Introduction
The cost of treating diabetes and its related complications represents a major economic burden for healthcare systems. The prevalence of diabetes is increasing and the global expenditure on diabetes is projected to reach $490 billion USD by 2030 [
1]. In the UK, diabetes cost approximately £23.7 billion in 2010/2011, and it is projected to cost an estimated £39.8 billion by 2035/2036 [
2]. The greatest proportion of diabetes expenditure is for treatment of micro- and macrovascular complications, which are consequences of prolonged hyperglycaemia [
2]. A key treatment goal of diabetes therapy is to keep blood glucose levels within recommended targets and ultimately limit the development of diabetes-related complications [
3,
4].
Insulin is essential for the treatment of type 1 diabetes (T1DM) [
5]. Type 2 diabetes (T2DM) is a progressive disease and although glycaemic control can often be achieved with other classes of glucose-lowering therapies following diagnosis, a significant proportion of patients will eventually need insulin therapy to achieve optimal blood glucose targets [
6]. Insulin is the most effective method of reducing blood glucose concentrations; however, despite evidence-based consensus guidance and documented benefits of good glycaemic control, many patients fail to achieve glycaemic targets [
7]. Key barriers to insulin therapy include fear and risk of hypoglycaemia, weight gain, restricted lifestyle, reluctance to inject and difficulties with complex treatment regimens [
8,
9].
New basal insulin analogues with improved pharmacodynamic and pharmacokinetic profiles, which confer a lower risk of hypoglycaemia and more flexible dosing schedules, have been developed with the aim of improving long-term glycaemic control and the patient’s experience with basal insulin therapy.
Insulin degludec (IDeg) is a basal insulin with an ultra-long duration of action (more than 42 h) and a flat and stable action profile [
10,
11]. It has four times less day-to-day variability in glucose-lowering effect than insulin glargine U100 (IGlar U100) [
12]. In meta-analyses of phase 3a clinical trials, IDeg showed equivalent reductions in HbA
1c with a lower risk of hypoglycaemia versus IGlar U100, and at a significantly lower daily dose when compared with IGlar U100 in T1DM (12% lower) and T2DM basal oral therapy (10% lower) [
13,
14]. The benefits of IDeg have also been reported in real world clinical practice. A study of 51 patients in routine practice in the UK, who were suffering from recurrent hypoglycaemia on IGlar U100 or insulin detemir, found that switching to IDeg resulted in significant reductions in hypoglycaemia (>90%) and improved glycaemic control [
15].
With increasing constraints on healthcare budgets, it is important that new therapies represent good value for money. Cost-effectiveness models estimate the costs of interventions or services in relation to their expected health benefits. Cost-effectiveness modelling helps decision makers determine whether the health benefits associated with adopting the novel treatment are worth the cost compared with existing therapies.
Cost-effectiveness models are developed to compare the overall costs and health outcomes of two or more treatments. Results of an economic model are typically presented as an incremental cost-effectiveness ratio (ICER), which is the difference in cost between one healthcare intervention and an alternative, divided by the difference in health effects. A generally accepted effectiveness measure used in cost-effectiveness analyses is the quality-adjusted life year (QALY). The QALY is an overall measure of health as a combination of the duration of life and the health-related quality of life [
16]. The incremental cost-effectiveness per additional QALY gained (cost/QALY) allows decision makers to broadly compare across different disease areas to determine where the provision of healthcare resources will lead to maximal economic and clinical benefits. A financial threshold is often set at which cost-effectiveness is accepted. For the National Institute for Health and Care Excellence, this is £20,000–£30,000/QALY [
17].
Previous cost-effectiveness analyses, using a short-term model and data from the phase 3a clinical trials, have demonstrated that IDeg is cost-effective versus IGlar U100 in patients with T1DM and T2DM on basal oral therapy [
18‐
20]. However, since the publication of those evaluations, new basal insulin analogues have come to market: IGlar U300 (Toujeo
®) and IGlar biosimilar (Abasaglar
®), thus adding more therapeutic options for patients and crowding the basal insulin analogue market. Furthermore, the list price for IDeg was lowered by 35% in July 2016.
The objective of this study was to re-evaluate the cost-effectiveness of IDeg versus IGlar U100 from the perspective of the UK National Health Service, in light of the recent reduction in price of IDeg and the addition of new basal insulin analogues to the market place. The revised model evaluates a more generalisable patient population, including patients with T2DM on a basal-bolus regimen.
Results
In T1DM, total costs in the IDeg group are estimated at £1330 per patient per year (Table
4). Approximately 52% of this is the cost of insulin and other pharmacy costs, and the remainder is other health care costs associated with hypoglycaemic events, primarily the severe events. The total cost per patient per year in the IDeg group is £41 lower than that in the IGlar U100 group, primarily due to lower insulin costs. The costs of hypoglycaemic events are almost unchanged due to the fact that only the non-severe nocturnal events showed a statistically significant difference between IDeg and IGlar U100, while the severe and daytime events were unchanged. IDeg is associated with significantly fewer non-severe nocturnal hypoglycaemic events, which leads to a QALY gain of 0.0044 versus IGlar U100. Thus, IDeg is the dominant treatment, as it is more effective and less costly than IGlar U100 (Table
4).
Table 4
Total costs per patient and incremental cost-effectiveness
Pharmacy costs |
Insulin | 556.26 | 595.27 | −39.02 | 527.98 | 522.44 | 5.54 | 1357.87 | 1214.70 | 143.16 |
Needles | 141.57 | 141.47 | 0.00 | 35.39 | 35.39 | 0.00 | 141.57 | 141.57 | 0.00 |
Hypoglycaemic events |
Non-severe daytime events | 68.09 | 68.09 | 0.00 | 12.17 | 12.17 | 0.00 | 29.02 | 34.97 | −5.94 |
Non-severe nocturnal events | 10.80 | 13.02 | −2.21 | 4.09 | 6.39 | −2.30 | 6.52 | 8.70 | −2.17 |
Severe events | 553.70 | 553.70 | 0.00 | 5.80 | 41.41 | −35.61 | 289.86 | 289.86 | 0.00 |
Total costs | 1330.42 | 1371.65 | −41.23 | 585.43 | 617.80 | −32.37 | 1824.85 | 1689.80 | 135.05 |
Incremental QALYs (IDeg–IGlar U100) | 0.0044 | 0.0073 | 0.0084 |
ICER (cost/QALY) | Dominant | Dominant | 15,983.37 |
In T2DM
BOT, total costs in the IDeg group are calculated at £585 per patient per year, of which more than 96% is pharmacy costs (insulin and needles) and the remainder is costs of hypoglycaemic episodes (Table
4). Total costs per patient per year are £32 lower than in the IGlar U100 group, driven by lower costs of severe hypoglycaemic events due to the significant reduction in the number of severe hypoglycaemic events with IDeg versus IGlar U100 in this patient group. Due to the significantly fewer nocturnal and severe hypoglycaemic events in this group, IDeg is associated with a QALY gain of 0.0074 versus IGlar U100. Thus, IDeg is again the dominant treatment versus IGlar U100 (Table
4).
In T2DM
B/B, the total cost in the IDeg group is £1825, which is £135 (8%) higher than in the IGlar U100 group (Table
4). In this setting, 82% of the costs are pharmacy costs. IDeg is associated with significantly fewer non-severe daytime and nocturnal hypoglycaemic events, which leads to a QALY gain of 0.0084 versus IGlar U100. The incremental cost per incremental QALY gained with IDeg versus IGlar U100 is estimated at £15,983 (Table
4). This result falls below commonly accepted thresholds for cost-effectiveness. The higher incremental cost for this group is driven mainly by the slightly higher dose of basal insulin required in the IDeg arm of the clinical trial. In the T2DM
B/B clinical trial [
14], high insulin doses were observed in both the IDeg and the IGlar U100 treatment arms. The high doses observed in the trial are not expected to be representative of a real-world setting for patients initiating a basal-bolus regimen, as the trial mainly recruited patients who were already uncontrolled on an intensive basal-bolus regimen or uncontrolled on a pre-mixed insulin regimen.
Sensitivity Analysis
In T1DM, the favourable cost-effectiveness results are robust and invariant to changes in most of the parameters (Table S2 in the ESM). When equal insulin doses are assumed, the ICER is £8813/QALY gained, or when the price of IGlar U100 is reduced by 15%, the ICER is £2027/QALY gained; both of these are well below commonly accepted thresholds of cost-effectiveness. The ICER remains dominant in all other scenarios tested.
A largely similar pattern is observed for the T2DMBOT treatment regimen. The favourable cost-effectiveness results are invariant to changes in most of the parameters, with the ICER remaining dominant in the majority of analyses (Table S2 in the ESM). As with T1DM, when equal insulin doses are assumed or when the price of IGlar U100 is reduced by 15%, the ICER is no longer dominant, but it still falls well below commonly accepted thresholds of cost-effectiveness (£3609/QALY and £6313/QALY, respectively).
In the T2DM
B/B group, the results fluctuate above and below the base case ICER of £15,983/QALY gained, but most results remain below the threshold of £20,000–£30,000/QALY gained (Table S2 in the ESM). Varying the rate of non-severe hypoglycaemia has an impact on the ICER in this group due to the significant reduction of non-severe events with IDeg versus IGlar U100. When the number of non-severe events/year is reduced to 8.3 using data from Dornhorst [
39], the ICER increases to £19,862/QALY gained. Conversely, when the annual number of non-severe hypoglycaemic events is increased to 48, using data from the real-world study by Frier [
40], the ICER drops to £2640/QALY gained. The price of IGlar U100 also has a noticeable impact on the ICER. When the price of IGlar U100 is reduced by 15%, the ICER is increased to £27,932/QALY gained, and when the price of IGlar U100 is increased by 15%, the ICER is reduced to £4035/QALY gained.
Discussion
This simple, short-term cost-utility analysis suggests that the use of IDeg is highly likely to be cost-effective compared with IGlar U100 in the UK. IDeg is dominant (i.e. both more effective and less costly) versus IGlar U100 in patients with T1DM and patients with T2DMBOT, and is cost-effective versus IGlar U100 in patients with T2DMB/B (ICER £15,983/QALY). In T1DM, lower costs are primarily driven by lower insulin costs, as a result of a lower daily dose of IDeg. In T2DMBOT, lower overall costs with IDeg are driven by lower costs of severe hypoglycaemic events, due to the significant reduction in the number of severe hypoglycaemic events with IDeg versus IGlar U100 in this patient group. Improvements in clinical outcomes in all three patient groups are a result of the reduced incidence of hypoglycaemic events.
Sensitivity analyses demonstrate that the results are robust and invariant to changes in most of the input parameters. In patients with T1DM and T2DMBOT, the ICER remains dominant in the majority of analyses conducted. In patients with T2DMB/B, the ICER remains below the threshold of £20,000–£30,000/QALY gained in almost all analyses. PSA shows that there is a high probability that IDeg will be cost-effective versus IGlar U100 in all three patient groups.
With a number of new insulin formulations on the market, decision-making based on clinical and economic evidence is essential, as healthcare providers aim to maximise health outcomes with restricted budgets. Scenario analyses were conducted to estimate cost-effectiveness versus two new-to-market basal insulin analogues. In the absence of a direct comparison between IDeg and these new comparators, the analyses were based on available data and plausible assumptions, and the results should be interpreted accordingly. In patients with T1DM and T2DM
BOT, IDeg is likely to be highly cost-effective versus IGlar biosimilar (Abasaglar
®) and dominant to IGlar U300 (Toujeo
®), and in T2DM
B/B, IDeg is cost-effective versus both comparators with ICERs below the £20,000/QALY gained threshold. IDeg has recently been approved by the Scottish Medicines Consortium and All Wales Medicines Strategy Group for the treatment of diabetes mellitus in adults in Scotland [
41] and Wales [
42], respectively.
Cost-effectiveness analyses of diabetes interventions are traditionally performed by estimating the long-term clinical consequences as a function of differences in glycaemic control. However, the treat-to-target clinical trial design enforces a similar level of glycaemic control across interventions, resulting in non-inferior and non-significant differences, and thus rendering long-term modelling based on HbA1c differences inappropriate. This short-term approach focuses on the impact of other important aspects of insulin therapy such as hypoglycaemia and dosing, and enables economic evaluation of new insulin analogues based on data derived from treat-to-target studies. Although a short-term (1 year) time horizon is used, results are not only applicable for the cost-effectiveness of IDeg within the first year of treatment. As the model can be replicated for subsequent years, the outcomes represent the average annual cost-effectiveness.
This model has been previously used to evaluate the cost-effectiveness of IDeg versus IGlar U100 in patients with T1DM and T2DM. In this re-evaluation, a number of revisions were made to the modelling framework. As a consequence of the ultra-long duration of action, flat and stable action profile [
10,
11], and lower variability over the day than IGlar U100 [
12], there is evidence to suggest that titration and maintenance with IDeg is possible with fewer weekly SMBG tests [
43]. Cost savings may therefore be made through the use of fewer SMBG tests with IDeg; however, a change in testing behaviour may take time to translate into clinical practice, so it was excluded from this re-evaluation. Similarly, if administration at the same time of day is not possible, the ultra-long and stable action profile of IDeg allows for flexibility of dosing time without compromising efficacy or risk of hypoglycaemia. In the previous evaluation, an estimate of the utility benefit associated with the option of flexible dosing with IDeg was applied for the calculation of QALYs. This was excluded from the current re-evaluation in recognition that not all patients will benefit from this attribute, but it was included as a sensitivity analysis. The potential for flexible dosing may translate into additional economic value in patients who find it difficult to adhere to a strict dosing regimen (e.g. shift workers or frequent travellers), or those who rely on a carer to administer their insulin.
As with all modelling studies, the limitations of this study should be considered when putting the findings into context. Meta-analyses of clinical trial data are used in our model to increase the sample size and power of the parameter estimates derived from individual studies. However, it is assumed that the data collected in the clinical trials is replicated in routine clinical practice. The clinical trials used a treat-to-target approach, where insulin doses were titrated until the glycaemic target was achieved. In clinical practice, optimal glycaemic control may not be achieved for a variety of reasons, such as non-adherence or missed clinic appointments. However, the extensive sensitivity analyses suggest that the conclusions are robust and invariant to changes in a variety of alternative modelling assumptions.
Real-world studies are a valuable source of evidence and are increasingly being used to complement clinical trial data in the decision-making process. A study has evaluated the real-world cost-effectiveness of switching patients with T1DM (
n = 35) to IDeg in clinical practice in the UK [
15]. The long-term cost-effectiveness of IDeg versus IGlar U100 or insulin detemir in people with T1DM experiencing hypoglycaemia was evaluated using the IMS CORE Diabetes Model [
44]. The model was run over a patient lifetime and the benefits and costs were discounted at 3.5%. Over a lifetime, treatment with IDeg is less costly and more effective than treatment with IGlar/insulin detemir (dominant). This is driven by a reduction in HbA
1c and the lower rate of hypoglycaemia [
15]. This evaluation of real-world data supports that from the clinical trial programme, and indicates that IDeg is a cost-effective alternative to IGlar in patients experiencing problems with hypoglycaemia in clinical practice. The analysis was conducted using the old pack price of IDeg (£72.00/pack); thus, with the recent price reduction to £46.60/pack, IDeg represents even better value. Another study evaluated the cost-effectiveness of switching to IDeg from other basal insulins in people with T1DM (
n = 476) using real-world evidence from Sweden [
45]. The Core Diabetes Model was used to predict long-term outcomes, and the costs associated with treatment and long-term complications of diabetes were included. Again, the results of the analysis showed that IDeg was less costly than the patients’ previous insulin treatment and was associated with improvements in health-related quality of life (dominant). Thus, for patients with T1DM in Sweden, switching to IDeg was cost-effective when compared with treatment with their prior insulin.
Another economic assessment which may be informative for decision makers is a budget impact analysis. A budget impact analysis estimates the financial consequences of adopting a new intervention for local, regional and national budgets. It identifies the size of the population affected by the intervention and the effect of implementation on costs over the short term. This study calculated the total cost per patient per year, comprisiing the annual pharmacy cost and the annual cost of hypoglycaemic events, for a patient with T1DM, T2DM
BOT or T2DM
B/B treated with IDeg or IGlar U100 (Table
4). These costs can be utilised to calculate the annual budget impact of treatment with IDeg or IGlar U100 for a defined local patient population, whereby the annual per patient cost is simply multiplied by the number of patients treated. The breakdown of costs in Table
4 allows the impact on different budgets to be calculated.
In phase 3a clinical trials, IDeg showed equivalent reductions in HbA
1c with a lower risk of hypoglycaemia versus IGlar U100 [
13,
14]. The hypoglycaemia benefits of IDeg have also been reported in real-world clinical practice, with reductions of up to 90% observed in patients switching to IDeg because of problems with hypoglycaemia on IGlar or insulin detemir [
15]. Two phase 3b studies, SWITCH 1 and SWITCH 2, in patients with T1DM and T2DM, respectively, were designed to confirm the hypoglycaemia benefit observed with IDeg versus IGlar U100 in the phase 3a studies [
46,
47]. These studies sought to investigate the efficacy and safety of IDeg in diabetes populations with an increased risk of hypoglycaemia and to assess the safety of IDeg in transfers from other basal insulins. IDeg demonstrated non-inferiority to IGlar U100 in glycaemic control (HbA
1c) in patients with T1DM and T2DM in these treat-to-target trials. Equivalent reductions in HbA
1c were achieved with a lower total daily insulin dose at end-of-trial, and with a lower risk of hypoglycaemic episodes versus IGlar U100 [
46,
47]. An economic evaluation of the data from these clinical trials would be beneficial to demonstrate the cost-effectiveness of IDeg in these high hypoglycaemia risk populations.
Acknowledgements
The study and article processing charges were funded by Novo Nordisk. The authors acknowledge writing and editorial support from Carrie Fidler of DRG Abacus (sponsored by Novo Nordisk).
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.
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.