EMPEROR-Preserved Cost, Cost-Effectiveness, and Health-Economic Implications

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:

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:

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, $420,000 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:

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, 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)

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

›Is empagliflozin cost-effective for HFpEF at standard US prices?

At net prices (after rebates), most published models find empagliflozin cost-effective below the commonly used $100,000/QALY threshold. At full list price, some analyses exceed this threshold but remain below $150,000/QALY. The drug is generally considered good value relative to other cardiovascular therapies.

›How much does empagliflozin actually cost patients with HFpEF per month?

With manufacturer copay assistance, commercially insured patients typically pay $0, $10/month. Without assistance, costs range from $35 to over $250 monthly depending on insurance type, formulary tier, and deductible status. Medicare beneficiaries are protected by the $2,000 annual out-of-pocket cap.

›Does insurance cover empagliflozin specifically for heart failure with preserved ejection fraction?

Yes. Following the 2022 FDA label expansion and the 2022 AHA/ACC/HFSA heart failure guidelines, major payers cover empagliflozin for HFpEF. Prior authorization requirements vary but typically require documented heart failure diagnosis and EF above 40%.

›What drives the cost-effectiveness of empagliflozin in HFpEF?

Avoided hospitalizations account for the majority of economic benefit. Each prevented HF admission saves $15,000, $23,000. The EMPEROR-Preserved trial showed approximately 4.5 fewer hospitalizations per 100 patient-years, creating substantial cost offsets against the annual drug expenditure.

›Is empagliflozin more cost-effective for HFpEF patients who also have diabetes?

Yes. Patients with coexisting type 2 diabetes receive glycemic control, cardiovascular risk reduction, and renal protection from a single medication. Multi-indication models attribute only a fraction of drug cost to HFpEF, producing ICERs of $25,000, $40,000/QALY for diabetic HFpEF patients.

›How does the EMPEROR-Preserved economic data compare to HFrEF cost-effectiveness?

Empagliflozin is generally more cost-effective in HFrEF (where the mortality benefit is clearer and hospitalization reductions are larger). HFpEF ICERs run 20 to 40% higher than HFrEF ICERs in head-to-head model comparisons, primarily due to the weaker mortality signal in preserved EF populations.

›Will generic empagliflozin change the cost-effectiveness picture?

Substantially. Patent expiration is anticipated around 2028 to 2030. Models incorporating generic entry (at 80 to 90% price reduction) show ICERs dropping below $35,000/QALY. For payers, the drug becomes dominantly cost-effective once generic pricing applies.

›Which HFpEF patients get the best value from empagliflozin?

Patients hospitalized for heart failure within the prior 12 months derive the greatest economic benefit. They have high baseline event rates, larger relative risk reductions (HR 0.67 in this subgroup), and each avoided readmission carries maximum dollar value. This subgroup likely achieves cost-effectiveness even at full list price.

›Did NICE approve empagliflozin for HFpEF as cost-effective?

NICE recommended empagliflozin for HFpEF in 2023, contingent on a confidential patient access scheme (discount). This indicates the list-price ICER exceeded their £30,000/QALY threshold but the negotiated net price brought it within acceptable range.

›How do hospitalization cost assumptions affect the economic models?

Heavily. Models using Medicare inpatient costs ($20,000, $23,000 per HF admission) produce more favorable ICERs than those using commercial averages ($15,000, $17,000). Geographic variation in hospitalization costs means empagliflozin may be more cost-effective in high-cost healthcare markets.

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