The cost-effectiveness of dulaglutide versus liraglutide for the treatment of type 2 diabetes mellitus in Spain in patients with BMI ≥30 kg/m²

Figures & data

Figure 1. Diagrammatic representation of the IMS CORE Diabetes Model of Palmer et al.¹⁸

Table 1. Baseline cohort characteristics BMI ≥30 kg/m² (AWARD-6).

Characteristic^a	Mean	SD	Source
HbA1c (%)	8.05	0.8	AWARD-6 trial^8
Age (years)	55.79	9.66	AWARD-6 trial^8
Duration of diabetes (years)	6.73	5.28	AWARD-6 trial^8
Male (proportion)	0.464	NA	AWARD-6 trial^8
Ethnicity (proportion)
Caucasian	0.737		AWARD-6 trial^8
African-descent	0.051		AWARD-6 trial^8
Hispanic	0.210		AWARD-6 trial^8
Native American	0.000		AWARD-6 trial^8
Asian/Pacific Islander and other	0.002		AWARD-6 trial^8
Systolic blood pressure (mmHg)	132.22	14.85	AWARD-6 trial^8
Baseline total cholesterol (mg/dL)	181.03	41.84	AWARD-6 trial^8
Baseline HDL-C (mg/dL)	45.44	11.18	AWARD-6 trial^8
Baseline LDL-C (mg/dL)	97.78	33.46	AWARD-6 trial^8
Baseline triglycerides (mg/dL)	191.44	127.05	AWARD-6 trial^8
Body mass index (kg/m^2)	33.85	5.28	AWARD-6 trial^8
Proportion of smokers^b	0.3	NA	WHO 2013^21
Cigarettes per day^b	26	NA	WHO 2013^21
Alcohol consumption (oz/week)^b	7.56	NA	WHO 2014^22

^a Baseline cohort defined according to these characteristics in analyses comparing dulaglutide against liraglutide.

^b Values derived from World Health Organization (WHO) statistics.

Table 2. Modeled rates of diabetes complications at baseline.

Complication	Mean (percentage points)	Source
Myocardial infarction	0.037	Controlled at AWARD-6^8
Angina	0.009	Controlled at AWARD-6^8
Peripheral vascular disease	0.030	Controlled at AWARD-6^8
Stroke	0.014	Controlled at AWARD-6^8
Congestive heart failure	0.005	Controlled at AWARD-6^8
Atrial fibrillation	0.023	Controlled at AWARD-6^8
Left ventricular hypertrophy	0.000	Not reported inNICE NG28^23
Microalbuminuria^a	0.006	NICE NG28^23
Gross protenuria^a	0.001	NICE NG28^23
End-stage renal disease	0.000	NICE NG28^23
Background diabetic retinopathy^b	0.159	NICE NG28^23
Proliferative diabetic retinopathy^b	0.018	NICE NG28^23
Severe vision loss	0.000	Not reported inNICE NG28
Macular edema	0.000	Not reported inNICE NG28^23
Cataract	0.000	Not reported inNICE NG28^23
Uninfected ulcer	0.000	Not reported inNICE NG28^23
Infected ulcer	0.000	Not reported inNICE NG28^23
Healed ulcer	0.000	Not reported inNICE NG28^23
Amputation	0.000	Not reported inNICE NG28^23
Neuropathy	0.065	NICE NG28^23

^a NICE NG28 reported prevalence of nephropathy of 0.7% (assumed equivalent to albuminuria); of patients with albuminuria, 9,368 of 11,723 have microalbuminuria, 2,355 of 11,723 have microalbuminuria (Parving et al.²⁴).

^b NICE NG28 reported 17.7% prevalence of retinopathy; of patients with diabetic retinopathy, 719 of 798 had non-proliferative retinopathy, 79 of 798 had proliferative diabetic retinopathy.

Table 3. Treatment effects for BMI ≥30 kg/m² (AWARD-6).

Characteristic	Mean treatment effect (Standard error, 95% CI)
	Dulaglutide 1.5 mg	Liraglutide 1.8 mg
HbA1c (%)	−1.42 (0.06, −1.53 to −1.31)	−1.37 (0.06, −1.48 to −1.25)
Systolic blood pressure (mmHg)	−2.98 (0.92)	−2.76 (0.94)
Total cholesterol (mg/dL)	−5.35 (2.37)	−0.99 (2.45)
LDL-C (mg/dL)	−4.06 (1.98)	0.07 (2.05)
HDL-C (mg/dL)	2.24 (0.5)	1.69 (0.52)
Triglycerides (mg/dL)	−15.64 (8.69)	−15.26 (9.0)
Body mass index (kg/m^2)	−1.03 (0.09, −1.22 to −0.85)	−1.36 (0.1, −1.55 to −1.17)
Nausea (event rate per 100 patient years)^a	40.00	33.00
Major hypo (event rate per 100 patient years)	0.00	0.00
Minor hypo (event rate per 100 patient years)^b	18.00	48.00

^a Input converted from provided data on proportion of patients at 12 months experiencing nausea.

^b Please note that the “minor hypo” refers to non-severe symptomatic hypo events as reported in the AWARD trials, which were based upon documented symptomatic and probable (not documented symptomatic) hypoglycemia.

Table 4. Health state and treatment related utilities.

Health state	Input value^a	Reference
T2DM without complication	0.785	Beaudet et al.^27
Myocardial infarction	−0.055	Beaudet et al.^27
Post-myocardial infarction	0.730	Assumed equal to baseline utility minus MI event^27
Ischemic heart disease	0.695	Beaudet et al.^27
Heart failure	0.677	Beaudet et al.^27
Stroke	−0.164	Beaudet et al.^27
Post-stroke	0.621	Assumed equal to baseline utility minus MI event^27
Severe vision loss	0.711	Beaudet et al.^27
Amputation	−0.280	Beaudet et al.^27
Post-amputation	0.505	Assumed equal to baseline utility minus MI event
Peripheral vascular disease	0.724	Beaudet et al.^27
Proteinuria	0.737	Beaudet et al.^27
Neuropathy	0.701	Beaudet et al.^27
Active ulcer	0.615	Beaudet et al.^27
Hemodialysis	0.621	Beaudet et al.^27
Peritoneal dialysis	0.581	Beaudet et al.^27
Renal transplant	0.762	Beaudet et al.^27
Cataract	0.769	Beaudet et al.^27
Diabetic retinopathy	0.745	Beaudet et al.^27
Macular edema	0.785	Beaudet et al.^27
Vision threatening diabetic retinopathy	0.715	Beaudet et al.^27
Excess BMI (each unit above 25 kg/m^2)^b	−0.006	Beaudet et al.^27
Major hypoglycemia event^c	−0.012	Beaudet et al.^27
Minor hypoglycemia event^c	−0.004	Beaudet et al.^27
Nausea^d	−0.04	Matza et al.^30
Injection site reaction (ISR)^e	−0.011	Boye et al.^29
Dosing frequency utility^f	0.023	Boye et al.^29

^a Within the CDM utilities associated with MI, stroke, amputation, nausea, hypoglycemia, and weight gain are input as utility decrements; all other values are input as expected utilities.

^b Disutility due to nausea and excess BMI were included in the base case. The impact of the exclusion of nausea and excess BMI disutilities was tested in two sensitivity analyses.

^c Disutility due to a hypoglycemic event was included in the base case. The impact of the exclusion of hypoglycemic event disutilities was tested in a sensitivity analysis

^d Nausea was searched for in the systematic review, but not reported, within the model, nausea is applied for 6 months only to reflect the transient nature of the condition (reported annual disutility is halved).

^e ISR disutility is applied to those patients experiencing ISR.

^f Dosing frequency utility is related to the utility gain associated with weekly vs daily/more frequent dosing.

Table 5. Drug prices (€2014) in Spain.

Comparator	Units per pack	Pack price (€)	Dosage	Cost per day (€)	Source
Dulaglutide	1.5 mg	140.06	1.5 mg/week	5.00	BotPLUS^31
Liraglutide	3*3 ml pens, 6 mg/ml	128.20	1.8 mg/day	6.41	BotPLUS^31
Insulin Glargine (Lantus SoloStar)	5*3 ml pens, 100 U/ml	71.40	40 IU/day	1.90	BotPLUS^31

Table 6. Needle and SMBG prices (€2014) in Spain.

	Unit cost (€)	Source
Needle cost
Needle (AGO BD MICROFINE G31 5MM 100PZ)	0.065	Guisasola^33
SMBG cost
Lancet (One Touch Comfort Blood lancet)	0.11	Farmacia En-casa^34
Strips (One Touch Ultra)	0.39	Guisasola^33

Table 7. Annual treatment costs (€) in Spain.

Drug	Drug annual cost (€)	Needles annual cost (€)	Blood glucose monitoring annual cost (€)		Total annual cost (€)
			Lancets	Strips
Dulaglutide 1.5 mg once weekly	1,826.25	0.00	0.00	0.00	1,826.25
Liraglutide 1.8 mg once daily	2,341.19	23.75	0.00	0.00	2,364.94
Rescue Treatment (Insulin glargine 40 IU once daily)	695.44	23.75	40.47	142.45	902.12

Table 8. Management costs (€annual).

Management costs	Unit cost (€2014)*	Reference
Annual statins	20.40	WHO ATC/DDD index^49; BOTPlus^31
Annual aspirin	16.96	WHO ATC/DDD index^49; BOTPlus^31
Annual angiotensin-converting-enzyme inhibitor (ACE –I)	31.34	WHO ATC/DDD index^49; BOTPlus^31
Annual eye screening	124.53	eSalud database – Hernandez-Pastor^41
Annual screening for microalbuminuria (MA)	776.99	eSalud database – Osakidetza^44
Annual screening for gross proteinuria (GRP)	204.87	eSalud database – Servicio de Salud de Castilla^39
Annual foot screening program	14.54	Ray et al.^47
Stopping ACE due to systemic embolism (SE)	55.32	Assumption based on Ray et al.^47
Myocardial infarction 1st year	8,578.70	eSalud database – Ministerios de Sanidad^43
Myocardial infarction 2nd + years	5,260.31	eSalud database – Ministerios de Sanidad^43
Angina 1st year	2,660.61	eSalud database – Schwander et al.^48
Angina 2nd + years	562.15	eSalud database –Schwander et al.^48
Congestive heart failure 1st year	4,407.30	eSalud database – Ministerios de Sanidad^43
Congestive heart failure 2nd + years	4,407.30	Assumed the same as the first year
Stroke 1st year	5,950.22	eSalud database – Pinol et al.^46
Stroke 2nd + years	2,209.20	eSalud database – Pinol et al.^46
Stroke death within 30 days	4,106.65	eSalud database – Pinol et al.^46
Peripheral vascular disease 1st year	6,903.44	eSalud database – Ministerios de Sanidad^43
Peripheral vascular disease 2nd + years	6,903.44	Assumed the same as the first year
Hemodialysis 1st year	37,903.89	eSalud database – Parra-Moncansi et al.^45
Hemodialysis 2+ years	37,903.89	Assumed the same as first year, based on Ray et al.^47
Peritoneal Dialysis 1st year	43,218.25	Ray et al.^47
Peritoneal Dialysis 2+ years	43,218.25	Assumed the same as first year, based on Ray et al.^47
Renal transplant costs 1st year	37,488.59	Ray et al.^47
Renal transplant 2+ years	11,015.33	Ray et al.^47
Major hypoglycemia (per event)	5,900.50	eSalud database – Ministerio de Sanidad^43
Minor hypoglycemia (per event)	446.639	Ray et al.^47
Ketoacidocis event	4,851.94	eSalud database – Ministerio de Sanidad^43
Lactic acid event	5,918.01	eSalud database – Ministerio de Sanidad^43
Laser treatment	130.05	eSalud database – Departament de Salut^37
Cataract operation	1,367.49	eSalud database- Consellaria de Sanidade^36
Cost following cataract operation	3,823.74	eSalud database – Ministerio de Sanidad^43
Cost blindness - year of onset	5,000.74	eSalud database – Ministerio de Sanidad^43
Cost blindness - following years	5,000.74	Assumed the same as the first year
Neuropathy 1st year	4,675.91	eSalud database – Ministerio de Sanidad^43
Neuropathy 2nd + years	4,675.91	Assumed the same as the first year
Amputation (event based)	12,535.15	eSalud database – Ministerio de Sanidad^43
Amputation prosthesis (event based)	23,27.74	eSalud database Departamento de Sanidad^38
Gangrene treatment (monthly)	11,485.81	eSalud database – Ministerio de Sanidad^43
Healed ulcer	6,736.96	eSalud database – Ministerio de Sanidad^43
Infected ulcer (monthly)	2,401.06	Assumed based on Goodall et al.^40
Standard uninfected ulcer (monthly)	1,372.20	Assumed based on Goodall et al.^40
Healed ulcer history of amputation	0.00	Assumed

* Inflated to 2014 costs using CPI indices by Instituto National de Estadistica¹⁹.

Table 9. Parameters and distributions used in PSA.

	Parameter	Distribution
Events	Probability for 1st MI, 1st stroke, angina, heart failure	For these probabilities, we sample the coefficients applied in respective risk regression equations. While the sampling distribution for the coefficients is normal (Gaussian), the resulting distribution of probabilities is beta.
Cohort characteristics	Start age, Duration of diabetes, HbA1c, SBP, Total cholesterol, HDL cholesterol, LDL cholesterol, Triglycerides, BMI	Normal distribution, gamma (triglycerides only)
Treatment effect	Change from baseline in: HbA1c, SBP, total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, BMI	Beta distribution (using standard error values, as reported in Table 3)
Costs	Statins, ACE inhibitor, aspirin, all health state costs	Log-normal
Utilities	All utility values used in the base case	Beta distribution (using standard error values, as reported in Table 4)

Table 10. Base case outputs (dulaglutide 1.5 mg – liraglutide 1.8 mg).

	Dulaglutide 1.5 mg	Liraglutide 1.8 mg	Difference
Quality-adjusted life expectancy (QALYs)	10.281	10.259	0.021
Life expectancy (years)	15.808	15.770	0.037
Lifetime direct costs (EUR)	108,489	109,653	-1,165
ICER (Incremental costs/Incremental life expectancy)	Dulaglutide is dominant
ICER (Incremental costs/Incremental QALYs)	Dulaglutide is dominant
Cumulative incidence of complications
Background retinopathy	33.653	33.655	−0.002
Proliferative retinopathy	4.634	4.732	−0.098
Macular edema	27.807	27.720	0.087
Severe vision loss	17.140	17.075	0.065
Cataract	13.934	13.808	0.126
Microalbuminuria	47.566	47.384	0.182
Gross proteinuria	19.923	19.766	0.157
End-stage renal disease	7.226	7.211	0.015
Foot ulcer, first event	47.593	47.676	−0.083
Recurring foot ulcer	94.230	94.503	−0.273
First amputation	21.013	21.020	−0.007
Amputation recurrent ulcer	8.452	8.401	0.051
Neuropathy	76.802	76.654	0.148
Congestive heart failure events	17.431	17.000	0.431
Peripheral vascular disease onset	18.052	18.132	−0.080
Angina	12.237	12.774	−0.537
Diabetes mortality	18.142	18.353	−0.211
Stroke event	7.821	7.706	0.115
Myocardial infarction death	18.520	18.743	−0.223
Myocardial infarction event	18.736	19.396	−0.660
Nausea	0.399	0.330	0.069
Minor hypoglycemic events	0.373	0.970	−0.597

Table 11. Sensitivity analyses (dulaglutide 1.5 mg – liraglutide 1.8 mg).

Population/analysis	Cost (Euro)			QALYs
	Dulaglutide 1.5 mg	Liraglutide 1.8 mg	Difference	Dulaglutide 1.5 mg	Liraglutide 1.8 mg	Difference	ICER (€/QALY)
Base-case	108,489	109,653	−1,165	10.281	10.259	0.021	DOMINANT
PSA	105,134	106,408	−1,273	9.948	9.918	0.030	DOMINANT
Treatment effects
BMI Upper Limit CI (−0.85)	108,353	109,653	−1,301	10.278	10.259	0.018	DOMINANT
BMI Lower Limit CI (−1.22)	108,464	109,653	−1,190	10.284	10.259	0.024	DOMINANT
HBA1c Upper Limit CI (−1.31)	109,027	109,653	−627	10.275	10.259	0.016	DOMINANT
HBA1c Lower Limit CI (−1.53)	108,082	109,653	−1,572	10.304	10.259	0.045	DOMINANT
Treatment duration
1 year	107,297	107,912	−615	10.284	10.252	0.032	DOMINANT
3 years	109,643	111,447	−1,804	10.284	10.268	0.016	DOMINANT
Economics (cost of complications)
Economics −20%	90,082	91,213	−1,130	10.281	10.259	0.021	DOMINANT
Economics +20%	126,897	128,096	−1,199	10.281	10.259	0.021	DOMINANT
Disutility exclusions
BMI disutility	108,489	109,653	−1,165	11.316	11.290	0.026	DOMINANT
Nausea disutility	108,489	109,653	−1,165	10.288	10.266	0.022	DOMINANT
Hypoglycemia disutility	108,489	109,653	−1,165	10.282	10.263	0.019	DOMINANT
Time horizon
10 years	32,739	34,114	−1,375	5.456	5.455	0.001	DOMINANT
20 years	72,578	73,991	−1,413	8.650	8.635	0.015	DOMINANT
Discounting
0% discount	183,485	184,249	−764	14.967	14.924	0.043	DOMINANT
5% discount	80,302	81,558	−1,256	8.331	8.317	0.014	DOMINANT
Treatment switch
HBA1c threshold 7.5% (inadequately controlled disease^26)	110,662	113,155	−2,493	10.283	10.264	0.019	DOMINANT
Alternate price
Alternative Lira 1.8 mg price equal to L 1.5 mg dose price	108,489	108,911	−422	10.281	10.259	0.021	DOMINANT
Alternative Lira 1.8 mg price equal to L 1.36 mg dose price	108,489	108,564	−75	10.281	10.259	0.021	DOMINANT

Figure 2. Cost-effectiveness pairs for dulaglutide 1.5 mg vs liraglutide 1.8 mg.

Figure 3. Cost-effectiveness acceptability curve for dulaglutide 1.5 mg vs liraglutide 1.8 mg.

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