A Closer Look at the Updated ADA Standards of Medical Care Recommendations for Patients with Diabetes and ASCVD

Kirstin Gramith, Pharm.D., Essentia Health – Duluth, MN

Background: In 2008, the U.S. Food and Drug Administration (FDA) published a Guidance for Industry, which required sponsors of drug trials to conduct cardiovascular outcome trials (CVOTs) in order to demonstrate that their new antidiabetic therapy would not result in an unacceptable increase in cardiovascular risk.1,2

The results of recent CVOTs of antidiabetic medications have influenced the newly updated recommendations in the 2018 Standards of Medical Care in Diabetes. These guidelines suggest adding a second agent with evidence of cardiovascular risk reduction in patients with atherosclerotic cardiovascular disease (ASCVD) who are already on metformin and need additional therapy.3 Presently, options include SGLT-2 inhibitors Jardiance® (empagliflozin) and Invokana® (canagliflozin), and GLP-1 agonist Victoza® (liraglutide).

Evidence: EMPA-REG OUTCOME randomized participants to either empagliflozin 10 mg or 25 mg once daily to placebo.4 Over 7,000 patients with established CVD were followed for approximately 3.1 years. The primary endpoint was a composite endpoint of 3-point major adverse cardiovascular events (MACE): cardiovascular death, nonfatal MI, and nonfatal stroke. Use of empagliflozin was associated with reduced risk of the primary composite endpoint and met both non-inferiority and superiority criteria (HR 0.86 [0.74-0.99]; P=0.04).4 The significance of the primary composite endpoint was largely driven by reduction in cardiovascular death, which was the only significant individual component of the composite endpoint (HR 0.62 [0.49-0.77]; P<0.001).4

The CANVAS Program randomized participants to canagliflozin 100 mg or 300 mg once daily to placebo. The CANVAS Program included over 10,000 participants: over 4,000 from the CANVAS study and over 5,000 from the CANVAS-R study.5 Participants were followed for approximately 2.4 years on average. Interestingly, only 66% of CANVAS Program participants had established CVD at baseline, the remaining 34% participants had multiple risk factors for developing CVD. Canagliflozin use was associated with reduced risk of the primary composite endpoint, and this met non-inferiority and superiority criteria (HR 0.86 [0.75-0.97]; P=0.02).5 None of the individual components of the composite endpoint demonstrated a significant risk reduction and the use of canagliflozin was associated with increased risk of bone fracture (HR 1.26 [1.04-1.52]) and amputations (HR 1.97 [1.41-2.75]).5

LEADER randomized participants to liraglutide 1.8 mg once daily or to placebo. Approximately 80% of the participants in LEADER had established CVD, with others having high risk of developing CVD.6 Over 9,000 participants were followed for approximately 3.8 years. Use of liraglutide reduced the risk of the primary composite endpoint of 3-point MACE (HR 0.87 [0.78-0.97]; p=0.01).6  Similar to EMPA-REG OUTCOME and the CANVAS Program, both non-inferiority and superiority criteria were met. The significance of the primary composite endpoint was driven by reduction of cardiovascular death, which was the only significant individual component of the composite endpoint (HR 0.78 [0.66-0.93]; P=0.007).6

Discussion: EMPA-REG OUTCOME4 and the CANVAS Program5 demonstrated 14% risk reduction of 3-point MACE, and LEADER6 demonstrated a 13% risk reduction of 3-point MACE(NNT 63, 218, and 53 for empagliflozin, canagliflozin, and liraglutide, respectively). However, only EMPA-REG OUTCOME and LEADER demonstrated a lower risk of cardiovascular death (38 and 22%, respectively).4,5 Perhaps this is because the CANVAS Program included the lowest percentage of participants with established CVD. Interestingly, none of these CVOTs showed reduced risk of the individual components of nonfatal MI or nonfatal stroke. Admittedly, EMPA-REG OUTCOME and LEADER defined cardiovascular death in a controversial manner. Protocols for these studies confirm that all death not attributed to the categories of cardiovascular death or non-cardiovascular death was presumed to be cardiovascular in nature, which may have impacted the significance of findings from EMPA-REG OUTCOME and LEADER.4,6 A sensitivity analysis that removed non-assessable death from EMPA-REG OUTCOME no longer demonstrated superiority for the primary composite endpoint; however the superiority was maintained for the individual component of cardiovascular death.4 Thus, the results of EMPA-REG OUTCOME are highly debated between experts. In a sensitivity analysis of LEADER, superiority persisted for the primary composite endpoint. 

Clinical Impact: In patients with uncontrolled T2DM and comorbid ASCVD, the addition of empagliflozin, canagliflozin, or liraglutide to metformin is supported by the 2018 Standards of Medical Care in Diabetes.3,7 Clinicians should continue to demonstrate patient-centered care when deciding upon an individual medication. It is preferred to use a medication that has been shown to reduce risk of cardiovascular death in addition to 3-point MACE; however more studies are needed to yield robust statistical support for the use of various SGLT-2 inhibitors and/or GLP-1 agonists for risk reduction of cardiovascular disease in patients with T2DM.7   


  1. Martin-Timon I, Sevillano-Collantes C, Segura-Galindo A, del Canizo-Gomez FJ. Type 2 diabetes and cardiovascular disease: Have all risk factors the same strength? World J Diabetes. 2014;5(4):444-470.

  2. Food and Drug Administration. Guidance for industry: Diabetes mellitus – evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes.https://www.fda.gov/downloads/Drugs/.../Guidances/ucm071627.pdf. Published December 2008. Accessed May 3, 2018.

  3. American Diabetes Association. Pharmacologic approaches to glycemic treatment: Standards of medical care in diabetes – 2018. Diabetes Care. 2018;41(Suppl 1):S73-S85.

  4. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117-28.

  5. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377(7):644-57.

  6. Marso SP, Daniels GH, Brown-Frandsen K. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375(18):311-22.

  7. Cefalu WT, Kaul S, Gerstein HC, et al. Cardiovascular outcome trials in type 2 diabetes: where do we go from here? Reflections from a Diabetes Care editors’ expert forum. Diabetes Care. 2018;41(1):14-31.