Tanveer Brar, BSc, BSc(Pharm), ACPR. St. Paul’s Hospital, Vancouver, BC. University of Alberta, PharmD for Practicing Pharmacists. (biography, no disclosures).
Doson Chua, BSc(Pharm), PharmD, FCSHP, BCPS, BCCP. Clinical Pharmacy Specialist, Cardiology, St Paul’s Hospital, Vancouver, BC. (biography, no disclosures)
Laura Atiyeh, University of British Columbia PharmD Candidate 2021. No disclosures.
What I did before
Heart failure (HF) is a clinical syndrome associated with significant morbidity and mortality. In 2020, the prevalence of HF was approximately 64.34 million cases (8.52 per 1,000 inhabitants) worldwide and this number has been steadily increasing over time, with greater prevalence in older individuals.1, 2 Heart failure accounts for the second-highest number of hospital stays with the average length of hospitalization being 8 days and the estimated 1-year mortality due to HF after a first HF hospitalization is 35%.3
Management of heart failure with reduced ejection fraction (HFrEF) is well established with standard triple therapy consisting of beta blockers, angiotensin converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers (ARBs), and mineralocorticoid receptor antagonists (MRA).4 Angiotensin receptor neprilysin inhibitors (ARNI) have also shown a mortality benefit in HFrEF, and should be considered in individuals who continue to experience NYHA class II to IV symptoms despite optimal triple therapy.5 Even with major advances in HFrEF management over the last decade, the morbidity and mortality associated with heart failure continues to remain high, particularly in elderly, male patients.6
Sodium glucose cotransporter (SGLT2) inhibitors such as empagliflozin, dapagliflozin and canagliflozin are recommended in the management of patients with type 2 diabetes mellitus (T2DM) and established cardiovascular disease (CVD).7 This recommendation is based on compelling evidence from the EMPA-REG,8 DECLARE-TIMI 589 and CANVAS10 trials that demonstrated a cardiovascular (CV) benefit with SGLT2 inhibitors compared to placebo in individuals with T2DM. The CV benefits seen in these trials, including reduction in HF hospitalizations, raised the question of whether SGLT2 inhibitors have a similar benefit in individuals with HFrEF without diabetes.
What changed my practice
In 2019, the DAPA-HF trial was published in the New England Journal of Medicine.11 This was a large, multicentre, double-blind, parallel-group, placebo-controlled trial that included 4744 adults (≥18 years old) with HFrEF (LVEF ≤40%) and NYHA functional class II to IV. It evaluated dapagliflozin 10mg po daily versus placebo in HFrEF patients with or without diabetes. Enrollment also required a serum N-terminal pro B-type natriuretic peptide (NT-proBNP) of > 600 pg/mL (>400 if hospitalized within the past year, >900 if atrial fibrillation or flutter present). Baseline characteristics were adequately balanced between the dapagliflozin and placebo group. Importantly, 41.8% of the patients enrolled were diabetic. The primary composite endpoint of CV death and worsening HF (defined as hospitalization or urgent visit resulting in IV therapy for HF) was significantly lower in the dapagliflozin group compared to the placebo group (16.3% versus 21.2%, HR 0.74 (0.65 to 0.85), NNT 20). There was also a decrease in hospitalizations for heart failure (9.4% versus 13.4%, HR 0.70 (0.59 to 0.83), NNT 25) and all-cause mortality with dapagIiflozin (11.6% versus 13.9%, HR 0.83 (0.71 to 0.97), NNT 43) compared to placebo. A subgroup analysis of the primary composite outcome showed that the effect was observed in both diabetic and nondiabetic patients.
More recently, the EMPEROR-Reduced12 trial was published in the New England Journal of Medicine and assessed whether empagliflozin 10mg po daily decreases CV outcomes and mortality in HFrEF patients with or without diabetes. This landmark study was a randomized, double-blind, parallel-group, placebo-controlled, event-driven trial that included 3730 adults (≥18 years old) with HFrEF (LVEF ≤ 40%) and NYHA functional class II to IV. Inclusion criteria also required a HF hospitalization within the previous 12 months or an elevated NTpro-BNP (>2500 pg/mL if EF 36-40%, >1000 pg/mL if EF 31-35%, >600 pg/mL if EF <30%). Baseline characteristics were balanced between both groups. Notedly, 49.8% of the patients were diabetic. In this study, empagliflozin showed a significant reduction in primary composite outcome of hospitalization for heart failure and cardiovascular death (19.4% versus 24.7%, HR 0.75 (0.65 to 0.86), NNT 19). The number of hospitalizations for heart failure were also reduced by empagliflozin (p < 0.001). The primary composite endpoint for efficacy was sustained in both diabetic and non-diabetic subgroups. One notable difference between DAPA-HF and EMPEROR-Reduced was that there was no statistically significant benefit in the empagliflozin versus placebo group for CV death (10% versus 10.8%, HR 0.92 (0.75 to 1.12)).
The difference seen in CV mortality benefit with dapagliflozin versus empagliflozin can potentially be explained by the EMPEROR-Reduced population having more severe HF. The patients in EMPEROR-Reduced had a higher mean NT-proBNP level, lower mean EF, and 73% of the population had an EF ≤30%.12 Additionally, twice as many patients in EMPEROR-Reduced were already receiving an ARNI (Table 1). It may be harder to show a mortality benefit in a more medically optimized population. It should also be noted that in the T2DM SGLT2 inhibitor studies, empagliflozin showed a statistically significant mortality benefit and not dapagliflozin or canagliflozin.8-10
In terms of safety outcomes, dapagliflozin or empagliflozin did not seem to increase the risk of adverse events such as limb amputations, fractures, or hypoglycemic events in DAPA-HF or EMPEROR-Reduced. SGLT2 inhibitors are known to increase the risk of urinary tract and genital infections due to their mechanism of action, however this outcome was not statistically analyzed in the trials.11, 12
What I do now
After DAPA-HF, the Canadian Cardiovascular Society 2020 Heart Failure guidelines update recommends SGLT2 inhibitors, such as dapagliflozin, be used in individuals with mild to moderate HFrEF and without concomitant diabetes as a “Conditional Recommendation.”14 As of September 2020, dapagliflozin has also received Health Canada approval for the treatment of HFrEF.15 Now with EMPEROR-Reduced confirming cardiovascular benefit in individuals with HFrEF with or without diabetes, it is anticipated that the updated guidelines will strongly recommend SGLT2 inhibitors for all HFrEF individuals to prevent mortality as well as HF hospitalization.
After an individual has been hospitalized for HF, the risk of re-hospitalization is significant (25% at 30 days,16 and 43.9% at 1-year post-discharge16). Each hospitalization is associated with an increased risk of mortality.18 Given the compelling evidence for reducing HF associated hospitalizations, SGLT2 inhibitors should be added to triple therapy in all individuals with HFrEF who can tolerate them.
Currently, PharmaCare only covers empagliflozin under special authority for individuals with T2DM who have had inadequate glycemic control on maximum tolerated doses of dual therapy of metformin and a sulfonylurea.19 The evidence for this third line addition of empagliflozin is from the CV and mortality benefit seen in patients with T2DM in the EMPA-REG trial.7 For individuals with HFrEF who are willing to pay out-of-pocket or carry private insurance, empagliflozin 12.5mg (half of the 25mg tablet) po daily can be considered as the cost of the both 10 mg and 25 mg tablets is the same (approximately $3/tablet). There is also no difference in price between empagliflozin and dapagliflozin.20
There is compelling evidence to suggest that in individuals with HFrEF in the presence or absence of T2DM, both dapagliflozin and empagliflozin have profound effects on reduction of HF hospitalizations and possibly CV mortality. Given that HF hospitalizations are associated with significant morbidity, mortality, and cost to the health care system, all individuals with HFrEF should have their LV enhancing therapy reassessed and optimized at frequent intervals and this includes the addition of an SGLT2 inhibitor where possible.
Mechanism of Action and Pharmacology of SGLT2 inhibitors:
SGLT2 inhibitors exhibit their antihyperglycemic effect by inhibiting SGLT2 in the proximal renal tubules, thereby promoting urinary glucose excretion. There are several proposed mechanisms of action for SGLT2 inhibitors’ CV effect, such as their diuretic effect. They also may have an effect on myocardial metabolism, ion transporters, fibrosis, adipokines, and vascular function.11 SGLT2 inhibitors have also shown a benefit in renal outcomes,12,13 which would also benefit HFrEF patients regardless of diabetic status. It should be noted that given the modest diuretic effect of SGLT2 inhibitors, dosages of loop diuretics may need modification upon initiation of SGLT2 inhibitor therapy.
~66yo, NYHA II = 67%, III = 31%, IV = 0.8-1%
Mean LVEF = 31%; EF ≤30% = ?
Mean NT-proBNP 1437 pg/mL
DM = 41.8%
ARNI = 10.5%, ICD = 26.2%, CRT = 8.0%
~67yo, NYHA II = 75%, III = 24%, IV = 0.5-0.6%
Mean LVEF = 27%; EF ≤30% = 73%
Mean NT-proBNP 1907 pg/mL
DM = 49.8%
ARNI = 20%, ICD = 31%, CRT = 11.8%
|Intervention||Dapagliflozin 10mg po daily (median 18.2 months)||Empagliflozin 10mg po daily (median 16 months)|
|Outcome||1° composite outcome (CV death or worsening HF (hospitalization or urgent visit resulting in IV therapy for HF)) → 21.1% placebo vs 16.3% dapagliflozin (HR 0.74, 95% CI 0.65-0.85)||1° composite outcome (HF hospitalization or CV death) → 24.7% placebo vs 19.4% empagliflozin (HR 0.75, 95% CI 0.65-0.86)|
|– Hospitalization or urgent visit for HF → 13.7% vs 10% (HR 0.76, 95% CI 0.59-0.83)||– Hospitalization for HF → 18.3% vs 13.2% (HR 0.69, 95% CI 0.59-0.81)|
|– CV death → 11.5% vs 9.6% (HR 0.82, 95% CI 0.69-0.98)||– CV death → 10.8% vs 10% (HR 0.92, 95% CI 0.75-1.12)|
- Lippi G, Sanchis-Gomar F. Global epidemiology and future trends of heart failure. AME Medical Journal. 2020 Jun 25; 5:15 (View)
- Ponikowski P, Anker SD, AlHabib KF, et al. Heart failure: preventing disease and death worldwide. ESC Heart Fail. 2014;1(1):4-25. DOI: 10.1002/ehf2.12005. (View)
- Yeung DF, Boom NK, Guo H, Lee DS, Schultz SE, Tu JV. Trends in the incidence and outcomes of heart failure in Ontario, Canada: 1997 to 2007. CMAJ. 2012;184(14):E765-E773. DOI: 10.1503/cmaj.111958. (View)
- Ezekowitz JA, O’Meara E, McDonald MA, et al. 2017 Comprehensive update of the Canadian Cardiovascular Society guidelines for the management of heart failure. Can J Cardiol. 2017;33(11):1342-1433. DOI: 10.1016/j.cjca.2017.08.022. (View with CPSBC or UBC)
- McMurray JJ, Packer M, Desai AS, et al. Angiotensin–neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014;371:993-1004. DOI: 10.1056/NEJMoa1409077. (View)
- Mamas MA, Sperrin M, Watson MC, et al. Do patients have worse outcomes in heart failure than in cancer? A primary care‐based cohort study with 10‐year follow‐up in Scotland. Eur J Heart Fail. 2017;19(9):1095-1104. DOI: 10.1002/ejhf.822. (View)
- Diabetes Canada Clinical Practice Guidelines Expert Committee. Diabetes Canada 2018 clinical practice guidelines for the prevention and management of diabetes in Canada. Can J Diabetes. 2018;42(Suppl 1):S1-S325. DOI: 10.1016/j.jcjd.2017.10.002. (View with CPSBC or UBC)
- Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. New Engl J Med. 2015;373(22):2117-2128. DOI: 10.1056/NEJMoa1504720. (View)
- Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. New Engl J Med. 2019;380(4):347-357. DOI: 10.1056/NEJMoa1812389. (Request with CPSBC or view with UBC)
- Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. New Engl J Med. 2017;377(21): 2097-2099. DOI: 10.1056/NEJMc1712572. (Request with CPSBC or view with UBC)
- McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. New Engl J Med. 2019;381(21):1995-2008. DOI: 10.1056/NEJMoa1911303. (Request with CPSBC or view with UBC)
- Packer M, Anker SD, Butler J, et al. Cardiovascular and renal outcomes with empagliflozin in heart failure. New Engl J Med. 2020;383(15):1413-1424. DOI: 10.1056/NEJMoa2022190. (Request with CPSBC or view with UBC)
- Heerspink HJ, Stefánsson BV, Correa-Rotter R, et al. Dapagliflozin in patients with chronic kidney disease. New Engl J Med. 2020;383(15):1436-1446. DOI: 10.1056/NEJMoa2024816. (Request with CPSBC or view with UBC)
- O’Meara E, McDonald M, Chan M, et al. CCS/CHFS heart failure guidelines: clinical trial update on functional mitral regurgitation, SGLT2 inhibitors, ARNI in HFpEF, and tafamidis in amyloidosis. Can J Cardiol. 2020;36(2):159-169. DOI: 10.1016/j.cjca.2019.11.036. (View with CPSBC or with UBC)
- FORXIGA Product Monograph. Missassauga, ON. AstraZeneca Canada Inc; 2020. (View)
- Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation. 2013;128(16):1810-1852. DOI: 10.1161/CIR.0b013e31829e8807. (View with CPSBC or UBC)
- Maggioni AP, Dahlstrom U, Filippatos G, et al. Heart failure association of the European Society of C. EURObservational Research Programme: regional differences and 1-year follow-up results of the Heart Failure Pilot Survey (ESC-HF Pilot). Eur J Heart Fail. 2013;15(7):808-817. DOI: 10.1093/eurjhf/hft050. (View)
- Setoguchi S, Stevenson LW, Schneeweiss S. Repeated hospitalizations predict mortality in the community population with heart failure. Am Heart J.;154(2):260-266. DOI: 10.1016/j.ahj.2007.01.041. (View with CPSBC or UBC)
- PharmaCare Formulary Search. Government of British Columbia. (View). Updated 2021. Accessed October 2, 2020.
- Pharmacy Compass. Pacific Blue Cross Health Benefits Society. (View). Updated 2021. Accessed October 2, 2020.