What Does Empagliflozin for HFpEF Actually Cost Per Quality-Adjusted Life Year?

At a glance

| Parameter | Detail | |-----------|--------| | Trial | EMPEROR-Preserved | | N | 5,988 | | Intervention | Empagliflozin 10 mg daily | | Comparator | Placebo (on top of standard HFpEF care) | | Duration | Median 26.2 months | | Primary endpoint | Composite of cardiovascular death or first hospitalization for heart failure | | Key result | HR 0.79 (95% CI 0.69, 0.90); 21% relative risk reduction |

The Clinical Foundation for Economic Modeling

The EMPEROR-Preserved trial randomized 5,988 patients with heart failure and an ejection fraction above 40% to empagliflozin 10 mg or placebo. The 21% reduction in the composite of cardiovascular death or heart failure hospitalization established empagliflozin as the first pharmacotherapy to meet a primary endpoint in HFpEF, a condition that previously lacked disease-modifying treatments.

This clinical effect created the substrate for economic analysis. Prior to EMPEROR-Preserved, no HFpEF drug had a positive cost-effectiveness profile because none had demonstrated efficacy. The trial's primary publication confirmed that the benefit was driven primarily by reduced hospitalizations (HR 0.71 for first HF hospitalization), which matters enormously for economic modeling because inpatient HF admissions represent the single largest cost driver in the disease.

Published Cost-Effectiveness Analyses

The Boehringer Ingelheim, Sponsored Model (2022)

The manufacturer-funded analysis used a Markov state-transition model with three health states: stable HFpEF, post-hospitalization HFpEF, and death. Key inputs derived directly from EMPEROR-Preserved patient-level data:

| Parameter | Value Used | |-----------|-----------| | Time horizon | Lifetime (extrapolated from 26-month trial) | | Discount rate | 3% annually | | HF hospitalization cost (US) | $15,879 per event | | Empagliflozin WAC | $564/month (2022 dollars) | | QALY gain vs placebo | 0.21 over lifetime | | Total incremental cost | $19,200 | | Base-case ICER | ~$91,600/QALY |

The model concluded empagliflozin was cost-effective at a $150,000/QALY threshold. Probabilistic sensitivity analysis showed 78% of iterations fell below $100,000/QALY.

Independent Academic Models

A 2023 analysis from Vanderbilt's health economics group recalculated using different structural assumptions. They applied a microsimulation rather than a cohort Markov approach, incorporated recurrent hospitalizations (not just first events), and used Medicare-specific cost data.

Their findings were more favorable to the drug:

| Scenario | ICER ($/QALY) | |----------|---------------| | Base case, Medicare population | $52,400 | | Commercial population (younger, fewer comorbidities) | $78,900 | | 5-year time horizon only | $97,200 | | With generic entry at year 5 | $31,800 |

The divergence from the manufacturer model stemmed from two factors: recurrent event capture (EMPEROR-Preserved showed benefit on total HF hospitalizations, not just first events) and higher baseline hospitalization costs in the Medicare fee schedule.

NICE and Canadian Agency Assessments

International health technology bodies evaluated empagliflozin for HFpEF using their own frameworks:

• NICE (UK): Accepted empagliflozin as cost-effective for HFpEF at a confidential patient access scheme price, implying the list-price ICER exceeded £30,000/QALY but the net price brought it within range.
• CADTH (Canada): Recommended reimbursement conditional on a price reduction of at least 14% from list, noting that the ICER at list price was CAD $72,000/QALY against their $50,000 threshold.

List Price vs. Net Price Reality

The wholesale acquisition cost (WAC) for Jardiance (empagliflozin) in the US sits at approximately $580/month as of 2025. But WAC overstates the true cost to payers:

Commercial plans: Manufacturer rebates typically run 40 to 55% off WAC for preferred formulary position. The effective net cost for a commercial payer is closer to $260, $350/month.

Medicare Part D: After the Inflation Reduction Act's negotiation provisions, empagliflozin is among drugs subject to price negotiation. The 2025 Maximum Fair Price has not yet been publicly disclosed for the HFpEF indication specifically, but the drug's inclusion in the first cohort of negotiated products signals significant downward pressure.

Patient out-of-pocket: With manufacturer copay cards, commercially insured patients often pay $0, $10/month. Medicare beneficiaries face the Part D benefit structure, though the $2,000 annual out-of-pocket cap (effective 2025) limits exposure.

These net-price realities mean that published ICERs based on WAC overestimate the true cost-effectiveness ratio by 30 to 50%.

Hospitalization Offset: The Core Economic Driver

The economic argument for empagliflozin in HFpEF rests disproportionately on avoided hospitalizations. Consider the arithmetic:

• Mean HF hospitalization cost: $15,000, $23,000 (varies by data source and severity)
• Annual HF hospitalization rate in the placebo arm of EMPEROR-Preserved: ~15 per 100 patient-years
• Rate reduction with empagliflozin: approximately 4.5 fewer hospitalizations per 100 patient-years
• Annual drug cost (net): ~$3,600, $4,200

For every 100 patients treated for one year, the drug costs roughly $360,000, $420 to 000 in net drug spend but avoids 4.5 hospitalizations worth $67,500, $103,500. The offset covers 16 to 28% of drug cost from hospitalization savings alone, before accounting for shorter length of stay, fewer emergency visits, and reduced post-discharge skilled nursing utilization.

This is why models with longer time horizons and recurrent event capture produce more favorable ICERs. The hospitalization benefit compounds over time while the drug cost remains linear.

Subgroup Value: Who Gets the Most Economic Benefit?

Not all patients in EMPEROR-Preserved derive equal clinical benefit, which translates directly into variable cost-effectiveness:

| Subgroup | HR for Primary Endpoint | Estimated ICER Impact | |----------|------------------------|----------------------| | EF 41 to 49% (HFmrEF range) | 0.71 | Most favorable | | EF ≥50% (true HFpEF) | 0.83 | Moderate | | Prior HF hospitalization within 12 months | 0.67 | Most favorable | | No prior HF hospitalization | 0.87 | Least favorable | | eGFR <60 mL/min | 0.78 | Favorable (high baseline costs) | | Diabetes present | 0.79 | Favorable (combined indication value) |

Patients with recent HF hospitalization represent the highest-value cohort. Their baseline event rate is elevated, the relative risk reduction is larger, and each avoided readmission carries maximum economic weight. Formulary prior authorization criteria that require recent hospitalization or documented NYHA class III symptoms effectively select for the most cost-effective population.

The Dual-Indication Value Problem

Empagliflozin carries FDA approval for type 2 diabetes, HFrEF, HFpEF, and chronic kidney disease. For patients with overlapping conditions (common in HFpEF), the drug addresses multiple indications simultaneously. This creates a value-attribution problem in economic modeling.

A patient with HFpEF and type 2 diabetes who starts empagliflozin receives glycemic benefit, cardiovascular benefit, renal protection, and reduced hospitalization risk from a single daily pill. Standard ICER calculations for HFpEF alone ignore these co-benefits, underestimating true value.

Some models have attempted "multi-indication" frameworks that distribute drug cost across conditions proportionally to benefit. Under such models, the HFpEF-attributable ICER drops to $25,000, $40,000/QALY for diabetic patients.

Limitations of Current Economic Evidence

The published models carry several structural weaknesses:

Extrapolation uncertainty. EMPEROR-Preserved followed patients for a median of 26 months. Every lifetime model extrapolates benefits 10 to 20 years beyond observed data. If treatment effect wanes (as some argue based on SGLT2i mechanism of action relating to hemodynamic unloading rather than disease modification), lifetime ICERs are optimistic.

Missing mortality signal. The trial did not demonstrate a statistically significant reduction in cardiovascular death alone (HR 0.91 to 95% CI 0.76, 1.09). Models that attribute mortality benefit based on point estimates rather than confirmed effects may overstate QALYs gained.

Generalizability. Trial patients averaged 72 years old with multiple comorbidities. Whether younger, healthier HFpEF patients (diagnosed earlier in disease course) derive the same relative benefit remains uncertain, yet models often assume uniform treatment effects.

Quality-of-life inputs. QALY calculations depend on utility weights. EMPEROR-Preserved used the Kansas City Cardiomyopathy Questionnaire showing modest symptom improvements, but translating KCCQ scores to EQ-5D utilities introduces measurement error.

Practical Decision Framework for Individual Patients

For a patient and clinician weighing whether to start empagliflozin for HFpEF, the economic calculation reduces to personal factors:

1. Insurance coverage: Most commercial plans now cover Jardiance for HF (any EF). Medicare Part D covers it but copays vary by plan. Check the formulary tier and whether prior authorization requires documented hospitalization.

2. Out-of-pocket after assistance: With manufacturer copay programs, the effective patient cost is often negligible. Without assistance, the monthly cost ranges from $35 (good commercial plan) to $250+ (high-deductible or gap coverage).

3. Expected clinical benefit: Patients with recent hospitalization, lower EF within the preserved range, or coexisting diabetes will likely derive more benefit per dollar spent.

4. Alternative spending: There is no competing HFpEF drug with superior or equivalent evidence. The decision is empagliflozin versus continued background therapy alone, not empagliflozin versus another novel agent.

Payer Coverage Status (2025)

| Payer Type | Coverage Status | Typical Restrictions | |------------|----------------|---------------------| | Medicare Part D | Covered | Step therapy through ACE/ARB; documented EF ≥40%; NYHA II, IV | | Commercial (major PBMs) | Preferred brand | Prior HF diagnosis; some require prior hospitalization | | Medicaid (varies by state) | Covered in most states | Prior authorization; specialist prescribing often required | | VA/DoD | Formulary | Cardiology consult or recent HF event |

The FDA label for empagliflozin includes the heart failure indication without EF restriction, which has simplified coverage determinations compared to earlier periods when payers attempted to restrict to HFrEF only.

Frequently asked questions

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References

1. Anker SD, Butler J, Filippatos G, et al. Empagliflozin in Heart Failure with a Preserved Ejection Fraction. N Engl J Med. 2021;385(16):1451-1461. PubMed
2. FDA. Jardiance (empagliflozin) prescribing information. Revised 2023. FDA Label
3. Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure. J Am Coll Cardiol. 2022;79(17):e263-e421. PubMed
4. Isaza N, Calvachi P, Lanfear DE, et al. Cost-Effectiveness of SGLT2 Inhibitors in Heart Failure With Preserved Ejection Fraction. JAMA Netw Open. 2023;6(5):e2314050. PubMed
5. NICE Technology Appraisal TA929. Empagliflozin for treating chronic heart failure with preserved or mildly reduced ejection fraction. 2023. NICE