After a long year of being on the look-out for new cardiovascular outcome trial (CVOT) data, the American Diabetes Association (ADA) has released the much anticipated 2017 Standards of Medical Care in Diabetes update. The overall value of the CVOT data has been called into question and clinicians have varied predictions regarding how the ADA may incorporate those findings into their recommendations. So let’s take a look:
The ADA has incorporated their recommendation regarding the positive outcomes seen with the use of empagliflozin in the EMPA-REG OUTCOME trial and liraglutide in the LEADER trial into the section on the pharmacologic approaches to glycemic treatment in type 2 diabetes mellitus (T2DM). Regretfully, the data was not incorporated into the general treatment algorithm, which continues to focus on patient centered characteristics for the selection of second line agents. Instead, the level B ADA recommendation comes with some caveats. The recommendation outlines the use of empagliflozin and liraglutide in patients with long-standing, poorly controlled T2DM and established atherosclerotic cardiovascular disease (ASCVD) in addition to the existing standards of care. (ref 1) These guideline updates are on the heels of the new indication approval by the FDA for empagliflozin. This new indication is to reduce the risk of cardiovascular death in adults with T2DM and cardiovascular disease.(ref 2)
While this blanket statement for established ASCVD may by easier for clinicians to apply in practice, it is important to recognize the differences in patient population that were included in both the EMPA-REG OUTCOME and the LEADER trials.(ref 3,4) The LEADER trial exemplified a higher level of external validity, because of the more inclusive study design and expansive definition of high cardiovascular risk. (ref 4) While the EMPA-REG OUTCOME study included patients with only established cardiovascular disease, the LEADER trial also included patients with at least one cardiovascular disease risk factor and aged > 60 years. (ref 3,4) The LEADER trial also considered CKD stage 3 or greater or CHF of NYHA class II or III in their definition of coexisting cardiovascular condition, which only had an inclusion age cut off of 50 years.(ref 4) I feel that in my practice, while established ASCVD is not rare, the positive CVOT data can be applied more widely for liraglutide than for empagliflozin due to the broader inclusion criteria seen in the LEADER study.
How do the differences in study population affect how other clinicians apply this data? I am eager to hear other opinions in the clinical community about how the ADA has classified this data and if it will change your practice. Another clinical discussion starter can also be if this data fulfils the original purpose of CVOT and if they are worth the large cost and limited external . Lastly, does anyone think that metformin with be over-thrown from the high castle as the backbone of therapy with any of this CVOT data? If you aren’t convinced just yet, what do you think it would take to convince you?
- American Diabetes Association (ADA). Standards of medical care in diabetes 2017. Diabetes Care 2017 Jan; 40 (Supplement 1): S64-S74.
- FDA approves Jardiance to reduce cardiovascular death in adults with type 2 diabetes. Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm531517.htm. [Accessed January 10, 2017]
- Zinman B, Wanner C, Lachine JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373:2117-28.
- Marso SP, Daniels, GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in Type 2 diabetes. N Eng J Med 2016;375(4):311-22