Cost Offset of Dapagliflozin in the US Medicare Population with Cardio-Kidney Metabolic Syndrome.

INTRODUCTION: Cardiovascular-kidney-metabolic (CKM) syndrome is highly prevalent in the US Medicare population and is projected to increase further. Sodium-glucose co-transporter 2 inhibitors have indications in chronic kidney disease (CKD), heart failure (HF), and type 2 diabetes (T2D), providing protective efficacy across conditions within CKM syndrome. The objective of this study was to develop a model to extrapolate key outcomes observed in pivotal clinical trials to the US Medicare population, and to assess the potential direct cost offsets associated with dapagliflozin therapy. METHODS: All US 2022 Medicare beneficiaries (≥ 65 years of age) eligible to receive dapagliflozin were estimated according to drug label indication and Medicare enrollment and claims data. Incidence of key outcomes from the dapagliflozin clinical program were modelled over a 4-year time horizon based on patient-level data with CKD, HF, and T2D. Published cost data of relevant clinical outcomes were used to calculate direct medical care cost-offset associated with treatment with dapagliflozin. RESULTS: In a population of 13.1 million patients with CKM syndrome, treatment with dapagliflozin in addition to historical standard of care (hSoC) versus hSoC alone led to fewer incidents of HF-related events (hospitalization for HF, 613,545; urgent HF visit, 98,896), renal events (kidney failure, 285,041; ≥ 50% sustained decline in kidney function, 375,137), and 450,355 fewer deaths (of which 225,346 and 13,206 incidences of cardiovascular and renal death were avoided). In total this led to medical care cost offsets of $99.3 billion versus treatment with hSoC only (dapagliflozin plus hSoC, $310.3 billion; hSoC, $211.0 billion). CONCLUSION: By extrapolating data from trials across multiple indications within CKM syndrome, this broader perspective shows that considerable medical care cost offsets may result through attenuated incidence of clinical events in CKD, T2D, and HF populations if treated with dapagliflozin in addition to hSoC over a 4-year time horizon. Graphical abstract available for this article.

Assessment of a systematic approach for implementing novel medications in clinical practice: an observational study with dapagliflozin.

OBJECTIVE: To assess a systematic implementation approach for introducing dapagliflozin to individuals with heart failure and reduced ejection fraction in an outpatient clinical setting. METHODS: Retrospective medical record data were analysed. All individuals diagnosed with heart failure who resided within the hospital catchment area and had visited cardiology or internal medicine department between 2010 and 2019 were screened by using the main inclusion criteria from the DAPA-HF trial. The effectiveness of the previously described seven-step systematic implementation approach was assessed by the proportion receiving information letter, dapagliflozin treatment, follow-ups at 2-12 weeks and 12 months post-dapagliflozin initiation, persistence on dapagliflozin, adverse events, and reasons for discontinuation. RESULTS: Of the 2433 individuals, 352 met the main DAPA-HF trial criteria in step 2. After exclusions in steps 3 and 4, 191 individuals remained. Of these, 158 were invited for eligibility discussion in step 5, with 107 having received an information letter beforehand. In step 6, dapagliflozin was prescribed to 69 individuals, and in step 7, follow-ups were conducted with 56 individuals at 2-12 weeks and 62 individuals at 12 months. Sixty out of 69 persisted on dapagliflozin after 12 months. Adverse events were reported by nine individuals. Discontinuation was attributed to reasons such as urinary tract infections, genital or abdominal discomfort, and hypotension. CONCLUSION: The systematic introduction of dapagliflozin to heart failure patients was effective. Despite this, challenges in uniformly implementing procedures across patients were evident, emphasizing the necessity for a systematic implementation approach.

Assessment of radiosensitivity and enhancing key steviol glycosides in Stevia rebaudiana Bertoni through gamma radiation.

PURPOSE: Stevia rebaudiana Bertoni is a perennial herb, widely used as a natural sweetener around the globe. The key compounds responsible for its sweetness includes stevioside and rebaudioside-A. In order to improve these steviol glycosides, the present study was initiated to study the effect of induced mutagenesis on growth parameters, steviol glycosides and nuclear DNA content in Stevia rebaudiana Bertoni using ten doses of gamma-rays (5-100 kR). MATERIALS AND METHODS: Healthy seeds of 'Madhuguna' variety of Stevia rebaudiana Bertoni developed and maintained at stevia breeding farm, Agrotechnology division, CSIR-Institute of Himalayan Bioresource Technology, Palampur (HP), India were irradiated with ten doses of gamma rays (600 seeds each/dose) ranging from 5 kR to 100 kR (i.e., 5, 10, 15, 20, 30, 40, 50, 60, 80 and 100 kR) using Co60 gamma irradiation chamber at CCS Haryana Agricultural University, Hisar, (Haryana), India. RESULTS: Significant variations were recorded for all the seedling traits studied while major impact was noticed on the seedling after reaching the cotyledonary stage and doses above 40 kR showed absolute mortality of the seedlings. Based on probit analysis, the optimum LD50 dose lies in the range of 20-23 kR. Glycosidic profiling of 296 mutants using high-performance liquid chromatography showed decreased total steviol glycoside content with increased radiation dose. Doses 5 kR and 10 kR, were found to be effective in increasing the overall glycosidic content. A total of 72 promising mutants were also screened for increased rebaudioside-A stevioside ratio. Comparison of nuclear DNA content using flow cytometry revealed a similar decrease in the total nuclear DNA content with increase in dosage of gamma rays. The average genome size at 5, 10, 15, 20 and 30 kR treatments were 2.72, 2.69, 2.68, 2.70 and 2.66 pg as compared to 2.72 pg in control. CONCLUSIONS: Mild dose of gamma rays (5 and 10 kR) in stevia were found to be effective in improving the mean steviol glycoside content and may be used in future stevia mutation programmes.

Phytochemical analysis of Cichorium bottae root and anti-inflammatory potential assessment of isolates.

The Cichorium plants are particularly notable due to their remarkable therapeutic and medicinal properties, besides being used as food and conventional medication. Although Cichorium plants have been studied for their phytoconstituents and biological activities, there is limited knowledge about the constituents of the roots of C. bottae. A phytochemical study of the 90% MeOH extract of C. bottae roots resulted in the isolation of twelve compounds belonging to guaianolide sesquiterpene lactones, sesquiterpene lactone glucosides, and phenolic derivatives, of which two compounds designated as 9α-hydroxycrepediaside B (1) and cichobotinal (2) were previously undescribed. The isolated compounds were assessed for their anti-inflammatory potential through the inhibition of inducible nitric oxide synthase (iNOS) and resultant decrease in nitric oxide generation in LPS-induced macrophages. Among the isolates, compounds 2 and 11 (8-deoxylactucin) inhibited iNOS activity with IC50 values of 21.0 ± 4 and 6.8 ± 0.1 µM, respectively. The methanolic extract of C. bottae inhibited iNOS with an IC50 of 10.5 ± 0.5 µg/mL.

Assessment of drug-drug interaction of dapagliflozin with LCZ696 based on an LC-MS/MS method.

The co-administration of dapagliflozin (DPF) and sacubitril/valsartan (LCZ696) has emerged as a promising therapeutic approach for managing heart failure. Given that DPF and LCZ696 are substrates for P-glycoprotein, there is a plausible potential for drug-drug interactions when administered concomitantly. To investigate the pharmacokinetic changes when these drugs are co-administered, we have established and validated a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method capable of simultaneously detecting DPF, LBQ657 (the active metabolite of sacubitril) and valsartan in rat plasma. This method has demonstrated selectivity, sensitivity, and accuracy. Drug-drug interactions were examined by the LC-MS/MS method. The mechanisms were investigated using everted intestinal sac models and Caco-2 cells. The results showed that DPF significantly increased the area under the curve (AUC(0-t)) (3,563.3 ± 651.7 vs. 7,146.5 ± 1,714.9 h µg/L) of LBQ657 (the active metabolite of sacubitril) and the AUC(0-t) (24,022.4 ± 6,774.3 vs. 55,728.3 ± 32,446.3 h µg/L) of valsartan after oral co-administration. Dapagliflozin significantly increased the amount of LBQ657 and valsartan in intestinal sacs by 1- and 1.25-fold at 2.25 h. Caco-2 cell uptake studies confirmed that P-glycoprotein is the transporter involved in this interaction. This finding enhances the understanding of drug-drug interactions in the treatment of heart failure and provides a guidence for clinical therapy.

Cost-effectiveness of add-on empagliflozin versus standard of care in management of CKD in Malaysia, Thailand and Vietnam - findings from a modelling study assessing an EMPA-KIDNEY eligible population, using CKD progression model.

BACKGROUND AND OBJECTIVES: Nearly one in ten individuals in South-East Asia are estimated to be affected by chronic kidney disease (CKD). The burden of end-stage kidney disease is significant and can be heavy on the healthcare system. The recent EMPA-KIDNEY trial demonstrated a significant reduction in the risk of kidney disease progression or cardiovascular death in patients with CKD with a broad range of kidney function using add-on empagliflozin versus standard of care (SoC) alone. The objective of this study was to estimate the economic benefit of empagliflozin for patients with CKD in Malaysia, Thailand and Vietnam. METHODS: An individual patient level simulation model with an annual cycle that estimates the progression of kidney function and associated risk-factors was employed. Local costs and mortality rates were estimated from a wide range of published literature. A healthcare perspective was used over a 50-year time horizon. RESULTS: The use of add-on empagliflozin versus SoC alone was found to be cost-saving in Malaysia and Thailand and cost-effective (ICER: 77,838,407 Vietnam Dong/QALY vs. a willingness to pay threshold of 96,890,026/QALY) in Vietnam. The bulk of the costs avoided over a lifetime is derived from the prevention or delay of dialysis initiation or kidney transplant - the cost offsets were nearly twice the additional treatment cost. The results were similar in patients with and without diabetes and across broad range of albuminuria. CONCLUSIONS: The use of add-on empagliflozin in a broad population of patients with CKD is expected to be cost-saving in Malaysia and Thailand and cost-effective in Vietnam and will help alleviate the increasing burden of CKD in the region.

Cost-effectiveness of empagliflozin as add-on to standard of care for chronic kidney disease management in the United Kingdom.

OBJECTIVE: The sodium-glucose co-transporter-2 inhibitor empagliflozin was approved for treatment of adults with chronic kidney disease (CKD) on the basis of its demonstrated ability to slow CKD progression and reduce the risk of cardiovascular death. This analysis was performed to assess the cost-effectiveness of empagliflozin plus standard of care (SoC) vs SoC alone in the treatment of CKD in the UK. METHODS: A comprehensive, patient-level CKD progression model that simulates the evolution of risk factors for disease progression based on CKD-specific equations and clinical data was used to project a broad range of CKD-related complications. Patient baseline characteristics, distribution across Kidney Disease Improving Global Outcomes (KDIGO) health states, and changes in estimated glomerular filtration rate (eGFR), urine albumin-creatinine ratio (uACR), and other parameters while on treatment were derived from the EMPA-KIDNEY trial. UK cost and utilities/disutilities were sourced from the literature. Univariate and probabilistic sensitivity analyses were conducted. Annual discounting of 3.5% was applied on costs and outcomes. RESULTS: Over a 50-year horizon, SoC resulted in per-patient costs, life years, and QALYs of £95,930, 8.55, and 6.28, respectively. Empagliflozin plus SoC resulted in an incremental gain in life years (+1.04) and QALYs (+0.84), while decreasing per-patient costs by £6,019. Empagliflozin was more effective and less costly (dominant) with a net monetary benefit of £22,849 at the willingness-to-pay threshold of £20,000. Although treatment cost was higher for empagliflozin, this was more than offset by savings in kidney replacement therapy. Empagliflozin remained highly cost-effective in patients with and without diabetes, and across scenario and sensitivity analyses. LIMITATIONS: This analysis is limited by reliance on short-term clinical trial data and by uncertainties in modelling CKD progression. CONCLUSIONS: Empagliflozin as an add-on to SoC for treatment of adults with CKD represents cost-effective use of UK National Health Service (NHS) resources.

Assessment on malvidin-3-glucoside interaction with TLR4 via multi-spectroscopic analysis and molecular docking.

As one innate immune pattern recognition receptor, Toll-like receptor 4 (TLR4) recently has been considered as a critical player in glucolipid metabolism. Blueberries contain high level of anthocyanins, especially malvidin-3-glucoside (Mv-3-glc), which contribute the anti-inflammatory, hypoglycemic, and hypolipidemic effects. It is speculated that Mv-3-glc is able to possess these functions by binding to TLR4. Here, the noncovalent interactions of Mv-3-glc and TLR4 was explored through multi-techniques including fluorescence and ultraviolet-visible (UV-Vis) absorption spectroscopy, as well as molecular docking. The results demonstrated that Mv-3-glc was able to quench TLR4 intrinsic fluorescence effectively. A stable complex was formed spontaneously and the reaction was exothermic. The degree of binding of Mv-3-glc to TLR4 showed a strong dependence on the chemical concentration, temperature, and pH values. The negative signs for enthalpy (ΔH = -69.1 ± 10.8 kJ/mol) and entropy (ΔS = -105.0 ± 12.3 J/mol/K) from the interaction of the Mv-3-glc and TLR4 shows that the major driving forces are the hydrogen bonding and van der Waals' force, which is consistent with the molecular docking results. In addition, molecular docking predicted that the active center with specific amino acid residues, Phe126, Ser127, Leu54, Ile153, and Tyr131 was responsible for the site of Mv-3-glc binding to TLR4/myeloid differentiation protein-2 (MD-2). These findings confirmed that Mv-3-glc could bind to TLR4, which would be beneficial to understand the target therapeutic effects of blueberry anthocyanins on TLR4 in regulating glucolipid metabolism.

The national financial burden of guideline directed medical therapy for heart failure patients from 2013 to 2021.

BACKGROUND: Guideline Directed Medical Therapy (GDMT) has been revolutionary in improving outcomes of heart failure patients. However, with the addition of more medication classes, the annual cost of these medications on the US healthcare system needs further evaluation. OBJECTIVES: We aim to evaluate the trend of annual cost of GDMT from 2013 to 2021 using the Medicare-part D Database. METHODS: Using Medicare Part D database (2013-2021), we determined the number of beneficiaries receiving these drugs, the total number of 30-day fills for each medication, and the total annual spending on these medications. Linear regression was used to analyze data using Python Programming Language. P value of less than 0.05 was considered to be statistically significant. RESULTS: The estimated annual Medicare- part D spending on empagliflozin had a 50 % increase in cost between 2020 and 2021, which could be attributed to its FDA approval for heart failure with reduced ejection fraction. Empagliflozin cost Medicare 3.73 billion USD in 2021 alone. In addition, sacubitril-valsartan had a strong trajectory since its introduction to the market in 2015. Since its approval in July 2015, it cost Medicare 4.51 billion USD. The Mineralocorticoid Receptor Antagonist class was the least costly class of GDMT. CONCLUSION: The rise in the cost of GDMT is not proportionate amongst the different classes of GDMT. Newer classes of medications cast a significant cost on Medicare in recent years.

LMD and LC-MS-based chemical constituents and pharmacological effects assessment for two different processing methods of the root of Paeonia lactiflora Pall.

The plant of Paeonia lactiflora Pall. belongs to Ranunculaceae, and its root can be divided into two categories according to different processing methods, which included that one was directly dried without peeling the root of the P. lactiflora (PR), and the other was peeled the root of the P. lactiflora (PPR) after boiled and dried. To evaluate the difference of chemical components, UPLC-ESI-Q-Exactive Focus-MS/MS and UPLC-QQQ-MS were applied. The distribution of chemical components in different tissues was located by laser microdissection (LMD), especially the different ingredients. A total of 86 compounds were identified from PR and PPR. Four kind of tissues were isolated from the fresh root of the P. lactiflora (FPR), and 54 compounds were identified. Especially the content of gallic acid, albiflorin, and paeoniflorin with high biological activities were the highest in the cork, but they were lower in PR than that in PPR, which probably related to the process. To illustrate the difference in pharmacological effects of PR and PPR, the tonifying blood and analgesic effects on mice were investigated, and it was found that the tonifying blood and analgesic effects of PPR was superior to that of PR, even though PR had more constituents. The material basis for tonifying blood and analgesic effect of the root of P. lactiflora is likely to be associated with an increase in constituents such as paeoniflorin and paeoniflorin lactone after boiled and peeled. The study was likely to provide some theoretical support for the standard and clinical application.

Health and economic impact of dapagliflozin for type 2 diabetes patients who had or were at risk for atherosclerotic cardiovascular disease in the Italian general practitioners setting: a budget impact analysis.

AIM: In 2022, in Italy, general practitioners (GPs) have been allowed to prescribe SGLT2i in Type 2 Diabetes (T2D) under National Health Service (NHS) reimbursement. In the pivotal clinical trial named DECLARE-TIMI 58, dapagliflozin reduced the risk of hospitalization for heart failure, CV death and kidney disease progression compared to placebo in a population of T2D patients. This study evaluated the health and economic impact of dapagliflozin for T2D patients who had or were at risk for atherosclerotic cardiovascular disease in the Italian GPs setting. METHODS: A budget impact model was developed to assess the health and economic impact of introducing dapagliflozin in GPs setting. The analysis was conducted by adopting the Italian NHS perspective and a 3-year time horizon. The model estimated and compared the health outcomes and direct medical costs associated with a scenario with dapagliflozin and other antidiabetic therapies available for GPs prescription (scenario B) and a scenario where only other antidiabetic therapies are available (scenario A). Rates of occurrence of cardiovascular and renal complications as well as adverse events were captured from DECLARE-TIMI 58 trial and the literature, while cost data were retrieved from the Italian tariff and the literature. One-way sensitivity analyses were conducted to test the impact of model parameters on the budget impact. RESULTS: The model estimated around 442.000 patients eligible for the treatment with dapagliflozin in the GPs setting for each simulated year. The scenario B compared to scenario A was associated with a reduction in the occurrence of cardiovascular and renal complication (-1.83%) over the 3 years simulated. Furthermore, the scenario A allowed for an overall cost saving of 102,692,305€: 14,521,464€ in the first year, 33,007,064€ in the second and 55,163,777€ in the third. The cost of cost of drug acquisition, the probability of cardiovascular events and the percentage of patients potentially eligible to the treatment were the factor with largest impact on the results. CONCLUSIONS: The use of dapagliflozin in GPs setting reduce the number of CVD events, kidney disease progression and healthcare costs in Italy. These data should be considered to optimize the value produced for the T2D patients who had or were at risk for atherosclerotic cardiovascular disease.

Cost-effectiveness analysis of dapagliflozin for people with chronic kidney disease in Malaysia.

INTRODUCTION: Chronic kidney disease (CKD) is a global health concern which results in significant economic burden. Despite this, treatment options are limited. Recently, dapagliflozin has been reported have benefits in people with CKD. This study aimed to evaluate the cost-effectiveness of dapagliflozin as an add-on to standard of care (SoC) in people with CKD in Malaysia. METHODS: A Markov model was adapted to estimate the economic and clinical benefits of dapagliflozin in people with Stage 2 to 5 CKD. The cost-effectiveness was performed based upon data from the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) trial supplemented with local costs and utility data whenever possible. RESULTS: In Malaysia, dapagliflozin in combination with SoC was the dominant intervention compared to SoC alone (RM 81,814 versus RM 85,464; USD19,762 vs USD20,644). Adding dapagliflozin to SoC in people with CKD increased life expectancy by 0.46 years and increased quality-adjusted life years (QALY) by 0.41 in comparison with SoC alone (10.01 vs. 9.55 years, 8.76 vs. 8.35 QALYs). This translates to a saving of RM8,894 (USD2,148) with every QALY gained. The benefits were due to the delay in CKD progression, resulting in lower costs of dialysis and renal transplantation. Results were robust to variations in assumptions over disease management costs as well as subgroup of population that would be treated and below the accepted willingness-to-pay thresholds of RM 46,000/QALY. CONCLUSION: The use of dapagliflozin was projected to improved life expectancy and quality of life among people with CKD, with a saving RM8,894 (USD2,148) for every quality-adjusted life-year gained and RM7,898 (USD1,908) saving for every life year gained.

Cost-effectiveness of dapagliflozin for patients with heart failure across the spectrum of ejection fraction: A pooled analysis of DAPA-HF and DELIVER data.

AIM: To assess the cost-effectiveness of dapagliflozin in addition to usual care, compared with usual care alone, in a large population of patients with heart failure (HF), spanning the full range of left ventricular ejection fraction (LVEF). METHODS AND RESULTS: Patient-level data were pooled from HF trials (DAPA-HF, DELIVER) to generate a population including HF with reduced, mildly reduced and preserved LVEF, to increase statistical power and enable exploration of interactions among LVEF, renal function and N-terminal pro-B-type natriuretic peptide levels, as they are relevant determinants of health status in this population. Survival and HF recurrent event risk equations were derived and applied to a lifetime horizon Markov model with health states defined by Kansas City Cardiomyopathy Questionnaire total symptom score quartiles; costs and utilities were in the UK setting. The base case incremental cost-effectiveness ratio (ICER) was £6470 per quality-adjusted life year (QALY) gained, well below the UK willingness-to-pay (WTP) threshold of £20 000/QALY gained. In interaction sensitivity analyses, the highest ICER was observed for elderly patients with preserved LVEF (£16 624/QALY gained), and ranged to a region of dominance (increased QALYs, decreased costs) for patients with poorer renal function and reduced/mildly reduced LVEF. Results across the patient characteristic interaction plane were mostly between £5000 and £10 000/QALY gained. CONCLUSIONS: Dapagliflozin plus usual care, versus usual care alone, yielded results well below the WTP threshold for the UK across a heterogeneous population of patients with HF including the full spectrum of LVEF, and is likely a cost-effective intervention.

A cost-effectiveness analysis of empagliflozin for heart failure patients across the full spectrum of ejection fraction in Spain: combined results of the EMPEROR-Preserved and EMPEROR-Reduced trials.

BACKGROUND: Heart failure (HF) is a chronic condition with considerable clinical burden for patients and economic burden for healthcare systems. Treatment for HF is typically based on ejection fraction (EF) phenotype. The cost-effectiveness of empagliflozin + standard of care (SoC) compared to SoC has been examined for HF phenotypes below or above 40% EF separately, but not across the full spectrum of EF in Spain. METHODS: The results of two preexisting, validated, and published phenotype-specific Markov cohort models were combined using a population-weighted approach, reflecting the incidence of each phenotype in the total HF population in Spain. A probabilistic sensitivity analysis was performed by sampling each model's probabilistic results. RESULTS: Empagliflozin + SoC compared to SoC resulted in increased life-years (LYs) (6.48 vs. 6.35), quality-adjusted LYs (QALYs) (4.80 vs. 4.63), and healthcare costs (€19,090 vs. €18,246), over a lifetime time horizon for the combined HF population in Spain. The incremental cost-effectiveness ratio (ICER) was €5,089/QALY. All subgroup, scenario, and probabilistic ICERs were consistently below €10,000/QALY. CONCLUSIONS: Empagliflozin is the first treatment with established efficacy and cost-effectiveness for HF patients across EF from the perspective of healthcare payers in Spain. Empagliflozin also proved to be cost-effective for all subgroups of patients included in the analysis.

Eligibility and Cost-Utility Analysis of Dapagliflozin in Patients with Heart Failure Across the Whole Spectrum of Ejection Fraction in South Korea.

BACKGROUND: The DAPA-HF and DELIVER trials demonstrated the clinical benefits of dapagliflozin in heart failure (HF) patients across the entire ejection fraction (EF) spectrum. However, further investigation is needed for the real-world application of dapagliflozin in HF patients. This study examines the proportion of real-world HF patients eligible for dapagliflozin and evaluates the cost-effectiveness of adding dapagliflozin to current HF therapy. METHODS: Data from the nationwide prospective registry, the Korean Acute Heart Failure (KorAHF) registry, were used to determine dapagliflozin eligibility based on the enrollment criteria of the DAPA-HF/DELIVER trials. A cost-utility analysis was conducted using a Markov model to assess the cost-effectiveness of dapagliflozin by comparing it to the standard of care. RESULTS: Out of 5178 KorAHF patients, 48.7% met the enrollment criteria of the DAPA-HF/DELIVER trials, while 89.5% met the label criteria (US Food and Drug Administration, European Medicines Agency, and Korean Ministry of Food and Drug Safety). Eligibility was highest among HF patients with preserved EF (55.3% vs. HF with mildly reduced EF and HF with reduced EF 46.4%). Dapagliflozin proved to be cost-effective, with an incremental cost-effectiveness ratio (ICER) of 4557 US dollar (US$) per quality-adjusted life year, which falls below the US$18,182 willingness-to-pay threshold. The cost-effectiveness benefit was more pronounced in patients with a left ventricular EF (LVEF) ≤ 40% (ICER US$3279 for LVEF ≤ 40% vs. US$8383 for LVEF > 40%). CONCLUSIONS: Discrepancies in dapagliflozin eligibility were observed between real-world data and clinical trial results. The addition of dapagliflozin to HF therapy proved to be highly cost-effective across the entire EF spectrum.

Cost­effectiveness of add­on dapagliflozin for heart failure with reduced ejection fraction patients without diabetes.

AIM: To evaluate the cost-effectiveness of dapagliflozin added to standard of care (SoC) versus SoC in heart failure with reduced ejection fraction (HFrEF) and without type 2 diabetes mellitus (T2DM) patients from the Qatari healthcare perspective. MATERIALS AND METHODS: A lifetime Markov model was developed to evaluate the cost-effectiveness of adding dapagliflozin to SoC based on the findings of Petrie et al. 2020, which were based on the DAPA-HF trial. The model was constructed based on four health states: "alive with no event", "urgent visit for heart failure", "hospitalization for heart failure", and "dead". The model considered 1,000 hypothetical HFrEF and without T2DM patients using 3-month cycles over a lifetime horizon. The outcome of interest was the incremental cost-effectiveness ratio (ICER) per quality-adjusted life-year gained (QALY) and years of life lived (YLL). Utility and cost data were obtained from published sources. A scenario analysis was performed to replace the transition probabilities of events in people without T2DM with the transition probabilities of events irrespective of T2DM status, based on findings of the DAPA-HF trial. Sensitivity analyses were conducted to confirm the robustness of the conclusion. RESULTS: Adding dapagliflozin to SoC was estimated to dominate SoC alone, resulting in 0.6 QALY and 0.8 YLL, at a cost saving of QAR771 (USD211) per person compared with SoC alone, with total healthcare costs of QAR42,413 (USD 11,620) versus 43,184 (USD11,831) per person, respectively. When replacing the transition probabilities of events in people without T2DM with the transition probabilities of events in people irrespective of T2DM status, dapagliflozin was cost-effective at ICER of QAR5,212 (USD1,428) per QALY gained and QAR3,880 (USD1,063) per YLL. In the probabilistic sensitivity analysis, dapagliflozin combined with SoC was cost saving in over 49% of the cases and cost-effective in over 43% of the simulated cases against QALYs gained and YLL. LIMITATIONS: Data from clinical trials were used instead of local data, which may limit the local relevance. However, evidence from the local Qatari population is lacking. Also, indirect costs were not included due to a paucity of available data. CONCLUSIONS: Adding dapagliflozin to SoC is likely to be a cost-saving therapy for patients with HFrEF and without T2DM in Qatar.

Heart failure with reduced ejection fraction is a type of heart failure characterized by left ventricular ejection fraction of 40% or less. Dapagliflozin is a novel therapy for this condition, which was initially designed to treat type 2 diabetes mellitus. It is unclear whether dapagliflozin is a cost-effective option for patients with heart failure with reduced ejection fraction and without type 2 diabetes. A lifetime Markov model was developed to evaluate the cost-effectiveness of adding dapagliflozin to standard of care from the Qatari healthcare perspective. Model results suggest that adding dapagliflozin to standard of care dominated standard of care alone, resulting in a gain of 0.8 years of life lived, a gain of 0.6 quality-adjusted life-years, and a cost saving of 211 United States dollars per person.

Cost-Effectiveness Analysis of Empagliflozin for Treatment of Patients With Heart Failure With Reduced Ejection Fraction in the United States.

BACKGROUND: In the EMPEROR-Reduced trial (Empagliflozin Outcome Trial in Patients with Chronic Heart Failure and a Reduced Ejection Fraction), empagliflozin plus standard of care reduced the composite of cardiovascular death or hospitalization for heart failure versus standard of care in adults with heart failure with reduced ejection fraction. This analysis investigated the cost-effectiveness of the 2 regimens from the perspective of US payors. METHODS AND RESULTS: A Markov cohort model was developed based on Kansas City Cardiomyopathy Questionnaire Clinical Summary Score quartiles and death. Transition probabilities between health states, risk of cardiovascular/all-cause death, hospitalization for heart failure and adverse events, treatment discontinuation, and health utilities were estimated from trial data. Medicare and commercial payment rates were combined for treatment acquisition, acute event management, and disease management. An annual discount rate of 3% was used. Empagliflozin plus standard of care yielded 18% fewer hospitalizations for heart failure and 6% fewer deaths versus standard of care over a lifetime, providing cost-offsets while adding 0.19 life years and 0.19 quality-adjusted life years at an incremental cost of $16 815/patient. The incremental cost-effectiveness ratio was $87 725/quality-adjusted life years gained. Results were consistent across payors, subpopulations, and in deterministic sensitivity analyses. In probabilistic sensitivity analyses, empagliflozin plus standard of care was cost-effective in 3%, 62%, and 80% of iterations at thresholds of $50 000, $100 000, and $150 000/quality-adjusted life years. CONCLUSIONS: Empagliflozin plus standard of care may prevent hospitalizations for heart failure, extend life, and increase quality-adjusted life years for patients with heart failure with reduced ejection fraction at an acceptable cost for US payors.

Cardiorenal effectiveness of empagliflozin vs. glucagon-like peptide-1 receptor agonists: final-year results from the EMPRISE study.

BACKGROUND: No randomized clinical trials have directly compared the cardiorenal effectiveness of empagliflozin and GLP-1RA agents with demonstrated cardioprotective effects in patients with a broad spectrum of cardiovascular risk. We reported the final-year results of the EMPRISE study, a monitoring program designed to evaluate the cardiorenal effectiveness of empagliflozin across broad patient subgroups. METHODS: We identified patients ≥ 18 years old with type 2 diabetes who initiated empagliflozin or GLP-1RA from 2014 to 2019 using US Medicare and commercial claims databases. After 1:1 propensity score matching using 143 baseline characteristics, we evaluated risks of outcomes including myocardial infarction (MI) or stroke, hospitalization for heart failure (HHF), major adverse cardiovascular events (MACE - MI, stroke, or cardiovascular mortality), a composite of HHF or cardiovascular mortality, and progression to end-stage kidney disease (ESKD) (in patients with chronic kidney disease stages 3-4). We estimated hazard ratios (HR) and rate differences (RD) per 1,000 person-years, overall and within subgroups of age, sex, baseline atherosclerotic cardiovascular disease (ASCVD), and heart failure (HF). RESULTS: We identified 141,541 matched pairs. Compared with GLP-1RA, empagliflozin was associated with similar risks of MI or stroke [HR: 0.99 (0.92, 1.07); RD: -0.23 (-1.25, 0.79)], and lower risks of HHF [HR: 0.50 (0.44, 0.56); RD: -2.28 (-2.98, -1.59)], MACE [HR: 0.90 (0.82, 0.99); RD: -2.54 (-4.76, -0.32)], cardiovascular mortality or HHF [HR: 0.77 (0.69, 0.86); RD: -4.11 (-5.95, -2.29)], and ESKD [0.75 (0.60, 0.94); RD: -6.77 (-11.97, -1.61)]. Absolute risk reductions were larger in older patients and in those with baseline ASCVD/HF. They did not differ by sex. CONCLUSIONS: The cardiovascular benefits of empagliflozin vs. cardioprotective GLP-1RA agents were larger in older patients and in patients with history of ASCVD or HF, while they did not differ by sex. In patients with advanced CKD, empagliflozin was associated with risk reductions of progression to ESKD.

Cost Effectiveness of Dapagliflozin for Heart Failure Across the Spectrum of Ejection Fraction: An Economic Evaluation Based on Pooled, Individual Participant Data From the DELIVER and DAPA-HF Trials.

BACKGROUND: The sodium glucose cotransporter-2 inhibitors are guideline-recommended to treat heart failure across the spectrum of left ventricular ejection fraction; however, economic evaluations of adding sodium glucose cotransporter-2 inhibitors to standard of care in chronic heart failure across a broad left ventricular ejection fraction range are lacking. METHODS AND RESULTS: We conducted a US-based cost-effectiveness analysis of dapagliflozin added to standard of care in a chronic heart failure population using pooled, participant data from the DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) and DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure) trials. The 3-state Markov model used estimates of transitional probabilities, effectiveness of dapagliflozin, and utilities from the pooled trials. Costs estimates were obtained from published sources, including published rebates in dapagliflozin cost. Adding dapagliflozin to standard of care was estimated to produce an additional 0.53 quality-adjusted life years (QALYs) compared with standard of care alone. Incremental cost effectiveness ratios were $85 554/QALY when using the publicly reported full (undiscounted) Medicare cost ($515/month) and $40 081/QALY, at a published nearly 50% rebate ($263/month). The addition of dapagliflozin to standard of care would be of at least intermediate value (<$150 000/QALY) at a cost of <$872.58/month, of high value (<$50 000/QALY) at <$317.66/month, and cost saving at <$40.25/month. Dapagliflozin was of at least intermediate value in 92% of simulations when using the full (undiscounted) Medicare list cost in probabilistic sensitivity analyses. Cost effectiveness was most sensitive to the dapagliflozin cost and the effect on cardiovascular death. CONCLUSIONS: The addition of dapagliflozin to standard of care in patients with heart failure across the spectrum of ejection fraction was at least of intermediate value at the undiscounted Medicare cost and may be potentially of higher value on the basis of the level of discount, rebates, and price negotiations offered. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifiers: NCT01035255 & NCT01920711.

Repurposing empagliflozin in individuals with glycogen storage disease Ib: A value-based healthcare approach and systematic benefit-risk assessment.

Off-label repurposing of empagliflozin allows pathomechanism-based treatment of neutropenia/neutrophil-dysfunction in glycogen storage disease type Ib (GSDIb). From a value-based healthcare (VBHC) perspective, we here retrospectively studied patient-reported, clinical and pharmacoeconomic outcomes in 11 GSDIb individuals before and under empagliflozin at two centers (the Netherlands [NL], Austria [AT]), including a budget impact analysis, sensitivity-analysis, and systematic benefit-risk assessment. Under empagliflozin, all GSDIb individuals reported improved quality-of-life-scores. Neutrophil dysfunction related symptoms allowed either granulocyte colony-stimulating factor cessation or tapering. Calculated cost savings per patient per year ranged between € 6482-14 190 (NL) and € 1281-41 231 (AT). The budget impact analysis estimated annual total cost savings ranging between € 75 062-225 716 (NL) and € 37 697-231 790 (AT), based on conservative assumptions. The systematic benefit-risk assessment was favorable. From a VBHC perspective, empagliflozin treatment in GSDIb improved personal and clinical outcomes while saving costs, thereby creating value at multiple pillars. We emphasize the importance to reimburse empagliflozin for GSDIb individuals, further supported by the favorable systematic benefit-risk assessment. These observations in similar directions in two countries/health care systems strongly suggest that our findings can be extrapolated to other geographical areas and health care systems.