The Role of SGLT-2 Inhibitors in Heart Failure: A Roundtable Discussion

CLINICAL BACKGROUND OF HEART FAILURE

“Heart failure is a complex clinical syndrome that occurs because of a structural or functional impairment of the heart muscle that impairs its ability to either pump blood to the other organs of the body, or to do so without increased pressures in the different heart chambers,” said Desai. Heart failure (HF) can be classified as either HF with reduced ejection fraction (HFrEF) or HF with preserved ejection fraction (HFpEF). HFrEF may be referred to as systolic HF, as the heart loses its ability to contract and pump blood forward to the rest of the body. Conversely, HFpEF is often regarded as a disease of diastolic dysfunction, where impaired relaxation of the heart chambers compromises their ability to fill with blood. Left ventricular ejection fraction (LVEF) is substantially reduced in patients with HFrEF (defined as LVEF ≤40%), whereas patients with HFpEF have normal or near-normal LVEF of at least 50%.¹

Regardless of primary HF classification, circulatory and neurohormonal abnormalities often result in symptoms of fatigue, shortness of breath, and fluid retention. The New York Heart Association (NYHA) functional classification and the American College of Cardiology (ACC)/American Heart Association (AHA) staging system² categorize HF based on these symptoms, as well as any existing structural abnormalities of the heart or functional impairment experienced by the patient.¹

HF is considered a chronic progressive disorder, featuring periods of clinical stability followed by acute decompensation. Desai addressed the general decline he sees in patients with HF, noting that it is “this continued pattern of hospitalization, decline, trying to get people back on a stable functional status…It is ongoing myocardial damage [and] kidney damage, and that interplay then continues to get us into trouble with our patients.”

Risk Factors

HF can develop as a result of multiple conditions, including, but not limited to, atherosclerotic cardiovascular disease (ASCVD), hypertension, diabetes, and valvular heart disease. Myocardial infarction (MI) is a common precursor to HF. “Unfortunately, we still see people after acute MI who are not treated appropriately and get this kind of late remodeling with dilation of the left ventricle,” said Nissen.

Hypertension, like obesity and cigarette smoking, is a modifiable risk factor that contributes to HF risk. Elevated blood pressure, particularly of both long duration and poor control, is inextricably linked to HF development. The results of one population-based study showed that 66% of the subjects with incident HF who were included in the study had hypertension.³ Obesity also increases the risk of HF; the lifetime risk of developing HF is roughly double for people with a body mass index (BMI) greater than 30 kg/m² compared with those with a BMI below 25 kg/m².⁴ Cigarette smoking promotes atherosclerosis, hypertension, and lung disease. “We still have a significant fraction of the population who smokes,” said Nissen. “They develop chronic obstructive pulmonary disease, their pulmonary artery pressures go up, [and then] they develop right-heart failure that can be very difficult to treat.”

Diabetes has consistently been shown to increase the risk of HF by 2- to 4-fold. The hallmark features of elevated blood glucose, insulin resistance, and hyperinsulinemia lead to a multitude of downstream consequences for the heart and circulatory system.⁵ In addition, diabetes is often associated with obesity, hypertension, and kidney disease, which further potentiate damage to the heart.

Burden and Cost to Society

HF is becoming more prevalent in the United States. According to estimates, more than 8 million people (3% of the population) will have HF by 2030.⁶ In 2012, the total cost of treating HF in the United States was estimated at $30.7 billion; projections suggest that figure will increase to nearly $70 billion by 2030.⁶ Hospitalizations are a main driver of cost. More than 40% of patients with HF will be hospitalized at least 4 times in their lifetime,⁷ with the average hospitalization costing roughly $23,000.⁸

Murillo acknowledged the spending increase for HF and highlighted the growing group of patients with both hypertension and HF. “We as a country have not done a good job controlling something as simple as blood pressure,” he said. “That’s a group where we have, I would argue, a huge opportunity.” Nissen discussed the struggle to treat hypertension in the African American population with whom he works in Cleveland. “Often we see patients coming in with [a] very thick ventricle, with heart failure, and you realize they’ve had hypertension for many years,” he said.

Concomitant diabetes and HF increases the overall burden of disease, given that both are independently complicated and expensive disorders. Murillo acknowledged that a better understanding of the interplay between diabetes and HF could change the trajectory of the burden. He referred to his work with the research and development team at UnitedHealth Group. “We are actually focusing on research trying to figure out the pathophysiology behind this. That intersection among the heart failure, the metabolic syndromes, the chronic kidney disease—what is common to them that we can address?” he asked.

TREATMENT

Standard of Care

HFrEF

The standard of care for patients with symptomatic HFrEF involves both medication and supportive devices.⁹ Medication management has historically involved β-blockers and use of either an angiotensin-converting enzyme (ACE) inhibitor or angiotensin-receptor blocker to blunt the renin-angiotensin-aldosterone system (RAAS). Diuretics are often added early in the disease to reduce signs and symptoms of congestion. Despite lacking the mortality benefit of β-blockers or RAAS inhibitors, diuretics remain an important mainstay in the treatment of HFrEF. More recently, mineralocorticoid receptor antagonists (MRAs), the angiotensin receptor–neprilysin inhibitor (ARNI) combination of sacubitril–valsartan, and ivabradine therapy have been included in HF guidelines for their ability to reduce morbidity and mortality in certain subgroups of patients.⁹

In addition to medications, the use of implantable cardioverter-defibrillator devices and cardiac resynchronization therapy is recommended as patients progress through different stages of HF. Ultimately, if optimal medication and device therapy fail to prevent decline, patients may progress to palliative care or receive either a heart transplant or a left ventricular assist device.⁹

HFpEF

There is a need for therapies that improve mortality and morbidity for patients with preserved ejection fraction, who comprise about half of all HF cases. Treatment is directed at controlling hypertension and using diuretics to relieve symptoms of volume overload. In addition, MRA therapy may be considered to decrease hospitalizations in a specific subset of patients with HFpEF.⁹ In the recent PARAGON-HF trial, ARNI therapy failed to reduce the incidence of cardiovascular death or hospitalization for HF when compared with valsartan.¹⁰

Goals of Treatment

Clinical trials often focus on the outcomes of reducing death and hospitalizations from HF. Improving quality of life for patients with HF should also be prioritized. Nissen cited the example of diuretics. “There’s not really been any evidence that furosemide makes people live longer, but they feel better. You decongest them. Then you have the drugs that have now been studied that make people live longer,” he said. “In some cases, we have pharmacotherapies that do both, and that’s fantastic.”

Desai echoed this 2-fold approach to HF goals. “Of course, we want to prevent rehospitalizations, we want to prevent death, we want to prevent ongoing kidney disease, [and] we want to prevent other downstream utilization, if you will, in the system,” he said. “And then at a population level, I think we want to try to reduce the burden of disease, improve health, and make sure that people are getting the best quality of care in a timely, efficient manner,” he added.

Achieving Outcomes

Underuse of evidence-based HF therapies is common. Nissen, who works primarily in the cardiovascular intensive care unit, noted a general underutilization of both old and new therapies for HF. “I see these people, and they come in and they’ve had progressive symptoms for years, but they’re maybe just on a low dose of an ACE inhibitor or maybe not even on β-blockers, certainly not on mineralocorticoid receptor antagonists, and I find it frustrating,” he said. He also acknowledged underuse of ARNI therapy. “I think we’ve got to do better about using the full continuum,” he stated. “And adding now to the armamentarium…the very impressive data for the SGLT-2 inhibitors.”

IMPROVING QUALITY OF CARE

Electronic health record (EHR) systems may be used to help improve HF care. “We’re implementing protocols that are EHR-driven, and the idea is to standardize care or minimize variations in care,” said Murillo of the 60,000-provider network with which he works. Nissen discussed another EHR-based approach. “Something we’ve done that [has] seemed to make a very large difference is a discharge checklist, an electronic checklist. You have to check off all the points on the checklist before the patient leaves [the hospital],” he said.

Although patients may be prescribed appropriate therapy in the clinic or upon hospital discharge, they may not continue, or even start, treatment. Evidence shows that adherence to HF medication decreases in the 2 to 4 months after hospital discharge.¹¹ Desai suggested a strategy to help ensure medication adherence: “Have an early postdischarge follow-up visit…Get patients in [for that] in the first week or 10 days, and if you can’t do an in-person visit, at least do a phone call to make sure that they’ve got what they need, they have a good understanding of their medicines, they’re taking them, and that things are in place,” he said.

Care teams often use nontraditional means of connecting with patients, including telephone consults and virtual visits. “We have to get out of this paradigm of practicing medicine only when we have the patient in front of us in the office or when we see that patient in the hospital. It has to be a continuous virtual access, where everybody has an opportunity to say what they need to say or ask the questions that should be asked,” said Murillo.

INCENTIVIZING CARE

In the movement toward value-based care, payers and health care systems have begun to tie high-quality HF care to financial reimbursement. Incentives are generally tied to outcome measures, which, in many cases, can be satisfied by simply checking boxes to show that patients are on β-blocker or ACE inhibitor therapy. That simplistic approach may be short-sighted. “How about if we contract with a health care system, with a provider or whoever, and…the box that we check is, How are the outcomes at 6 months or 12 months? Are you keeping people out of the hospital, preventing readmissions? Is their quality of life better?” asked Murillo.

One progressive model of care under the Quality Payment Program from CMS is an accountable care organization (ACO). When an ACO delivers high-quality care and reduces excess health care spending, it will share in the savings that it achieves. Desai discussed how the strategy works at Yale, which participates in an ACO. “We are moving away from a transactional, siloed, fee-for-service kind of system, and increasingly moving to a value-based system of care where your reimbursement…is tied to the quality of care, to the outcomes that are achieved, and to the efficiency of the care that you are providing,” he said.

With value-driven payments, a proactive approach to HF treatment may be the most cost-effective. Recently introduced medications, such as sacubitril–valsartan and the SGLT-2 inhibitors, have demonstrated substantial benefit for patients with HF; however, these medications are associated with higher costs compared with medications that are available as generics. Murillo pointed out that the discussion isn’t as simple as looking only at a medication’s cost. “[Instead,] what’s the actual value that medication provides to the patient and to society in general? Keeping people out of the hospital is enough to justify making that investment when it’s important to public health and individual health,” he said.

CARDIOVASCULAR IMPACTS OF SGLT-2 INHIBITORS

For years, diabetes medications were approved solely for their ability to lower glucose, and little was known about their long-term cardiovascular consequences. In 2008, the FDA mandated that all new glucose-lowering drugs would be evaluated for cardiovascular safety.¹² Over the last 12 years, medications such as dipeptidyl peptidase-4 (DPP-4) inhibitors, the glucagon-like peptide-1 agonists, and the SGLT-2 inhibitors have been studied in cardiovascular outcomes trials (CVOTs). Data have shown that some of these newer medications are not only safe in terms of cardiovascular risk but can actually improve cardiovascular outcomes.

For Nissen, the pivotal moment came in 2015, with what he called the “striking” reduction in hospitalization for HF seen with empagliflozin in its CVOT. Results for other SGLT-2 inhibitors followed. “It was a very successful endeavor to require that we look at outcomes, not just at blood sugar lowering for diabetes drugs. The home run here was the SGLT-2 inhibitors and their ability to reduce hospitalization for heart failure,” said Nissen.

Cardiovascular Outcomes Trials

Empagliflozin

The Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients Removing Excess Glucose (EMPA-REG OUTCOME) trial was a randomized, double-blind study that compared empagliflozin with placebo in 7020 patients with both type 2 diabetes and established cardiovascular disease. The primary outcome was the occurrence of a major adverse cardiovascular event (MACE), defined as the composite of death from cardiovascular causes, nonfatal MI, or nonfatal stroke. After a follow-up period of 3.1 years, results showed a statistically significant reduction in MACE with empagliflozin (HR, 0.86; 95% CI, 0.74-0.99; P <.001 for noninferiority; P = .04 for superiority).¹³ Additionally, empagliflozin treatment resulted in a 38% lower risk of death from cardiovascular causes and a 35% decrease in hospitalization for HF.¹³ Results of the trial were first reported in 2015; in December 2016, the FDA added an indication for empagliflozin to reduce the risk of cardiovascular death in adults with type 2 diabetes and cardiovascular disease.¹⁴

Canagliflozin

The Canagliflozin Cardiovascular Assessment Study (CANVAS) Program combined data from 2 trials, CANVAS and CANVAS-R. A total of 10,142 patients with type 2 diabetes and high cardiovascular risk were randomly assigned to either canagliflozin or placebo. The majority (66%) of study patients had existing ASCVD; the remainder had at least 2 risk factors for ASCVD.¹⁵ Participants were followed for a mean of 3.6 years; all participants and investigators were blinded to the treatment assignment until completion of the study.

Results of the CANVAS Program showed a significant reduction in the primary outcome of MACE with canagliflozin (HR, 0.86; 95% CI, 0.75-0.97; P <.001 for noninferiority; P = .02 for superiority).¹⁵ In addition, hospitalization for HF was reduced by 33% in the canagliflozin group, and the composite of sustained reduction in estimated glomerular filtration rate (eGFR), the need for renal replacement therapy, or death from renal causes was reduced by 40%.¹⁵ In October 2018, as a result of the these findings, the FDA approved canagliflozin to reduce the risk of major adverse cardiovascular events, including heart attack, stroke or death due to a cardiovascular cause in adults with type 2 diabetes who have established cardiovascular disease.¹⁶

Although not specifically designed as an FDA-mandated CVOT trial, the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial also reported on several cardiovascular outcomes. CREDENCE was a double-blind, randomized trial that compared canagliflozin with placebo in 4401 patients with type 2 diabetes for a follow-up period of 2.6 years.¹⁷ The primary aim was to further characterize the renal benefits suggested by results of previous SGLT-2 inhibitor trials. Participants were required to have chronic kidney disease (defined as an eGFR of 30 to <90 mL/min/1.73m²) and albuminuria (defined as urinary albumin-to-creatinine ratio of >300 to 5000 mg/g).¹⁷

Canagliflozin treatment resulted in a statistically significant decrease in the primary composite of end-stage kidney disease, doubling of the serum creatinine level, or renal or cardiovascular death (HR, 0.70; 95% CI, 0.59-0.82; P = .00001).¹⁷ Prespecified analysis of key secondary outcomes showed a 31% reduction in the composite of cardiovascular death or hospitalization for HF, driven largely by a 39% reduction in hospitalizations.¹⁷ Based on results from the CREDENCE trial, in September 2019, the FDA added an indication for canagliflozin to reduce the risk of kidney decline, cardiovascular death, and hospitalization for HF in patients with diabetes and albuminuria.¹⁶

Dapagliflozin

The Dapagliflozin Effect on Cardiovascular Events–Thrombosis in Myocardial Infarction 58 (DECLARE–TIMI 58) trial was a randomized, double-blind trial that compared dapagliflozin with placebo in 17,160 patients with type 2 diabetes. Participants were required to have either established ASCVD or multiple ASCVD risk factors (40.6% and 59.4% of the study population, respectively).¹⁸ Two primary outcomes were investigated: MACE and the composite of cardiovascular death or hospitalization for HF.¹⁸

Dapagliflozin treatment did not produce a statistically significant decrease in MACE (HR, 0.93; 95% CI, 0.84-1.03; P = .17), although noninferiority to placebo was demonstrated. Dapagliflozin treatment did yield a significant decrease in the composite of cardiovascular death or hospitalization for HF (HR, 0.83; 95% CI, 0.73-0.95; P = .005); this decrease was independent of existing ASCVD. No significant difference in cardiovascular death was evident between groups, but hospitalization for HF was reduced by 27% with dapagliflozin.¹⁸ Accordingly, in October 2019, the FDA approved dapagliflozin to reduce the risk for HF hospitalization among adults with type 2 diabetes who also have cardiovascular disease or multiple CV risk factors.¹⁹

Ertugliflozin

The Evaluation of Ertugliflozin Efficacy and Safety Cardiovascular (VERTIS-CV) trial was a randomized, double-blind study that compared ertugliflozin with placebo in 8246 patients with type 2 diabetes and established ASCVD.²⁰ As with other CVOTs, the primary objective was to demonstrate the noninferiority of ertugliflozin compared with placebo for MACE. Secondary objectives aimed to demonstrate superiority of ertugliflozin for cardiovascular death; the composite of cardiovascular death or hospitalization for HF; and renal death, dialysis/transplant, or doubling of serum creatinine from baseline.²⁰

VERTIS-CV has been completed, and investigators presented their findings at the 2020 American Diabetes Association Virtual Scientific Sessions. Preliminary, unpublished data suggested no difference in the primary outcome of MACE between ertugliflozin and placebo (11.9% in each group; HR, 0.97; 95% CI, 0.85-1.11; P <.001 for noninferiority). Similar to previous CVOTs, however, data did indicate a 30% reduction in the risk of hospitalization from HF, although the combined composite of cardiovascular death or hospitalization for HF appeared similar between groups. Additionally, the renal composite end point trended in favor of ertugliflozin but the difference between groups did not appear to be statistically significant.²¹

SGLT-2 INHIBITORS FOR HEART FAILURE

Patients With Diabetes

Results from CVOTs indicate that SGLT-2 inhibitors benefit patients with type 2 diabetes in the context of a clinical trial, particularly with regard to reduction in hospitalization for HF. Two trials set out to investigate how SGLT-2 inhibitors would perform in real-world scenarios. In the Empagliflozin Comparative Effectiveness and Safety (EMPRISE) study, Patorno and colleagues analyzed claims data from 2 commercial sources and 1 federal source to examine cardiovascular outcomes in more than 32,000 patients with diabetes started on either empagliflozin or sitagliptin, a DPP-4 inhibitor.²² Compared with sitagliptin, empagliflozin use yielded a roughly 50% decreased risk of hospitalization for HF.²²

The results of the Comparative Effectiveness of Cardiovascular Outcomes in New Users of Sodium-Glucose Cotransporter-2 Inhibitors (CVD-REAL) study echoed the findings from EMPRISE. Data from medical claims, health system records, and national registries were collected for more than 300,000 patients who had recently been started on either an SGLT-2 inhibitor or another glucose-lowering medication.²³ Compared with other medications, treatment with SGLT-2 inhibitors yielded risk reductions of 39%, 51%, and 46% for hospitalization for HF, all-cause death, and the composite of hospitalization for HF or death, respectively. Regardless of predominant SGLT-2 inhibitor used (canagliflozin in the United States, dapagliflozin in Europe), results were consistent across countries, suggesting a class effect.

Patients Without Diabetes

Given the positive results seen in CVOT trials, investigators set out to determine whether SGLT-2 inhibitors could impact HF outcomes in patients without diabetes.

In the Dapagliflozin And Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) trial, 4744 patients with HFrEF were randomly assigned to receive either dapagliflozin or placebo. The primary outcome was the composite of death from cardiovascular causes or worsening of HF (defined as either an unplanned hospitalization or urgent visit resulting in intravenous therapy for HF).²⁴ Dapagliflozin was added on top of standard drug and device therapy. At baseline, the proportion of patients with diabetes was similar between groups, as was the NYHA functional status.

After a median follow-up of 18.2 months, the primary outcome occurred in 386 patients (16.3%) in the dapagliflozin group and in 502 patients (21.2%) in the placebo group (HR, 0.74; 95% CI, 0.65-0.85; P <.001). This effect was consistent across patients with and without diabetes. The incidence of the secondary composite outcome of cardiovascular death or hospitalization for HF was also significantly lower in the dapagliflozin group (HR, 0.75; 95% CI, 0.65-0.85; P <.001). This result was driven by an 18% decrease in death from cardiovascular causes and a 30% decrease in hospitalization for HF.²⁴

As a result of DAPA-HF, in May 2020, the FDA approved dapagliflozin for the reduction of risk of cardiovascular death and hospitalization for HF in adults with HFrEF.¹⁹ Desai discussed the impact of DAPA-HF. “The SGLT-2 inhibitors were developed as diabetes medications. What they have emerged as are cardiovascular risk-reducing medications, and also highly effective therapies for heart failure, whether you have diabetes or not,” he summarized.

Similar in design to DAPA-HF, the EMPEROR-Reduced trial is comparing empagliflozin with placebo for the treatment of HFrEF in patients with and without diabetes. The results of EMPEROR-Reduced could help to solidify the role of SGLT-2 inhibitors in HFrEF treatment for patients without diabetes.

Patients With Preserved Ejection Fraction

Both DAPA-HF and EMPEROR-Reduced enrolled patients with HFrEF, but trials are underway to determine whether SGLT-2 inhibitors can play a much-needed role in patients with preserved ejection fraction. The DELIVER trial with dapagliflozin is studying similar outcomes to DAPA-HF, but in patients with HFpEF rather than HFrEF. Additionally, the EMPEROR-Preserved trial, expected to be completed by the end of 2020, is comparing empagliflozin with placebo in patients with HFpEF. “I do think that EMPEROR-Preserved, if that reports out the way again that we all hope it will…will be a very important stride forward for the field and for our patients. That will be the first real therapy that can improve outcomes and the care of those patients who represent about half the patients with heart failure,” said Desai.

THE FUTURE OF SGLT-2 INHIBITORS IN HEART FAILURE

Guideline Adoption

As evidence of the cardiovascular benefit from SGLT-2 inhibitors has grown, this class of medications has been incorporated into guidelines for clinicians. In 2020, the American Diabetes Association (ADA) and the European Association for the Study of Diabetes published a joint consensus report that recommended the use of SGLT-2 inhibitors in both primary and secondary prevention scenarios,²⁵ regardless of baseline blood sugar control.²⁵ The ADA has also incorporated stronger recommendations for SGLT-2 inhibitor use into its annual update on diabetes care. Following the release of DAPA-HF results, the ADA revised their position to state: “In patients with type 2 diabetes and established heart failure with reduced ejection fraction, a sodium-glucose cotransporter-2 inhibitor with proven benefit in this patient population should be considered to reduce risk of worsening heart failure and cardiovascular death; this may be a class effect.”²⁶

The 2017 update to the joint HF management guidelines from ACC, AHA, and the Heart Failure Society of America (HFSA) did not address the use of SGLT-2 inhibitors. However, in 2018, the ACC did release a consensus decision pathway suggesting that SGLT-2 inhibitors be considered for diabetes treatment when patient and clinician priorities include reducing MACE, cardiovascular death, or preventing hospitalization for HF.²⁷ Additionally, in 2019, the ACC and HFSA published a joint scientific statement that listed metformin and SGLT-2 inhibitors as preferred therapy over sulfonylureas or insulin for patients with diabetes who are at high risk for HF or have established HF.⁵

The panelists expressed a general feeling that medical societies have not been quick enough to adapt their stances into official guidelines as evidence emerges. Speaking from the perspective of a payer, Murillo highlighted the importance of updating guidelines as evidence emerges. “Guidelines are very important to us when we design medical policies because we base [policies] on those guidelines. If we don’t have [updated guidelines], it really ties our hands,” he said. “We need to be more dynamic, and sometimes we have to be bolder in terms of moving forward.”

Barriers to Use

Setting Themselves Apart

“As we move to thinking about what is best medical therapy for our patients with HFrEF…the SGLT-2 inhibitors really have to come forward among a somewhat crowded field,” said Desai. Complicating their position in treatment, all CVOTs studied SGLT-2 inhibitor use on top of well-rounded, standard therapy. “I would not discount the fact that we have a long way to go in our clinical practice to try and mimic what has been done in these trials,” said Desai. “We’ve seen data from recent registry studies where about 1% of patients with systolic heart failure are actually on standard triple therapy with β-blocker, RAAS inhibitor, [and] mineralocorticoid receptor antagonists, at the doses that are recommended by our practice guidelines,” he continued.

The ability of the SGLT-2 inhibitors to prevent kidney disease progression may eventually help them stand out among other treatments for HF. “When you think about value, the value proposition: yes, they lower blood sugar, yes, they prevent heart failure, but they also seem to prevent progression of renal disease,” said Nissen.

COST AND ACCESS

The cost of SGLT-2 inhibitors affects their use. Cash-paying patients may find their cost prohibitive, and insurers often limit coverage to contain costs. Patients may be required to try and fail other diabetes or HF therapies before insurers agree to cover an SGLT-2 inhibitor. Nissen argued that the influence on HF hospitalizations must be part of the overall cost-effectiveness discussion for SGLT-2 inhibitors and other drugs. “When we have therapies that we know prevent recurrent hospitalization from heart failure, getting people on those therapies has to be a very high societal priority,” he said.

Murillo acknowledged that UnitedHealthcare is moving toward reducing barriers for SGLT-2 inhibitor use in patients without diabetes. He pointed out the importance of considering the overall picture. “What’s the real value that this medication will bring to lower the total cost among heart failure patients? That’s the perspective that we need to take into account, the pharmacoeconomics that are brought out by SGLT-2 [inhibitors] right now,” said Murillo.

LACK OF PRESCRIBING

“Today, across the country, there are going to be thousands and thousands of visits [to clinicians] of patients who have diabetes and heart disease, and the numbers would suggest to you that they are much, much more likely to walk out of that office with a script for a sulfonylurea or a DPP-4 inhibitor than they are an SGLT-2 inhibitor,” said Desai.

Cost and access concerns may contribute to the lack of prescribing, but knowledge of, and adherence to, evidence-based clinical practice guidelines likely plays a role as well. Nissen spoke to the problem of clinical inertia, in which clinicians fail to initiate or intensify therapy when indicated. “[When physicians] train, they learn a certain way of doing things; they seem to have some success with it and they kind of go with the flow,” said Nissen. “All of us have a role to play, both the payers and the people that are working in the clinical community, to educate people about this.”

Multidisciplinary, team-based care may help address these unmet needs. “What if we enroll or engage—like many ACOs do, for instance—a cardiologist and an endocrinologist working closely with the primary care community? At the end of the day, we’re all together and what really matters is that we keep [the patient] out of the hospital and they have a better quality of life,” said Murillo.

A better understanding of exactly how SGLT-2 inhibitors work may also help to increase their use and, potentially, identify other targets for HF treatment. The SGLT-2 inhibitors lower glucose by increasing the urinary excretion of glucose. In addition, they have modest diuretic and natriuretic effects that may impact HF, but there appears to be more to the picture. “As we work toward implementation, we also want to understand the science better, and I hope we can do that in coming years,” said Nissen.

CONCLUSIONS

Heart failure remains a leading cause of morbidity and mortality in the United States. Diabetes increases the risk of HF, and patients with both conditions often have worse outcomes. Since the FDA mandated CVOTs in 2008, recently approved classes of diabetes medications have shown not only cardiovascular safety, but, in some instances, substantial cardiovascular benefit. One of these classes, the SGLT-2 inhibitors, has demonstrated consistent reduction in the risk of hospitalization for HF.

The SGLT-2 inhibitors represent an important step forward in care for HF, both in patients with and without diabetes. Further evidence will help to solidify the role of SGLT-2 inhibitors for both HFrEF and HFpEF. Professional societies, payers, and clinicians will all play a role in increasing access and adoption of the SGLT-2 inhibitors into real-world practice. “It’s on all of us as clinicians and members of the community to come together, engage with our colleagues, reimagine and rethink what care should be for these patients, and to try and abandon some of the historical silos that have impeded progress,” noted Desai.

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