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Empagliflozin Use in People with Type 2 and History of Coronary Artery Bypass Graft Surgery (CABG)

Sep 15, 2018
 

Empagliflozin after CABG? Research still limited in regard to SGLT2 inhibitor use and its ability to reduce CVD risk in patients after revascularization

A well-known fact is that patients with type 2 diabetes are predisposed to cardiovascular complications like atherosclerotic cardiovascular disease, microvascular complications, and obstructive coronary artery disease. Research has found that people with diabetes requiring revascularization benefit more from coronary artery bypass grafts (CABG) than percutaneous coronary intervention (PCI). Still, even after the preferential treatment is done, cardiovascular risk remains. Given the continued risk, use of antidiabetic medications with beneficial cardiovascular outcomes should be considered in these patients.

The EMPA-REG OUTCOME trial looked to evaluate the benefits of empagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor, in patients with type 2 diabetes and cardiovascular disease (CVD). The study found empagliflozin was advantageous as noted by improved cardiovascular outcomes (i.e. risk reduction in cardiovascular and all-cause mortality). This finding led to the eventual indication stating that empagliflozin is approved for use in those with type 2 diabetes and established cardiovascular disease. Despite all of this information, research is limited in regard to SGLT2 inhibitor use and its ability to reduce CVD risk in patients after revascularization. Using data from the EMPA-REG OUTCOME trial, S. Verma, et al aimed to determine cardiovascular outcomes and mortality in patients after CABG.

Eligible patients had to have type 2 diabetes, cardiovascular disease, and an estimated glomerular filtration rate ≥ 30 mL/min/1.73 m2. History of CABG at baseline was determined from case reports; participants in the original trial self-reported their CV history. Those enrolled were randomized into one of three groups (i.e. empagliflozin 10 mg once daily, empagliflozin 25 mg once daily, and placebo once daily). The outcomes of the study were analyzed based on history of CABG at baseline. They can be found in Table 1: Outcomes.

Table 1: Outcomes
  • Three-point MACE: composite of CV death, non-fatal MI, fatal or non-fatal stroke
  • Four-point MACE: composite CV death, non-fatal MI, non-fatal stroke or hospitalization for UA
  • Fatal or non-fatal MI
  • Fatal or non-fatal stroke
  • Cardiovascular death
  • Hospitalization for HF
  • Composite of HF hospitalization or CV death
  • All-cause mortality
  • Incident or worsening nephropathy           
CV – cardiovascular; MI – myocardial infarction; HF – heart failure; UA – unstable angina

All in all, from September 2010 to April 2013, 7,020 patients were enrolled. The baseline characteristics and background medications were balanced between both the empagliflozin and placebo group. Baseline characteristics information can be found in Table 2: Baseline Characteristics and the various primary outcome results are located in Table 3: Cardiovascular, Mortality, and Renal Outcomes.

Table 2: Baseline Characteristics
History of CABG Empagliflozin group: 25% (1175/4687)

Placebo group: 24% (563/2333)

Age / Gender 65 years old ; Male (81%)
HbA1c 8.05%
Cardiovascular/

Renal Characteristics

Cardiovascular

History of MI: 51%

History of HF: 11%

Mean systolic BP: 135.6mmHg

Mean diastolic BP: 75.3mmHg

Renal

eGFR ≥ 90: 15%

eGFR 60 to <90: 52%

eGFR < 60: 33%

Table 3: Cardiovascular, Mortality, and Renal Outcomes
Cardiovascular Death All-cause Mortality
    • History of CABG – empagliflozin showed a 48% risk reduction for cardiovascular death (HR 0.52 95% CI 0.32-0.84)*
  • No difference found between subjects with or without baseline CABG (p = 0.3976)
    • History of CABG – empagliflozin showed a 43% risk reduction for all-cause mortality (HR 0.57 95% CI 0.39 – 0.83)*
  • No difference found between subjects with or without baseline CABG (p = 0.2695)
Three-point MACE Four-point MACE
  • History of CABG – empagliflozin vs placebo (HR 0.80 95% CI 0.60 – 1.06)
    • Without history of CABG – empagliflozin vs placebo (HR 0.88 95% CI 0.74 – 1.04)
  • No difference found between subjects with or without baseline CABG (p = 0.5586)
    • History of CABG – empagliflozin vs placebo (HR 0.89 95% CI 0.68 – 1.15)
    • Without history of CABG – empagliflozin vs placebo (HR 0.89 95% CI 0.76 – 1.04)
  • No difference found between subjects with or without baseline CABG (p = 0.9933)
Hospitalization for HF Incident or Worsening Nephropathy
    • History of CABG – empagliflozin showed a 50% risk reduction for hospitalization for HF (HR 0.50 95% CI 0.32 – 0.77)*
    • History of CABG – composite HF hospitalization or CV death (HR 0.52 95% CI 0.37 – 0.74)*
  • No difference found between subjects with or without baseline CABG for either association
    • History of CABG – empagliflozin use reduced, by 35%, the risk of incident/worsening nephropathy (HR 0.65 95% CI 0.50 – 0.84)*
  • No difference found between subjects with or without a baseline CABG (p = 0.5673)
Fatal or Non-fatal MI Fatal or Non-fatal Stroke
  • No difference between empagliflozin vs placebo in either group with or without CABG
  • No difference between empagliflozin vs placebo in either group with or without CABG

After post-hoc analysis, the following was discovered in patients with type 2 diabetes and baseline CABG history treated with empagliflozin: 1) 48% risk reduction for cardiovascular death, 2) 43% risk reduction for all-cause mortality, 3) 50% risk reduction for hospitalization for HF, 4) and 35% risk reduction of incident/worsening nephropathy.

Beyond cardiovascular, mortality, and renal outcomes, investigators looked at the adverse events caused by empagliflozin use in patients with or without a history of CABG. In general, more severe adverse events or events that prompted medication discontinuation were lower or similar with empagliflozin in those with or without a baseline CABG. Instances of hypoglycemia or hypoglycemic events requiring treatment were higher in those with CABG history, but no differences were noted in regard to treatment or placebo. Volume depletion was more common in those with CABG history, but similar in either treatment/placebo group. Acute renal failure, occurring in those with CABG history, was higher in the placebo group (11.0%) compared to empagliflozin (5.8%). Finally, lower limb amputations were consistent between both groups regardless of CABG history.

Ultimately, Verma, et al was able to show that empagliflozin would be a beneficial agent to add onto a regimen particularly in those with a history of CABG. The risk reductions noted after post-hoc analysis were consistent with the results found in the original research, thus providing additional support to the EMPA-REG OUTCOME trial. Inclusion of this SGLT2 inhibitor to an existing regimen is associated with increased reductions in CV death, all-cause mortality, hospitalization for HF, and, finally, incident/worsening nephropathy.

Practice Pearls:

  • Empagliflozin is indicated for the treatment of type 2 diabetes with cardiovascular disease.
  • Empagliflozin is successful in improving cardiovascular outcomes; previously minimal information was known about its use in patients with a history of CABG surgery, a revascularization procedure more beneficial in people with diabetes, which prompted this investigation.
  • Empagliflozin treatment in people with type 2 diabetes with CABG history showed the following risk reductions: 1) 48% reduction for CV death, 2) 43% reduction for all-cause mortality, 3) 50% reduction in hospitalization for HF, and finally 4) 35% reduction in incident/worsening nephropathy.
  • Study results suggest that empagliflozin would be beneficial in patients who have undergone a CABG.

References:

Practice Update: Empagliflozin Reduces Cardiovascular Events, Mortality, and Renal Events in Patients With Type 2 Diabetes After CABG. Diabetologia. 5 June 2018. Available from: https://www.practiceupdate.com/c/68496/2/8/?elsca1=emc_enews_daily-digest&elsca2=email&elsca3=practiceupdate_diab&elsca4=diabetes&elsca5=newsletter&rid=OTE0MTIxOTE4NTkS1&lid=10332481.

Verma, S., Mazer, C., Fitchett, D., Inzucchi, S., Pfarr, E., George, J., Zinman, B. Empagliflozin Reduces Cardiovascular Events, Mortality, and Renal Events in Patients With Type 2 Diabetes After coronary artery bypass graft surgery: subanalysis of the EMPA-REG OUTCOME randomized trial. Diabetologia. 2018. https://doi.org/10.1007/s00125-018-4644-9.

Kaytie A. Weierstahl, Pharm.D. Candidate, LECOM School of Pharmacy