http://orcid.org/0000-0001-5420-279X
Abstract
Aims: Controlling costs while maximizing healthcare gains is the predominant challenge for healthcare providers, and therefore cost-effectiveness analysis is playing an ever-increasing role in healthcare decision making. The aim of the present analysis was to assess the long-term cost-effectiveness of subcutaneous once-weekly semaglutide (0.5 mg and 1 mg) versus empagliflozin (10 mg and 25 mg) in the Spanish setting for the treatment of patients with type 2 diabetes (T2D) with inadequate glycemic control on oral anti-hyperglycemic medications.
Material and methods: The IQVIA CORE Diabetes Model was used to project outcomes over patient lifetimes with once-weekly semaglutide versus empagliflozin, with treatment effects based on a network meta-analysis. The analysis captured treatment costs, costs of diabetes-related complications, and the impact of complications on quality of life, based on published sources. Outcomes were discounted at 3.0% per annum.
Results: Once-weekly semaglutide 0.5 mg and 1 mg were associated with improvements in discounted quality-adjusted life expectancy of 0.12 and 0.15 quality-adjusted life years (QALYs), respectively, versus empagliflozin 10 mg and improvements of 0.11 and 0.14 QALYs, respectively, versus empagliflozin 25 mg. Treatment costs were higher with once-weekly semaglutide compared with empagliflozin, but this was partially offset by cost savings due to avoidance of diabetes-related complications. Once-weekly semaglutide 0.5 mg and 1 mg were associated with incremental cost-effectiveness ratios of EUR 2,285 and EUR 161 per QALY gained, respectively, versus empagliflozin 10 mg, and EUR 3,090 and EUR 625 per QALY gained, respectively, versus empagliflozin 25 mg.
Conclusions: Based on a willingness-to-pay threshold of EUR 30,000 per QALY gained, once-weekly semaglutide 0.5 mg and 1 mg were projected to be cost-effective versus empagliflozin 10 mg and 25 mg for the treatment of patients with T2D with inadequate glycemic control on oral anti-hyperglycemic medications in the Spanish setting, irrespective of patients’ BMI at baseline.
Introduction
Controlling costs while maximizing healthcare gains is the predominant challenge for healthcare providers. This is particularly true when treatments for diabetes are considered. The [email protected] Study found that the overall prevalence of diabetes in Spain in 2012 was 13.8% (95% confidence interval 12.8% to 14.7%), and the average annual cost per patient with diabetes was estimated to be EUR 3,110, resulting in annual healthcare expenditure of approximately EUR 10 billionCitation1. As the prevalence of diabetes continues to rise, and healthcare budgets come under increasing pressure, use of cost-effectiveness analysis allows healthcare payers to make informed decisions around the interventions they reimburse, aiming to maximize the health gains across the population within a constrained budget.
Controlling hyperglycemia remains the key treatment focus for patients with type 2 diabetes (T2D), with reductions in glycated hemoglobin (HbA1c) known to be associated with a lower risk of developing diabetes-related complicationsCitation2–4. A consensus report released by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) states that glycemic treatment targets should be individualized based on patient preferences and goals, risk of adverse effects of therapy (such as hypoglycemia and weight gain) and patient characteristics, including frailty and comorbid conditionsCitation5. However, modern care for T2D is less glucocentric, aiming to take a multifactorial approach by controlling additional risk factors for diabetes-related complications, such as body weight, blood pressure and serum lipidsCitation6–9. The impact of interventions on cardiovascular risk is also an increasingly important consideration when choosing therapies, with the latest guidelines recommending consideration of this much earlier than previous versions. Guidelines suggest use of a glucagon-like peptide-1 (GLP-1) receptor agonist or a sodium-glucose transporter-2 (SGLT-2) inhibitor with proven cardiovascular benefits in patients with established atherosclerotic cardiovascular disease not achieving adequate glycemic control with lifestyle modification and metforminCitation5. The first-choice GLP-1 receptor agonists are liraglutide and semaglutide, and the first-choice SGLT-2 inhibitors are empagliflozin and canagliflozinCitation5. Improving care and reducing the incidence of diabetes-related complications, through controlling risk factors and using interventions that reduce the risk of cardiovascular events, not only results in increased life expectancy and quality of life for patients, but can also reduce the cost related to the disease for healthcare payers, as complications are a key driver of the overall cost of the conditionCitation10.
Once-weekly semaglutide, a novel subcutaneous GLP-1 analogue, has been shown to be associated with improved glycemic control, weight loss, and low risk of hypoglycemic events across the SUSTAIN trial programCitation11–16. Similarly, the EMPA-REG trial program found that empagliflozin, an SGLT-2 inhibitor, was associated with reductions in HbA1c, body weight and blood pressure, with a low risk of hypoglycemic eventsCitation17–22. A network meta-analysis (NMA) has suggested that once-weekly semaglutide is associated with greater reductions in HbA1c than SGLT-2 inhibitors, while the SUSTAIN 8 trial provides a direct comparison between once-weekly semaglutide and canagliflozinCitation23,Citation24. In the SUSTAIN 8 trial, once-weekly semaglutide 1 mg was associated with superior reductions in HbA1c and body weight compared with canagliflozin 300 mg in patients with type 2 diabetes not meeting glycemic control targets on metformin monotherapy. Furthermore, both once-weekly semaglutide and SGLT-2 inhibitors have been shown to be associated with a significant reduction in major adverse cardiovascular events (MACE) compared with placebo, and are recommended as interventions for patients not achieving glycemic control targets on metformin where there is a need to minimize weight gain or promote weight loss, and in patients with established atherosclerotic cardiovascular diseaseCitation5,Citation25,Citation26.
Both once-weekly semaglutide and empagliflozin are associated with improved glycemic control, weight loss, a low risk of hypoglycemic events, and favorable impacts on cardiovascular risk and progression of chronic kidney disease, and therefore represent modern interventions for T2D. The aim of the present analysis was to assess the long-term cost-effectiveness of once-weekly semaglutide (0.5 mg and 1 mg) versus empagliflozin (10 mg and 25 mg) in the Spanish setting for the treatment of patients with T2D with inadequate glycemic control on oral anti-hyperglycemic medications.
Methods
Modeling approach
The analysis was performed using version 9.0 of the IQVIA CORE Diabetes Model. The model description of the IQVIA CORE Diabetes Model was first published in 2004, and the model is widely used in peer reviewed publications and as part of health technology assessmentsCitation27. Briefly, the model consists of a series of sub-models for each complication, each with a semi-Markov structure. The use of tracker variables overcomes the memory-less properties of the standard Markov model and allows interconnectivity and interaction between individual complication sub-models. Standard model outputs include complication rates and time to onset of complications, life expectancy, quality-adjusted life expectancy (expressed in quality-adjusted life years [QALYs]), direct costs and, where required, incremental cost-effectiveness ratios (ICERs), which describe the additional cost per additional unit of effectiveness gained for the intervention versus the comparator. Where an intervention is associated with reduced costs and increased clinical benefits, it is considered dominant versus the comparator, and no calculation of an ICER is required. Validation studies have been published in 2004 and more recently in 2014Citation28,Citation29.
The model was used to project outcomes over patient lifetimes, in line with guidance on the assessment of cost-effectiveness of interventions for diabetes.Citation30 This ensured that all relevant long-term complications, and therefore their impact on mortality, morbidity and costs, were captured in the analysis. Sensitivity analyses explored the impact of shortening the time horizon. As well as capturing mortality due to diabetes-related complications, the analysis captured background mortality based on Spain-specific life tables from the World Health Organization (WHO).Citation31 Clinical and cost outcomes were discounted at rates of 3.0% per annum, as per the guidelines for economic evaluation of health technologies in Spain.Citation32
Clinical data used in the analysis
To date, no head-to-head studies comparing once-weekly semaglutide with empagliflozin have been published. Therefore, treatment effect data applied in the first year of the analysis were taken from a published NMACitation23. The NMA used a Bayesian framework, with fixed- and random-effects models evaluated for each endpoint and model selection based on the deviance information criterion (DIC) and assessment of model appropriateness. Outcomes generated in the NMA that could be used in an analysis using the IQVIA CORE Diabetes Model were change in HbA1c, change in systolic blood pressure, and change in weight (converted to body mass index [BMI]). A total of eight, six, and seven trials were included in the HbA1c, systolic blood pressure and weight networks, respectively, with changes versus placebo applied in all arms of the present analysis (). The NMA found that both doses of once-weekly semaglutide were associated with significantly greater reductions in HbA1c versus both doses of empagliflozin. Reductions in systolic blood pressure were greater with once-weekly semaglutide, but differences did not reach statistical significance. Both doses of once-weekly semaglutide were associated with significantly greater weight reductions compared with empagliflozin 10 mg, but compared with empagliflozin 25 mg, the change with once-weekly semaglutide 0.5 mg was not significantly greater while the change with once-weekly semaglutide 1 mg was significant. Where parameters were not included in the NMA, inputs were assumed to be 0 in all arms to ensure that these did not drive cost-effectiveness outcomes.
Table 1. Treatment effects applied in the first year of the analysis.
Treatment effects from the NMA were applied in a cohort with baseline characteristics matching those of all patients included in the SUSTAIN 2 clinical trial. This trial was chosen as it was used in the NMA to inform the once-weekly semaglutide armsCitation23. SUSTAIN 2 was a 56-week, randomized, double-blinded trial comparing once-weekly semaglutide 0.5 mg and 1 mg with 100 mg once-daily sitagliptin in people with T2D uncontrolled on metformin, a thiazolidinedione, or a combination of metformin and a thiazolidinedione. The mean (standard deviation [SD]) age, duration of T2D, HbA1c, systolic blood pressure and BMI were 55.1 (10.0) years, 7.0 (5.1) years, 8.1 (0.9)%, 132.7 (15.9) mmHg, and 32.5 (6.2) kg/m2, respectively.
Treatment switching and long-term parameter progression
Due to the progressive nature of T2D, the majority of patients will require intensification from GLP-1 receptor agonist or SGLT-2 inhibitor therapy, and it is common in patients with long-standing T2D to require more than two anti-hyperglycemic agents, often including insulin. As once-weekly semaglutide and empagliflozin are both relatively new interventions, data on the duration of treatment is currently lacking, and therefore assumptions were required. A simple treatment algorithm was employed, with patients assumed to receive once-weekly semaglutide or empagliflozin treatment for 3 years. After 3 years, treatment with once-weekly semaglutide or empagliflozin was discontinued and patients were assumed to intensify to basal insulin therapy with insulin glargine U100 (i.e. treatment costs were equal in all treatment arms following intensification). Although it is common practice to continue GLP-1 receptor agonists and SGLT-2 inhibitors when basal insulin is initiated, this analytical approach was chosen as there is currently no evidence on the changes in risk factors when insulin is added to GLP-1 receptor agonist or SGLT-2 inhibitor treatment. Therefore any changes in risk factors on the addition of basal insulin to GLP-1 receptor agonists and SGLT-2 inhibitors would be associated with significant uncertainty and would not help address the research question (namely, if once-weekly semaglutide is cost-effective versus empagliflozin in the Spanish setting). This approach is in line with previous long-term cost-effectiveness analyses of GLP-1 receptor agonists in Spain published in peer-reviewed journalsCitation33.
After applying treatment effects based on the NMA in the first year of the analysis, benefits in terms of HbA1c were assumed to persist for the 3 years during which patients received once-weekly semaglutide or empagliflozin treatment, with the difference abolished on treatment intensification. On intensification, HbA1c was brought to 7% in all treatment arms, based on the consensus report released by the ADA and EASDCitation5.
BMI benefits were also assumed to persist while patients received either once-weekly semaglutide or empagliflozin treatment. On intensification, BMI reverted to baseline in all arms. Therefore, no differences in HbA1c and BMI were seen between the treatment arms following treatment intensification, resulting in a balanced cost-effectiveness analysis, with differences in HbA1c and BMI maintained only while there were differential costs.
Costs
Costs were accounted from a healthcare payer perspective in the Spanish setting, with all costs expressed in 2018 euros (EUR). Unit costs of T2D medications and consumables were based on wholesale purchasing prices (WPPs), obtained for each product from the pharmacy selling price (PSP) by applying the conversion factors according to Royal Decree-Law 4/2010, with rebates according to Royal Decree-Law 8/2010 applied where applicable. Both once-weekly semaglutide 0.5 mg and 1 mg were associated with a cost of EUR 86.28 per 28-day pack, and both empagliflozin 10 mg and 25 mg were associated with a cost of EUR 32.86 per 30-day pack. Medication resource use was based on the trials from which the data were taken for the NMA in each of the arms of the analysis. Following intensification after 3 years, patients were assumed to receive 40 U of insulin glargine U100 (based on the defined daily dose).
The costs of treating diabetes-related complications in the year of event and the annual follow-up costs (applied in each year of the simulation subsequent to the first event) were identified through literature reviews, with values inflated using rates published by the European Central Bank where required ()Citation34.
Table 2. Costs of treating diabetes-related complications.
Utilities
As T2D progresses, patients develop complications that influence their overall health-related quality of life, and therefore event utilities were applied in the year of an event and health state utilities were applied in subsequent years of the simulation to capture this impact. Utilities associated with T2D and diabetes-related complications were taken from a published review by Beaudet et al., with hypoglycemic event disutilities taken from Evans et al. (published after the literature searches by Beaudet et al. had been conducted)Citation35,Citation36.
Sensitivity analyses
Sensitivity analyses were prepared for once-weekly semaglutide 1 mg versus empagliflozin 10 mg and 25 mg, as it is anticipated that the majority of patients will receive the higher dose of once-weekly semaglutide due to the greater efficacy and equal price compared with the lower dose.
To assess the key drivers of clinical benefits, a series of three simulations were run for the two comparisons with only the difference in one of HbA1c, systolic blood pressure or BMI applied in the once-weekly semaglutide arm, with all other parameters equal to the empagliflozin 10 mg or 25 mg arm.
To assess the impact of uncertainty around the outcomes of the NMA used to inform the treatment effects, only the treatment effects that were significantly different between once-weekly semaglutide 1 mg and the empagliflozin arms were applied. The influence of time horizon on the outcomes projected by the model was investigated by running analyses over 10, 20 and 35 years (it should be noted that a time horizon of 50 years was required for all modeled patients to have died, and therefore shorter time horizons do not capture all complications and costs). To examine the effect of discounting on cost-effectiveness outcomes, simulations were performed with (symmetric) discount rates of 0% and 5% applied, in line with guidance for the Spanish settingCitation32.
The base case analyses assumed that the BMI benefit associated with once-weekly semaglutide 1 mg was abolished instantaneously on treatment switching and an alternative to this was explored, with BMI differences between once-weekly semaglutide and empagliflozin maintained for the duration of the simulation. An alternative approach to HbA1c progression was also explored, applying the UKPDS HbA1c progression equation in both arms after application of treatment effects in the first year of the analysis, resulting in HbA1c increasing in both arms of the analysis with the difference between the arms gradually reduced. The impact of alternative changes in HbA1c and BMI were assessed in four simulations. Simulations were run in turn with the upper and lower limits of the 95% confidence intervals of the estimated treatment differences in HbA1c and BMI applied in the once-weekly semaglutide arm.
To investigate the effect of the timing of treatment switching on cost-effectiveness, simulations were performed with the year of treatment switch to insulin glargine U100 pushed back to the end of year 5 in both arms, and, in a separate analysis, with the UKPDS HbA1c progression equation applied and treatment switching occurring when HbA1c exceeded 7.5% (a commonly used threshold for treatment intensification). The effect of over- or underestimating the direct cost of treating diabetes-related complications was investigated in two scenarios, with the cost of treating complications increased and decreased by 10%.
In February 2014, an update to the IQVIA CORE Diabetes Model was released, incorporating data from the UKPDS 82, and an analysis using this version of the model was run (whilst a validation study of the revised model has been published, the model proprietors suggest that the update is used in a sensitivity analysis, with the previous version used in the base case)Citation29. To assess the importance of quality of life changes resulting from weight loss, an analysis was prepared with an alternative BMI disutility, sourced from a publication by Lee et al., applied in all treatment arms, with this larger disutility giving greater impact to weight changes compared with the conservative disutility used in the base case analysisCitation37. Probabilistic sensitivity analysis (PSA) was performed using the predefined function in the IQVIA CORE Diabetes Model, with cohort characteristics, treatment effects, complication costs, and utilities sampled from distributions, and the simulation run using a second order Monte Carlo approach.
Compliance with ethics guidelines
This article is based on previously conducted studies and does not contain any studies with human participants or animals performed by any of the authors.
Results
Base case analysis
When compared with empagliflozin 10 mg, once-weekly semaglutide 0.5 mg and 1 mg were associated with improvements in discounted life expectancy of 0.13 and 0.16 years, respectively, and discounted quality-adjusted life expectancy of 0.12 and 0.15 QALYs, respectively (). Differences were smaller versus empagliflozin 25 mg, with once-weekly semaglutide 0.5 mg and 1 mg associated with improvements in discounted life expectancy of 0.12 and 0.15 years, respectively, and discounted quality-adjusted life expectancy of 0.11 and 0.14 QALYs, respectively, versus empagliflozin 25 mg (). In all comparisons, clinical benefits resulted from a reduced incidence and delayed time to onset of diabetes-related complications in the once-weekly semaglutide arms compared with the empagliflozin arms over the 50-year time horizon of the analysis (). Mean time to onset of any complication, compared with empagliflozin 10 mg, was increased by 0.38 years with once-weekly semaglutide 0.5 mg and by 0.48 years with once-weekly semaglutide 1 mg, and by 0.35 years and 0.45 years with once-weekly semaglutide 0.5 mg and 1 mg, respectively, versus empagliflozin 25 mg.
Figure 1. Mean time to onset of diabetes-related complications.
Table 3. Base case results.
Total costs over patient lifetimes were higher with both doses of once-weekly semaglutide than with both doses of empagliflozin. The mean cost per patient was EUR 270 and EUR 25 higher in the once-weekly semaglutide 0.5 mg and 1 mg arms, respectively, versus empagliflozin 10 mg, and EUR 335 and EUR 89 higher, respectively versus empagliflozin 25 mg. Treatment costs were higher with once-weekly semaglutide 0.5 mg and 1 mg compared with empagliflozin 10 mg and 25 mg, driven by the higher acquisition costs over the first 3 years of the analysis and the increased survival and further treatment of patients over the long term. However, this was partially offset by cost savings due to avoidance of diabetes-related complications, most notably ulcer, amputation and neuropathy complications (mean cost savings of EUR 1,562 and EUR 1,922 per patient with once-weekly semaglutide 0.5 mg and 1 mg, respectively, versus empagliflozin 10 mg, and mean cost savings of EUR 1,511 and EUR 1,871 per patient with once-weekly semaglutide 0.5 mg and 1 mg, respectively, versus empagliflozin 25 mg).
Estimation of long-term cost-effectiveness outcomes indicated that both life expectancy and quality-adjusted life expectancy were improved with once-weekly semaglutide 0.5 mg and 1 mg treatment compared with empagliflozin 10 mg and 25 mg, at increased costs from a healthcare payer perspective. Once-weekly semaglutide 0.5 mg and 1 mg were therefore associated with ICERs of EUR 2,285 and EUR 161 per QALY gained, respectively, versus empagliflozin 10 mg, and ICERs of EUR 3,090 and EUR 625 per QALY gained, respectively, versus empagliflozin 25 mg (). Based on the commonly quoted willingness-to-pay threshold of EUR 30,000 per QALY gained, once-weekly semaglutide 0.5 mg and 1 mg were projected to be cost-effective versus both empagliflozin 10 mg and 25 mg, for treatment of patients with T2D not achieving glycemic control on oral anti-hyperglycemic medications in the Spanish setting.
Sensitivity analyses
Testing for the key drivers of clinical benefits showed that greater HbA1c reductions associated with once-weekly semaglutide 1 mg was the biggest contributor to improved clinical outcomes versus both doses of empagliflozin. Once-weekly semaglutide was associated with quality-adjusted life expectancy benefits of 0.12 QALYs and 0.10 QALYs versus empagliflozin 10 mg and 25 mg, respectively, when only this difference between the treatment arms was applied (). Changes in blood pressure and BMI made smaller contributions to overall clinical benefit with once-weekly semaglutide.
Table 4. Key drivers of clinical outcomes with once-weekly semaglutide 1 mg.
Sensitivity analyses showed that the results were robust to changes in the input parameters and assumptions, with all ICERs remaining below EUR 30,000 per QALY gained (). Including only the statistically significant differences between the treatment arms resulted in slightly decreased clinical benefits and increased incremental costs with once-weekly semaglutide 1 mg compared with empagliflozin 10 mg and 25 mg, leading to slightly increased ICERs. Shortening the time horizon of the analysis to 35 or 20 years resulted in once-weekly semaglutide 1 mg becoming dominant versus empagliflozin 10 mg and 25 mg, as clinical benefits were maintained but cost differences were smaller. However, decreasing the time horizon further to 10 years led to increased ICERs, as the long-term benefits of once-weekly semaglutide treatment were not fully captured. Altering the discount rate also reflected the long-term benefits associated with once-weekly semaglutide 1 mg, with once-weekly semaglutide dominant versus empagliflozin 10 mg and 25 mg when no discounting was applied and associated with increased ICERs when discount rates of 5% were used.
Table 5. Sensitivity analysis results.
Maintaining the BMI difference between the once-weekly semaglutide 1 mg and empagliflozin arms following treatment intensification led to reduced ICERs, as clinical benefits associated with once-weekly semaglutide were maintained for longer. Application of the UKPDS HbA1c progression equation resulted in once-weekly semaglutide 1 mg becoming dominant versus empagliflozin 10 mg, but a small increase in the ICER versus empagliflozin 25 mg. Applying the upper 95% confidence interval of the estimated treatment difference in HbA1c led to once-weekly semaglutide being considered dominant versus both doses of empagliflozin, while ICERs increased when the lower 95% confidence interval of the estimated treatment difference was applied. In the comparison with empagliflozin 10 mg, once weekly semaglutide 1 mg became dominant when the upper and lower 95% confidence intervals of the estimated treatment difference in BMI were applied, with the ICERs falling in the comparison with empagliflozin 25 mg. Delaying treatment switching until after 5 years of initial treatment resulted in once-weekly semaglutide 1 mg becoming dominant versus both doses of empagliflozin, driven by differences in HbA1c and BMI being maintained for longer, which offset the greater difference in treatment costs. Application of the UKPDS HbA1c progression equation with treatment switching when HbA1c exceeded 7.5% resulted in a similar ICERs to the base case analyses.
Increasing the cost of complications by 10% resulted in once-weekly semaglutide becoming dominant, while decreasing the costs by 10% resulted in increased ICERs. When the UKPDS 82 risk equations were used to project outcomes, once-weekly semaglutide was found to be dominant versus empagliflozin 10 mg and 25 mg. Application of a larger disutility relating to BMI resulted in similar but slightly decreased ICERs for once-weekly semaglutide 1 mg versus both doses of empagliflozin.
PSA with sampling around cohort characteristics, treatment effects, complication costs and utilities showed similar mean results to the base case but increased measures of variance around the mean outcomes. In the PSA, once-weekly semaglutide 1 mg was associated with ICERs of EUR 2,358 per QALY gained versus empagliflozin 10 mg, and EUR 3,492 per QALY gained versus empagliflozin 25 mg. At a willingness-to-pay threshold of EUR 30,000 per QALY gained, the modeling analysis indicated that the probability of once-weekly semaglutide 1 mg being cost-effective was 77.1% versus empagliflozin 10 mg and was 75.8% versus empagliflozin 25 mg ().
Figure 2. Cost-effectiveness acceptability curves from the probabilistic sensitivity analysis. Abbreviations. EUR, 2018 euros; QALY, quality-adjusted life year.
Discussion
The present analysis indicated that once-weekly semaglutide 0.5 mg and 1 mg were likely to be cost-effective versus both empagliflozin 10 mg and 25 mg, for the treatment of patients with T2D not achieving glycemic control on oral anti-hyperglycemic medications in the Spanish setting. Calculated ICERs for once-weekly semaglutide 1 mg versus empagliflozin 10 mg and 25 mg were particularly notable, at only EUR 161 and EUR 625 per QALY gained, respectively, falling well below commonly quoted willingness to pay threshold of EUR 30,000 per QALY gained. Extensive sensitivity analyses were conducted for comparisons using the 1 mg dose of once-weekly semaglutide (likely to be the more frequently used dose given the greater efficacy and equal price compared with once-weekly semaglutide 0.5 mg), and these showed that the results and conclusions of the base case analysis were robust to changes in the input parameters and modeling assumptions applied. These wide-ranging sensitivity analyses represent a key strength of the present analysis. The long-term cost-effectiveness analysis was based on changes in risk factors taken from an NMA, and the clinical significance of these changes should be considered. Physicians generally consider a change in HbA1c of 0.5% to be clinically meaningful, and the NMA found that once-weekly semaglutide 0.5 mg and 1 mg, and empagliflozin 10 mg and 25 mg were all associated with a clinically meaningful reduction in HbA1c from baselineCitation38. According to guidelines released by the American College of Cardiology, the American Heart Association, and The Obesity Society in 2013, clinically meaningful health improvements can be seen with weight loss in the range of 2–5%Citation39. Improvements in this range were achieved with patients receiving once-weekly semaglutide 0.5 mg, once-weekly semaglutide 1 mg, and empagliflozin 25 mg based on the NMA, and the SUSTAIN trial program consistently found that a greater percentage of patients receiving once-weekly semaglutide achieved weight loss ≥5%Citation11–16,Citation23. Reductions in weight may lead to improvements in multiple obesity-associated comorbidities such as hypertension, dyslipidemia and sleep apnea, along with reductions in doses of insulin which could result in cost savings from a healthcare payer perspective.
Analyses assessing the long-term cost-effectiveness of once-weekly semaglutide versus dulaglutide 1.5 mg and liraglutide 1.2 mg in patients with inadequate glycemic control on oral anti-hyperglycemic medications have been published for the UK, Canadian, Swedish and Estonian settingsCitation40–43. In these analyses, both once-weekly semaglutide 0.5 mg and 1 mg were found to be dominant versus dulaglutide 1.5 mg in the UK, once-weekly semaglutide 0.5 mg was dominant versus dulaglutide 0.75 mg and once-weekly semaglutide 1 mg was dominant versus dulaglutide 1.5 mg in Canada, and once-weekly semaglutide 1 mg was dominant versus dulaglutide 1.5 mg in Sweden. In Estonia, once-weekly semaglutide 1 mg was found to be cost-effective versus liraglutide 1.2 mg. However, the present analysis is the first long-term cost-effectiveness analysis to compare once weekly semaglutide with an SGLT-2 inhibitor. This comparison is highly relevant to healthcare providers, as both interventions are recommended for patients not achieving glycemic control targets on metformin where there is a need to minimize weight gain or promote weight loss, and in patients with established atherosclerotic cardiovascular diseaseCitation5.
Currently, in Spain, the reimbursement of GLP-1 receptor agonists is restricted to patients with a BMI ≥30 kg/m2. Conversely, no restrictions based on BMI are applied to the reimbursement of SGLT-2 inhibitors. The present analysis suggests that once-weekly semaglutide is cost-effective in the Spanish setting, irrespective of patients’ BMI, and, therefore, that the reimbursement restrictions should be relaxed. Other treatment options for patients not achieving glycemic control on oral anti-hyperglycemic medications include dipeptidyl peptidase-4 (DPP-4) inhibitors and other GLP-1 receptor agonists. Once-weekly semaglutide has been shown to be more efficacious than the DDP-4 inhibitor sitagliptin in the SUSTAIN 2 trialCitation11. Furthermore, no DPP-4 inhibitor has demonstrated a favorable impact on cardiovascular risk, with sitagliptin, saxagliptin, alogliptin and linagliptin all shown to be non-inferior to placebo in terms of their impact on MACECitation44–47. The SUSTAIN 7 trial provides head-to-head evidence of once weekly semaglutide (0.5 mg and 1.0 mg) versus dulaglutide (0.75 mg and 1.5 mg), with once-weekly semaglutide shown to be more effectiveCitation16. Furthermore, the SUSTAIN 3 study compared once-weekly semaglutide 1 mg with exenatide extended release, with once-weekly semaglutide again shown to be more effectiveCitation13. An NMA to compare once-weekly semaglutide with GLP-1 receptor agonists not included in the SUSTAIN trial program has been conductedCitation48. Once-weekly semaglutide 1 mg was associated with significantly greater reductions in HbA1c and body weight than all included comparators, while once-weekly semaglutide 0.5 mg was associated with significantly greater reductions in HbA1c and body weight than the majority of comparators. Once-weekly semaglutide has been shown to reduce the risk of MACE in the SUSTAIN 6 trialCitation25. Likewise, liraglutide, dulaglutide and albiglutide (now withdrawn from sale) have demonstrated cardiovascular benefits in the LEADER, REWIND and HARMONY Outcomes trials, respectivelyCitation49–51. Further cost-effectiveness analyses are therefore required to assess the cost-effectiveness of all available alternative treatments, in order to provide a complete evidence base for healthcare decision makers.
No head-to-head clinical trials comparing once-weekly semaglutide with empagliflozin have been published, and therefore an NMA was used to inform the analysis, which could be considered a limitation. However, selection of the most appropriate comparators was the first priority in the analysis, and use of evidence synthesis, using recommended methodologies, is becoming increasingly important and accepted for health technology assessment globallyCitation52,Citation53.
A further limitation of the analysis is that adverse events could not be included in the assessment of cost-effectiveness, as these were not included in the NMA. While both once-weekly semaglutide and empagliflozin are associated with low rates of hypoglycemic events, and these would be unlikely to change the conclusions of the analysis, adverse events specific to each intervention should be considered. GLP-1 receptor agonists are associated with gastrointestinal side effects, while SGLT-2 inhibitors are associated with genital mycotic infections and urinary tract infections, but these events were not included in the NMA. Data on the frequency of adverse events with GLP-1 receptor agonists and SGLT-2 inhibitors have recently become available from the SUSTAIN 8 (once-weekly semaglutide versus canagliflozin) clinical trialCitation24. In the SUSTAIN 8 trial, gastrointestinal disorders, most commonly nausea, were the most frequently reported adverse events with once-weekly semaglutide 1 mg, whereas urinary tract infections were the most frequently reported adverse event with canagliflozin 300 mg.
As with all long-term assessments of cost-effectiveness, the study was reliant on relatively short-term data to make long-term projections. However, long-term projections remain a valuable tool to inform healthcare decision making, and projecting outcomes over patient lifetimes are recommended in guidelines for economic evaluation of interventions for patients with T2DCitation30. Whilst there is always an element of doubt around the accuracy of long-term projections, a model of T2D that has been extensively published and validated against real-life data both on first publication and recently following a series of model updates was used to mitigate this, in addition to conducting extensive sensitivity analysesCitation28,Citation29.
Conclusions
Data from an NMA have shown that once-weekly semaglutide is associated with improved short-term clinical outcomes compared with empagliflozin in patients with T2D with inadequate glycemic control on oral anti-hyperglycemic medications. The present analysis suggests that these short-term improvements result in long-term benefits, including a reduced cumulative incidence and delayed time to onset of diabetes-related complications, increased life expectancy, and increased quality-adjusted life expectancy. Therefore, based on a willingness-to-pay threshold of EUR 30,000 per QALY gained, once-weekly semaglutide 0.5 mg and 1 mg were projected to be cost-effective versus empagliflozin 10 mg and 25 mg for the treatment of patients with T2D with inadequate glycemic control on oral anti-hyperglycemic medications in the Spanish setting, irrespective of patients’ BMI at baseline.
Transparency
Declaration of funding
The present cost-effectiveness analysis and article processing charges were supported by funding from Novo Nordisk A/S.
Declaration of financial/other interests
Juan José Gorgojo-Martínez has the following financial relationships: advisor on scientific boards for AstraZeneca, Janssen Pharmaceuticals, Eli Lilly and Company, Merck Sharp & Dohme, Mundipharma, Novo Nordisk and Pfizer; lectures for Abbott, AbbVie Inc, AstraZeneca, Boehringer Ingelheim Pharmaceuticals Inc, Esteve, Janssen Pharmaceuticals, Eli Lilly and Company, Merck Sharp & Dohme, Novo Nordisk, Pfizer, Roche Pharma and Sanofi Aventis, and research activities for AstraZeneca, Novo Nordisk and Sanofi Aventis. Virginia Martín is an employee of Novo Nordisk Pharma SA. Nino Hallén is an employee of Novo Nordisk A/S. Samuel Malkin and Barnaby Hunt are employees of Ossian Health Economics and Communications, which received consulting fees from Novo Nordisk A/S to support the preparation of the analysis. JME peer reviewers on this manuscript have no relevant financial or other relationships to disclose.
Author contributions
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval for the version to be published. All authors had full access to all of the data in this study and take complete responsibility for the integrity of the data and accuracy of the data analysis.
The study was conceived and designed by Barnaby Hunt and Virginia Martín. Data were collected by Barnaby Hunt, Sam Malkin, and Virginia Martín. The analysis was performed by Barnaby Hunt. The manuscript was written by Juan José Gorgojo-Martínez, Samuel Malkin, Virginia Martín, Nino Hallén and Barnaby Hunt.
Previous presentations
This analysis has not been presented previously.
Acknowledgements
No assistance in the preparation of this article is to be declared.
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