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Cost-Effectiveness Analysis of Incretin Therapy for Type 2 Diabetes in Spain: 1.8 mg Liraglutide Versus Sitagliptin

Objectives Metformin is the first-line therapy for most patients with type 2 diabetes, but the majority require treatment intensification at some stage due to the progressive nature of the disease. The 1860-LIRA-DPP-4 trial showed that liraglutide exhibited greater improvements compared with sitagliptin in glycated hemoglobin and body mass index in patients with type 2 diabetes inadequately controlled on metformin monotherapy. As a follow-up to a previously published cost-effectiveness analysis of 1.2 mg liraglutide versus sitagliptin in Spain, the aim of this analysis was to compare long-term projections of the clinical and cost implications associated with 1.8 mg liraglutide and sitagliptin. Methods For the modeling analysis, 52-week treatment effect data (as opposed to 26-week data in the previous analysis) were taken from the 1860-LIRA-DPP-4 trial, for adults with type 2 diabetes receiving 1.8 mg liraglutide or 100 mg sitagliptin daily in addition to metformin. Long-term (patient lifetime) projections of clinical outcomes and direct costs (2012 EUR) were made using a published and validated model of type 2 diabetes, with modeling assumptions as per the 1.2 mg liraglutide analysis. Results Liraglutide was associated with increased life expectancy (14.24 versus 13.87 years) and quality-adjusted life expectancy [9.24 versus 8.84 quality-adjusted life years (QALYs)] over sitagliptin. Improved clinical outcomes were attributable to the improvement in glycemic control, leading to a reduced incidence of diabetes-related complications, including renal disease, cardiovascular disease, ophthalmic and diabetic foot complications. Liraglutide was associated with increased direct costs (EUR 56,628 versus EUR 52,450), driven by increased pharmacy costs. Based on these estimates, liraglutide was associated with an incremental cost-effectiveness ratio of EUR 10,436 per QALY gained versus sitagliptin. Conclusions A previous analysis has suggested that 1.2 mg liraglutide is cost-effective from a healthcare payer perspective in Spain, and the present analysis suggests that the 1.8 mg dose is also likely to be cost-effective. Electronic supplementary material The online version of this article (doi:10.1007/s13300-015-0103-5) contains supplementary material, which is available to authorized users.


INTRODUCTION
Hyperglycemia in type 2 diabetes results from insulin resistance in the peripheral tissues, insulin deficiency due to insufficient pancreatic output, and excessive hepatic glucose output and is associated with serious microvascular and macrovascular complications [1]. Early initiation of treatment can delay disease progression, and achieving evidencebased clinical goals by implementing effective management strategies substantially reduces the risk of morbidity and mortality and ultimately improves patient outcomes [2][3][4].
Metformin remains the first-line therapy for most patients with type 2 diabetes mellitus.
However, due to the progressive nature of the disease, with beta cell function declining over time, the majority of patients require additional therapy to maintain glycemic control. Long-standing second-line interventions include sulfonylureas and thiazolidinediones, and whilst these therapies are effective in achieving glycemic control, they are associated with weight gain, increased risk of hypoglycemic events, and/or cardiovascular concerns [5].
In an attempt to improve treatment of type 2 diabetes, a number of new therapies targeting the incretin axis have been developed [6]. These therapies exert effects in a number of different target tissues to address the complex pathophysiology of the disease. Incretin-based therapy has been shown to stimulate glucosedependent insulin secretion, reduce glucagon secretion, improve beta cell function, slow gastric emptying, increase satiety, reduce appetite, and general benefits beyond the pancreas. Two classes of incretin therapy have with reductions in glycated hemoglobin (HbA1c), but reductions may be more substantial with GLP-1 receptor agonists (0.5-1.6% reduction versus 0.5-1% reduction) [7]. Furthermore, GLP-1 receptor agonists are associated with weight loss [8][9][10][11][12][13] whereas DPP-4 inhibitors have been associated only with the prevention of weight gain [14][15][16][17].
Whilst the interventions that target the incretin axis provide a more rounded approach to treatment of type 2 diabetes than traditional second-line interventions, they also come at an increased cost in the short term, although this can be partially offset by avoidance of treatment of diabetes-related complications over a patient's lifetime as a result of better control. In a publically funded healthcare system, such as Spain, the aim is to maximize health outcomes across the population with the finite resources available. Healthcare payers must make decisions on how best to allocate these scarce resources, and economic evaluation of new and existing healthcare interventions is playing an increasingly important role in informing these decisions [18,19].
A previous study investigating the costeffectiveness analysis of liraglutide 1.2 mg versus sitagliptin in the Spanish setting demonstrated that liraglutide was associated with improved life expectancy and qualityadjusted life expectancy but was associated with increased costs [20]. The analysis concluded that liraglutide 1.2 mg was costeffective compared to sitagliptin over patient lifetimes. However, liraglutide is available in two doses, either 1.2 or 1.8 mg per day. The liraglutide trial program has shown that the increased dose is associated with improved clinical outcomes over the lower dose, but this increased efficacy comes at an increased pharmacy cost.
As a follow-up analysis to the previously published cost-effectiveness analysis of liraglutide 1.2 mg versus sitagliptin, the present analysis aimed to assess the costeffectiveness of liraglutide 1.8 mg versus sitagliptin in patients failing to achieve adequate glycemic control on metformin monotherapy in the Spanish setting. A secondary analysis was also conducted, in which the cost-effectiveness of delaying GLP-1 receptor agonist therapy, with a year of DPP-4 inhibitor therapy first, was investigated.

Modeling Analysis
The present analysis is a further extension of the cost-effectiveness analysis of liraglutide 1.2 mg versus sitagliptin in Spain, with two major differences. The first is the evaluation of the 1.8 mg dose of liraglutide (rather than the 1.2 mg dose), and the second is the use of trial data from the 52-week endpoint (rather than the 26-week endpoint). The methods used in this analysis are consistent with the previously published cost-effectiveness analysis of liraglutide 1.2 mg versus sitagliptin, and therefore are only outlined briefly here [20]. The analysis was performed using the CORE Diabetes Model (IMS Health, Basel, Switzerland), a non-product specific diabetes policy analysis tool. The model functionality has been previously described, and the longterm outcomes projected by the model have been validated against real-life data at first publication in 2004 and following a series of updates in 2013 [21][22][23].
The model was used to project life expectancy, quality-adjusted life expectancy, cumulative incidence of diabetes-related complications, time to onset of diabetesrelated complications and direct medical costs for patients receiving liraglutide 1.8 mg daily or sitagliptin 100 mg daily in the Spanish setting.
In line with published health economic guidance for Spain, future costs and clinical benefits were discounted symmetrically by 3% per annum [24]. The time horizon was set to patient lifetimes in the base case to capture all relevant long-term complications, associated costs, and to assess their impact on life expectancy and quality-adjusted life expectancy.

Treatment Effects and Risk Factor Progression
In the previously published cost-effectiveness analysis of liraglutide 1.2 mg daily, treatment effect data were taken from the 26-week primary endpoint [20,25]. In the present analysis, the treatment effects applied in the first year of the modeling analysis (Table 1) were taken from the 52-week time point as this longer follow-up data may represent a more robust source for longterm modeling, although it was not the primary endpoint of the trial (a sensitivity analysis using the primary endpoint data was conducted) [26].
Assumptions regarding progression of risk factors in the following years of the simulation were aligned with the cost-effectiveness analysis of liraglutide 1.2 mg versus sitagliptin [20].
HbA1c was assumed to remain unchanged for the duration of the analysis, as this allows the modeling analysis to capture the legacy effect, where benefits of reductions in HbA1c early in a patient's life persist even after the HbA1c reduction has been abolished. Systolic blood pressure increased based on the UKPDS progression equation, whilst serum lipids followed the Framingham progression equations [21]. As in the previous analysis, patients were assumed to receive incretin therapy for 5 years, before intensifying treatment to basal insulin (with the previously received incretin therapy withdrawn). On treatment intensification, BMI was assumed to return to baseline and hypoglycemia event rates were assumed to be the same in both arms, but no other treatment effects were applied. HbA1c glycated hemoglobin, HDL high-density lipoprotein, LDL low-density lipoprotein, SBP systolic blood pressure, SD standard deviation * p\0.001 [26] Costs and Utilities Costs were accounted from the perspective of a healthcare payer in Spain in 2012 EUR. All costs were as per the previous cost-effectiveness evaluation of liraglutide 1.2 mg versus sitagliptin in Spain [20]. Utilities were in line with the previous cost-effectiveness analysis in Spain, and a cost-effectiveness analysis of liraglutide versus sitagliptin carried out in the UK setting [20,27]. Full details of the costs and utilities are provided in the online supplementary information.

Sensitivity Analyses
A number of sensitivity analyses were conducted to evaluate the robustness of the modeled outcomes to changes in input parameters, and to identify key drivers of results. These were consistent with the previously published analysis of liraglutide

Base Case Analysis
Treatment with liraglutide 1.8 mg was associated with a mean increase in discounted life expectancy of 0.37 years over treatment with sitagliptin (Table 3)

Sensitivity Analyses
Sensitivity analyses found that the costeffectiveness outcomes were most sensitive to changes in the time horizon of the modeling analysis, with liraglutide less cost-effective over shorter time horizons (Table 4). As the time horizon was reduced, the ICER increased, with a    stable when the costs of complications were varied, when treatment switching was assumed to take place earlier or later, and when the 26-week trial data were used.

Secondary Analysis
In the secondary analysis, receiving sitagliptin for 1 year followed by liraglutide 1. Sensitivity analyses showed the same patterns as in the primary analysis. Analyses identified that the key driver of costeffectiveness was the HbA1c improvement seen when patients switched from sitagliptin to liraglutide at the end of the first year of the analysis. Switching patients to liraglutide was found to be cost-effective as a result of a reduced incidence of diabetes-related complications over the long term, as shown by the analyses in which the time horizon and discount rates were changed.

DISCUSSION
A previous cost-effectiveness analysis in the Spanish setting has suggested that liraglutide 1.2 mg is a cost-effective treatment option, versus sitagliptin, for patients with type 2 diabetes not achieving glycemic control on metformin monotherapy [20]. The present analysis has aimed to expand on the previously published work, by investigating the cost-effectiveness of liraglutide 1.8 mg in Spain based on the 52-week trial data. It was found that liraglutide 1.8 mg was associated with improved life expectancy and qualityadjusted life expectancy compared with sitagliptin in the Spanish setting. Clinical improvements resulted from a reduced incidence and increased time to onset of diabetes-related complications, driven predominantly by a greater reduction in HbA1c, but changes in systolic blood pressure, serum lipid levels and BMI were also found to be important. Liraglutide was associated with an increase in direct medical costs over patient lifetimes. This resulted from the increased acquisition cost of liraglutide over the short term, but was partially offset by avoidance of treatment of diabetes-related complications over the long term. Based on the projected outcomes, liraglutide 1.8 mg was associated with an ICER of EUR 10,436 versus sitagliptin in the Spanish setting for patients with type 2 diabetes not achieving glycemic targets on metformin monotherapy. This ICER falls below the commonly quoted willingness to pay threshold of EUR 30,000 per QALY gained [29][30][31], and therefore liraglutide 1.8 mg is likely to be considered a cost-effective treatment option in patients failing to meet glycemic targets on metformin monotherapy.
In the 1860-LIRA-DPP-4 study, the 1. NCT01794143] study, due to report in 2020 [33]. Patients will be randomly assigned to one of four diabetes medications (liraglutide, sitagliptin, glimepiride, and insulin glargine) and followed for 7 years. When this study is complete it will provide a large amount of clinical effectiveness data, and will form a key data source for future economic evaluation when the study reports in 2020.  [25,26].
The impact of adherence to the two diabetes medications evaluated should also be considered. It has been suggested that injectable diabetes medications may be associated with lower adherence than oral medications as a result of the method of delivery [34]. However, it has also been proposed that the favorable clinical profile of incretin therapies, in terms of low hypoglycemic event rates and weight loss, may result in improved adherence compared to conventional diabetes treatments [35]. Whilst adherence to alternative GLP-1 receptor agonists has been assessed, currently there is no evidence to suggest that injectable GLP-1 receptor agonists are associated with lower adherence rates than oral DPP-4 inhibitors [36,37]. Moreover, the impact of adherence on costeffectiveness is difficult to assess, as both clinical outcomes and costs will be affected by adherence rates. The conclusions of the present analysis may only be valid for patients who are adherent to the diabetes medications received.
In conclusion, clinical trials have shown that both liraglutide and sitagliptin are effective treatments for patients not achieving glycemic targets on metformin monotherapy. In the recently published 1860-LIRA-DPP-4 trial, liraglutide 1.8 mg was associated with greater improvements in HbA1c and BMI than sitagliptin [25,26]. Projecting these outcomes over patient lifetimes using a published and validated cost-effectiveness model suggested that liraglutide 1.8 mg is likely to be costeffective versus sitagliptin in the Spanish setting for patients failing to meet glycemic targets on metformin monotherapy. The secondary analysis suggests that initiating liraglutide earlier, rather than after a year of sitagliptin therapy first, is the optimum method for maximizing health outcomes and costeffectiveness. The results of the previous and present analyses suggest that both the 1.2 and 1.8 mg doses of liraglutide are likely to be costeffective for patients with type 2 diabetes not achieving glycemic targets on metformin monotherapy from a healthcare payer perspective in Spain.