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Cost-Effectiveness of Insulin Degludec/Insulin Aspart Versus Biphasic Insulin Aspart in Patients with Type 2 Diabetes from a Danish Health-Care Perspective

Introduction To evaluate the cost-effectiveness of the co-formulation insulin degludec/insulin aspart (IDegAsp) versus biphasic insulin aspart (BIAsp 30), both administered twice daily, in patients with type 2 diabetes mellitus (T2DM), using a short-term cost-effectiveness model. Methods Data from two phase 3a treat-to-target clinical trials were used to populate a simple and transparent short-term cost-effectiveness model. The costs and effects of treatment with IDegAsp versus BIAsp 30 were calculated over a 5-year period, from a Danish health-care cost perspective. One-way and probabilistic sensitivity analyses were conducted to assess the degree of uncertainty and robustness of the results. Results The base-case incremental cost-effectiveness ratio (ICER) of 81,507.91 Danish Kroner (DKK) per quality-adjusted life year (QALY) demonstrates that IDegAsp is a cost-effective treatment compared with BIAsp 30, over a 5-year time horizon. One-way sensitivity analyses show that the ICERs remain within an acceptable range when the rates of hypoglycemia, unit cost of hypoglycemia, disutilities of hypoglycemic events, and the time horizon are varied, ranging from 71,012 DKK to 209,446 DKK. The probabilistic sensitivity analysis demonstrates that the probability that IDegAsp is cost-effective relative to BIAsp 30 is 99.50%, assuming a cost-effectiveness threshold of 250,000 DKK per QALY. Conclusion This short-term cost-effectiveness model shows that IDegAsp is a cost-effective treatment compared with BIAsp 30 for patients with T2DM. This result is primarily driven by significant reductions in severe hypoglycemia and insulin dose observed with IDegAsp versus BIAsp 30. Sensitivity analyses demonstrate the robustness of these results. Funding Novo Nordisk A/S, Søborg, Denmark. Electronic supplementary material The online version of this article (doi:10.1007/s13300-016-0195-6) contains supplementary material, which is available to authorized users.


INTRODUCTION
Due to the progressive nature of type 2 diabetes mellitus (T2DM), patients usually require treatment intensification to maintain glycemic control, eventually resulting in insulin therapy [1]. After treatment failure on basal insulin, guidelines recommend intensification with either a glucagon-like peptide-1 receptor agonist (GLP-1RA) or mealtime (bolus) insulin [1]. Premixed insulin can offer a convenient alternative to basal-bolus therapy, controlling both fasting and postprandial glucose with fewer injections. However, premixed insulin requires resuspension, and insufficient mixing can result in incorrect dosing [2].
Insulin degludec/insulin aspart (IDegAsp) is the first soluble co-formulation of a basal and a rapid-acting insulin analog in a single injection.
The unique properties of insulin degludec (IDeg) enable combination with the rapid-acting insulin, insulin aspart [3]. IDeg has a long duration of action, with a longer half-life and less within-patient variability versus insulin glargine [4,5]. The IDegAsp soluble co-formulation has the additional advantage that it does not require resuspension, eliminating the risk of incomplete mixing, which can lead to hypoglycemia [6]. The efficacy and safety of IDegAsp was investigated in a phase 3 clinical program (BOOST). A combined analysis of two trials [7,8] comparing IDegAsp twice daily (BID) with biphasic insulin aspart (BIAsp 30) BID in insulin-experienced patients with T2DM showed that, at similar levels of glycemic control, IDegAsp resulted in a lower fasting plasma glucose (PG), lower rate of overall and nocturnal hypoglycemia and less weight gain compared with BIAsp 30, all at a lower insulin dose [9].
To optimize the use of health-care resources, the decision to prescribe a particular product is dependent on clinical and economic evidence. Therefore, it is important that the cost-effectiveness of diabetes interventions is investigated. The cost-effectiveness analyses of diabetes interventions have historically been conducted by estimating the long-term clinical consequences as a function of differences in HbA 1c . However, according to the US Food and Drug Administration guidance, new insulins should be compared with a standard insulin (and not placebo or a non-insulin agent), aiming to achieve similar glycemic control, thus allowing the comparison of safety end points, such as hypoglycemia, body weight, and insulin dose [10,11]. This approach is known as 'treat-to-target'. It follows that there are no differences in long-term risk parameters related to HbA 1c , and a short-term cost-effectiveness model is more appropriate for an economic evaluation of these secondary end points than a long-term model. Such a model has been used to compare treatment with IDeg versus insulin glargine in patients with type 1 diabetes mellitus (T1DM) and T2DM, from Swedish and UK health-care perspectives [12][13][14].  [7]. The second trial (Intensify All; ClinicalTrials.gov identifier: NCT01059812) was a pan-Asian study involving patients from five countries randomized 2:1 to IDegAsp or BIAsp 30, with T2DM for C6 months, C18 years of age (C20 years for Japan and Taiwan), HbA 1c of 7.0-10.0%, and BMI B35 kg/m 2 , who were previously treated with basal, premixed, or self-mixed insulin ± metformin for C3 months [8]. The trial designs were similar, and the patient characteristics are summarized in the primary publications [7,8]. In total, 868 patients were included (IDegAsp n = 504; BIAsp 30 n = 364). Insulin was titrated weekly to a pre-meal SMBG target of 4.0-5.0 mmol/L. Patients with significant concomitant illness [e.g., history of cardiovascular disease (heart failure: New York Heart Association class III or IV, unstable angina pectoris, or a myocardial infarction) within 6 months preceding the trial and uncontrolled severe hypertension (systolic blood pressure C180 mmHg or sitting diastolic blood pressure C100 mmHg)] and those with recurrent severe hypoglycemia or hypoglycemic unawareness were excluded.

Clinical Data
Insulin Dose Daily insulin dose in units (U) was captured during the clinical trials. In this combined analysis, the BIAsp 30 dose was 45.7 U/day at baseline, 81.8 U/day at the end of titration, and 86.2 U/day at the end of the trial (Table 1a). The dose ratios (IDegAsp/IAsp 30) were 0.84 at both the end of titration and end of trial in the combined analysis and assumed to be 1 at baseline ( Hypoglycemia Rates Baseline values for severe and non-severe hypoglycemia were based on the UK Hypoglycaemia Study Group (UKHSG) observational study [18]. The rates represent a better estimation of real-life rates compared with data from clinical trials, where a bias in patient selection and treatment setting occurs, resulting in potentially lower rates of Fig. 1 Structure of the cost-effectiveness model. The model captured treatment costs (including insulin, needles, and costs associated with SMBG testing) and costs associated with hypoglycemic events (the resource used to treat the event multiplied by the hypoglycemic event rate) for both IDegAsp and comparator. QALYs were calculated by applying disutilities (reduction in HRQoL) per hypoglycemic event, SMBG test, and BMI gain. BIAsp 30 biphasic insulin aspart, BMI body mass index, HC health care, HRQoL health-related quality of life, ICER incremental cost-effectiveness ratio, IDegAsp insulin degludec/insulin aspart, QALY quality-adjusted life year, SMBG self-measured blood glucose hypoglycemia due to the exclusion of patients with recurrent severe hypoglycemia or hypoglycemic unawareness [19][20][21][22][23][24][25]. The T2DM group which used insulin for more than 5 years was perceived as being representative of the population who would consider using IDegAsp. BIAsp 30 biphasic insulin aspart, BID twice daily, BMI body mass index, IDegAsp insulin degludec/insulin aspart, NS non-significant, T2DM type 2 diabetes mellitus, UKHSG UK Hypoglycaemia Study Group * Significant, P\0.05 a Derived from a combined analysis of insulin dose (a post hoc analysis) b Dose ratio assumed equal at baseline c Insulin dose ratios derived from the combined analysis [9] d Baseline hypoglycemia rates are mean rates for patients with T2DM using insulin for more than 5 years included in UKHSG [18] e Proportion of daytime/nocturnal events for BIAsp 30 taken from the combined analysis (a post hoc analysis) f Event rate ratios were derived from the combined analysis [9], and the relative rates were adjusted for treatment, trial, anti-diabetic therapy at screening, sex, and region as fixed factors and age as a continuous covariate. In case of non-significant results, a relative rate of one was used in the calculation g Derived from a combined analysis of BMI (a post hoc analysis) h Calcuated from BIAsp30 BID change from baseline and subtracting the treatment difference The rates of hypoglycemia reported were 10.2 and 0.7 events per patient year of exposure (PYE) for non-severe and severe hypoglycemia, respectively [18]. These estimates were taken as the base case for the comparator BIAsp 30 group (Table 1b). To estimate the corresponding hypoglycemic event rates for IDegAsp, the relative rate ratio of hypoglycemia derived from the combined analysis was applied ( with an average of 5.6 additional SMBG tests per non-severe hypoglycemic event [30], and a study that reported an increase of 3.7 SMBG tests per event in Denmark [31]. It was conservatively assumed that this testing pattern was similar for severe events as the extra SMBG tests following hypoglycemic events were collected for the non-severe events only in the clinical trials.

Utility Data
The effects that were incorporated in the model were the disutility (reduction in quality of life) associated with hypoglycemia [32], weight gain (measured as BMI) [33], and frequency of SMBG testing [34]. The multiplication of utilities and life years then provided QALYs.  [32]. Disutility values were 0.057 for a severe event and 0.004 and 0.007 for non-severe daytime and non-severe nocturnal hypoglycemic events, respectively [32]. There was a significant difference in disutility associated with non-severe daytime and non-severe nocturnal hypoglycemia [32]. To investigate the incremental impact of IDegAsp, the disutility per hypoglycemic event was multiplied by the event rate per year. This was estimated separately for severe, non-severe daytime, and non-severe nocturnal hypoglycemic events.

Disutility per Hypoglycemic Event
Disutility of SMBG testing The disutility (pain and discomfort) associated with SMBG testing was also investigated using a TTO survey, giving a disutility per additional SMBG of 0.0000221 [34], which was multiplied by the number of SMBG tests per year.  [33].

One-Way Sensitivity Analyses
To assess the robustness of these data and the impact of varying key assumptions and outcomes used in the base case on the cost-effectiveness results, several one-way sensitivity analyses were conducted (Table S1 in the supplementary material).
The base-case time horizon was 5 years, so the effects of time horizons of 1, 2, 3, and 10 years were investigated. Sensitivity analyses with discount rates of 0% and 5% were applied to investigate the effect of discounting.
Hypoglycemia event rates for Denmark from a recent multinational observational study were included as a sensitivity analysis, which reported severe, non-severe daytime, and nocturnal rates of 0.3, 13.6, and 8.3 events per  [29] e Hospitalization fee assumed (DRG 1013 charge) [47] f Assumed to be a fee of an acute hospital service for B24 h (DAGS AA01C charge) [48] g Assumed to be a GP visit fee (0101). Danish Medical Association fee [49] h Assumed to be an ambulatory hospital visit (BG50A) [48] i Assumed to be the cost of telephone consultation with a GP (0201). Danish Medical Association fee [49] j The cost of an SMBG test was calculated as the price of one test strip plus one lancet based on the lowest price of SMBG test strips and lancets on the wholesaler Nomeco's price list [28] ( The disutility associated with BMI was assumed to be zero in a sensitivity analysis.  (Table S2 in the supplementary material). The PSA allows for an estimate of the certainty that a given intervention is cost-effective at different cost-effectiveness thresholds to be evaluated.

Probabilistic Sensitivity Analysis
The PSA were repeated with 10,000 iterations.

Compliance with Ethics Guidelines
This article is based on previously conducted studies and does not involve any new studies of human or animal subjects performed by any of the authors.

RESULTS
This analysis shows that IDegAsp is a cost-effective treatment option compared with BIAsp 30 in patients with T2DM. The estimated ICER in the base-case analysis was 81,507.91 DKK ( Table 4).
The total incremental discounted cost per patient over 5 years of IDegAsp compared to BIAsp 30 treatment was 18,125.94 DKK, mainly due to an increased insulin cost (Table 4). A lower incremental cost of treating non-severe and severe hypoglycemia was observed (Table 4), due primarily to the statistically significant reduction in hypoglycemic events in the maintenance period with IDegAsp versus BIAsp 30 in the combined analysis (Table 1).

One-Way Sensitivity Analyses
In all sensitivity analyses, ICERs were below normally accepted thresholds, with estimates ranging from 71,012 DKK to 209,446 DKK per QALY gained (Table S1). Varying the time horizon had a small impact on the ICER, with a lower cost per QALY gained with a 10 year time horizon. Similarly, changing the discount rate did not have a significant impact on the ICER. The rate of hypoglycemia applied to the model had a larger impact on the results, with the higher published rates from Denmark [35,36] resulting in a lower ICER (71,012 DKK) compared to the base case.
Using the observed hypoglycemia event rates from the combined analysis, where fewer severe hypoglycemic events were observed than in the UKHSG study, IDegAsp was cost-effective with an ICER of 153,440 DKK per QALY gained.
When the cost of hypoglycemia was increased or decreased by 20%, IDegAsp was still cost-effective versus BIAsp 30, with ICERs of 76,049 DKK and 86,968 DKK, respectively.
Using the disutilities per hypoglycemic event published by Currie et al. [37] resulted in an ICER of 209,446 DKK. Using the clinical data from the global trial instead of the combined analysis resulted in an ICER of 100,289 DKK [7].
Assuming a disutility per SMBG test of 0 did not have a significant impact on the ICER, compared with the base case.

Probabilistic Sensitivity Analysis
The PSA input variables are outlined in Table S2 in the supplementary material. At a willingness-to-pay threshold of 250,000 DKK per QALY gained, the probability that IDegAsp was cost-effective relative to BIAsp 30 was 99.5% (Fig. S1 in the supplementary material).  [39,40]. The two-trial combined analysis was used in the base-case model to increase the sample size and thereby strengthen the certainty of the parameter estimates derived from individual trials. Previously, a pre-specified hypoglycemia meta-analysis using pooled data from seven trials in the IDeg clinical program was conducted [41].
The combined analysis used here was not pre-specified; however, it was conducted using the same methodology as the IDeg meta-analysis [41] the hypoglycemia classification described in a second IDeg meta-analysis [42].
The combined analysis showed that, at similar HbA 1c levels, IDegAsp resulted in lower rates of overall and nocturnal confirmed hypoglycemia, particularly during the maintenance period, and less weight gain compared with BIAsp 30, while using a lower dose [9]. Although hypoglycemia is not a problem for all insulin-treated patients, its frequency tends to increase with longer disease duration and more intensive insulin regimens [23]. Additionally, treatment of hypoglycemia is associated with considerable resource use and cost and is a burden to patients [29,43,44]. In this analysis, the difference in the rates of hypoglycemia had a noticeable impact on the ICER. In this model, the mean population rates of hypoglycemia from published studies were used in the base case and sensitivity analysis [18,35,36]  All modeling approaches are critically influenced by the quality of the input parameters. This model only used parameter estimates for which a statistically significant difference between the treatment arms was documented and assumed that all other differences were due to random variation. This cost-effectiveness model is limited by a variety of factors. The clinical data are derived from post hoc analyses of two clinical trials. The generalizability of clinical trials with high internal validity but usually low external validity, due to the highly selected population, which may not be representative of a real world clinical practice setting, is a common limitation inherent to economic modeling. The model assumed patients continued treatment with IDegAsp and BIAsp 30 for the 5-year period, without changing to another insulin regimen.
As the data are based on treat-to-target clinical trials with no differences in HbA 1c , any differences in mortality and morbidity are not expected and so not included in the model.
As with most models, the cost data for hypoglycemia were collected from a variety of publicly available sources, which measure parameters differently and may not accurately