By: Sarah Lothspeich, PharmD, MPH; PGY2 Ambulatory Care Resident, CoxHealth - Springfield
Program Number: 2021-03-03
Approval Dates: April 7, 2021 to October 1, 2021
Approved Contact Hours: 1 hour
According to the Centers for Disease Control and Prevention (CDC), more than an estimated 6.2 million adults were diagnosed with heart failure in the United States between 2013 and 2016.1 This number has grown and is predicted to continue to grow. In fact, between 2009 and 2012, the estimated number of adults with heart failure was around 5.7 million.1 The growth is especially concerning considering the significant healthcare costs associated with caring for patients with heart failure. In 2012, it was estimated that heart failure alone cost the nation $30.7 billion dollars.1,2
The National Institute of Health (NIH) defines heart failure simply as the inability of the heart to pump effectively enough to meet the needs of the body. Right-sided heart failure results in the heart not being able to pump enough blood to the lungs to become oxygenated, while left-sided heart failure results in the heart being unable to effectively pump oxygen-rich blood throughout the body. A person can have one or both types of heart failure. Heart failure is a progressive disease and typically occurs due to the progression of heart damage or weakening over time. Common causes of heart failure are ischemic heart disease, uncontrolled diabetes, and hypertension. Specifically, ischemic heart disease causes a build-up of plaque in the arteries limiting blood flow to the heart, thus weakening it. In uncontrolled diabetes, elevated blood sugars contribute to blood vessel and heart damage. Hypertension causes heart failure because increases in the force of blood flow on the artery walls weakens the heart and can lead to additional plaque build-up. Other conditions, such as arrythmias and congenital heart defects can also progress to heart failure. Common risk factors for heart failure include age 65 years or older, African American race, being overweight and a previous myocardial infarction (MI). Symptoms associated with heart failure are largely due to fluid overload. The most common manifestations are shortness of breath, fatigue and swelling in ankles, legs, or abdomen. Jugular vein distention (JVD) can also occur in right-sided heart failure.3
Heart failure is categorized into two groups for the purposes of treatment - heart failure with reduced ejection fraction (HFrEF) or heart failure with preserved ejection fraction (HFpEF). An echocardiogram is performed to estimate the left ventricular ejection fraction (LVEF). HFrEF is defined as a LVEF ≤40%. HFpEF is defined as a LVEF ≥ 50%. Borderline HFpEF is defined as LVEF 41 to 49%. There is currently no cure for heart failure, however the American College of Cardiology (ACC) and American Heart Association (AHA) guidelines recommend drug therapies that have been shown to increase left ventricular ejection fraction, decrease symptoms/improve quality of life and decrease morbidity and/or mortality.4 Treatment recommendations within the ACC/AHA guideline are based on ACC/AHA stage and New York Heart Association (NYHA) function class. This is depicted in Table 1.
Table 1: ACC/AHA Staging and NYHA Function Class from 2017 ACC/AHA/HFSA Focused Update
Heart Failure Therapies
Before diving into heart failure treatments, it is important to review goals of care for these patients. Common goals include modifying or controlling risk factors, managing structural heart disease, reducing morbidity and/or mortality, eliminating or minimizing symptoms, and lastly, slowing progression of worsening cardiac function. Additionally, nonpharmacological treatments also have an important role in heart failure management. These include smoking cessation, weight optimization, decreasing alcohol and sodium intake and treating sleep apnea. Adequately treating and controlling diseases contributing to heart failure, such as diabetes and hypertension is also recommended.3 As previously mentioned, the ACC/AHA Heart Failure guideline separate therapy recommendations based on whether a patient has HFrEF or HFpEF. HFpEF guideline recommendations are limited. In general, the goal for those patients is to target symptoms, comorbidities and risk factors that could potentially worsen cardiovascular disease.4
For patients with HFrEF, it is recommended that all patients are on an Angiotensin-Converting Enzyme Inhibitor (ACE-I) or Angiotensin II Receptor Blocker (ARB) or Angiotensin Receptor-Neprilysin Inhibitor (ARNI) and beta blocker therapy if they are able. It is also noted in the ACC/AHA Heart Failure guideline that while a specific ACE-I is not singled out as being the more effective, there is limited evidence for the use of fosinopril and quinapril. The preferred beta blockers listed in the guideline are bisoprolol, carvedilol, and metoprolol succinate as they have been specifically studied in this population. ACE-I, ARB, ARNI and beta blockers have all been shown to decrease mortality and hospitalizations in HFrEF patients. Aldosterone receptor antagonists (spironolactone and eplerenone) have also been shown to decrease mortality and hospitalizations and are recommended for patients with NYHA class II-IV who have an LVEF ≤ 35%. This class of medications is also recommended in patients after a MI if they have an LVEF ≤ 40% with heart failure symptoms or an LVEF ≤ 40% with diabetes. Ivabradine, an inhibitor of hyperpolarization-activated cyclic nucleotide-gated channels in the sinoatrial node, has also been shown to decrease mortality and hospitalizations and is beneficial for patients who are symptomatic (NYHA class II and III) with stable, chronic HFrEF and are currently on evidence-based therapies. Clinically the use of ivabradine may be limited as it requires a baseline heart rate of at least 70 beats per minute to initiate. Thiazide and loop diuretics are recommended for symptom management in patients with fluid retention. Digoxin can be used to decrease hospitalizations in HFrEF patients who are on other appropriate guideline-recommended therapies. It is important to note that when digoxin is used in HFrEF patients, it does not require a loading dose and the target level is 0.5 to 0.9 ng/mL. Lastly, hydralazine and isosorbide dinitrate decrease mortality and are recommended in addition to ACE-I and beta blockers for African American patients who have NYHA Class III or IV HFrEF. These medications may also be useful for symptomatic HFrEF patients who are unable to tolerate ACE-I/ARB therapy.4
Review of SGLT2 Inhibitor Indications and cardiovascular outcomes trials in diabetic patients
There are currently four sodium-glucose cotransporter-2 (SGLT2) inhibitors that are Food and Drug Administration (FDA) approved for the treatment of Type II Diabetes. These include: canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin. Three of these four medications underwent trials in diabetic patients to evaluate cardiovascular outcomes with the intent to demonstrate no increased risk of cardiovascular harm. The names of the trials are listed in Table 2. Brief summaries of the cardiovascular outcome trials are detailed below. These studies are significant because the benefit they showed led to the evaluation of SGLT2 inhibitors for heart failure in patients without diabetes.
Table 2: SGLT2 inhibitor diabetes cardiovascular outcome trials
EMPA‐REG OUTCOME investigated the effect of empagliflozin on cardiovascular outcomes in patients with type II diabetes. The study included 7,020 participates with type II diabetes and established atherosclerotic disease. The results of this study showed empagliflozin significantly reduced the risk of heart failure hospitalization compared to placebo with a relative risk reduction (RRR) of 35% and an absolute risk reduction (ARR) of 1.4% in the exploratory end point.5 After the successful EMPA‐REG OUTCOME trial, CANVAS program trials evaluated canagliflozin in 6,656 patients with type II diabetes and established atherosclerotic disease and 3,486 patients with type II diabetes and at high risk for cardiovascular events. Canagliflozin significantly reduced heart failure hospitalization versus placebo with a RRR of 33% and an ARR of 3.2% in the exploratory end point.6 The DECLARE‐TIMI 58 trial investigated dapagliflozin versus placebo in 17,160 patients with type II diabetes who had either multiple cardiovascular risk factors or established atherosclerotic disease. Dapagliflozin showed a statistically significant reduction in heart failure hospitalization or cardiovascular death versus placebo, primarily due to decreased heart failure hospitalization which was associated with an ARR of 0.8% and a RRR of 27%. The heart failure hospitalization benefit was consistent regardless of recognized atherosclerotic disease and history of heart failure.7
Literature Supporting SGLT2 Inhibitors in Heart Failure without Diabetes
After the positive results in the cardiovascular outcome trials for diabetic patients, further evaluation regarding the use of SGLT2 inhibitors in heart failure patients without diabetes was warranted. In 2019, DAPA-HF was published after evaluating dapagliflozin in heart failure patients without diabetes and, nearly a year later in October 2020, EMPEROR-REDUCED was published evaluating empagliflozin in heart failure patients without diabetes.8,9 The full titles of these studies are listed in Table 3.
Table 3: SGLT2 inhibitor heart failure trials
DAPA-HF was a multicenter, double-blind, parallel-group, randomized controlled trial. This study took place in 410 centers in 20 countries. Enrollment occurred from 2017 to 2018 and a total of 4,744 patients with HFrEF (LVEF ≤ 40%) and NYHA II-IV symptoms were included with 2,373 in the dapagliflozin group versus 2,371 in the placebo group. Once patients were enrolled, there was a 14-day screening period after which patients were randomly assigned to receive dapagliflozin 10 mg once daily or placebo. Median follow-up for this study was 18.2 months. The primary outcome was worsening heart failure (hospitalization or urgent visit resulting in intravenous therapy for heart failure) or cardiovascular mortality. Baseline characteristics for the study population showed the following: 42% had type II diabetes, mean age was 66 years old, mean BMI was 28 kg/m2, 24% of patients were female, mean LVEF was 31% and mean estimated glomerular filtration rate (eGFR) 66 mL/min/1.73 m2. Additionally, 68% of participants were NYHA class II, 32% were NYHA class III, and 1% were NYHA class IV. A majority of the patients were on guideline-directed therapy including: 93% were on ACE-I/ARB/ARNI, 96% were on a beta blocker, 71% were on an aldosterone antagonist, and 93% were on diuretic therapy. The primary outcome of worsening heart failure (hospitalization or urgent visit resulting in IV therapy for HF) or cardiovascular mortality was significantly lower occurring in 16.3% in the dapagliflozin group versus 21.2% in the placebo group (hazard ratio 0.74, 95% confidence interval 0.65 to 0.85, P < 0.001). The authors of the study concluded that dapagliflozin use was associated with a lower risk of worsening heart failure or death from cardiovascular causes in patients with and without diabetes.8 This study led to the FDA approval of dapagliflozin to decrease hospitalizations and mortality in heart failure patients without diabetes.10
EMPEROR-REDUCED was a multicenter, double-blind, parallel-group, randomized controlled trial. This study took place in 520 centers in 20 countries. Enrollment occurred from 2017 to 2019 and a total of 3,730 patients with HFrEF (LVEF ≤ 40%) and NYHA II-IV symptoms were included with 1,863 in the empagliflozin group versus 1,876 in the placebo group. Once patients were enrolled, there was a 4 to 28-day screening period after which patients were randomly assigned to receive empagliflozin 10 mg once daily or placebo. Median follow-up for this study was 16 months. The primary outcome was composite of adjudicate cardiovascular death or hospitalization for heart failure. Baseline characteristics for the study population showed the following: 50% had type II diabetes, mean age was 67 years old, mean BMI was 28 kg/m2, 24% of patients were female, mean LVEF was 27% and 48% of patients had a eGFR < 60 mL/min/1.73 m2. Additionally, 75% of participants were NYHA class II, 24% were NYHA class III, and 0.6% were NYHA class IV. A majority of the patients were on guideline-directed therapy including: 70% were on ACE-I/ARB, 19% ARNI, 94% were on a beta blocker, and 71% were on an aldosterone antagonist. The composite outcome of cardiovascular death or hospitalization for heart failure was significantly lower occurring in 19.4% in the empagliflozin group versus 24.7% in the placebo group (hazard ratio 0.75, 95% confidence interval 0.65 to 0.86, P < 0.001). The authors of the study concluded that empagliflozin use was associated with a lower risk of cardiovascular death or hospitalization compared to placebo for heart failure patients with and without diabetes.9
It is important to note that in both studies outlined above, approximately 90% of the patients were on ACE-I/ARB or ARNI and approximately 95% of the patients were on a beta-blocker. It is not known, however, if they were on the max tolerated doses targeted in heart failure. While both studies include patients in NYHA class II through IV, a majority of patients were in class II. There was also no difference in adverse events between SGLT2 inhibitor use and placebo.8,9 The positive outcomes for heart failure patients shown in DAPA-HF and EMPEROR-REDUCED led to the 2021 update to the 2017 ACC Expert Consensus Decision Pathway for Optimization of Heart Failure Treatment. This update does include the recommendation to consider an SGLT2 inhibitor for patients with HFrEF and NYHA class II to IV after initiation of beta-blocker and angiotensin antagonist.11
Mechanism of SGLT2 Inhibitors in Heart Failure
SGLT2 is responsible for 90% of glucose and sodium reabsorption in the proximal convoluted tubules of the kidney. The mechanism of SGLT2 inhibitors in heart failure is unknown likely because it involves many different mechanisms. The three proposed hypotheses include the diuretic hypothesis, the thrifty substrate hypothesis and the NHE hypothesis.12
The diuretic mechanism of SGLT2 inhibitors differs from that of loop or thiazide diuretics because of the osmotic diuresis that results from glucose and sodium reabsorption. This leads to more fluid clearance from the interstitial fluid than the circulation preserving blood volume, organ perfusion and arterial filling. Additionally, SGLT2 inhibitors exert their activity in the proximal tubule where they activate tubuloglomerular feedback by increasing fluid and electrolyte delivery to the macula densa. By acting at different sites of the nephron SGLT2 inhibitors are able to produce greater electrolyte-free water clearance, resulting a more potent diuresis and natriuresis compared to thiazide and loop diuretics.12
The thrifty substrate hypothesis is related to increased oxidation of beta-hydroxybutyrate (BHOB) by the heart and kidneys which produces ATP more efficiently than fatty acids and glucose. This results from hyperketonaemia caused by increased hepatic synthesis and decreased urinary excretion of ketones by SGLT2 inhibitors. Utilizing a more energy-efficient fuel leads to improved cardiac and renal function.12
Lastly, the NHE hypothesis refers to the sarcolemmal sodium-hydrogen exchanger NHE1, which is in the heart and vascular and NHE3, which functionally interacts with SGLT2 at the apical surface of renal epithelial cells. Heart failure patients have increased activity of NHE1 and NHE3. Although SGLT2 is not expressed in the heart, it is thought that SGLT2 are able bind to and inhibit NHE1. Reducing NHE1 decreases the concentrations of intracellular sodium and calcium and increases the concentration of mitochondrial calcium. This improves systolic heart function by activating ATP production and reviving mitochondrial function.12
Heart failure affects over 6 million adults in the United States and that number is only expected to grow in the coming years.1,2 Current therapy is well-established, but heart failure is still associated with significant morbidity and mortality and thus accounts for a significant portion of healthcare spend. The potential benefits of SGLT2 inhibitors in heart failure patients stems from the cardiovascular outcome studies that were completed to show no additional cardiovascular harm in diabetic patients. The exact mechanism by which SGLT2 inhibitors provide benefit in heart failure patients is unknown but likely is a combination of multiple mechanisms. Randomized controlled trials in which only 40 to 50% of the patients had diabetes still resulted in significant heart failure benefits.8,9 The updated 2021 ACC Expert Consensus Decision Pathway does now include the consideration of SGLT2 inhibitors in patients with HFrEF and NYHA Class II to IV symptoms who are already on guideline-directed therapy with ACE-I/ARB/ARNI and beta blocker.11 It is worthy to note that much like in diabetic patients, the use of SGLT2 inhibitors in heart failure patients will be limited by the cost of the medication. If a patient is able and willing to take an SGLT2 inhibitor, the safety profile, limited drug-drug interactions, and therapeutic benefits shown in clinical trials favor its use.