-REG OUTCOME trial, an RCT including more than 7000 patients with type 2 diabetes and high cardiovascular (CV) risk, demonstrated that compared with placebo, over a median observation time of 3.1 years, empagliflozin reduced risk of cardiovascular death by 38%, hospitalisation for heart failure by 35% and death from any cause by 32%. The primary outcome, a composite of death from CV causes, nonfatal myocardial infarction or nonfatal stroke, was significantly reduced by 14% in comparison with standard care. The favourable effect of empagliflozin on CV death was demonstrated not only in high risk patients with established CV disease, but also it remained robust and significant even in patients with a low to average risk.

Now new results from the real-world EMPagliflozin compaRative effectiveness and SafEty (EMPRISE) study provide support for the findings from EMPA-REG and reassurance that those results observed in the large RCT are reflected also in day-to-day clinical practice.8 The initial data, derived from more than 35 000 patients treated in routine clinical practice, were presented at the American Heart Association 2018 Scientific Sessions in November.

EMPRISE showed that, compared with dipeptidyl-peptidase-4 (DPP-4) inhibitors, empagliflozin was associated with an overall 44% relative risk reduction in hospitalisation for heart failure. Importantly, this treatment effect remained consistent regardless of history of cardiovascular disease, reiterating that the benefits of empagliflozin extend across a broad range of patients with differing degrees of cardiovascular risk.8  

The SGLT-2 inhibitors are a novel class of antihyperglycaemic agents. They reduce rates of hyperglycaemia in patients with type 2 diabetes by decreasing renal glucose absorption and thereby increasing urinary glucose excretion. They have a half-life of longer than 10 hours and are administered orally once a day. Empagliflozin is the most specific of the three for SGLT-2.1 In addition to reducing glycaemia, empagliflozin is associated with weight loss, reductions in blood pressure without increases in heart rate, and favourable effects on markers of arterial stiffness and vascular resistance.The exact mechanisms responsible for the cardiovascular outcome benefits are uncertain, but additional drug effects that might contribute include reduced pre- and afterload (diuretic effect, reduced blood pressure and arterial stiffness), improvement in efficiency of cardiac mitochondrial energy output, delayed progression of renal dysfunction, delay in emergence of micro- and macro-albuminuria, reduced epicardial adipose tissue, and reduction in uric acid.1  

Empagliflozin is currently the only SGLT-2 inhibitor to be approved by the FDA for CVD benefit and is recommended by the ADA as a second line treatment of patients with type 2 diabetes and ASCVD.2  

The EMPRISE study is ongoing and is expected to be completed by September 2019. Future analyses will include increasing numbers of patients and additional clinical, safety and economic outcomes.8  

 

References
  1. Zelniker TA, Braunwald E. Cardiac and renal effects of sodium-glucose co-transporter 2 inhibitors in diabetes: JACC state-of-the-art review. J Am Coll Cardiol 2018. Published online. DOI: 10.1016/j.jacc.2018.06.040
  2. American Diabetes Association. Summary of revisions: Standards of medical care. In Standards of medical care in diabetes – 2018. Diabetes Care 2018; 41(Suppl 1). https://doi.org/10.2337/dc18-SREV01
  3. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes and mortality in type 2 diabetes.  N Engl J Med 2015; 373:2117-2128.
  4. Neal B, Mahaffey KW, de Zeeuw D, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 2017; 377: 644-657.
  5. Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2018. Published online 10 Nov 2018. DOI: 10.1056/NEJMoa1812389
  6. Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med 2016; 375: 323‐334.
  7. Fitchett D, Butler J, van de Borne P, et al. Effects of empagliflozin on risk for cardiovascular death and heart failure hospitalization across the spectrum of heart failure risk in the EMPA-REG OUTCOME trial. Eur Heart J 2018; 39: 363-370.
  8. Patorno E, Pawar A, Frnklin JM, et al. Empagliflozin and the risk of heart failure hospitalisation in routine clinical care: A first analysis from the Empagliflozin Comparative Effectiveness And Safety (EMPRISE) Study. Abstract and poster presented at the American Heart Association (AHA) Scientific Sessions, 10-12 Nov 2018, Chicago, IL, USA.

 

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