Economic Evaluation of Canagliflozin Versus Glimepiride and Sitagliptin in
Dual Therapy With Metformin for the Treatment of Type 2 Diabetes in Italy
R. Ravasio,1 P. Pisarra,2,* M. Comaschi3
1
Health Publishing & Services Srl, Milan, Italy; 2Janssen-Cilag S.p.A., Cologno Monzese, Milan, Italy; 3Diabetologia, Endocrinologia, Medicina Interna ICLAS, GVM Care & Research, Rapallo, Genoa, Italy.
*Presenting author.
◾ Data from the 2013 Italian National Institute of Statistics statistical yearbook indicated that >3 million
people (5.4% of the Italian population) have diabetes2; of these, ~90% have type 2 diabetes mellitus
(T2DM)1
◾ Lifestyle changes are initially recommended for the treatment of T2DM and remain the backbone of
therapy, even after pharmacological intervention with metformin is initiated3,4
◾ When additional glycaemic control is needed, other medications can be added to metformin3,5-7;
however, some treatments have negative side effects (eg, weight gain, hypoglycaemia)3
◾ Sodium glucose co-transporter 2 (SGLT2) inhibitors are a new class of medications for the treatment
of adults with T2DM that lower blood glucose by increasing urinary glucose excretion (UGE) via an
insulin-independent mechanism that is complementary to other classes of diabetes medications8
– Increased UGE also results in a mild osmotic diuresis and a net loss of calories in patients with T2DM,
which may lead to weight loss and blood pressure reduction8
◾ In contrast, dipeptidyl peptidase-4 (DPP-4) inhibitors (eg, sitagliptin) lower blood glucose but are not
associated with weight loss or blood pressure reduction, and sulphonylureas (eg, glimepiride) are
associated with weight gain and hypoglycaemia3
Genital Mycotic Infection Costs
◾ No cost was associated with genital mycotic infections, which were assumed to be self-managed with
over-the-counter, antimycotic medications (eg, canacid)
Projection Period
– Canagliflozin 100 mg demonstrated non-inferiority in HbA1c lowering and canagliflozin 300 mg
demonstrated superiority in HbA1c lowering as add-on to metformin versus either glimepiride or
sitagliptin 100 mg at Week 5210,11
◾ Sensitivity analyses were conducted to examine the uncertainty of the base case results per Italian
guidelines for health care–related financial evaluations18
B.
◾ A literature search identified 1 article for glimepiride (Cefalu et al10) and 1 article for sitagliptin
(Lavalle-González et al11) that were suitable for inclusion in the analysis
◾ Univariate analyses were conducted that varied the following parameters:
– Costs and treatment setting of a hypoglycaemia episode
◾ Threshold analyses were also carried out on the following parameters:
– Reduction in weight loss efficacy with canagliflozin
◾ In the add-on to metformin versus sitagliptin study, patients (N = 1,284) were randomised (2:2:2:1) to
receive canagliflozin 100 or 300 mg, sitagliptin 100 mg, or placebo for 26 weeks; patients randomised
to placebo switched to sitagliptin 100 mg during the 26-week extension period11
◾ Baseline characteristics and a summary of the key results from both studies at Week 52 are shown in
Table 1
Table 1. Clinical Inputs: Baseline Characteristics and Key Results at Week 52
Canagliflozin versus glimepiride10
Canagliflozin versus sitagliptin11
Canagliflozin Canagliflozin
Canagliflozin Canagliflozin Sitagliptin
100 mg
300 mg Glimepiride
100 mg
300 mg
100 mg
Baseline
characteristics
Number of patients
Age, y
Female, %
Weight, kg
BMI, kg/m2
HbA1c, %
Duration of T2DM, y
Results at Week 52
Change in HbA1c, %
Total hypoglycaemia
episodes,† %
Mild to moderate‡
Severe
Genital mycotic
infections, %
Change in weight
%
kg
483
56.4
48
86.9
31.0
7.8
6.5
–0.82*
485
55.8
50
86.6
31.2
7.8
6.7
–0.93*
482
56.3
45.0
86.5
30.9
7.8
6.6
–0.81
368
55.5
52.7
88.8
32.4
7.9
6.7
–0.73*
367
55.3
55
85.4
31.4
7.9
7.1
–0.88*
366
55.5
53.0
87.7
32
7.9
6.8
–0.73
5.6
4.9
34.2
6.8
6.8
4.1
5.2
0.4
4.3
0.6
31.1
3.1
6.5
0.3
6.8
0.0
3.8
0.3
8.9
11.1
1.7
8.4
6.5
1.9
–4.2
–3.7
–4.7
–4.0
1.0
0.7
–3.8
–3.3
–4.2
–3.7
–1.3
–1.2
BMI, body mass index.
*Canagliflozin 100 mg demonstrated non-inferiority in HbA1c lowering and canagliflozin 300 mg demonstrated superiority in HbA1c lowering versus either
glimepiride or sitagliptin 100 mg at Week 52.
†Includes documented hypoglycaemia episodes from the clinical trial, defined as biochemically documented episodes (ie, glucose levels ≤3.9 mmol/L) with or
without symptoms and severe episodes (ie, those requiring the assistance of another individual or resulting in seizure or loss of consciousness).
‡Includes documented hypoglycaemia episodes from the clinical trial that were not considered severe.
◾ Based on a conservative hypothesis of therapeutic equivalence, the models estimate the economic
impact associated with the introduction of canagliflozin in the treatment of T2DM compared to the
most common and widely used oral antidiabetic drugs (sulphonylureas) and those of the latest
generation (DPP-4 inhibitors)
◾ The comparison of canagliflozin versus glimepiride and sitagliptin was assessed in the context of
a cost-minimisation analysis (CMA) that considered only direct health care costs (eg, medicinal
products, hospitalisations, specialist medical care, glycaemic self-monitoring, hypoglycaemic events)
associated with the treatment of T2DM and body weight changes in patients with T2DM12
Use of Health Care Resources and Value Analysis
Diabetes Medication Costs
◾ Diabetes medication costs were calculated based on dosages used in the studies; the average daily
costs for canagliflozin 100 and 300 mg, sitagliptin 100 mg, and glimepiride were €1.34, €1.99, €1.28, and
€0.118, respectively13
Weight Changes
◾ The relationship between weight change and health care costs was obtained from a study in patients
with T2DM, where each 1% loss in body weight significantly decreased health care costs associated
with T2DM management by 3.6% (P <0.05) and each 1% weight gain was not related to a statistically
significant increase in treatment costs12
Patient Costs
◾ An Italian national survey estimated the total annual cost incurred by a patient with T2DM to be €2,756
(€814 for medications, €1,569 for hospitalisations, and €373 for specialist medical care)14
◾ For this analysis, a total cost of €2,585 was used, with the cost of antidiabetic medications (€171)
excluded to avoid a double-counting error
Hypoglycaemia Costs
◾ It was assumed that a hypoglycaemia episode could be treated at home, with access to emergency
care or hospitalisation if needed15
– No cost was associated with a hypoglycaemia episode treated at home (assumed 86% of mild-tomoderate episodes15)
– The cost for emergency care was €133.89 based on the national fees associated with health care
services provided to the patient16 (assumed 14% of mild-to-moderate episodes and 29.8% of severe
episodes15)
5
10
Glimepiride
15
20
25
30
2,600
2,300
5
10
◾ Canagliflozin 100 and 300 mg were associated with a lower annual cost per patient than sitagliptin
100 mg (Table 2)
– The cost savings with canagliflozin 100 and 300 mg were due primarily to the differences in costs
related to a greater loss in body weight; cost differences associated with other components
(eg, management of hypoglycaemia, SMBG) were negligible
Medications for
diabetes
Other medications
Hospitalisations
Specialist medical
care
Hypoglycaemia
(mild to moderate)
Hypoglycaemia
(severe)
Hypoglycaemia
self-monitoring
Total per treated
patient
20
25
30
€43.05
€487.76
€724.36
€465.92
€545.78
€1,331.77
€534.20
€1,303.53
€643.00
€1,569.00
€555.04
€1,354.36
€545.78
€1,331.77
€612.91
€1,495.57
€316.60
€309.89
€373.00
€321.97
€316.60
€355.54
Average costs per patient (€)
Canagliflozin 300 mg
p = 39.8%
3,200
2,900
2,600
2,300
0
5
10
15
20
25
30
35
40
Percent reduction in the number of SMBG measurements with glimepiride
Note that p represents the percent reduction at which canagliflozin is no longer cost-saving versus glimepiride.
Figure 2. Threshold analysis results for (A) reduction in weight loss efficacy with
canagliflozin and (B) reduction in patient treatment costs.
Canagliflozin Canagliflozin
Canagliflozin Canagliflozin Sitagliptin
100 mg
300 mg
Glimepiride
100 mg
300 mg
100 mg
€724.36
Canagliflozin 100 mg
2,000
Canagliflozin versus sitagliptin
€487.76
Glimepiride
3,500
A.
Sitagliptin 100 mg
3,300
Canagliflozin 100 mg
Canagliflozin 300 mg
p = 4.2%
3,200
3,100
3,000
2,900
2,800
2,700
0
5
10
15
20
25
30
Percent reduction in weight loss efficacy with canagliflozin
€0.97
€0.81
€5.83
€1.22
€1.27
€0.72
€8.40
€12.55
€63.13
€5.51
€0.00
€5.54
€94.18
€94.18
€470.89
€94.18
€94.18
€94.18
€2,785.46
€2,979.52
€3,167.90
€2,820.05
€3,013.96
€3,030.38
Sensitivity Analyses
B.
◾ Threshold analyses showed that canagliflozin 100 or 300 mg continued to represent a cost-saving
option versus glimepiride, unless the number of SMBG measurements was reduced substantially
(>39.8%; Figure 1)
◾ Threshold analyses confirmed the base case results that canagliflozin 100 mg was associated with cost
savings versus sitagliptin 100 mg at all values for reduction in weight loss efficacy with canagliflozin
and reduction in costs for managing a patient with T2DM, while uncertainty was greater for the
comparison of canagliflozin 300 mg and sitagliptin 100 mg (Figure 2)
– Canagliflozin 300 mg provided cost savings compared with sitagliptin 100 mg unless weight loss
efficacy with canagliflozin was reduced by >4.2% or patient treatment costs were reduced by >6.1%
Canagliflozin 300 mg
3,200
p = 6.1%
2,900
2,600
2,300
2,000
0
5
10
15
20
25
30
Percent reduction in patient treatment costs
Note that p represents the percent reduction at which canagliflozin is no longer cost-saving versus sitagliptin.
DISCUSSION
◾ This CMA identifies canagliflozin 100 or 300 mg as a cost-saving treatment option compared with
glimepiride and sitagliptin 100 mg for the treatment of patients with T2DM inadequately controlled
with metformin
Canagliflozin versus sitagliptin
Canagliflozin Canagliflozin
Canagliflozin Canagliflozin Sitagliptin
100 mg
300 mg
Glimepiride
100 mg
300 mg
100 mg
€2,979.52
Canagliflozin 100 mg
– Results from the present CMA, conducted from the Italian perspective, are consistent with
cost-efficiency data from the United States, which demonstrated lower annual costs for treatment
with canagliflozin 300 mg versus sitagliptin 100 mg19
Table 3. Sensitivity Analysis Results
Base case
€2,785.46
Costs for genital mycotic
infection treatment
One canacid
package, Italian
€2,787.07
National Health
Service
Costs for hypoglycaemia
hospitalisation
ICD-9-CM 250.3
and 250.8
€2,787.91
secondary
diagnosis
ICD-9-CM 250.3
and 250.8 main
€2,787.03
and secondary
diagnosis
Costs for emergency
care of hypoglycaemia
–25%
€2,785.17
+25%
€2,785.74
Hypoglycaemia setting
Mild to moderate:
100% treated in
€2,791.42
emergency care
facilities
Severe: 100% treated
in emergency
€2,788.79
care facilities
Sitagliptin 100 mg
3,500
◾ Sensitivity analyses confirmed the base case results, which indicated that canagliflozin 100 and 300 mg
were associated with lower costs versus glimepiride or sitagliptin 100 mg (Table 3)
Univariate
analysis
15
Percent reduction in patient treatment costs
◾ Canagliflozin 100 and 300 mg were associated with a lower annual cost per patient compared with
glimepiride and, therefore, resulted in cost savings (Table 2)
Cost items
Canagliflozin 300 mg
2,900
0
Base Case
Canagliflozin versus glimepiride
Canagliflozin 100 mg
3,200
– Reduction in the number of SMBG measurements associated with glimepiride
Canagliflozin versus glimepiride
Study Design
2,800
2,000
– Decrease in treatment costs for a patient with T2DM
Table 2. Base Case Results
Clinical Inputs
◾ In the add-on to metformin versus glimepiride study, patients (N = 1,450) were randomised (1:1:1) to
receive canagliflozin 100 or 300 mg or glimepiride over 52 weeks10
2,900
3,500
Average costs per patient (€)
◾ Based on the availability of head-to-head clinical trials with canagliflozin and their use in Italian clinical
practice, 1 sulphonylurea (glimepiride) and 1 DPP-4 inhibitor (sitagliptin) were selected for this
financial evaluation
3,000
Sensitivity Analyses
Average costs per patient (€)
Clinical Data and Treatments
3,100
Percent reduction in weight loss efficacy with canagliflozin
– Costs for diabetes medications were higher with canagliflozin 100 and 300 mg compared with
glimepiride; these higher costs were completely offset by cost differences related to a reduction in
body weight (ie, other medications, hospitalisations, and specialist medical care) and a reduction in
costs associated with the management of SMBG
METHODS
3,200
0
RESULTS
◾ To determine the cost savings associated with canagliflozin 100 or 300 mg compared with either
glimepiride or sitagliptin 100 mg for a patient with T2DM inadequately controlled with metformin,
from the perspective of the Italian National Health Service
Canagliflozin 300 mg
2,700
C.
OBJECTIVE
Canagliflozin 100 mg
3,300
◾ The projected period for this analysis was 12 months (ie, 52 weeks), consistent with the duration of the
2 clinical studies
– Costs for the treatment of a genital mycotic infection
◾ Canagliflozin, an SGLT2 inhibitor, has been associated with improvements in glycaemic control, body
weight and blood pressure reductions, and a low risk of hypoglycaemia across studies in patients with
T2DM who were on various background therapies, including metformin9
Glimepiride
A.
Average costs per patient (€)
◾ Surging obesity, an aging population, and increasingly sedentary lifestyles have led to a progressive
worldwide increase in the observed prevalence of diabetes1
Figure 1. Threshold analysis results for (A) reduction in weight loss efficacy with canagliflozin,
(B) reduction in patient treatment costs, and (C) reduction in the number of SMBG
measurements with glimepiride.
Average costs per patient (€)
INTRODUCTION
Self-monitoring of Blood Glucose Costs
◾ The costs associated with self-monitoring of blood glucose (SMBG) were calculated by attributing a
value to the daily average usage of reaction strips and finger pricks per Italian guidelines (an average of
2 per day for patients treated with glimepiride and an average of 3 per week for patients treated with
sitagliptin and canagliflozin),7 and an average national cost calculated based on regional
reimbursement prices, when available
€3,167.90
€2,820.05
€3,013.96
◾ Cost savings per patient treated with canagliflozin versus glimepiride were attributable to all the cost
items being considered in this analysis (ie, weight loss, reduced risk of hypoglycaemia, lower number
of SMBG measurements)
€3,030.38
◾ Cost savings per patient with canagliflozin versus sitagliptin 100 mg primarily resulted from lower
treatment costs associated with body weight reduction
◾ Sensitivity analyses generally support the base case findings
€2,981.51
€3,168.20
€2,821.55
€3,015.13
€3,030.72
CONCLUSION
€2,983.18
€3,186.34
€2,821.66
€3,013.96
€3,032.00
€2,981.86
€3,179.72
€2,821.08
€3,013.96
€3,031.42
◾ This analysis demonstrates that canagliflozin 100 or 300 mg are likely to be the best
cost-saving options compared with glimepiride and sitagliptin 100 mg in the treatment
of patients with T2DM inadequately controlled with metformin in Italy, which may allow
for more efficient allocation of resources available to the Italian National Health Service
REFERENCES
€2,979.25
€2,979.78
€3,166.13
€3,169.67
€2,819.71
€2,820.38
€3,013.64
€3,014.28
€3,030.17
€3,030.59
€2,984.50
€3,203.73
€2,827.56
€3,021.79
€3,034.79
€2,984.49
€3,192.93
€2,822.23
€3,013.96
€3,032.58
ICD-9-CM, International Classification of Diseases, 9th Revision, Clinical Modification.
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ARNO_Diabete_2011.pdf. Accessed 4 August 2015.
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ACKNOWLEDGEMENTS
This analysis was made possible by an unconditional grant provided by Janssen-Cilag S.p.A., and
was based on data from clinical studies funded by Janssen Research & Development, LLC. Medical
writing support was provided by Alaina DeToma, PhD, of MedErgy, and was funded by Janssen
Pharmaceutica NV.
Canagliflozin has been developed by Janssen Research & Development, LLC, in collaboration with
Mitsubishi Tanabe Pharma Corporation.
– The average (weighted) cost per hospitalisation was €2,833 based on diagnosis-related group (DRG)
tariffs, as identified in a study conducted by Fondazione Mario Negri Sud17 (assumed 70.2% of severe
episodes15)
POSTER PRESENTED AT THE INTERNATIONAL SOCIETY FOR PHARMACOECONOMICS AND OUTCOMES RESEARCH (ISPOR) 18TH ANNUAL EUROPEAN CONGRESS; 7-11 NOVEMBER 2015; MILAN, ITALY.