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Cost‐effectiveness of second‐line empagliflozin versus liraglutide for type 2 diabetes in the United States

Abstract Aim To estimate the cost‐effectiveness of sequential use of the sodium‐glucose co‐transporter‐2 inhibitor empagliflozin and glucagon‐like peptide‐1 receptor agonist liraglutide after metformin in patients with type 2 diabetes (T2D) from the US payer perspective. Materials and Methods An economic simulation model with a lifetime horizon was developed to estimate T2D‐related complications (including cardiovascular [CV] death, myocardial infarction, stroke, and renal outcomes) using EMPA‐REG OUTCOME data or UK Prospective Diabetes Study risk equations, in patients with or without a history of cardiovascular disease (CVD), respectively. Evidence synthesis methods were used to provide effectiveness inputs for empagliflozin and liraglutide. Population characteristics, adverse event rates, treatment escalation, costs ($2019), and utilities (both discounted 3%/year) were taken from US sources. Results Compared with second‐line liraglutide in the overall T2D population, second‐line empagliflozin was dominant as it was associated with lower total lifetime cost ($11 244/patient less) and resulted in a quality‐adjusted life‐year (QALY) gain (0.32/patient). Second‐line empagliflozin was associated with reductions in CV death (by 5%) and lower cumulative complication rates in patients with CVD (by 2%), relative to second‐line liraglutide. These findings were consistent among patients with co‐morbid CVD, with gains in incremental QALYs (0.43/patient) and lower lifetime cost (by $10 175/patient) relative to second‐line liraglutide. Scenario analyses consistently showed dominance for second‐line empagliflozin. Conclusion For patients with T2D, use of second‐line empagliflozin combined with metformin was a dominant strategy for US payers, associated with extended survival, improved QALYs, and lower costs compared with second‐line liraglutide.


| INTRODUCTION
Type 2 diabetes (T2D) is a leading cause of premature morbidity and mortality in the adult population within the United States (US). 1 Alone, or combined with risk factors (e.g. high blood glucose, overweight/ obesity, and high blood pressure), patients with T2D are at a high risk of microvascular and macrovascular complications, including cardiovascular disease (CVD), kidney disease, blindness, and lower-limb Clinical trials do not capture the potential sequences of therapies that physicians could recommend in real-world practice, and there is a lack of published data documenting the economic implications of sequential use of these therapies to ensure healthcare decision-makers recommend therapies that bring value to patients, healthcare systems, and payers. This analysis estimated the costeffectiveness of adding empagliflozin as a second-line agent followed by liraglutide as third line compared with liraglutide as a second-line agent followed by empagliflozin as third line, in patients with T2D from the US payer perspective. A counterfactual comparison of projected lifetime health outcomes and costs of these two treatment pathways was performed, where the main difference was the drug added as second-line therapy, to understand the costs and benefits of initiating empagliflozin earlier in the treatment pathway rather than later. By combining clinical trial data and economic modelling methods, this study contributes a novel analysis of two alternative treatment escalation pathways in T2D that have not been directly compared in clinical research, focusing on long-term patient outcomes and direct medical costs for US payers. This study was conducted using a previously published model for the United States that assessed sequential treatment with second-line empagliflozin versus sitagliptin, with appropriate modifications to reflect clinical efficacy, drug adverse events (AEs), health-related quality of life (QoL), and costs with liraglutide. 6 2 | MATERIALS AND METHODS clinical event history, using a 3% annual discount rate for costs and QALYs as recommended for US cost-effectiveness analysis. 8 The

| Treatment initiation
Treatment initiation was based on a mean rate of initiations for third-line   Table SM2). These parameters were derived from an indirect treatment comparison (ITC) performed in a network meta-analysis, in which the relative clinical efficacy of treatment was compared with placebo in adult patients with T2D who were inadequately controlled with metformin (Appendix S1). The model considered treatment effects during the first year of treatment and assumed that patients progressed subsequently according to the UKPDS Outcomes Model 1 (UKPDS-OM1) 11 equations for evolving risk factors. The efficacy of these treatments as third-line therapy was assumed to be the same as for second-line therapy.

| Clinical and treatment efficacy inputs
In patients with CVD, published event-free survival (EFS) curves developed from EMPA-REG OUTCOME CVOT data were applied to estimate the time to non-fatal MI, non-fatal stroke, HF, UA, TIA, revascularization, macroalbuminuria, renal injury, renal failure, and CV death using baseline (i.e. at the time CVD is established) and time-dependent covariates. 12 These complications were defined as reported by Kansal et al. 12 The shape of the EFS curves were assumed to implicitly capture HbA1c and other evolving risk factors that contribute to changing rates of complications and disease progression over time. Thus, the treatment benefit of glycaemic control was not directly modelled in patients with CVD. The equations were supplemented with non-CV death according to US age-and sex-adjusted life table data. 13 Time to each T2D-related complication was estimated with empagliflozin treatment as a covariate to capture efficacy shown in the EMPA-REG OUTCOME CVOT. The relative clinical efficacy of liraglutide was taken from an ITC, 14 in which liraglutide was compared with empagliflozin in treating adult patients with T2D and established CVD based on EMPA-REG OUTCOME and published LEADER CVOT data. A hazard ratio (HR) for liraglutide versus empagliflozin on each complication except UA, TIA, and revascularization was obtained (Table SA1). 14 Data on these complications were not available from the LEADER CVOT publication, 5 therefore risks were assumed to be similar to the placebo arm of the EMPA-REG OUTCOME CVOT. The HRs were applied to the EFS functions for empagliflozin to estimate outcomes among simulated patients treated with liraglutide.

Risks of treatment-related AEs for empagliflozin and liraglutide
were based on US prescribing labels; AEs with 5% or more incidence or key adverse reactions were selected, specifically urinary tract infection, genital mycotic infection, nausea, hypoglycaemia, and injection site reaction. 15,16 AE occurrence was assumed to be mutually exclusive and not impact treatment use.

| Utility inputs
Utility scores that captured the QoL of modelled patients with different health status were used to adjust survival and estimate QALYs (- Table SA2). Utility values were sourced from published literature and the algorithm developed by Sullivan and Ghushchyan 17 was used (Appendix S1). The same study reported US-specific values for patient utility at baseline and disutilities for most clinical events. 17 Other  (Tables SA6 and SA7).
Costs for the overall population were estimated by weighting costs for a commercially-insured (55% <65 years of age) and Medicare (45% ≥65 years of age) payer. Refer to Appendix S1 for additional details.  Tables SA1, SA2, SA5, and SA7.

| Model validation and verification
Model validation and verification included evaluation of face validity, technical validity, and predictive validity. The validation approach and results are provided in Tables SA8 and SA9; Appendix S1.

| Base case results
Base case results are shown in Table 1

| Sensitivity analyses results
In DSA, all scenarios showed that second-line empagliflozin provides QALY improvement with cost savings compared with second-line liraglutide ( Figure 2). Empagliflozin also provides survival benefits at  Figure S2A).

| Scenario analyses results
The results of scenario analyses are shown in Table 2 The strengths of the model include that outcomes in patients with CVD were based on hard endpoint data from CVOTs to more accurately capture observed CV event rates. Furthermore, analyses were based on US-specific inputs for the population, non-CV death rates, treatment escalation rates, utilities, and costs.
The model included several assumptions. The occurrence of diabetes-related complications estimated from the UKPDS data was assumed to reflect rates observed in T2D patients without CVD in the United States. As the UKPDS-OM2 equations have been broadly used in diverse T2D populations worldwide, the applicability of these equations to a US population without CVD is reasonable. 38 Next, the treatment effect of liraglutide on revascularization, UA, and TIA in patients with CVD was assumed to be similar to the placebo arm in the EMPA-REG OUTCOME CVOT, because the LEADER CVOT publication did not report treatment benefit on these outcomes. This was challenged in sensitivity analyses by assuming: (a) liraglutide had the same effect as empagliflozin on these outcomes; and (b) the effect of UA and revascularization to be the same as MI, and the effect of TIA to be the same as stroke. Results were insensitive to this assumption.

PEER REVIEW
The peer review history for this article is available at https://publons. com/publon/10.1111/dom.14625.

DATA AVAILABILITY STATEMENT
Our study data (which is based on de-identified data from a clinical trial) is not in a repository, but is available upon reasonable request from the corresponding author.