Objectives: The cost-utility analysis of Liraglutide is aimed at evaluating whether Liraglutide is cost-effective or not after Chinese reformation on medical insurance. The analysis is based on the results of clinical trial conducted in Asia. Methods: We applied a Markov model to estimate the quality-adjusted life years, medical cost and incidence of diabetes-related complications for patients receiving the Liraglutide as an add-on to the metformin treatment. Baseline characteristics were taken from a China’s study while the treatment effect is from an Asian study. The related medical cost and utility score were obtained from a local study in China. Having set 30 years’ simulations, the incremental cost-effectiveness ratio was calculated comparing with glimepiride treatment. The ratio would be compared with the willingness to pay for a quality-adjusted-life-year (QALY) which is three times of the GDP per capita in Beijing. Sensitivity analysis was also performed. Result: During a period of 30 years, the base-case analysis which takes discount rate at 3% shows that Liraglutide 1.8 mg results in an average incremental cost of CNY 82,671.49, an improvement in 0.12 QALYs and a reduction of incidence of diabetes-related complications comparing to glimepiride. The associated incremental cost-effectiveness ratio is CNY 688,929.08. Conclusion: Long-term project shows that taking Liraglutide as an add-on to the metformin treatment will lead to increasing quality-adjusted life years and reduction of incidence of diabetes-related complications. When the price of Liraglutide is reduced by 43 percent in China’s yuan, Liraglutide will be cost-effective in China from the healthcare system perspective taking three times of GDP per capita as our WTP threshold.
Type 2 Diabetes Mellitus (T2DM) is a progressive endocrine disease caused by insulin resistance or impaired insulin secretion. According to estimation, the prevalence of T2DM has been increased significantly since 1970s, reaching 9.7% in 2010-2014 [
As the reforming of Chinese medical care system, the expanding of medical insurance area has attracted a lot of attention. In 2017, the Ministry of Human Resources and Social Security of the People’s Republic of China (now the medical insurance managed by the Ministry of Medical Security of the People’s Republic of China) has announced that 36 drugs could be covered by our medical insurance, which means that people could buy these 36 drugs at a lower price [
Liraglutide was introduced into China in 2011 as a T2DM drug, which is a glucagon-like peptide-1 (GLP-1) receptor agonist. It has 97% amino acid sequence identity (homology) to human endogenous GLP-1, which accounts for <20% of total circulating endogenous GLP-1, but it has an Arg 34 replacing Lys 34 at the N-terminal and a fatty acid chain added to Lys 26. With such features, Liraglutide could bind to and activate the GLP-1 receptor which results in increasing of intracellular cylic adenosine monophosphate (cAMP) and releasing of insulin [
Recently, some new researches have demonstrated that Liraglutide has other several effects including controlling weight [
We applied a state-transition Markov model [
In this model, we distinguish different states of diabetes patients on the basis of complications of the disease. Based on that we divided our model into three states which are diabetes, diabetes complications and death. People in the “Diabetes” states are defined as only suffering from diabetes. Likewise, “Diabetes complications” states are defined as patients suffering from more than one kind of diabetes-related complications. Finally, if patients died from any cause related to diabetes or its complications, they enter intothe “Death” state. We define one year as a cycle length (
And then we simulated 1000 patients whose baseline characteristics and risk factors were based on the Chinese study [
Treatment effect of Liraglutide added to metformin was taken from the clinical trial (NCT0061412) which aims at comparing the effect on glycaemia control of Liraglutide. This trial was conducted in Asian countries such as China, South Korea and India and was designed similarly as LEAD-2 trial except for a metformin plus placebo arm. In the 16-week trial, Liraglutide led to significant glycemic control but with less obvious loss in weight. In this trial Liraglutide could make reduction in HbA1c for 1.0 percent (0.6 mg), 1.3 percent (1.2 mg) and 1.4 percent (1.8 mg) comparing to the initial HbA1c rate. The baseline of HbA1c was extracted from a clinical trial conducted in China [
study [
The clinical cost for diabetes patients could be divided into direct clinical cost and indirect clinical cost. The direct clinical cost includes managing diabetes, anti-diabetes treatments and curing diabetes complications. All the direct clinical costs are derived from the clinical trial in China and the acquisition cost of Liraglutide, insulin, glimepiride and metformin were derived from official web sites of Chinese government [
Since our main focus is the benefits of the price change of Liraglutide, it is appropriate for us to use quality-adjusted-life-years (QALYs) and incremental cost per QALYs (ICRE) as our principal outcomes. The initial score of our model were taken from a study conducted in Nanjing, China [
Both the discount rate of cost and QALYs are 3% according to the recommendation of World Health Organization (WHO) [
Based on the article dealing with the maximum willing to pay (WTP) for a QALY gained in China [
Since the gross domestic product differs greatly in different part in China, we use the gross domestic product (GDP) per capita in Beijing. In 2017, the gross domestic product (GDP) per capita in Beijing was 128,927 RMB (8826 US$). Using this figure, we could assume that the maximum WTP for a QALY gained in China might be about 386,781 RMB.
We applied several one-way sensitivity analyses to test the robustness of our primary model. To analyze the uncertainty of the medical cost on different studies, two different methods were applied for sensitivity analysis, which are increasing and decreasing the medical cost by 20 percent respectively. These two methods are used in both medical cost of diabetes and its complications. The impact of discount rate was analyzed by using different discount rates, which are 0 percent and 6 percent. Additionally, to investigate the influence of different time duration towards QALYs and expected cost the time, we changed the horizon from 10 years to 20 years.
The direct medical cost of patients both with and without complications are derived from a study of China [
Based on the Markovian assumption [
The duration of the clinical trial (NCT00614120) that was included in was 16 weeks. Based on the Clark’s study [
Mostly the transition information in the clinical trial is shown in “rate” but not “probability’ and so as the UKPDS information in
The annual state transition probability in group with different dosage of Liraglutide can be obtained from
By assuming that the transformation for a fixed number of patients at certain states will comply with certain probability, we could cumulatively calculate the average time in different states to do the cohort analysis. The calculation process is implemented in TreeAge Pro Suite 2011. In the 30 years’ simulations for patients treated with 1.2 mg Liraglutide per day, there are 70.9% of patients remain at diabetes states, while 20.9% of patients transform into diabetes complications states and 8.1% of patients die during in this 30-year simulations. Comparing with the previous treatment, only 18.7% of patients transfer into diabetes complications and 6.5% of patients die during the simulations.
The effects and costs of the two treatments during 30 years of follow-up are summarized in
Without changing the cost and discount rate, both the discount rate of 0% and 6% only led to 0.06 QALYs change from the base case, and the associated ICER is 403 K RMB/QALY and 1104 K RMB/QALY respectively. When the simulation period changing from 10 years to 20 years, ICER change from 1379 K RMB/QALY to 4148 K RMB/QALY. When changing the diabetes’ complications medical cost from 7013.448 RMB to 10,520.172 RMB, analysis results in ICERs ranging from 1 K RMB/QALY to 402 K RMB/QALY. While likewise for the diabetes’ medical cost change, it results in ICERs ranging from 371 K RMB/QALY to 407 K RMB/QALY. So ICER is more sensitive to discount rate, time duration and the diabetes-related complications cost. The details of sensitivity analysis result are summarized in
Mean (SD) | Median (IQR) | |
---|---|---|
No complications | 1414.0 (1388.5) | 1086.1 (485.4 - 1849.5) |
Microvascular complications | 2470.2 (4396.0) | 1545.2 (841.1, 2431.0) |
Macrovascular complications | 2248.7 (2958.8) | 1594.3 (848.6 - 2930.1) |
Micro- & Macro vascular complications | 2715.7 (3107.9) | 2036.2 (1362.1 - 2971.7) |
SD: standard deviation. IQR: interquartile range.
HbA1c reduction from baseline (%) | HbA1c relative reduction from baseline (%) | Change in related prevalence of complications | |
---|---|---|---|
Treatments | |||
1.2 mg Lirag + Glim + Met | −1.3% | −16.67% | −66.67% |
1.8 mg Lirag + Glim + Met | −1.4% | −17.95% | −71.79% |
Glim 4 g + Met | −1.3% | −16.67% | −66.67% |
Lirag: Lilraglutide; Glime: Glimpepirid; Met: Metformin.
baseline | 1.2 mg Lirag + Glim | 1.8 mg Lirag + Glim | |
---|---|---|---|
Events | |||
Mircrovascular complications | 0.0210 | 0.0069 | 0.0059 |
Macrovascular complications | 0.0067 | 0.0022 | 0.0019 |
Non-vascular disease mortality | 0.0068 | 0.0023 | 0.0019 |
death | 0.0135 | 0.0045 | 0.0038 |
Lirag: Lilraglutide; Glime: Glimpepirid; Met: Metformin.
Values for 1.2 mg | Value for 1.8 mg | Value for Glime group | ||
---|---|---|---|---|
Parameter | Event | |||
P1 | State I toState I or II | 0.9977 | 0.9981 | 0.9977 |
P2 | State I to State I | 0.0091 | 0.0078 | 0.0091 |
P3 | State I to State III | 0.0023 | 0.0019 | 0.0023 |
P4 | State II to State II | 0.9932 | 0.9943 | 0.9932 |
P5 | State II to State III | 0.0068 | 0.0057 | 0.0068 |
P6 | Stay in State I | 0.9909 | 0.9922 | 0.9909 |
P7 | Stay in State II | 0.0091 | 0.0078 | 0.0091 |
State I: Patients with diabetes state in model; State II: Patients with diabetes complications in model; State III: Patients die in model.
Strategy | Cost (RMB) | Incremental costs | Effectiveness | Incremental effectiveness | C/E | Incremental C/E (ICER) |
---|---|---|---|---|---|---|
Glimepiride + metformin | 210,502.91 | 16.68 QALY | 12,620.07 | |||
1.2 mg | 265,854.60 | 55,351.69 | 16.68 QALY | 0 | 15,938.53 | 0 |
1.8 mg | 293,174.43 | 82,671.49 | 16.80 QALY | 0.12 | 17,450.86 | 40,256.58 |
1.2 mg: patients receive 1.2 mg liraglutide per day; 1.8 mg: patients receive 1.8 mg liraglutide per day; C/E: cost/effectiveness.
1.8 mg Lirag | Glim | |||||
---|---|---|---|---|---|---|
Cost/RMB | QALYs | Cost/RMB | ICER | QALYs | Cost/RMB | |
Trial 20 | 214,026.96 | 12.90 | 241,436.06 | 1,379,344.167 | 12.84 | 158,675.41 |
Trial 10 | 145,333.51 | 7.49 | 172,951.67 | 4,148,488.5 | 7.47 | 89,981.90 |
Discount rate 0 | 373,685.54 | 24.80 | 402,867.79 | 403,140.23 | 24.58 | 314,176.94 |
Discount rate 6% | 203,222.49 | 12.21 | 228,851.81 | 1,104,957.71 | 12.14 | 151,504.77 |
complications − 20% | 199,511.61 | 12.21 | 225,601.41 | 301,783.86 | 12.14 | 204,476.54 |
Comp cost + 20% | 206,933.38 | 12.21 | 232,102.21 | 1275.42 | 12.14 | 216,529.29 |
Diabetes cost − 20% | 180,400.75 | 12.21 | 208,899.32 | 407,122.43 | 12.14 | 179,614.29 |
Diabetes cost + 20% | 226,044.50 | 12.21 | 252,054.96 | 371,578.00 | 12.14 | 241,391.54 |
Lirag: liraglutide; Glim: glimepiride; Comp: Complications;
The process of Chinese health care system reformation has already drawn a lot of attention all over the world. In the reformation on health care insurance, Chinese government has done a series of negotiations with pharmaceutical companies on cutting customs in order to relief the economics burden of Chinese patients. During recent years, the prices of nearly 50 kinds of drugs have already been cut down to be affordable, which has brought good news to Chinese people in many aspects.
When Liraglutide was firstly introduced to the market in China, the majority of patients couldn’t afford due to its expensive cost. However, in 2017, its price has been cutting down about 45% to 410 yuan per 18 mg and has been included into Chinese medical insurance. In 2012, some researchers have already done some researches using cost-utility analysis on the Liraglutide in Chinese market [
The result of our model shows that Liraglutide treatment might not be cost-effective if we choose glimepiride treatment as comparator. The ICER value obtained from our cost-utility analysis shows that the ICER of Liraglutide exceeds too much from the threshold of 386,781 RMB/QALY, which is the calculated from the three times of GDP [
While comparing to the previous study on Liraglutide in China [
There are some limitations in our study. Firstly, the transition probability between each states differ from age and duration of diabetes. However, because of the lack of related data in China, patients in different ages share the same transition probability and possibility of death, which might cause inaccuracies in our model. Secondly, our study was based on a 16-week-study, which is a relatively short duration. Type 2 diabetes is a chronic disease, even in our model we pre-assume that this 16 weeks’ study share the same effect as a one-year treatment, the ongoing glycemic control over time is still not quite accurate. Secondly, we adopt 3 times GDP per capita in Beijing as WTP threshold. Even the GDP per capita varies greatly in different areas of China and the prevalence of diabetes increases rapidly, especially in big cities, the generality of this method still need to be considered. Finally, WTP is highly associated with the physical and psychological effect of disease [
According to the annual report of Novo Nordisk [
In the Chinese market, we used the example of Iressa (gefitinib) which entered the medical insurance in 2016 as a reference to the Liraglutide. After a sharp price cut, it could be seen that in the first quarter of 2018, Iressa sales reached 849,000 boxes, comparing to 2016 with a 678,000 boxes growth rate, and the quarter-on-quarter growth was as high as 22.2%. Although the price cut exceeded 50%, in terms of sales, the sales in the first quarter of 2018 was 183 million yuan, which was more than doubled before the price cut. Although the price of it has decreased, there was an increase in sales.
Although this is also due to the successful market strategy of Iressa, we can assume this on Liraglutide. The population of type 2 diabetes in China has reached 120 million. With the increase in the number of diagnosed patients, the demand for diabetes drugs will be more extensive. Liraglutide, a GLP-1 receptor agonist, has been confirmed to have weight loss. It could also regulate cardiovascular function and has anti-dementia effect. The market space of Liraglutide is huge.
According to Novo Nordisk’s first quarter earnings conference call in 2018 [
Although Novo Nordisk can still make profits due to the price reduction of drugs at this stage, according to our research results, for the current GDP of the Chinese capital Beijing, to achieve the best economic benefits, the price of Liraglutide must be 231.3 yuan. Moreover, because the GDP of the Chinese capital has a large gap with the national average GDP, in fact, to spread to the whole country, it needs to be sold at a lower price. The current sales of Liraglutide may come from propaganda and other reasons, but from the patient’s point of view, prices still need to be lowered. The generic drug of Liraglutide is already under development and hopes to bring tangible gospel to patients in the future.
Although the Chinese government has made a lot of efforts to reduce the price of imported drugs, in fact, the price of Liraglutide still does not reach the cost-effective price. Because we use GDP as a reference for patients’ willing to purchasing in the calculation, this may also be due to the low level of China’s GDP. However, there are still many people with type 2 diabetes in China. To truly extend the lifespan of patients, it is still necessary to encourage drug research and development so that patients can really afford the drug price.
The authors declare no conflicts of interest regarding the publication of this paper.
Xie, G.Y. and Zhao, S.N. (2018) Cost-Utility Analysis of Liraglutide in Type 2 Diabetes Patients in China after Chinese Reformation of Medical Care System. Journal of Biosciences and Medicines, 6, 13-25. https://doi.org/10.4236/jbm.2018.612002