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Arkansas Geriatric Education Collaborative

Beyond Diabetes: Use of Antidiabetic Agents in Heart Failure

Winter 2021 Newsletter

By Tyler R. Walsh, PharmD and Lisa C. Hutchison, PharmD, MPH
University of Arkansas for Medical Sciences (UAMS) College of Pharmacy

According to the Centers of Disease Control, diabetes is a risk factor for developing heart failure.1   Many patients with diabetes will develop heart failure, so clinicians would be excited to have medications that could treat diabetes and also improve heart failure outcomes.  The sodium-glucose cotransporter 2 (SGLT-2) inhibitors are possibly those medications.

SGLT-2 inhibitors work in diabetes by inhibiting the reabsorption of glucose in the kidney causing more glucose to be excreted in the urine .2 Two of the SGLT-2 inhibitors have evidence of benefit in heart failure.  The exact mechanism of action for the SGLT-2 inhibitors in heart failure remains unknown.  Dapagliflozin (Farxiga) has FDA approval for treatment of heart failure in addition to diabetes mellitus type 2.3 This approval was based on results of the Dapagliflozin and Prevention of Adverse Outcomes in heart Failure (DAPA-HF) trial.5  Another SGLT-2 inhibitor, empagliflozin (Jardiance), showed benefit in the Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure (EMPEROR) trial but currently is not FDA approved for heart failure treatment.6 The third SGLT-2 inhibitor, canagliflozin (Invokana), is not currently seeking FDA approval for heart failure treatment.

Table 1. Dapagliflozin and Empagliflozin in Heart Failure Trials

 Dapagliflozin5Empagliflozin6
Patients4,744 (2,373 treatment, 2,371 placebo)3,730 (1,863 treatment, 1,876 placebo)
Percentage of patients with DM41.7% in both treatment and placebo arms49.8% in both treatment and placebo arms
Primary outcome was a composite of:Worsening HF or death from CV causesAdjudicated CV death or first hospitalization for HF
Efficacy resultsDapagliflozin 16.3%  vs. Placebo 21.2%  HR 0.75 (95% CI 0.65-0.85, p<0.001)Empagliflozin 19.4% vs. Placebo 24.7%  HR 0.75 (95% CI 0.65-0.85, p<0.001)
Safety resultsNo difference between groupsUncomplicated UTIs 4.9% empagliflozin 4.5% placebo

DM = diabetes mellitus type 2; HF = heart failure; CV = cardiovascular; UTIs = urinary tract infections

Based on the data from each of these trials, both agents are effective in the treatment of heart failure independent of their effectiveness in diabetes.6 Of note, in both studies patients with a New York Heart Association (NYHA) classification of II had more benefit compared to patients with an NYHA classification of III or IV.5,6 In a post-hoc analysis of the DAPA-HF trial researchers analyzed the efficacy and safety of dapagliflozin based on age.  The benefit/risk profile of dapagliflozin was as favorable in older adults as in younger adults.7 However, some key exclusion criteria were patients with hypotension (systolic reading <95 mmHg at two readings), patients with current or recent decompensated heart failure, and patients with recent revascularization, so caution should be used if dapagliflozin is initiated in a patient with any of these characteristics.8

Lastly, it is important to consider the disadvantages of these medications.  Both of these medications are contraindicated with a creatine clearance less than 30 mL/min.2,4  Also, since these medications increase glucose in the urine, the risk of developing a urinary tract infection is about 6% in men and 18% in women.2,4  Finally, we must consider the financial burden of these medications on our patient population.  These medications cost about $21 per tablet ($630 per month).2,4 These medications could be covered by a patient’s Medicare Part D plan, but they are currently only available as name brand and are not generic.  While these medications are promising for clinical outcomes many patients may be unable to afford them.

The prevalence of diabetes and heart failure is high in the older adult.  These medications should be considered as add on therapy to standard of care regimens for the treatment of diabetes and heart failure.  The use of SGLT-2 inhibitors, dapagliflozin and empagliflozin, can help treat diabetes as well as improve outcomes directly related to heart failure. 

References:

  1. Heart Failure (2020). Centers for Disease Control and Prevention. Retrieved from https://www.cdc.gov/heartdisease/heart_failure.htm.
  2. Dapagliflozin (2021). Lexicomp. Retrieved on January 11, 2021.
  3. FDA approves new treatment for a type of heart failure (2020). U.S. Food and Drug Administration. Retrieved from https://www.fda.gov/news-events/press-announcements/fda-approves-new-treatment-type-heart-failure.
  4. Empagliflozin (2021). Lexicomp. Retrieved on January 11, 2021.
  5. McMurray, J. J., Solomon, S. D., Inzucchi, S. E., Køber, L., Kosiborod, M. N., Martinez, F. A., … & Langkilde, A. M. (2019). Dapagliflozin in patients with heart failure and reduced ejection fraction. New England Journal of Medicine, 381(21), 1995-2008.
  6. Packer, M., Anker, S. D., Butler, J., Filippatos, G., Pocock, S. J., Carson, P., … & Zannad, F. (2020). Cardiovascular and renal outcomes with empagliflozin in heart failure. New England Journal of Medicine, 383(15), 1413-1424.
  7. Martinez, F. A., Serenelli, M., Nicolau, J. C., Petrie, M. C., Chiang, C. E., Tereshchenko, S., … & McMurray, J. J. (2020). Efficacy and safety of dapagliflozin in heart failure with reduced ejection fraction according to age: insights from DAPA-HF. Circulation, 141(2), 100-111.
  8. McMurray, J. J., DeMets, D. L., Inzucchi, S. E., Køber, L., Kosiborod, M. N., Langkilde, A. M., … & Selvén, M. (2019). A trial to evaluate the effect of the sodium–glucose co‐transporter 2 inhibitor dapagliflozin on morbidity and mortality in patients with heart failure and reduced left ventricular ejection fraction (DAPA‐HF). European journal of heart failure, 21(5), 665-675.