The cost-effectiveness of dulaglutide versus insulin glargine for the treatment of type 2 diabetes mellitus in Japan

Abstract

Aims: Dulaglutide is a new once weekly glucagon-like peptide-1 (GLP-1) receptor agonist administered via a disposable auto-injection pen for the management of type 2 diabetes mellitus (T2DM). The objective of this study was to estimate the cost-effectiveness of dulaglutide vs insulin glargine for the management of T2DM from a Japanese healthcare perspective, in accordance with recently approved Japanese Cost-Effectiveness Guidelines.

Methods: The IQVIA CORE Diabetes Model (version 9) was used to estimate the long-term costs and effects of treatment with dulaglutide and insulin glargine. Direct comparative data from the Araki 2015 trial (NCT01584232) was used to inform the analysis. Costs associated with treatment and complications were derived from Japanese sources wherever possible and inflated to 2015 Japanese Yen (JPY). Utilities were based upon a European systematic review of diabetes utilities and adjusted for use in a Japanese population. One-way and probabilistic sensitivity analyses (OWSA and PSA) were conducted on all inputs and key modeling assumptions.

Results: Dulaglutide 0.75 mg was associated with higher quality-adjusted life years (QALYs), life years (LYs), and total costs, compared to insulin glargine, resulting in an incremental cost-effectiveness ratio (ICER) of 416,280 JPY/QALY gained. Treatment with dulaglutide increased the time alive and free from diabetes-related complications by 4 months. OWSA and PSA indicated that results were robust to plausible variations in input parameters and modeling assumptions.

Limitations: Key limitations of this study are similar to other cost-utility analyses of diabetes, including the extrapolation of short-term clinical trial data into lifelong durations. In addition, due to the lack of robust published Japanese data, some values were derived from non-Japanese sources.

Conclusions: This analysis suggests that dulaglutide 0.75 mg may be a cost-effective treatment alternative to insulin glargine for patients with T2DM in Japan.

Keywords:

• Type 2 diabetes
• cost-effectiveness
• Japan
• dulaglutide
• insulin glargine

Introduction

Diabetes mellitus is a metabolic disorder characterized by the development of hyperglycemia resulting from a deficiency in insulin secretion, insulin action, or a combination of both¹. The vast majority of diabetes patients (∼90%) suffer from type 2 diabetes mellitus (T2DM), a progressive disease, which, if uncontrolled, can result in significant long-term morbidity and early mortality². In Japan, the prevalence of T2DM in 2015 was estimated by the International Diabetes Federation (IDF) to be 7.2 million (7.6% of population aged 20–79)³. Due to an aging population, as well as changes in lifestyle and diet, it is expected that the absolute number of patients in Japan will rise in future years^4,5.

Increasing costs in the Japanese health system, partly due to the aging population, increased costs of new technologies, and a rise in the prevalence of non-communicable diseases, has seen predictions that healthcare expenditures will increase from the current 8% of GDP to 11% by 2025⁶. Currently, the estimated cost per diabetic patient per year in Japan is ∼475,000 Japanese Yen (JPY)⁷. This cost burden, largely resulting from the complications of diabetes, accounts for between 4–6% of the total Japanese healthcare budget, and this proportion is likely to rise as more individuals develop the disease⁸. It is widely recognized that improving glycemic control and other cardiovascular risk factors can substantially reduce the risk of diabetes-related complications^9,10 and the associated costs¹¹. The high economic burden, coupled with a significant negative impact on patient quality-of-life, therefore, makes reducing the incidence of diabetes complications a key aim of treatment for policy-makers and healthcare providers alike.

To address increasing future health expenditure, the Japanese Government has introduced various strategies to improve health outcomes and healthcare value over the longer term. These included a determination to introduce cost-effectiveness in the form of Health Technology Assessment (HTA), with a pilot for pharmaceuticals commencing in 2016^12,13. Recently, the Japanese Government approved a Cost-Effectiveness Guideline outlining the preference for economic evaluations using an incremental cost-effectiveness ratio (ICER) assessment system, which will incorporate Japanese healthcare system costs and benefits measured in terms of quality adjusted life years (QALYs) gained¹³. The following study presents a cost-utility analysis to investigate the cost-effectiveness of a new diabetes medication, dulaglutide, compared to the current Japanese standard of care, insulin glargine, from the Japanese healthcare perspective.

Dulaglutide is a new glucagon-like peptide-1 (GLP-1) receptor agonist administered once weekly via a disposable auto-injection pen with a fixed dosage of 0.75 mg, which is approved for use in Japan. Dulaglutide 0.75 mg exhibits GLP-1-mediated effects, including glucose-dependent potentiation of insulin secretion, inhibition of glucagon secretion, delay of gastric emptying, and weight loss. The combination of these effects results in a decrease in both fasting and postprandial glucose concentrations, thereby leading to improvement in overall glycemic control^14–22. The efficacy and safety of dulaglutide has been demonstrated in Japanese as well as Asian and European populations, during dulaglutide Phase III clinical trial programs.

Methods

For the economic analyses, the IQVIA CORE Diabetes Model (CDM) model (version 9), a validated T2DM economic model²³, was used to estimate the cost-effectiveness of dulaglutide 0.75 mg vs insulin glargine, the existing injectable standard of care in Japan.

The simulation model determines long-term health outcomes and economic consequences of treatments, with disease progression based upon a series of inter-dependent sub-models simulating key complications of diabetes. The complications modeled included: cardiovascular, renal, eye, neuropathy and ulcer related diseases, as well as acute events such as hypoglycemia. In order to model complication outcomes and mortality, the UK Prospective Diabetes study (UKPDS) 68 risk equations, which were derived from a population including Asian patients, were applied^24,25. In addition, scenario analyses applying the Hong Kong Registry risk equations were conducted²⁶.

Patient population data were taken from the Araki 2015 trial (NCT01584232)²¹. This was a Phase III, randomized, open-label study of 361 T2DM Japanese patients who were randomized to receive either dulaglutide 0.75 mg once weekly or insulin glargine (dose dependent on target fasting blood glucose ≤110 mg/dL) as part of a combination therapy with oral anti-hyperglycemic medication (OAM). OAMs included sulfonylureas and/or biguanides. Inputs regarding treatment efficacy were drawn from the direct comparative 26-week results from the study.

The analyses were conducted from the perspective of the Japanese health system, capturing direct medical costs, including pharmacy costs, costs of complications, and costs of management of disease. Given the chronic nature of the disease, a lifetime horizon (50 years) was used in the analysis. Costs and benefits were discounted at 2% annually, in accordance with Japanese Guidelines²⁷.

Key outcomes from the analysis included incremental differences in life years (LYs), QALYs, and cost outcomes (in JPY), including costs of treatment and managing complications. An ICER, representing the additional cost (in JPY) per QALY gained for treatment with dulaglutide vs insulin glargine, was also reported.

Baseline characteristics

The baseline characteristics of the cohort were drawn from the demographics of the Araki 2015 trial²¹ wherever possible. Smoking and average alcohol intake baseline data were derived from World Health Organization (WHO) data^28,29. Key baseline characteristics are presented in Table 1.

Table 1. Baseline cohort characteristics.

Characteristic	Mean	SD	Source
HbA1c (%)	8.03	0.85	Araki et al.^21 2015 trial*
Age (years)	56.83	10.91	Araki et al.^21 2015 trial
Duration of diabetes (years)	8.84	6.41	Araki et al.^21 2015 trial
Male (proportion)	0.71	–	Araki et al.^21 2015 trial
Asian (proportion)	1.00	–	Araki et al.^21 2015 trial
Systolic blood pressure (mmHg)	128.88	13.86	Araki et al.^21 2015 trial
Baseline total cholesterol (mg/dL)	186.12	34.81	Araki et al.^21 2015 trial
Baseline HDL-C (mg/dL)	55.65	14.80	Araki et al.^21 2015 trial
Baseline LDL-C (mg/dL)	102.12	29.45	Araki et al.^21 2015 trial
Baseline triglycerides (mg/dL)	146.67	100.75	Araki et al.^21 2015 trial
Body mass index (kg/m^2)	25.97	3.72	Araki et al.^21 2015 trial
Proportion smokers (proportion)	0.23	–	WHO Report Tobacco Epidemic^28
Alcohol consumption (Oz/week)	6.74	–	WHO Global Alcohol Report, Japan: (L/Year to Oz/week)^29

* The number of subjects in the Araki et al.²¹ 2015 trial was 361.

Baseline rates of diabetes-related complications, including cardiovascular (CV) event history, were derived from the Araki 2015 trial²¹ or from the T2DM cohort defined in the NICE Clinical Guideline 28³⁰. As the Araki 2015 trial and NICE cohorts were similar in age and duration of diabetes, as well as physiological parameters, these rates were deemed applicable and generalizable to the Japanese population (refer to Supplementary Material for full details).

Treatment effects

Treatment effects for both interventions were derived directly from 26-week comparative data from the Araki 2015 trial, in which 361 subjects were treated (dulaglutide 0.75 mg = 181; insulin glargine = 180)²¹. Consistent with dose regimens used in Japan and in the clinical trial, the average daily dose of insulin glargine was 12.5 IU/day, and dulaglutide was administered at a once weekly dose of 0.75 mg. Both treatment regimens were administered for 2 years prior to escalation to rescue therapy. This assumption was based on currently available GLP-1 treatment effectiveness in Japan³¹.

Treatment effects incorporated in the analysis included the change from baseline in all major physiological parameters (including hemoglobin A1c (HbA1c), systolic blood pressure (SBP), total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglycerides, and body mass index (BMI)), as well as rates of hypoglycemia and nausea associated with treatment. Details of applied treatment effects, and plausible ranges tested during one-way sensitivity analysis (OWSA), are presented in Table 2.

Table 2. Treatment effects.

Characteristic	Mean treatment effect (SE, 95% CI)
	Dulaglutide 0.75 mg	Insulin glargine
HbA1c (%)	−1.44 (0.05, –1.54 to –1.34)	−0.90 (0.05, –1.00 to –0.80)
Systolic blood pressure (mmHg)	0.40 (0.85, –1.27 to 2.07)	2.50 (0.84, 0.85 to 4.15)
Total cholesterol (mg/dL)	−8.50 (1.78, –11.98 to –5.02)	1.40 (1.91, –2.34 to 5.14)
LDL-C (mg/dL)	−6.60 (1.48, –9.51 to –3.69)	2.90 (1.64, –0.31 to 6.11)
HDL-C (mg/dL)	0.90 (0.59, –0.25 to 2.05)	0.40 (0.65, –0.88 to 1.68)
Triglycerides (mg/dL)	−16.20 (5.18, –26.35 to –6.05)	−10.70 (7.80, –25.99 to 4.59)
Body mass index (kg/m^2)	−0.19 (0.06, –0.31 to –0.07)	0.32 (0.06, 0.20 to 0.44)
Nausea (event rate per 100 patient years)*	19.79	2.24
Major hypo (event rate per 100 patient years)	0.00	0.00
Minor hypo (event rate per 100 patient years)	136.05	355.13
Injection site reactions (proportion)	0.02	0.01

Note: Treatment effects are presented as the change from baseline from the Araki et al.²¹ 2015 trial.

* Rate applied at the beginning of treatment for 3 months.

After 2 years of treatment, both treatment groups escalated to rescue therapy with basal insulin glargine at a daily dose of 20 IU. Treatment switch was assumed to not affect physiological parameters, with the exception of BMI, as there would be no incremental difference between treatment arms. BMI returned to baseline levels upon treatment switch if initial treatment decreased BMI; however, if initial treatment increased BMI this increase was maintained. Following treatment switch, physiological parameters, including HbA1c, were assumed to follow natural disease progression, as reported from the UKPDS 68 cohort²⁴.

Utilities and disutilities

Due to a lack of robust published Japanese utility data, health state related utilities for T2DM and associated complications were derived from a recent systematic literature review in a European population³². In order to account for the observed differences between European and Japanese health utility values, a conversion algorithm, utilized in a previous study³³, was applied. The impact of applying this utility conversion was explored in the sensitivity analysis by investigating the effect of increasing or decreasing the values of the converted utilities, and also by applying the European utilities directly.

A full table of utilities both before and after the conversion can be found in the Supplementary Materials.

In addition to the utilities related to complications, disutilities associated with treatment-related events were derived from multiple sources^32,34,35. A disutility of 0.0061 was applied for each unit of BMI increase above 25 kg/m² to reflect the direct impact of BMI on utility³². A disutility of 0.04 was applied to patients experiencing nausea for the first 3 months of treatment during the simulation (a total disutility of 0.01 over the first year), reflecting the temporary nature of the condition³⁵. In addition, a utility equal to 0.023 was added when undergoing treatment with dulaglutide 0.75 mg, to reflect differences in injection frequency³⁴. Disutilities associated with patients experiencing injection site reactions³⁴ and hypoglycemia³² were also applied; further details can be found in the Supplementary Materials.

Treatment costs

Treatment costs included drug acquisition, self-monitoring of blood glucose (SMBG) management fees, and self-injection management fees³⁶. The SMBG management costs include physician monitoring of self-obtained blood glucose and the provision of required materials for SMBG, such as test strips. The self-injection management fee includes training on the appropriate use of the injection device and the provision of the required materials, such as injection needles and alcohol cotton for the sanitation of injection site. Both management fees were introduced by the Japanese government under the national health insurance system; healthcare providers charge the fees depending on the frequency of SMBG testing or self-injection. For instance, when the total number of self-injections per month is less than 28, the monthly self-injection management fee is 6,500 JPY; when the number of self-injections per month is 28 or greater, this rises to 7,500 JPY.

Costs associated with OAMs utilized in the trial were not included in the analyses, as these costs were assumed equivalent across treatment arms. Annual treatment costs can be found in Table 3.

Table 3. Annual therapy costs (all values in JPY).

Therapy	Drug acquisition cost	Self-monitoring of blood glucose	Management fee	Total annual cost
Dulaglutide 0.75 mg/week	187,112	39,276	78,000	304,388
Insulin glargine 12.5 IU/day	30,957	49,356	90,000	170,313
Insulin glargine 20 IU/day*	49,650	49,356	90,000	189,006

* Escalated dose of insulin glargine applied as rescue therapy to both treatment arms after 2 years.

Complication costs

Costs of complications, both event-related and for years following events, were derived from Japanese literature wherever possible. Complication costs for neuropathy in the first year and years following (2+ years) were generated from database research using the Japan Medical Data Center (JMDC)^37,38. In addition, it was not possible to identify suitable Japanese sources for some ulcer related complications. For these inputs, UK costs, converted to JPY at a rate of 1 GBP to 131 JPY³⁹, were applied. All costs were inflated to 2015 prices using health indices from E-stat⁴⁰ for Japanese inputs and Personal Social Services Research Unit (PSSRU) for UK inputs⁴¹. UK inputs were inflated using the UK indices prior to conversion to JPY.

Further details of complication costs can be found in the Supplementary Materials.

Sensitivity analyses

OWSA and probabilistic sensitivity analyses (PSA) were performed on all key variables to explore the robustness of base-case results to parameter uncertainties and modeling assumptions.

The OWSA explored varying physiological parameters to their upper and lower 95% credible intervals, as well as key scenarios including time horizon, treatment duration, discount rates, risk equation, and utility conversion.

A second order Monte Carlo simulation was used to perform PSA with parameter inputs (utilities, costs, treatment effects, cohort characteristics, and clinical events) sampled from fixed distributions. The PSA used 25,000 simulated patients over 1,000 iterations to ensure stability of results. An additional PSA was also conducted applying the Hong Kong registry cardiovascular risk equations to further test the impact of risk equation on outcomes.

Results

In the base case, dulaglutide 0.75 mg was more effective and more costly compared to insulin glargine, resulting in an incremental cost-effectiveness ratio (ICER) of 416,280 JPY/QALY gained, which was below the nominated threshold of 5,000,000 JPY used in previous economic analyses^42–44. Over a lifetime time horizon, dulaglutide 0.75 mg was associated with additional QALYs of 0.309 (dulaglutide = 15.304 vs insulin glargine = 14.995), additional LYs of 0.186 (dulaglutide = 19.039 vs insulin glargine = 18.853), and an overall cost increase of 128,464 JPY (dulaglutide = 10,026,292 JPY vs insulin glargine = 9,897,828 JPY). Dulaglutide increased treatment-specific costs (additional treatment acquisition costs = 294,197 JPY), and marginally increased disease management costs (due to increased life expectancy) (additional disease management costs = 4,428 JPY); however, this was partially offset by reductions in the costs of treating complications (reduction in complication costs = 170,161 JPY), with a notable reduction in cardiovascular complication costs (reduction in cardiovascular complication costs = 113,841 JPY). A breakdown of total costs can be seen in Table 4.

Table 4. Breakdown of direct costs (base case analysis—all values in JPY).

	Dulaglutide 0.75 mg	Insulin glargine	Incremental
Total costs	10,026,292	9,897,828	128,464
Treatment	3,936,629	3,642,432	294,197
Disease management	385,955	381,527	4,428
Complication	5,703,707	5,873,868	−170,161
Cardiovascular	2,857,605	2,971,446	−113,841
Renal	525,781	536,128	−10,347
Ulcer/Amputation/Neuropathy	2,191,387	2,233,828	−42,441
Eye	128,934	132,466	−3,532

Treatment with dulaglutide increased the average time alive and free from any diabetes related complication by ∼4 months compared to insulin glargine (dulaglutide = 4.88 years vs insulin glargine = 4.55 years). The additional 4 months complication free was consistent across all complications, including cardiovascular, renal, and eye diseases.

The OWSA indicated that the base case result was robust to variation in key parameters and modeling assumptions, with no scenarios resulting in an ICER greater than 1,250,000 JPY. The results were most sensitive to reducing the time horizon to 10 years, resulting in an ICER of 1,235,687 JPY. Changes to the assumptions around converted health state utilities did not substantially alter the results, application of the unconverted (European) utilities resulted in an ICER of 425,942 JPY, and increasing or decreasing the converted utilities by 10% resulted in ICERs of 394,183 JPY and 440,852 JPY, respectively. Full OWSA results are presented in Table 5.

Table 5. OWSA results.

Analysis	Costs (JPY)			QALYs (JPY)			ICER (JPY/QALY)
	Dulaglutide 0.75 mg	Insulin glargine	Incremental	Dulaglutide 0.75 mg	Insulin glargine	Incremental
Base case	10,026,292	9,897,828	128,464	15.304	14.995	0.309	416,280
Treatment effects
HbA1c Lower 95% CI	9,984,119	9,897,828	86,290	15.314	14.995	0.319	270,418
HbA1c Upper 95% CI	10,035,265	9,897,828	137,437	15.298	14.995	0.303	453,439
BMI Lower 95% CI	10,032,401	9,897,828	134,573	15.306	14.995	0.311	433,268
BMI Upper 95% CI	10,030,445	9,897,828	132,616	15.302	14.995	0.307	431,835
SBP Lower 95% CI	10,008,744	9,897,828	110,916	15.314	14.995	0.319	347,698
SBP Upper 95% CI	10,027,465	9,897,828	129,637	15.295	14.995	0.299	432,990
Only significant treatment differences included	10,026,292	9,893,453	132,839	15.304	15.032	0.272	487,842
Treatment duration
Time on treatment 1 year (both arms)	9,895,072	9,920,304	–25,232	15.306	15.051	0.255	DOMINANT
Time on treatment 3 year (both arms)	10,136,723	9,896,733	239,991	15.319	14.947	0.372	645,136
Time on treatment 5 year (both arms)	10,365,960	9,874,180	491,780	15.321	14.849	0.473	1,040,143
Utilities/disutilities
European utility values (no conversion)	10,026,292	9,897,828	128,464	13.418	13.117	0.302	425,942
Converted (European to Japanese) utilities decreased by 10%	10,026,292	9,897,828	128,464	13.764	13.472	0.291	440,852
Converted (European to Japanese) utilities increased by 10%	10,026,292	9,897,828	128,464	16.844	16.518	0.326	394,183
BMI disutility excluded	10,026,292	9,897,828	128,464	15.407	15.133	0.274	468,847
Nausea disutility excluded	10,026,292	9,897,828	128,464	15.306	14.996	0.310	413,866
Injection site reaction disutility excluded	10,026,292	9,897,828	128,464	15.304	14.996	0.309	415,876
Treatment frequency utility excluded	10,026,292	9,897,828	128,464	15.259	14.995	0.264	486,422
Costs
Complication and management costs decreased by 20%	8,808,360	8,646,749	161,611	15.304	14.995	0.309	523,690
Complication and management costs increased by 20%	11,244,225	11,148,908	95,318	15.304	14.995	0.309	308,871
Complication and management costs not sourced from Japanese literature   decreased by 20%	9,820,057	9,686,977	133,080	15.304	14.995	0.309	431,239
Complication and management costs not sourced from Japanese literature   increased by 20%	10,232,528	10,108,680	123,848	15.304	14.995	0.309	401,322
Time horizon
10-year time horizon	3,195,600	3,013,336	182,264	7.132	6.985	0.147	1,235,687
20-year time horizon	6,404,452	6,310,076	94,375	11.923	11.702	0.221	427,618
40-year time horizon	9,908,715	9,810,207	98,508	15.248	14.937	0.311	316,339
60-year time horizon	10,015,251	9,908,736	106,516	15.316	15.001	0.315	338,360
Modeling assumptions
0% discount rate (costs and outcomes)	14,264,518	14,140,192	124,326	20.225	19.809	0.416	298,645
6% discount rate (costs and outcomes)	5,652,451	5,505,367	147,084	9.763	9.562	0.200	733,587
Hong Kong Registry risk equation	9,625,695	9,493,580	132,115	14.784	14.592	0.192	688,818
UKPDS82 risk equation	7,936,368	7,794,078	142,290	14.037	13.738	0.300	474,775

The PSA results were consistent with the base case, resulting in an average ICER of 295,466 JPY/QALY. Dulaglutide was more effective and less costly in 20.6% of simulations (dominant intervention), and more effective and more costly in the remaining 79.4% of simulations. No PSA iterations resulted in dulaglutide being less effective than insulin glargine. The incremental cost-effectiveness pairs for costs and QALYs are presented in Figure 1. The resulting cost-effectiveness acceptability curve is presented in Figure 2, a 100% probability of cost-effectiveness is reached at a willingness-to-pay threshold of 1,300,000 JPY. The additional PSA conducted using the Hong Kong Registry risk equations generated results similar to the base case, resulting in an average ICER of 725,584 JPY/QALY. In this scenario, dulaglutide was more effective and less costly in 9.6% of simulations (dominant intervention), and more effective and more costly in the remaining 90.4% of simulations. No PSA iterations resulted in dulaglutide being less effective than insulin glargine.

Figure 1. Incremental cost-effectiveness pairs for costs and QALYs during PSA.

Figure 2. Cost-effectiveness acceptability curve.

Discussion

To date, there has been limited published evidence on the cost-effectiveness of pharmaceutical interventions for the treatment of T2DM patients in Japan. Results showed that patients gained an average of 0.309 QALYs (equal to 3.7 months of life in perfect health) at a total addition cost of 128,464 JPY. Using the nominated threshold of 5,000,000 JPY used in previous economic analyses^42–44, the resultant ICER of 416,280 JPY/QALY suggests that treatment with dulaglutide 0.75 mg, when compared to insulin glargine, would be a cost-effective option for patients and the Japanese health system alike, with dulaglutide offering patients improved gains in life expectancy and quality-of-life at an acceptable cost. Results were driven by greater improvements in initial HbA1c, SBP, and BMI compared to insulin glargine, resulting in reductions in the rates of all diabetes-related complications, and remained stable to plausible changes in model parameters and scenarios explored within sensitivity analyses. All key model inputs were explored in the sensitivity analyses, including both clinical and economic inputs. While the apparent differences in parameters such as SBP and BMI appeared relatively small, these are important to the development of diabetes-related complications, and were, therefore, included in the sensitivity analysis.

The economic evaluation used demographic and treatment effects derived from a Japanese population and clinical trial, and, where possible, converted utilities to ensure applicability to a Japanese setting. This is important as Japanese patients have a lower prevalence of obesity, lower microvascular event incidence rates, and differing risk factor profiles for diabetes complications compared to Caucasian patients⁴⁵. While the applied risk equations (UKPDS 68) were derived from a population that included Asian patients, further scenario analyses applying risk equations derived from the Hong Kong Registry were conducted to ensure results were applicable to the population. The scenarios resulted in conclusions unchanged from the base case and generated similar ICERs in both the main analysis and the PSA (688,818 JPY/QALY and 725,584 JPY/QALY, respectively), implying that the analysis is robust to the choice of risk equation and potential differences in cardiovascular risk between Japanese and Caucasian populations.

Regarding treatment effects, the data incorporated into the model were from clinical trial settings; thus, as with all clinical trials, the observed outcomes in a real-world setting may be different (e.g. treatment response rate and adverse events). Our study used a disutility of 0.04 applied for 3 months for patients experiencing nausea (19.79/100 patient years for dulaglutide 0.75 mg and 2.24/100 patient years for insulin glargine). Nausea with GLP-1 medications are generally reported as mild-to-moderate and, therefore, the applied disutility may be overstating the expected impact on patient quality-of-life. To assess the impact of this disutility we conducted a scenario analysis excluding nausea from the analysis, the result showed minimal change in outcomes: the incremental QALY gain increased by 0.01 and ICER decreased from 416,280 to 413,866 JPY/QALY.

As with all diabetes modeling analyses, this study is subject to limitations. First, as with any cost-effectiveness model, in the absence of lifetime data, a number of key assumptions were applied in order to extrapolate clinical trial data to long-term outcomes. These assumptions were consistent with observed disease progression and based on established and validated risk equations. Nonetheless, the UKPDS risk equations may not provide an ideal representation of treatment and disease progression in a modern Japanese treatment setting. Future long-term studies conducted in a Japanese diabetic population are required to provide further clarity. It is a significant challenge to identify accurate data on the various inputs required for modeling diabetes. The best available data were utilized wherever possible, and tested thoroughly throughout sensitivity analyses. Although Japan has a number of database registries^46,47, it was not possible to identify some complication costs for ulcer-related complications from these sources or Japanese publications and, therefore, the best available proxies from UK sources^48,49 were applied and converted to JPY. Sensitivity analyses involving these specific inputs indicated that the model was not sensitive to changes in these parameters. Continuing to improve public access to de-identified patient level data⁴⁶, contained in existing registries and standardizing hospital information systems across the Japanese prefectures, should improve the consistency and availability of Japanese data to support HTA analyses in the future⁵⁰.

Due to the lack of robust published Japanese utilities, European values were converted to reflect a Japanese population. While the conversion methodology is established, this process adds additional uncertainty into the analysis, which was explored during the sensitivity analyses. Future studies to develop robust diabetes-related utilities and disutilities specific to a Japanese population are likely to reduce this current uncertainty.

Conclusions

Dulaglutide has been approved for reimbursement by the Japanese Ministry of Health and Welfare and is currently available in Japan. Adhering to recently approved Japanese Cost-Effectiveness Guidelines and incorporating Japanese clinical trial data, this cost-utility analysis showed that dulaglutide provided additional QALYs of 0.309, additional LYs of 0.186, and an overall cost increase of 128,464 JPY compared to insulin glargine, suggesting that, from a Japanese healthcare perspective, dulaglutide 0.75 mg is a cost-effective treatment alternative to insulin glargine, the current standard of care, for Japanese patients with T2DM.

Transparency

Declaration of funding

This paper was funded by Eli Lilly and Company.

Declaration of financial/other relationships

HI has received lecture fees from AstraZeneca K.K., Daiichi Sankyo Co. Ltd, Eli Lilly Japan K.K., Mitsubishi Tanabe Pharma Co., MSD K.K., Nippon Boehringer Ingelheim Co. Ltd, Novartis Pharma K.K., Novo Nordisk Pharma Ltd, Ono Pharmaceutical Co. Ltd, Sanofi K.K., Sumitomo Dainippon Pharma Co. Ltd, Takeda Pharmaceutical Co. Ltd, and grant/research support from Astellas Pharma Inc., AstraZeneca K.K., Daiichi Sankyo Co. Ltd., Eli Lilly Japan K.K., Kyowa Hakko Kirin Co. Ltd, Mitsubishi Tanabe Pharma Co., MSD K.K., Novo Nordisk Pharma Ltd, Ono Pharmaceutical Co. Ltd, Shionogi & Co. Ltd, Takeda Pharmaceutical Co. Ltd, and Taisho Toyama Pharmaceutical Co. Ltd. MMW and LTJ are full-time employees of IQVIA, London, UK. AS is a full-time employee of Eli Lilly and Company. SS is a full-time employee of Eli Lilly Japan. JME peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Previous presentations

The data was published in the form of an abstract and a podium presentation at the 2016 Annual Meeting of the Japan Diabetes Society, Kyoto, Japan, on May 21, 2016.

Acknowledgments

The authors wish to acknowledge the reviewers and the editor for their detailed and helpful comments, which have contributed to the strength of this research.