ORIGINAL RESEARCH

Long-Term Cost-Effectiveness Analysesof Empagliflozin Versus Oral Semaglutide, in Additionto Metformin, for the Treatment of Type 2 Diabetesin the UK

Mafalda Ramos . Michael H. Cummings . Anastasia Ustyugova .

Syed I. Raza . Shamika U. de Silva . Mark Lamotte

Received: June 5, 2020 / Published online: July 22, 2020� The Author(s) 2020

ABSTRACT

Introduction: International guidelines recom-mend treatment with a sodium-glucosecotransporter-2 (SGLT-2) inhibitor or glucagon-like peptide-1 (GLP-1) receptor agonist fortreatment intensification in type 2 diabetesmellitus (T2DM) patients with progression onmetformin. In the randomised, controlled,

Peptide Innovation for Early Diabetes Treat-ment (PIONEER) 2 trial, the SGLT-2 inhibitorempagliflozin was compared with the GLP-1receptor agonist oral semaglutide, in addition tometformin. The aim of the current study was toassess the long-term cost-effectiveness ofempagliflozin 25 mg versus oral semaglutide14 mg, in addition to metformin, for T2DMpatients in the UK.Methods: Analyses were conducted from theUK healthcare payer perspective, using theIQVIA Core Diabetes model, with a time hori-zon of 50 years. Patients received either empa-gliflozin or oral semaglutide, in addition tometformin, until Hba1c threshold of 7.5%(58 mmol/mol) was exceeded, following whichtreatment intensification with insulin glarginein addition to empagliflozin or oral semaglutideplus metformin was assumed. Baseline cohortcharacteristics and 52-week treatment effectswere derived from the PIONEER 2 trial. Treat-ment effects of empagliflozin and GLP-1 recep-tor agonists on hospitalisation for heart failure(hHF) were based on the Empagliflozin Com-parative Effectiveness and Safety (EMPRISE)real-world study. Utilities, treatment costs andcosts of diabetes-related complications wereobtained from published sources.Results: Direct costs for empagliflozin plusmetformin were considerably lower than thosefor oral semaglutide plus metformin (by morethan GBP 6000). Compared with oral semaglu-tide plus metformin, empagliflozin plus

Digital Features To view digital features for this articlego to https://doi.org/10.6084/m9.figshare.12630701.

Electronic supplementary material The onlineversion of this article (https://doi.org/10.1007/s13300-020-00883-1) contains supplementary material, which isavailable to authorized users.

M. RamosGlobal HEOR/Real World Solutions, IQVIA,2740-266 Porto Salvo, Portugal

M. H. CummingsAcademic Department of Diabetes andEndocrinology, Queen Alexandra Hospital,Portsmouth PO6 3LY, Hampshire, UK

A. UstyugovaBoehringer Ingelheim International GmbH,55216 Ingelheim Am Rhein, Germany

S. I. Raza � S. U. de SilvaBoehringer Ingelheim Ltd., Bracknell RG12 8YS,Berkshire, UK

M. Lamotte (&)Global HEOR/Real World Solutions, IQVIA,1930 Zaventem, Belgiume-mail: Mark.lamotte@iqvia.com

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https://doi.org/10.1007/s13300-020-00883-1

metformin was a cost-effective treatment forT2DM patients in all scenarios tested. Proba-bilistic sensitivity analysis showed cost-effec-tiveness in [ 95% of the iterations using athreshold of 20,000 GBP/QALY.Conclusion: Empagliflozin 25 mg is a cost-ef-fective treatment option versus oral semaglutide14 mg, when used in addition to metformin, forthe treatment of T2DM patients in the UK.

Keywords: Costs and cost analysis; Cost-effectiveness; Diabetes mellitus; Empagliflozin;GLP-1 receptor agonists; Oral semaglutide;SGLT-2 inhibitors; Treatment intensification;United Kingdom

Key Summary Points

Why carry out this study?

Clinical guidelines recommend treatmentwith a sodium-glucose cotransporter-2(SGLT-2) inhibitor or a glucagon-likepeptide-1 (GLP-1) receptor agonist in type2 diabetes mellitus (T2DM) patients withestablished cardiovascular disease.

As treatment with SGLT-2 inhibitors orGLP-1 receptor agonists, in addition tometformin, are to be continued lifelong, itis important to understand the long-termcost-effectiveness of these therapies forT2DM treatment.

An analysis of the long-term cost-effectiveness of treatment withempagliflozin 25 mg versus oralsemaglutide 14 mg, in addition tometformin, was performed for T2DMpatients in the UK setting, including thosewith hospitalisation for heart failure(hhF).

What was learned from the study?

Empagliflozin 25 mg is a cost-effectivetreatment option versus oral semaglutide14 mg, when used in addition tometformin, for the treatment of T2DMpatients in the UK.

Empagliflozin plus metformin wasdominant (less costly and generated morehealth gains) to oral semaglutide plusmetformin in the treatment of T2DMpatients with hHF.

INTRODUCTION

Management of type 2 diabetes mellitus(T2DM) is associated with considerable burdento the health care system in the UK, estimatedto cost £10 billion each year [1]. Hypoglycaemicepisodes, diabetes-related complications andcomorbidities contribute to reduced health-re-lated quality of life (HRQL) and increasedhealth care resource utilisation and costs inpatients with T2DM [2]. Inadequate glycaemiccontrol is associated with the development ofmacrovascular complications (coronary ischae-mia, stroke, myocardial infarction [MI] andangina pectoris) [3] and microvascular compli-cations (e.g. retinopathy, nephropathy andneuropathy) [2]. T2DM patients have a two- tofour-fold increased risk of cardiovascular disease(CVD) compared with a nondiabetic popula-tion, and more than half die from CVD com-plications [4, 5]. By reducing adverse outcomes,effective diabetes management providing evenmodest improvements in glycaemic control canachieve considerable cost savings [3, 6].

Since 2008, based on US Food and DrugAdministration recommendations, any newT2DM therapy must demonstrate that it is notassociated with an unacceptable increase incardiovascular risk, which has led to severalcardiovascular outcomes trials (CVOTs) [7].Many studies have demonstrated that the trialtherapy does not result in an unacceptable in-crease in cardiovascular risk such as major car-diovascular events (MACE) and all-causemortality [7]. Additionally, treatments with thesodium-glucose cotransporter-2 (SGLT-2) inhi-bitor class of glucose-lowering agents togetherwith standard of care have shown a significantreduction in MACE in a number of meta-anal-yses of CVOT trials in patients with T2DM[8–11]. Tang et al. in 2016 [12] conducted a

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meta-analysis including 37 trials and 29,859patients with T2DM, comparing canagliflozin,dapagliflozin and empagliflozin with placeboand other glucose-lowering treatments. Onlyempagliflozin was associated with a signifi-cantly lower risk of MACE compared with pla-cebo [odds ratio (OR): 0.81; 95% CI: 0.70–0.93][12]. Real-world data from the EMPRISE (Em-pagliflozin Comparative Effectiveness andSafety) study [13] has shown that empagliflozinis associated with reduced hospitalisation forheart failure (hHF) compared with dipeptidylpeptidase 4 (DPP-4) and glucagon-like peptide-1(GLP-1) receptor agonists.

The aim of T2DM treatment is to achieveglycaemic control according to individualisedhaemoglobin A1C (HbA1c) targets, initiallyusing metformin together with lifestyle inter-ventions. As T2DM is a chronic, progressivecondition, most patients ultimately requireintensification of treatment to maintain gly-caemic control [14]. Timely intensification oftreatment is important to avoid exposure ofpatients to chronic elevations of HbA1c thatmay increase the risk of diabetes-related com-plications and long-term healthcare costs[15, 16]. When glycaemic control is no longerachieved with metformin alone, dual therapywith glucose-lowering agents is recommendedtaking into consideration the clinical charac-teristics of the patient, according to the con-sensus guidelines of the American DiabetesAssociation (ADA) and the European Associa-tion for the Study of Diabetes (EASD) [17].Established CVD is considered a compellingindication for treatment with an SGLT-2 inhi-bitor or GLP-1 receptor. The guidelines furtherstate that the decision to treat appropriate high-risk individuals to reduce MACE, hHF, cardio-vascular death or chronic kidney disease (CKD)progression should be considered indepen-dently of baseline HbA1c or individualisedHbA1c target [17]. In the UK, the NationalInstitute for Health and Care Excellence (NICE)recommends SGLT-2 inhibitors such as empa-gliflozin for the treatment of T2DM, in combi-nation with insulin with or without otherglucose-lowering drugs, or in triple regimens incombination with metformin [18]. GLP-1receptor agonists are recommended for patients

who require subsequent treatment intensifica-tion and for whom insulin therapy would havesignificant occupational implications or forwhom weight loss would benefit other obesity-related comorbidities [19].

However, it can be envisaged that NICE rec-ommendations could be adapted in the nearfuture, based on the recent ADA/EASD recom-mendations. Thus, providing results of a cost-effectiveness analyses that compares an SGLT-2inhibitor and a GLP-1 receptor agonist can be ofinterest for the payer.

Oral semaglutide is a new formulation of theGLP-1 receptor agonist semaglutide developedfor once-daily oral administration [20–22]. Theefficacy and safety of oral semaglutide wasassessed in the Peptide Innovation for EarlyDiabetes Treatment (PIONEER) trial programme[23], including a comparison versus once-dailyempagliflozin (PIONEER 2 trial) [22]. As thereare only few direct clinical comparisons avail-able between a SGLT-2 inhibitor and a GLP-1receptor agonist, it seemed of interest to use thisPIONEER 2 trial as the basis for a cost-effec-tiveness analysis.

The objective of the current study was toevaluate the long-term cost-effectiveness oftimely initiation of treatment with empagli-flozin 25 mg versus oral semaglutide 14 mg, inaddition to metformin, for T2DM patients inthe UK. Separate scenarios were modelledincorporating the treatment effect on hHF.

METHODS

Modelling Approach

Using the IQVIA Core Diabetes Model (CDM)version 9.5, long-term projections of clinicaland cost outcomes were performed from the UKNational Health Service perspective. CDM is aproprietary, interactive, internet-based, com-puter simulation model developed to determinethe long-term health outcomes and economicimplications of therapeutic interventions fortype 1 and type 2 diabetes. The CDM and itsvalidation studies have been previously descri-bed [24–26].

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Projected outcomes include incidence ofcomplications, rates of clinical events, perpatient costs, life-years gained and quality-ad-justed life-years (QALYs) gained, over a lifelongtime horizon (up to 50 years). Cost-effectivenesswas described in terms of: the incremental cost-utility ratio (ICUR), which is the cost per addi-tional unit of QALY gained for the interventionversus the alternative; the net monetary benefit(NMB), which represents the value of an inter-vention in monetary terms when a willingness-to-pay (WTP) threshold for a unit of benefit isknown. Both costs and effects were discountedby 3.5% annually, in line with the NICE refer-ence case [27].

Two main scenarios were examined in themodelling analyses: treatment benefit on riskfactors, e.g. HbA1c, body-mass index (BMI) andblood pressure; potential hHF treatment benefitof empagliflozin.

Clinical Data

The cost-effectiveness analysis is based on theefficacy results of the PIONEER 2 study, whichenrolled T2DM patients with HbA1c valuesbetween 7.0 and 10.5% (53–91 mmol/mol),who were treated with metformin. Hence, thebaseline characteristics incorporated in themodel are the reported weighted average of thebaseline cohort from the published clinical trial[22] or cost-effectiveness analyses [20]. BaselineCVD and microvascular complications werebased on cohort data from other studies thatenrolled a similar patient population (Supple-mentary material Table S1).

The effects of each of the drugs on HbA1c,systolic blood pressure (SBP), diastolic bloodpressure (DBP), total cholesterol, HDL-choles-terol and BMI (Table 1), as well as on hypogly-caemia rates (Table 2), were as reported in thePIONEER-2 study [20, 22] and were alsoobtained from the PIONEER-2 study [22]. In the

Table 1 Treatment effects applied in the analysis

Empagliflozin (SE) Oral semaglutide (SE) Source

Change in baseline HbA1c, % - 0.90 (0.026) - 1.30 (0.026) Rodbard et al. 2019 [22]

SBP change from baseline, mmHg - 4.34 (0.63) - 4.85 (0.65) Bain et al. 2020 [20]

DBP change from baseline, mmHg - 2.67 (0.44) - 2.27 (0.45) Bain et al. 2020 [20]

Total cholesterol change from baseline, mg/dl 4.74 (1.57) - 5.08 (1.62) Bain et al. 2020 [20]

HDL cholesterol change from baseline, mg/dl 3.11 (0.34) 0.73 (0.35) Bain et al. 2020 [20]

BMI change from baseline, kg/m2 - 1.294 (0.028) - 1.357 (0.028) Rodbard et al. 2019 [22]

For the base case analysis, results based on the treatment estimand of the PIONEER 2 study were usedBMI body mass index, DBP diastolic blood pressure, HbA1c haemoglobin A1c, HDL high-density lipoprotein, SBP systolicblood pressure, SE standard error

Table 2 Adverse events applied in the analysis

Empagliflozin Oral semaglutide Source

NSHE rate, per 100 patient–years 9.535 10.976 Rodbard et al. 2019 [22]

SHE1 rate, per 100 patient–years 0.244 0.244 Rodbard et al. 2019 [22]

SHE2 rate, patient–years 0 0 Rodbard et al. 2019 [22]

NSHE non-severe hypoglycaemia rate, SHE1 severe hypoglycaemia rate (not requiring medical assistance), SHE2 severehypoglycaemia rate (requiring medical assistance)

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PIONEER 2 study, efficacy was assessed in thecontext of two estimands: treatment policy andtrial product. The treatment policy estimandevaluated the treatment effect for all ran-domised patients, regardless of trial productdiscontinuation or use of rescue medication(intention-to-treat principle). The trial productestimand evaluated the treatment effect for allrandomised patients under the assumption thatall patients remained on trial product for theentire planned duration of the trial and did notuse rescue medication, thus reflecting the effectof oral semaglutide compared with empagli-flozin without the confounding effect of rescuemedication [22]. In the current cost-effective-ness analysis, the data from the treatment pol-icy estimand were used for treatment effects.Additional analyses were performed using thedata on treatment effects from the trial productestimand (Supplementary material Table S2).

Treatment Intensification and Long-TermDisease Progression

Disease progression may be observed as a rise inHbA1c while on the same drug regimen,requiring intensification of therapy in order toregain glycaemic control [28]. Patients wereassumed to receive either empagliflozin or oralsemaglutide, in addition to metformin, untilHba1c of 7.5% (58 mmol/mol) was exceeded;this is the threshold for treatment intensifica-tion, defined in the NICE guidelines [19]. Assoon as this threshold was exceeded, patientswere assumed to intensify treatment withinsulin glargine in addition to empagliflozin ororal semaglutide plus metformin, which wouldbe continued lifelong in line with the combinedADA/EASD recommendations that SGLT2 andGLP1 receptor agonists are to be administeredirrespective of the HbA1c measure [17].

Following the first year of treatment (studyduration was 52 weeks), HbA1c and bloodpressure were modelled to follow the UKPDS 68progression equation for the remainder ofpatient lifetimes. Mortality was calculated usingthe UKPDS 82 combined mortality approach.The effect on BMI was assumed to be

maintained while the patient remained onempagliflozin or oral semaglutide.

Effect on hHF

In the EMPRISE study [13], empagliflozin wascompared with DPP4 inhibitors and GLP1receptor agonists in terms of hospitalisation forhHF and atherosclerotic cardiovascular events(MI, unstable angina, stroke and coronaryrevascularisation), using real-world data fromMedicare and two commercial insurance claimsdatabases in the US, over a period of 5 years. Forempagliflozin, there was a significant reductionin the rate of hospitalisation for hHF, and afavourable (but statistically non-significant)trend in the rate of atherosclerotic cardiovas-cular events, compared with DPP4 inhibitorsand GLP1 receptor agonists [13]. In the basecase analysis and exploratory scenario analysesthe potential hHF treatment benefit of empa-gliflozin was considered (Table 1).

Patient Management

Patient management inputs included the pro-portion of patients on preventative medication,proportion of patients undergoing routinescreening for diabetic complications and thesensitivity and specificity of the screening testsperformed, using UK-specific data whereavailable.

Utilities

Health-state utilities and event disutilities werebased on published sources (Supplementarymaterial Table S3).

Costs

Costs were accounted from a UK healthcarepayer perspective. In addition to treatmentcosts (Supplementary material Table S4), directcosts also included the costs of treating hypo-glycaemic events and long-term complicationsassociated with T2DM (Supplementary materialTable S5). In terms of the latter, a distinction

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was made between costs arising in the first yearafter disease onset and subsequent years, assome complications are associated with highinitial costs arising from the need for hospital-isation in the acute phase. Follow-up costs wereaccounted for every year until resolution of thespecific complication.

In the modelling analysis, treatment doses of25 mg for empagliflozin and 14 mg for oralsemaglutide were used, as in the PIONEER-2trial. Metformin was included at a dose of1500 mg/day in both treatment arms. Costs ofempagliflozin, oral semaglutide and metforminwere obtained from Bain et al. [20] and cross-checked against the British National Formulary.

For insulin glargine, the cost of biosimilarAbasaglar (0.24 £/U) was used. Costs of glucosemonitoring and injection needles wereobtained from [20] (supplementary material)[20]. Reduction in HbA1c was based on aninsulin-naive population derived from the‘‘Core’’ multivariate equations estimated byWillis et al. [29]. For initial treatment intensifi-cation, insulin glargine at a dose of 0.7 IU/kgwas assumed, and for further treatment inten-sification (exploratory analysis), a dose of0.9 IU/kg was assumed for an average bodyweight of 91.6 kg [29].

Analytical Approach

The base case analysis examined treatment withempagliflozin or oral semaglutide, in additionto metformin, until Hba1c of 7.5% was excee-ded, following which patients underwenttreatment intensification with insulin glarginein addition to empagliflozin or oral semaglutideplus metformin. The value of empagliflozin plusmetformin was quantified by calculating thenet monetary benefit (NMB). NMB is defined asthe change in health outcomes in terms ofQALYs (DE) multiplied by the amount thedecision maker is willing to pay (WTP) per unitof increased effectiveness, minus the aggregatedirect and treatment costs (DC), relative to oralsemaglutide plus metformin. Thus, NMB = WTP* DE – DC. In the current analyses, a willingness-to-pay/accept threshold of GBP 20,000 per

QALY gained was used, in line with the typicalthreshold used by NICE [30].

As extrapolation of long-term clinical out-comes is associated with uncertainty, explora-tory scenario analyses were conducted toevaluate how changes to key parameters in themodelling analyses influence the results of thebase case analyses. In one of the exploratoryscenarios, following initial treatment intensifi-cation with insulin glargine in addition toempagliflozin or oral semaglutide, patients whosubsequently exceeded the HbA1c threshold of7.5% again underwent further intensificationwith a higher dose of insulin glargine alone toachieve glycaemic control. In these patients, itwas assumed that upon further treatmentintensification and discontinuation of empa-gliflozin or oral semaglutide, BMI revertedimmediately to baseline values. Anotherexploratory analysis considered the impact ofBMI on health-related quality of life (HRQL),selecting the polynomial model within theCDM to determine BMI utilities. This approachuses polynomial equations to calculate HRQLassociated with different BMI values; thus, los-ing one unit of BMI does not have the sameeffect on HRQL for a baseline BMI of 27 or 37.Two separate polynomial equations were usedto account for differences in gender, as descri-bed in Soltoft et al. [31]. Other exploratoryanalyses included: shortening the time horizonof the analyses to 5 years; treatment intensifi-cation with insulin glargine plus empagliflozinor oral semaglutide occurring when HbA1cthreshold of 8% is exceeded. All exploratoryanalyses were conducted for comparisonsincluding both treatment effect on hHF andexcluding treatment effect on hHF.

Probabilistic sensitivity analyses were per-formed to ascertain the uncertainty aroundcost-effectiveness outcomes, using Monte Carlosimulations together with a non-parametricbootstrapping approach. Treatment effects,complication costs and utilities were sampledfrom distributions. Progression of diabetes wassimulated in cohorts of 1000 patients runthrough the model 1000 times.

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Compliance with Ethics Guidelines

This article is based on previously conductedstudies and does not contain any studies withhuman participants or animals performed byany of the authors.

RESULTS

Primary Scenario Analyses

In long-term projections of clinical outcomestaking into account the effect of the treatmenton hHF, empagliflozin plus metformin wasassociated with a gain in life-years of 0.086 anda gain in QALYs of 0.023 compared with oralsemaglutide plus metformin. Overall costs oftreatment with empagliflozin plus metforminwere considerably lower than that of oralsemaglutide plus metformin (by GBP 6248;Table 3). Assuming a willingness to pay/acceptthreshold of GBP 20,000 per QALY gained,empagliflozin plus metformin resulted in aNMB of 6708. Thus, in the base case scenario inwhich patients underwent treatment intensifi-cation with empagliflozin or oral semaglutideupon exceeding HbA1c levels at a threshold of7.5%, empagliflozin was dominant to oralsemaglutide, i.e. empagliflozin is both lesscostly and results in better health outcomesthan oral semaglutide (Table 4).

When the effect of treatment on hHF wasnot taken into account, empagliflozin plusmetformin was associated with decreases inoverall costs of GBP 6161 and also resulted inslightly lower life-years gained (- 0.007) andQALYs gained (-0.033) compared with oralsemaglutide plus metformin. Assuming a will-ingness to pay/accept threshold of GBP 20,000per QALY gained, empagliflozin plus metforminresulted in a NMB of GBP 5501. As the NMB isgreater than the incremental cost, empagliflozinplus metformin can be considered cost-effectivecompared with oral semaglutide plus met-formin, even when the effect of treatment onhHF is not taken into consideration.

Exploratory Scenario Analyses

The results of the exploratory scenario analysesare presented in Table 4. In the first scenarioanalysis, following initial treatment intensifi-cation with insulin glargine plus empagliflozinor oral semaglutide, patients who subsequentlyexceeded the HbA1c threshold of 7.5% under-went further intensification with a higher doseof insulin glargine alone. Empagliflozin plusmetformin provided additional life-years gain(0.012) but a slightly lower QALY gain (- 0.025)and was less costly compared with oralsemaglutide plus metformin (-GBP 2094) in theanalysis that included the benefit on hHF. Thus,empagliflozin plus metformin can be consid-ered dominant compared with oral semaglutideplus metformin. When the benefit on hHF wasnot considered, empagliflozin plus metforminwas less costly (-GBP 2048) and resulted in amarginally lower life-years gain (- 0.01) andQALY gain (- 0.04) compared with oralsemaglutide plus metformin.

Similar to the base case analysis, when ahigher HbA1c threshold of 8% was applied fortreatment intensification (addition of insulinglargine to either empagliflozin or oralsemaglutide), the use empagliflozin plus met-formin as initial treatment remained dominant,with additional life-years (0.09) and QALYs(0.02) gained, and lower costs (-GBP 6279),compared with oral semaglutide plus met-formin. In this analysis, patients on empagli-flozin plus metformin underwent treatmentintensification after 4 years, while patients onoral semaglutide plus metformin underwenttreatment intensification after 5 years. Whenthe effect of treatment on hHF was not consid-ered, empagliflozin plus metformin was associ-ated with marginally lower gains in life-years(- 0.02) and QALYs (- 0.05), but was also lesscostly (-GBP 6268) compared with oralsemaglutide plus metformin (Table 4).

Use of the polynomial approach to deter-mine utilities associated with BMI led toincreased QALYs with both treatments com-pared with the base case scenario. Empagliflozinplus metformin remained dominant comparedwith oral semaglutide plus metformin, with aNMB of 6768. When the benefit on hHF was not

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considered, a NMB of GBP 5398 was obtainedfor the use of empagliflozin plus metformincompared with oral semaglutide plus met-formin. Thus, empagliflozin plus metformincan be considered cost-effective compared withoral semaglutide plus metformin when usingthe polynomial approach to determine BMI-as-sociated utilities (Table 4).

Applying a shorter time horizon of 5 yearsled to a reduction in life-years and QALYsgained with either treatment. Overall costs,including both treatment costs and costs asso-ciated with diabetes-related complications, werelower with empagliflozin plus metformin com-pared with oral semaglutide plus metformin(Table 3). A NMB of GBP 1116 was obtainedwhen the effect on hHF was considered and GBP1040 when the effect on hHF was not consid-ered. Thus, empagliflozin plus metformin canbe considered cost-effective compared with oralsemaglutide plus metformin over a 5-year timehorizon (Table 4).

Probabilistic Sensitivity Analysis

Differences in costs and health outcomesbetween the two treatments resulting from eachsimulation were presented in a cost-effective-ness plane and cost-effectiveness acceptabilitycurve. In the analysis including the hHF benefit,the results were delivered in the south-west andsouth-east of the quadrants (Fig. 1a), indicatingthat empagliflozin plus metformin generateslower costs compared with oral semaglutideplus metformin. Empagliflozin plus metforminwas dominant (less costly and generated morehealth gains) in 61% of simulations, and theprobability of being cost-effective comparedwith oral semaglutide plus metformin at thedefined WTP threshold of GBP 20,000 per QALYgained was 97% (Fig. 1b). In the probabilisticsensitivity analysis that did not consider thetreatment effect on hHF, the results were alsodelivered in the south-west and south-east ofthe quadrants (Fig. 1c). Empagliflozin plusmetformin was dominant in 44% of simula-tions, and the probability of being cost-effectivecompared with oral semaglutide plus

metformin at the definedWTP threshold of GBP20,000 per QALY gained was 95% (Fig. 1d).

DISCUSSION

Empagliflozin plus metformin is a cost-effectivetreatment option versus oral semaglutide plusmetformin for patients with T2DM requiringtreatment intensification. Treatment costs wereconsiderably lower with empagliflozin plusmetformin than with oral semaglutide, withclinical benefits also observed with the formerin terms of reduced incidence of hHF. There-fore, in patients undergoing treatment intensi-fication, empagliflozin plus metformin wasdominant to oral semaglutide plus metforminat a WTP threshold of GBP 20,000. Even with-out the inclusion of treatment effect on hHF, apositive NMB was observed for empagliflozinplus metformin compared with oral semaglu-tide plus metformin, with treatment costs beingthe key driver of cost-effectiveness. Theexploratory analyses supported the results ofthe base case analyses, demonstrating the cost-effectiveness of empagliflozin plus metformincompared with oral semaglutide plus met-formin from the UK healthcare perspective, ineach of the scenarios examined.

A separate cost-effectiveness analysis wasrecently published [20], comparing oralsemaglutide and empagliflozin, which projectedthat oral semaglutide would be a cost-effectivetreatment option versus empagliflozin. Similarto the current study, the modelling analysis byBain et al. [20] was based on the results of thePIONEER 2 clinical trial, which did not includecardiovascular outcomes. The current studyadditionally utilises real-world data on hHFfrom the EMPRISE study to separately considerthe clinical benefits of empagliflozin on hHF inthe base case analysis and each of the explora-tory analyses. SGLT-2 inhibitors with evidenceof reducing hHF are recommended in T2DMpatients with hHF [17]; therefore, this is anadditional important consideration assessed inthe current cost-effectiveness study.

As EMPRISE was a real-world evidence study,the data provided are for GLP-1 receptor ago-nists that were currently available for clinical

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use and therefore did not include oralsemaglutide. Thus, a limitation of the currentstudy is the use of data describing a class effectof GLP-1 receptor agonists rather than thespecific effect of oral semaglutide on hHF in thescenarios that consider this treatment effect.However, as the results have shown, even whenthe impact on hHF was not considered, empa-gliflozin plus metformin remained cost-effectivecompared with oral semaglutide plusmetformin.

In the PIONEER 2 trial, two sets of dataanalyses were reported: the trial product esti-mand (on trial product and without the use ofrescue medication) and the treatment policyestimand (which represents an intention-to-treat approach) [22]. The cost-effectivenessanalyses by Bain et al. [20] were based on datafrom the trial product estimand, whereas thetreatment policy estimand was chosen for thecurrent cost-effectiveness analyses, as this is

more reflective of the real-world situation bynot excluding discontinuation of the drug orrescue medication. However, it should be notedthat the use of rescue medication and otherdiabetes medication was not significantly dif-ferent between the two arms [22]. In additionalmodelling analyses performed using the trialproduct estimand, empagliflozin plus met-formin remained cost-effective compared withoral semaglutide plus metformin (Supplemen-tary material Table S6).

Based on the NICE algorithm for blood glu-cose-lowering therapy in T2DM patients [32],those receiving dual therapy with metforminand SGLT-2 (or another oral agent) wouldundergo treatment intensification when HbA1cthreshold of 7.5% is exceeded. In the modellinganalysis conducted by Bain et al. [20], treatmentwith empagliflozin or oral semaglutide, inaddition to metformin, was ceased when HbA1cthreshold of 7.5% was exceeded, assumed to

Fig. 1 Cost-effectiveness scatterplots and acceptabilitycurves based on the probabilistic sensitivity analyses.a Cost-effectiveness plane of the base case analysis withhHF benefit (QALY). b Cost-effectiveness acceptabilitycurve of the base case analysis with hHF benefit (QALY).c Cost-effectiveness plane of the base case analysis without

hHF benefit (QALY). d Cost-effectiveness acceptabilitycurve of the base case analysis without hHF benefit(QALY). GBP Pound sterling, hHF hospitalisation forheart failure, QALY quality-adjusted life year, WTPwillingness to pay

Diabetes Ther (2020) 11:2041–2055 2049

occur after 2 years of treatment with empagli-flozin and after 3 years of treatment with oralsemaglutide, and patients were switched totreatment with insulin glargine alone. Thus, inthe Bain et al. study, [20] the treatment effectsand costs of empagliflozin or oral semaglutideconsider a short duration of 2–3 years of treat-ment only. This is a key difference from thecurrent modelling analysis, in which treatmentwith empagliflozin or oral semaglutide, inaddition to metformin, was continued lifelong,with insulin glargine added to the drug regimenfor treatment intensification when HbA1cthreshold of 7.5% was exceeded. The latterapproach is in line with the combined ADA/EASD recommendations that treatments withSGLT2 and GLP1 receptor agonists are to becontinued irrespective of the HbA1c measure[17].

Based on NICE guidance [NG28] [19], treat-ment intensification involves triple therapywith metformin in combination with other oralagents, or insulin-based treatment. Combina-tion therapy with metformin and a GLP-1receptor agonist would be considered only inthose patients who have a BMI of 35 kg/m2 orhigher and specific psychological or othermedical problems associated with obesity, or forwhom insulin therapy would have significantoccupational implications, or weight loss wouldbenefit other significant obesity-related comor-bidities [32]. There is little clinical evidence onthe individual effects of oral agents when usedin triple therapy regimens. Hence, modelling oftriple oral therapy regimens would be basedpurely on assumptions regarding efficacy, safetyand occurrence of diabetes-related complica-tions. Therefore, as in the current study, otherstudies modelling T2DM treatment regimens

Table 3 Direct medical costs (base case analysis)

Including hHF impact Excluding hHF impact

Empagliflozin 1 metformin Empagliflozin 1 metformin Oralsemaglutide 1 metformin

Total cost (GBP) 28,193 28,280 34,441

Treatment 15,979 15,888 22,192

Management 731 727 727

CVD 6785 6954 6960

Renal 873 924 896

Ulcer/amputation/

neuropathy

945 935 911

Eye 2406 2381 2310

Non-severe hypoglycaemia 284 282 264

Severe hypoglycaemia

(required non-medical

assistance)

140 140 135

Severe hypoglycaemia

(required medical

assistance)

51 50 46

Costs presented are for empagliflozin or oral semaglutide in addition to metformin as dual therapyCVD cardiovascular disease, GBP Pound sterling, hHF hospitalisation for heart failure

2050 Diabetes Ther (2020) 11:2041–2055

Table

4Cost-effectivenessresults:scenarioswithandwithout

treatm

enteffect

onhH

F

Analysis

Includ

ingtreatm

enteffect

onhH

F

Life-years(years)

QALY(years)

Total

cost

(£)

ICUR

Empagliflozin

Oral

semaglutide

Empagliflozin

Oral

semaglutide

Empagliflozin

Oral

semaglutide

Basecasescenario

analyses

Treatmentintensification

atHbA

1cthreshold

of7.5%

a

14.01

13.93

9.27

9.25

28,1

9334,4

41Dom

inant

Exploratory

analyses

Furtherintensification

b13.95

13.94

9.17

9.19

24,302

26,396

83,748*

Treatmentintensification

atHbA

1cthreshold

of8%

a

14.01

13.92

9.30

9.28

27,021

33,300

Dom

inant

BMIpolynomialutility

approach

b13.95

13.94

9.51

9.53

24,302

26,396

91030*

Tim

ehorizonof

5years

4.37

4.37

3.02

3.04

6,202

7738

73152*

Analysis

Excluding

treatm

enteffect

onhH

F

Life-years(years)

QALY(years)

Total

cost

(£)

ICUR

Empagliflozin

Oralsemaglutide

Empagliflozin

Oralsemaglutide

Empagliflozin

Oralsemaglutide

Basecasescenario

analyses

Treatmentintensification

atHbA

1cthresholdof

7.5%

a

13.93

13.93

9.22

9.25

28,2

8034,4

41186,

690

Exploratory

analyses

Furtherintensification

b13.94

13.94

9.16

9.19

24,3

4826,3

9653,8

74*

Treatmentintensification

atHbA

1cthresholdof

8%a

13.90

13.92

9.23

9.28

27,032

33,300

394,892*

BMIpolynomialutility

approach

bNA

NA

NA

NA

NA

NA

NA

Diabetes Ther (2020) 11:2041–2055 2051

have used insulin as the treatment option forintensification [20, 33–35], and this is acceptedby health technology assessment agencies.

Also, the Institute for Clinical and EconomicReview (ICER), an independent research insti-tution in the US, estimated the cost-effective-ness of oral semaglutide versus severalcomparators including empagliflozin [36]. Thisstudy showed that, at the estimated net price,oral semaglutide is unlikely to meet cost-effec-tiveness thresholds compared with empagli-flozin. The methodology followed by the ICERinvestigators deviated in many ways from theone applied in the current manuscript and fromthe one applied by Bain et al. Main differencesare that they started from a US cohort and notthe PIONEER 2 cohort and that they combinedthe treatment effects on risk factors measured inPIONEER 2 with direct treatment effects onCVD taken from PIONEER 6 combined with anetwork meta-analysis to obtain the effects ofempaglifozin.

At the latest ADA conference, a poster waspresented, based on PIONEER 2 but using twodifferent cost-effectiveness models, on the cost-effectiveness of oral semaglutide and empagli-flozin [37]. As it was only a poster, comparingthe methodologies is difficult. HbA1c of 8% wasconsidered the moment to switch to insulin andstop oral semaglutide and empagliflozin (likeBain et al.) and analyses were run over 40 years.Here, the authors conclude that oral semaglu-tide is cost-effective.

In the above paragraphs, some of the limi-tations and how they were addressed werereported. Below, they are briefly repeated andsome more are added. First, the UK cost of oralsemaglutide is not yet plublicly available. Weused the same cost as used by the manufacturerin their analyses. Second, the RR on hHF ofempagliflozin versus GLP1 receptor agonists wasused as no specific oral semagluide data areavailable. Hard outcomes were not included inPIONEER 2. Analyses without an impact on hHFhave also been presented. Third, it is not knownhow long the therapy will be applied and whatthe next line therapy will be. A scenario analysiswith three lines of therapy was added in whichoral semaglutide and empagliflozin are stoppedin third line, being after 4 to 5 years of therapy.T

able

4continued

Analysis

Excluding

treatm

enteffect

onhH

F

Life-years(years)

QALY(years)

Total

cost

(£)

ICUR

Empagliflozin

Oralsemaglutide

Empagliflozin

Oralsemaglutide

Empagliflozin

Oralsemaglutide

Tim

ehorizonof

5years

4.37

4.37

3.02

3.04

6238

7738

65,233*

The

ICURrefersto

thecost(G

BP)

perQALYforem

pagliflozin

plus

metform

inversus

oralsemaglutide

plus

metform

inGBPPo

undsterlin

g,HbA

1cglycated

haem

oglobin,

hHFhospitalisationforheartfailure,ICURincrem

entalcost-utilityratio,

NAnotapplicable,Q

ALYquality-

adjusted

lifeyear

aTwolin

esof

treatm

ent:em

pagliflozin

ororalsemaglutide

inaddition

tometform

in;treatm

entintensification—em

pagliflozin

ororalsemaglutide

inaddition

toinsulin

glargine

bThree

lines

oftreatm

ent:em

pagliflozin

ororalsemaglutide

inaddition

tometform

in;initialintensification—em

pagliflozin

ororalsemaglutide

inaddition

toinsulin

glargine;furtherintensification—high-doseinsulin

glargine

alone

*Withpositive

netmonetarybenefit

2052 Diabetes Ther (2020) 11:2041–2055

Fourth, studies on empagliflozin have shownthat it reduces the declines over time of eGFRand resulted in less end-stage renal disease [38].So far, on oral semaglutide, based on publishedstudies effects on albuminuria and ESRD are notshown. The occurrence of nephropathy in themodel is driven by HbA1c reduction at themoment. As oral semaglutide results in astronger reduction of HbA1c, this is a conser-vative approach for empagliflozin.

CONCLUSIONS

Driven by the strong difference in treatmentcosts, empagliflozin 25 mg is a cost-effectivetreatment option versus oral semaglutide14 mg, when used in addition to metformin, forthe treatment of T2DM patients in the UK.Adding benefits on hospitalisation for heartfailure empagliflozin becomes the dominanttreatment.

ACKNOWLEDGEMENTS

The authors thank Andrew Ternouth for criticalreview of the manuscript and Manisha Panchalfor supporting with data analysis.

Funding. This study and the Rapid ServiceFee for publication were supported by fundingfrom Boehringer Ingelheim, Ingelheim amRhein, Germany.

Authorship. All named authors meet theInternational Committee of Medical JournalEditors (ICMJE) criteria for authorship of thisarticle, take responsibility for the integrity ofthe work as a whole, and have given theirapproval for this version to be published.

Disclosures. Mafalda Ramos and MarkLamotte are employees of IQVIA, whichreceived consulting fees from BoehringerIngelheim for their contribution to this work.Michael H. Cummings has received honorariafrom Boehringer Ingelheim, Eli Lilly, Mylan,Napp, AstraZeneca, MSD and Amgen for expertadvice on advisory boards and/or educational

delivery. Anastasia Ustyugova is an employee ofBoehringer Ingelheim International GmbH.Syed I. Raza is an employee of BoehringerIngelheim Ltd. Shamika U. de Silva is a formeremployee of Boehringer Ingelheim Ltd. Hercurrent affiliation is Market Access, Biogen,Maidenhead, Berkshire SL6 4AY, UK.

Compliance with Ethics Guidelines. Thisarticle is based on previously conducted studiesand does not contain any studies with humanparticipants or animals performed by any of theauthors.

Data Availability. All data generated oranalysed during this study are included in thispublished article/as supplementary informationfiles.

Open Access. This article is licensed under aCreative Commons Attribution-NonCommer-cial 4.0 International License, which permitsany non-commercial use, sharing, adaptation,distribution and reproduction in any mediumor format, as long as you give appropriate creditto the original author(s) and the source, providea link to the Creative Commons licence, andindicate if changes were made. The images orother third party material in this article areincluded in the article’s Creative Commonslicence, unless indicated otherwise in a creditline to the material. If material is not includedin the article’s Creative Commons licence andyour intended use is not permitted by statutoryregulation or exceeds the permitted use, youwill need to obtain permission directly from thecopyright holder. To view a copy of this licence,visit http://creativecommons.org/licenses/by-nc/4.0/.

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