VALUE IN HEALTH REGIONAL ISSUES 8C (2015) 8–19
Available online at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/vhri
Cost-Effectiveness of Canagliflozin versus Sitagliptin as Add-on
to Metformin in Patients with Type 2 Diabetes Mellitus
in Mexico
Cheryl Neslusan, PhD1,*, Anna Teschemaker, PhD1, Pierre Johansen, MSc2, Michael Willis, PhD2,
Atanacio Valencia-Mendoza, MS3, Andrea Puig, PhD4
1
Janssen Global Services, LLC, Raritan, NJ, USA; 2The Swedish Institute for Health Economics, Lund, Sweden; 3Janssen Cilag Mexico,
Mexico; 4Johnson and Johnson International, New Brunswick, NJ, USA
AB STR A CT
Objective: To assess the cost-effectiveness of canagliflozin versus
sitagliptin for the treatment of type 2 diabetes mellitus (T2DM) as
an add-on to metformin in Mexico. Methods: A validated model
(Economic and Health Outcomes [ECHO]-T2DM) was used to estimate
the cost-effectiveness of canagliflozin 300 or 100 mg versus sitagliptin
100 mg in patients with T2DM inadequately controlled on metformin
monotherapy. Data from a head-to-head, phase III clinical trial,
including patients’ baseline demographic characteristics, biomarker
values, and treatment effects, were used to simulate outcomes and
resource use over 20 years from the perspective of the Mexican health
care system. Costs of complications and adverse events were tailored
to the Mexican setting and discounted at 5%. Cost-effectiveness was
assessed using willingness-to-pay thresholds equivalent to 1 times
the gross domestic product per capita (locally perceived to be “very
cost-effective”) and 3 times the gross domestic product per capita
(locally perceived to be “cost-effective”) on the basis of recommendations of the Mexican government and the World Health Organization.
Results: Owing primarily to better glycated hemoglobin (HbA 1c),
body weight, and systolic blood pressure values, canagliflozin
300 and 100 mg were associated with an incremental benefit of 0.16
and 0.06 quality-adjusted life-years (QALYs) versus sitagliptin 100 mg,
respectively, over 20 years. The mean differences in cost for canagliflozin 300 and 100 mg versus sitagliptin 100 mg were Mexican pesos
(MXP) 1797 (US $134) and MXP 7262 (US $540), respectively, resulting in
a cost per QALY gained of MXP 11,210 (US $834) and MXP 128,883 (US
$9590), respectively. Both of these cost-effectiveness ratios are below
the very cost-effective willingness-to-pay threshold in Mexico. The
general finding that canagliflozin is cost-effective versus sitagliptin in
Mexico was supported by sensitivity analyses. Conclusion: In Mexico,
both doses of canagliflozin are likely to be cost-effective versus
sitagliptin in patients with T2DM who have inadequate glucose
control on metformin, primarily because of better biomarker control
and higher QALYs.
Keywords: cost-effectiveness, dipeptidyl peptidase-4 inhibitor, SGLT2
inhibitor, type 2 diabetes.
Introduction
nature of T2DM and associated comorbidities. There are direct
costs incurred in managing the hyperglycemia associated with
T2DM. It is notable, however, that most of the costs are
attributable to T2DM-related complications (e.g., myocardial
infarction, stroke, nephropathy, neuropathy, and retinopathy),
the rates of which are inversely related to disease control [5]. In
Mexico, the direct costs of diabetes were estimated at approximately US $1.16 billion (15 billion Mexican pesos [MXP]) in
2006, and these figures have steadily increased [4]. Estimates
suggest that diabetes-related complications can substantially
increase patient costs in Mexico [4]. As noted in a recent
consensus statement from the Latin American Diabetes Association, the Latin American health care system has historically
focused on the treatment of acute health conditions, primarily
The number of people with diabetes in Latin American countries
is growing, likely because of widespread increases in obesity in
the region, and it is expected to increase by approximately 60%,
from 24.1 million today to 38.5 million by 2035 [1]. About 90% of
patients have type 2 diabetes mellitus (T2DM) [2]. In Mexico, the
prevalence of diagnosed patients increased from 7.3% of the
population in 2006 to 9.2% in 2012 [3], and it is believed that
many cases remain undiagnosed [2]. Diabetes has been the
leading cause of death since 2000, and was estimated to account
for nearly 14% of deaths in 2009 [4].
T2DM imposes a significant economic burden on health care
in Latin America due to the increasing prevalence and chronic
Copyright & 2015, International Society for Pharmacoeconomics and
Outcomes Research (ISPOR). Published by Elsevier Inc.
Conflicts of interest: C.N. and A.T. are full-time employees of Janssen Global Services, LLC. M.W. and P.J. are employees of the
Swedish Institute for Health Economics, which has provided consulting services for Janssen Global Services, LLC. A.V.-M. is a full-time
employee of Janssen Cilag Mexico. A.P. is a full-time employee of Johnson & Johnson International.
* Address correspondence to: Cheryl Neslusan, Janssen Global Services, LLC, 920 Route 202 South, Raritan, NJ 08869.
E-mail: [email protected].
2212-1099$36.00 – see front matter Copyright & 2015, International Society for Pharmacoeconomics and Outcomes Research (ISPOR).
Published by Elsevier Inc.
http://dx.doi.org/10.1016/j.vhri.2015.01.002
VALUE IN HEALTH REGIONAL ISSUES 8C (2015) 8–19
due to limited resources [5]. As chronic diseases such as T2DM
become more common in Latin America, payers and clinicians
will face challenges unique to this region in helping patients
achieve health-related goals.
Maintaining near-normal blood glucose levels has been
shown to improve key T2DM-related outcomes [6]. The Latin
American Diabetes Association and the Institute of Mexican
Social Security (IMSS) recommend maintaining a glycated hemoglobin (HbA1c) level of less than 7.0%, blood pressure of less than
or equal to 130/80 mmHg, and low-density lipoprotein cholesterol
(LDL-C) level of less than 100 mg/dL in most patients [5,7],
consistent with the recommendations of the American Diabetes
Association [8]. In addition, guidelines emphasize the importance
of weight loss/control in T2DM management, reflecting acknowledgement of the detrimental effects of excess weight on health
outcomes [5,7,8].
Many patients do not meet or maintain glycemic goals with
available treatments [9,10]. According to data from the 2006
Mexican National Nutrition Survey, only 5.3% of the patients
with T2DM were found to have an HbA1c level of 7.0% or less
despite treatment [11]. Notably, more than half had an HbA1c
≥11.0%. Similarly, data indicate widespread failure to meet blood
pressure and lipid goals in Mexico. In 2006, for example, approximately one-third of the Mexican population had a systolic blood
pressure (SBP) of ≥140 mmHg and approximately 75% had LDL-C
≥100 mg/dL [12,13]. Moreover, two-thirds were classified as being
overweight or obese [14].
Canagliflozin is an agent that inhibits sodium glucose cotransporter 2 (SGLT2), which is approved in numerous countries
[15], including Mexico, for the treatment of adults with T2DM
[16,17]; the efficacy and safety of canagliflozin have been demonstrated in phase III clinical trials of up to 2 years in a broad
range of patients with T2DM [18–27]. Canagliflozin leads to
inhibition of glucose reabsorption and increased urinary glucose
excretion, thereby reducing blood glucose, body weight (predominantly due to fat loss), and SBP (from weight loss and mild
osmotic diuresis), with a low risk of hypoglycemia, which can be
a limiting factor for achieving treatment goals [28]. This insulinindependent mechanism differentiates canagliflozin from other
classes of antihyperglycemic agents (AHAs), such as dipeptidyl
peptidase-4 inhibitors, including sitagliptin, which act directly on
β cells to lower blood glucose.
The present analysis is based on results from a clinical
study that directly compared canagliflozin 300 and 100 mg
versus sitagliptin 100 mg in dual therapy with metformin in
patients with T2DM [20]. This was a randomized, double-blind,
four-arm, parallel-group, placebo- and active-controlled, phase
III study. Change in HbA1c from baseline to week 52 was a key
end point, with a hypothesis that canagliflozin 300 mg or both
doses would demonstrate noninferiority in lowering HbA1c
versus sitagliptin 100 mg. In the clinical study, canagliflozin
300 mg demonstrated superiority and canagliflozin 100 mg
demonstrated noninferiority compared with sitagliptin 100 mg
in lowering HbA1c at 52 weeks (–0.88%, –0.73%, and –0.73%,
respectively). Canagliflozin 300 and 100 mg also provided
reductions compared with sitagliptin 100 mg in body weight
(–4.2%, –3.8%, and –1.3%, respectively) and SBP (–4.7, –3.5, and
–0.7 mmHg, respectively). Both doses of canagliflozin were
generally well tolerated. Although the incidences of adverse
events (AEs) potentially related to the mechanism of SGLT2
inhibition, such as male and female genital mycotic infections
(e.g., yeast infections), osmotic diuresis–related AEs (e.g., pollakiuria, polyuria, and nocturia), and volume depletion–related
AEs (e.g., orthostatic hypotension and postural dizziness), were
higher with both canagliflozin doses than with sitagliptin in the
study, AE-related discontinuation rates were similar across
treatment groups.
9
Because T2DM is chronic and progressive, the costs and
health benefits of interventions are fully realized only over long
time horizons. Ideally, therefore, cost-effectiveness analyses of
T2DM interventions would be informed by long-term, naturalistic, randomized clinical trials [29,30]. Clinical trials of sufficient
duration, however, are rarely (if ever) available at the time that
initial coverage decisions are made. As such, economic computer
modeling that extrapolates the available clinical trial data to
long-term health economic outcomes has been widely accepted
as a way to assess the cost-effectiveness of alternative T2DM
treatment strategies [29,30].
Given the growing economic burden of T2DM in Latin America
and specifically in Mexico, cost-effectiveness evaluations can
inform decisions about the efficient allocation of limited health
care resources. Mexico’s independent health technology assessment body, Centro Nacional de Excelencia Tecnológica en Salud,
encourages the use of cost-effectiveness analysis and states a
willingness-to-pay (WTP) threshold of 1 times the gross domestic
product (GDP) per capita as “very cost-effective” (MXP 141,120 or
US $10,500; exchange rate as of September 26, 2014 of US $1 ¼
MXP 13.44) [31]. Centro Nacional de Excelencia Tecnológica en
Salud further states that for treatments with costs per QALY
gained of ≥1 and ≤3 times the GDP per capita, a detailed analysis
should be performed; those with costs per QALY gained of >3
times the GDP per capita should not be considered “cost-effective” [32,33]. These WTP thresholds are in line with those
recommended by the World Health Organization [34].
Comparing diabetes treatment alternatives over the long term
from the perspective of the Mexican health care system is
necessary to direct resources in the most efficient manner,
enabling better patient outcomes from available resources. In
this study, the cost-effectiveness of adding canagliflozin 300 or
100 mg versus sitagliptin 100 mg in patients with T2DM inadequately controlled on metformin monotherapy was determined
using the 1 and 3 times the GDP per-capita thresholds. The
incremental cost-effectiveness ratios (ICERs) were estimated
using a validated microsimulation model, Economic and Health
Outcomes (ECHO)-T2DM, with local cost data [35].
Methods
Model Overview and Simulation Description
ECHO-T2DM is a stochastic microsimulation (patient-level) costeffectiveness model of the treatment of T2DM (see Fig. 1 for a
diagrammatic overview) [35]. The physiology of T2DM is captured
using Markov health states for microvascular and macrovascular
complications and death. The cycle length is 1 year, and the time
horizon is defined by the user. ECHO-T2DM accounts explicitly for
both first-order uncertainty (associated with interpatient variability) and second-order uncertainty (uncertainty regarding the
true value of the underlying parameters) and is programmed in R
using user-friendly front- and back-end Excel interfaces. Because
of space limitations, technical details including a conceptual
walk through, parameterization of macrovascular and microvascular complications (i.e., chronic kidney disease, neuropathy,
retinopathy), and parameters related to uncertainty and heterogeneity can be found in the Appendix in Supplemental Materials
found at http://dx.doi.org/10.1016/j.jval.2014.12.017.
Cohorts of hypothetical patients are generated at the start of
the simulation. Each patient is defined by age, sex, disease
duration, HbA1c, biomarker values, smoking status, and preexisting health conditions (micro- and macrovascular disease). Biomarker values at the individual level tend to be correlated; for
example, the clustering of poor glycemic control, hypertension,
dyslipidemia, and overweight affected 41.6% of the Mexican
10
VALUE IN HEALTH REGIONAL ISSUES 8C (2015) 8–19
Fig. 1 – ECHO-T2DM model. BDR, background diabetic retinopathy; CHF, congestive heart failure; CVD, cardiovascular disease;
ECHO-T2DM, Economic and Health Outcomes model of type 2 diabetes mellitus; eGFR, estimated glomerular filtration rate; HDL-C,
high-density lipoprotein cholesterol; IHD, ischemic heart disease; LDL-C, low-density lipoprotein cholesterol; LEA, lower extremity
amputation; ME, macular edema; MI, myocardial infarction; PDR, proliferative diabetic retinopathy; PVD, peripheral vascular
disease; QALY, quality-adjusted life-year; SBP, systolic blood pressure; TGR, triglycerides; UKPDS, UK Prospective Diabetes Study.
population in 2006 [36]. As such, ECHO-T2DM samples an individual patient’s biomarkers, accounting for key correlations between
the biomarkers themselves (and age) explicitly [37].
ECHO-T2DM includes a comprehensive set of health complications. Microvascular health states reflect increasing severity of
chronic kidney disease (tracked by both the albumin-to-
VALUE IN HEALTH REGIONAL ISSUES 8C (2015) 8–19
creatinine ratio and the estimated glomerular filtration rate
[eGFR]), retinopathy, and neuropathy (see Appendix Sections
2.1, 2.2, and 2.3 in Supplemental Materials found at http://dx.
doi.org/10.1016/j.jval.2014.12.017). HbA1c- and T2DM-duration–
specific progression rates steer transition between the different
health states, and are largely taken from previous modeling work
[38–40]. Macrovascular health states consist of ischemic heart
disease, myocardial infarction, stroke, and congestive heart failure; myocardial infarction and stroke can occur multiple times.
ECHO-T2DM includes four different sets of macrovascular risk
equations, including both the new and the original UK Prospective Diabetes Study risk functions [41,42], the Action in Diabetes
and Vascular Disease: Preterax and Diamicron Modified-release
Controlled Evaluation (ADVANCE) risk function, and the Swedish
National Diabetes Registry risk function [43]. The new UK Prospective Diabetes Study risk functions (UK Prospective Diabetes
Study 82 [42]) were used in this application to model macrovascular (and mortality) risks because they include separate risks
for second events for some complications and because the
developers suggest they do not have the tendency to overpredict
risks, as was seen with the original set (likely due, in part, to the
doubling of follow-up to >20 years). Mortality consists of four
equations covering general mortality; case fatality in the year
following a primary event (e.g., stroke); excess mortality risk
related to a history of diabetes complications such as myocardial
infarction, stroke, and end-stage renal disease; and excess mortality risk in the years following an event [42].
The algorithm for drug intensification in ECHO-T2DM is
designed to maintain HbA1c target values, including an option
for contraindication and discontinuation due to health conditions
(including, e.g., end-stage renal disease and macrovascular disease). Failure to achieve the glycemic target can lead to dose
increases (if available) or the addition of new agents (previous
agents can be continued or discontinued at failure).
Patient biomarker values (i.e., HbA1c, SBP, body mass index
[BMI], and lipids) are updated each cycle and incorporate annualized drug-specific “drifts,” which capture deterioration in these
biomarkers over time, net of the treatment effects [6,44].
To account for the observed changes in the efficacy of agents
with SGLT2 activity (such as canagliflozin) with declining eGFR,
HbA1c-, SBP-, and BMI-lowering can be adjusted. Specifically
in these analyses, when eGFR was simulated to drop below
60 mL/min/1.73 m2, the treatment effects of canagliflozin on
these biomarkers were adjusted to correspond to estimates
obtained from a pooled analysis of subjects in the clinical
trial program with moderate renal impairment (eGFR Z45 and
o60 mL/min/1.73 m2) [45]. Treatment with canagliflozin (though
not with sitagliptin) was discontinued if eGFR fell below
30 mL/min/1.73 m2 per the Mexican label at the time of the
analysis [17].
Although neither canagliflozin nor sitagliptin is associated
with an increased risk of hypoglycemia on the basis of their
mechanism of action [16,46], nonsevere symptomatic hypoglycemic episodes and severe hypoglycemic episodes (i.e., those
requiring third-party assistance) were modeled using data from
the clinical study [20]. Data from the clinical study [20] were also
used as model inputs for AEs potentially related to the mechanism of action of SGLT2 inhibition, including male and female
genital mycotic infections (i.e., yeast infections) [47], lower and
upper urinary tract infections [48], and osmotic diuresis–related
AEs and volume depletion–related AEs [49]. The risk of volume
depletion–related AEs was adjusted using the pooled renal
impairment data for those with an eGFR of less than 60 mL/
min/1.73 m2, for those aged 75 years or older, and for those on a
loop diuretic [50]. Note that AEs potentially associated with the
mechanism of action of dipeptidyl peptidase-4 inhibitors (e.g.,
pancreatitis [51]) were not modeled.
11
Antihypertension and antidyslipidemia treatment algorithms
based on meeting blood pressure and lipid targets can also be
applied. The hypothetical patients in the present analysis were
treated to an SBP target of 140 mmHg and an LDL-C target of 100
mg/dL using a treatment algorithm consistent with Mexican
guidelines [52], with treatment effect data obtained from the
literature [53–55].
Costs can be assigned for treatment interventions and AEs,
initial-year medical events, and resources related to the disease
history and follow-up. Patient preferences for health are captured
using quality-adjusted life-year (QALY) disutility weights (i.e.,
decrements in quality of life associated with a negative impact
of particular health states) for patients’ demographic characteristics (including age and sex), clinical characteristics (including
disease duration and BMI), the presence of individual microvascular and macrovascular complications, hypoglycemia,
and AEs.
Outcomes include the cumulative incidence of each type of
health outcome and relative risk reductions in microvascular and
macrovascular events, life-years and QALYs, biomarker evolution
curves, and cost and cost-effectiveness metrics.
The external (predictive) validity of ECHO-T2DM has been
assessed by replicating the design of a number of clinical trials
and simulating various outcomes over the respective time horizons, and then comparing model predictions with the observed
trial results (see Willis et al. [35] for a full description). Results
demonstrated that ECHO-T2DM simulated patient outcomes for
various microvascular and macrovascular outcomes observed in
important clinical trials with an accuracy that is consistent with
that of other well-accepted models.
Simulation Parameters
In the base case, a total of 1000 cohorts of 2000 hypothetical
patients with T2DM (i.e., 2 million unique hypothetical patients)
were randomly generated and simulated over 20 years to ensure
that long-term costs and benefits of treatment intervention in
chronic and progressive T2DM were captured. The large number
of patients per cohort ensures that the first-order uncertainty is
small, and the large number of cohorts ensures that the secondorder uncertainty is captured. All future costs and health benefits
(i.e., life-years, QALYs) were discounted at 5% per Centro Nacional de Excelencia Tecnológica en Salud guidelines [56]. In this
analysis, cost-effectiveness was assessed using the WTP thresholds of 1 times GDP per capita (i.e., MXP 141,200/QALY) and 3
times GDP per capita (i.e., MXP 423,600/QALY) suggested by the
Mexican government and the World Health Organization [57].
Note that an ICER below the more conservative threshold of 1
times GDP per QALY is considered to be very cost-effective per
the World Health Organization.
Patient Profiles
Baseline demographic and disease characteristics reflecting the
distribution of those from the head-to-head study of canagliflozin
versus sitagliptin described above [20] were randomly generated
for each hypothetical patient (Table 1).
Treatment Comparisons and Algorithm
Two treatment comparisons were simulated: (1) canagliflozin
300 mg versus sitagliptin 100 mg and (2) canagliflozin 100 mg
versus sitagliptin 100 mg added to maximally tolerated metformin. Treatment effects for canagliflozin 300 and 100 mg and
sitagliptin 100 mg were obtained from the clinical trial data
(Table 1; see Appendix Table 5 in Supplemental Materials found
at http://dx.doi.org/10.1016/j.jval.2014.12.017). Treatment effects
(i.e., HbA1c, weight gain) and hypoglycemia incidences for basal
12
VALUE IN HEALTH REGIONAL ISSUES 8C (2015) 8–19
Table 1 – Key baseline patient characteristics and clinical inputs for canagliflozin 300 and 100 mg and
sitagliptin 100 mg. *
Characteristic†
Overall population total (N ¼ 1284)
Latin American sample total (N ¼ 240)
55.4 ⫾ 9.4
54.8 ⫾ 9.2
47.1
52.9
6.9 ⫾ 5.3
7.9 ⫾ 0.9
189.8 ⫾ 39.9
107.9 ⫾ 33.6
45.3 ⫾ 11.2
128.2 ⫾ 13.0
31.8 ⫾ 6.2
12.5
0.8
6.6
0.1
0.1
0.5
0.4
2.6
36.1
63.9
7.7 ⫾ 5.6
7.9 ⫾ 0.9
196.2 ⫾ 35.5
112.3 ⫾ 30.5
45.2 ⫾ 11.4
124.4 ⫾ 13.4
30.7 ⫾ 5.5
7.5
0
2.9
0
0
1.1
0
0.4
Age (y)
Sex (%)
Male
Female
Duration of T2DM (y)
HbA1c (%)
Total cholesterol (mg/dL)
LDL-C (mg/dL)
HDL-C (mg/dL)
SBP (mmHg)
BMI (kg/m2)
Current smoker (%)
Atrial fibrillation (%)
Background diabetic retinopathy (%)
Macular edema (%)
Proliferative diabetic retinopathy (%)
Microalbuminuria (%)
Macroalbuminuria (%)
Symptomatic neuropathy (%)
Treatment effects‡
HbA1c (%)
Total cholesterol (mg/dL)
LDL-C (mg/dL)
HDL-C (mg/dL)
Triglycerides (mg/dL)
SBP (mmHg)
BMI (kg/m2)§
Annual “drift” in HbA1c (%)||
Annual “drift” in SBP (mmHg)||
Annual “drift” in lipid
parameters (mg/dL)||
AEs, per patient-year of
exposure (%)
Severe hypoglycemia
Nonsevere symptomatic
hypoglycemia
Volume depletion–related
AEs
Osmotic diuresis–related AEs
Male genital mycotic
infection
Female genital mycotic
infection
Lower UTI
Upper UTI
Overall population
Latin American sample
CANA 300 mg
(n ¼ 367)
CANA 100 mg
(n ¼ 368)
SITA 100 mg
(n ¼ 366)
CANA 300 mg
(n ¼ 79)
CANA 100 mg
(n ¼ 80)
SITA 100 mg
(n ¼ 81)
–0.88
7.08
4.40
5.51
–16.61
–4.65
–1.35
0.14
0.3
0.03
–0.73
6.11
4.33
4.50
–11.05
–3.53
–1.22
0.14
0.3
0.03
–0.73
3.37
3.12
2.36
–13.51
–0.66
–0.45
0.14
0.3
0.03
–0.94
8.42
5.63
5.56
–9.22
–4.36
–1.31
0.14
0.3
0.03
–0.95
3.63
4.25
5.13
–27.50
–3.61
–1.11
0.14
0.3
0.03
–0.73
11.23
9.29
2.32
–6.36
–0.40
–0.22
0.14
0.3
0.03
0
8.5
0.3
8.8
0.3
4.4
0
15.8
1.4
27.1
1.4
9.7
1.3
1.3
2.7
1.4
1.4
1.4
4.1
2.7
8.5
5.9
1.0
1.3
4.3
10.6
6.6
16.0
1.4
2.8
11.1
12.9
3.0
19.0
15.8
2.4
7.4
0.3
9.3
0.6
7.8
0.3
12.6
0
17.2
0
11.8
1.3
AE, adverse event; BMI, body mass index; CANA, canagliflozin; HbA1c, glycated hemoglobin; HDL-C, high-density lipoprotein cholesterol;
LDL-C, low-density lipoprotein cholesterol; SBP, systolic blood pressure; SD, standard deviation; SITA, sitagliptin; T2DM, type 2 diabetes
mellitus; UTI, urinary tract infection.
* All data are from the clinical study unless otherwise noted [20].
†
Data are mean ⫾ SD from baseline to week 52 (modified intent-to-treat) unless otherwise indicated.
‡
Data are least squares mean changes from baseline to week 52 (modified intent-to-treat) unless otherwise indicated.
§
Some weight loss was seen in the sitagliptin arm because all patients followed a regimen of diet and exercise in addition to pharmacologic
treatment (a requirement in registration trials in diabetes).
||
Sourced from the literature [6,44].
13
VALUE IN HEALTH REGIONAL ISSUES 8C (2015) 8–19
Table 2 – AHA treatment intensification algorithm.
and prandial insulin were sourced from the literature [58–60].
Details of the AHA treatment intensification algorithm applied in
these simulations are given in Table 2.
Hypothetical patients entered the model uncontrolled on
background metformin and were assigned to treatment with
canagliflozin 300 or 100 mg or sitagliptin 100 mg.
Patients meeting the HbA1c target level of o7.0% continued on
their assigned treatment.
Patients were discontinued from treatment with canagliflozin
or sitagliptin because of AEs in the first cycle at the rates
observed in the clinical trial. Otherwise, patients remained on
their assigned treatment unless the HbA1c level was Z7.0% or
eGFR was o30 mL/min/1.73 m2 (eGFR threshold applied only to
canagliflozin).
When the HbA1c level was Z7.0%, AHA treatment was
intensified by adding basal insulin (i.e., neutral protamine
Hagedorn [NPH]) insulin), initially at 10 IU/d; the dose could be
titrated up to 60 IU/d as needed to maintain HbA1c o7.0%.
When the HbA1c level was Z7.0% at the maximum dose of
basal insulin, prandial insulin was added (and titrated as
required to maintain control up to 200 IU/d).
Costs
AE, adverse event; AHA, antihyperglycemic agent; eGFR, estimated
glomerular filtration rate; HbA1c, glycated hemoglobin; NPH, neutral protamine Hagedorn.
The costs of myocardial infarction, stroke, and lower extremity
amputation were sourced from the diagnostic-related groups
issued by the IMSS in 2012 (Table 3). Costs for macular edema,
proliferative retinopathy, and blindness were obtained from the
Mexican health care administration agency, the Instituto de
Seguridad y Servicios Sociales de los Trabajadores del Estado,
the costing table, and the IMSS. Costs for end-stage renal disease
were obtained from literature searches of studies and articles
related to diabetes [61]. The remaining cost inputs were obtained
from interviews that were conducted with clinicians in public
Mexican hospitals to assess how most patients would be treated
and mapping to the Instituto de Seguridad y Servicios Sociales de
los Trabajadores del Estado costing table [62,63]. Resource utilization was matched with cost data using several sources as
follows. Costs for laboratory studies, physician visits, hospitalizations, intensive care, and emergency visits were matched to
those from established sources [64,65]. Unit costs of medications
used to treat comorbidities were sourced from the IMSS and the
Table 3 – Event-year and state costs and QALY utility weight inputs.
Clinical event
Macrovascular
Ischemic heart disease
Myocardial infarction
Congestive heart failure
Stroke
Peripheral vascular disease
Microvascular
Microalbuminuria
Macroalbuminuria
eGFR o15 mL/min/1.73 m2 (1st year)
eGFR o15 mL/min/1.73 m2 (end-stage renal
disease)
Macular edema
Proliferative retinopathy
Blindness in both eyes
Symptomatic neuropathy
Diabetic foot ulcer
Lower extremity amputation
Hypoglycemia
Nonsevere symptomatic hypoglycemic event
Severe hypoglycemic event
Overweight/obesity
For each 1 kg/m2 over 25 kg/m2
AEs
Lower UTI (male)
Lower UTI (female)
Upper UTI (male)
Upper UTI (female)
GMI (male)
GMI (female)
Volume depletion–related AEs
Osmotic diuresis–related AEs
Event-year cost*
(MXP)
State, annualized cost
(MXP)
QALY utility
weights
39,816
172,872
27,469
54,835
26,290
16,898
16,898
11,991
16,313
23,669
–0.028
–0.028
–0.028
–0.115
–0.061
723
723
0
179,003
41
41
NA
170,923
0 [38]
–0.048 [38]
–0.175 [38]
–0.175 [38]
1,307
5,546
14,231
15,960
7,745
74,373
652
652
652
7,980
NA
NA
NA
0 [38]
–0.057 [38]
–0.084 [38]
–0.17 [38]
–0.272 [38]
0
2,651
NA
NA
–0.005 [69]
–0.06 [69]
NA
NA
–0.0171 [72]
925
881
6,018
5,883
6,348
1,518
2,080
1,418
NA
NA
NA
NA
NA
NA
NA
NA
–0.00123 [70]
–0.00123 [70]
–0.00729 [70]
–0.00729 [70]
–0.0046 [70]
–0.0046 [70]
–0.005 [69]†
–0.005 [71]
[38]
[38]
[38]
[38]
[38]
AE, adverse event; GMI, genital mycotic infection; MXP, Mexican peso; NA, not applicable; QALY, quality-adjusted life-year; UTI, urinary tract
infection.
* Event costs are associated with management of the acute episode and any subsequent care in the first year.
†
Assumed equal to the value of a nonsevere symptomatic hypoglycemic event.
14
VALUE IN HEALTH REGIONAL ISSUES 8C (2015) 8–19
Diario Oficial de la Federación [66,67]. The unit prices for canagliflozin 300 and 100 mg and sitagliptin 100 mg were specified as
MXP 27.11, MXP 27.11, and MXP 26.07 per day, respectively. These
prices were sourced from a local retail pharmacy (i.e., Walmart)
because they are not yet widely available in the institutional
formularies of the public sector, and represent the cost that
would be paid out of pocket. All costs were converted to 2012 MXP
using the National Consumer Price Index released by the Mexican
government [68].
QALY Disutility
QALY disutility weights are given in Table 3. Because detailed
utility studies do not exist for diabetes in the Mexican population,
utility values were obtained from established sources based on
other T2DM populations. Values assigned to microvascular and
macrovascular complications were obtained from a widely used
source in the economic modeling of T2DM [38], which used
multivariate regression techniques to isolate the unique contribution of each health outcome. The study did not estimate
disutility estimates for hypoglycemia and AEs. Disutilities for
nonsevere symptomatic and severe hypoglycemic events were
sourced from a recent time trade-off study in 1603 individuals
with T2DM [69]. Disutility values for urinary tract infections and
genital mycotic infections were taken from a new time trade-off
study in T2DM that was, in large part, performed to provide
estimates for these selected AEs potentially related to SGLT2
inhibition [70]. The disutility for the group of osmotic diuresis–
related AEs was derived from a study of symptoms associated
with overactive bladder in the general population [71]. The
disutility associated with volume depletion–related AEs was
assumed to be equal to that of nonsevere symptomatic hypoglycemia because symptoms of these events are somewhat
similar. The estimate of the disutility-associated weight gain of
1 BMI unit (kg/m2; applied only when the BMI was 425 kg/m2)
was obtained from the most recent article investigating this issue
[72].
Sensitivity Analyses
One-way sensitivity analyses were conducted to explore the
robustness of the base-case results to scenarios potentially more
reflective of Mexico and to key assumptions related to the profile
of canagliflozin. These sensitivity analyses are described in
logical groups:
1. Clinical characteristics, efficacy, and AE rates: set to those
obtained from a post hoc subgroup analysis of subjects from
Latin America in the clinical trial (SA1; see Table 1, Latin
American sample).
2. Treatment rules: AHA treatment intensification threshold set
to 8.0% (vs. the base-case assumption of 7.0%; SA2), a level
that may be more reflective of Mexico.
3. Time horizon: shorter time horizon of 10 years (SA3) and
longer time horizons of 30 years (SA4) and 40 years (SA5).
4. Disutility associated with weight change: more conservative
disutility estimate associated with weight gain in individuals
with a BMI of more than 25 kg/m2 (0.0061 per unit gained
above 25 kg/m2) [38] (SA6).
5. AEs potentially related to SGLT2 inhibition: double associated
costs (SA7); double associated QALYs (SA8).
Note that the number of hypothetical patients simulated in
each of the 1000 cohorts was 1000 for the sensitivity analyses (i.e.,
1 million hypothetical patients). This has been shown to be of
sufficient size to generate stable results (data available on
request).
Outcomes Reporting and Statistical Analyses
The cumulative incidence rates for each type of microvascular
and macrovascular outcome, event rates for AEs, their associated
costs (both total and disaggregated), and mean life-years and
QALYs experienced over the simulation period were calculated
for each treatment arm. Relative risk reductions for canagliflozin
versus sitagliptin were generated for microvascular and macrovascular complications; hazard ratios for the AEs and differences
for the costs, life-years, and QALYs were also generated. The
ICERs were computed, as were scatterplots of cost-effectiveness
planes and cost-effectiveness acceptability curves.
Results
Base-Case Analyses
Canagliflozin 300 and 100 mg were associated with improved life
expectancy and QALY gains of 0.16 and 0.06, respectively, relative
to sitagliptin 100 mg (Table 4). The incremental lifetime costs per
patient associated with adding canagliflozin 300 or 100 mg for
patients with uncontrolled HbA1c on a background of metformin
were estimated at MXP 1797 and MXP 7262, respectively. The
resulting ICERs of MXP 11,210 and MXP 128,883 for canagliflozin
300 and 100 mg versus sitagliptin 100 mg, respectively, are below
the WTP threshold of 1 times the GDP per capita for a QALY
gained, suggesting that both doses are very cost-effective (Table 4).
Because the hypothetical patients were treated with rescue
medications to meet HbA1c, SBP, and lipid goals, differences in
key biomarkers driving event risks for macrovascular and especially microvascular events were effectively minimized, with the
consequence that cost offsets and avoided QALY losses related to
these complications were smaller than would have been the case
without strict treatment-to-goal rescue medication (see base case
results for cumulative incidences and relative risk reductions in
Supplemental Table 1 in Supplemental Material found at http://dx.
doi.org/10.1016/j.jval.2014.12.017 and associated costs in Table 4).
The greater initial HbA1c lowering for canagliflozin 300 mg
translated into a reduced need for insulin rescue therapy, which
resulted in cost offsets of MXP –2686 in overall insulin therapy use
associated with canagliflozin 300 mg relative to sitagliptin 100 mg.
In the simulation of canagliflozin 100 mg versus sitagliptin 100 mg,
estimated insulin costs were higher in the canagliflozin arm,
owing largely to the discontinuation of canagliflozin (but not
sitagliptin) if an eGFR of less than 30 mL/min/1.73 m2 was
eventually reached. In addition, decreases in SBP contributed to
decreased costs for the treatment of hypertension with canagliflozin 300 and 100 mg (MXP –1154 and –947, respectively).
As previously mentioned, both doses of canagliflozin generated QALY gains versus sitagliptin. The largest drivers of QALY
differences were lower disutility associated with overweight/
obesity (–0.129 and –0.097, respectively) and with mortality
(–0.017 and –0.012, respectively; see Supplemental Table 2 in
Supplemental Materials found at http://dx.doi.org/10.1016/j.jval.
2014.12.017). For canagliflozin 300 mg, less need for insulin rescue
therapy also contributed to reduced disutility associated with
hypoglycemic events. For canagliflozin 100 mg, the difference in
the estimated disutilities associated with hypoglycemia favored
sitagliptin, in part owing to the discontinuation of canagliflozin
and start of insulin for patients who reached an eGFR of less than
30 mL/min/1.73 m2. This result may be compounded, moreover,
by the likely spurious differences observed in rates of hypoglycemia between canagliflozin 100 mg and sitagliptin 100 mg in the
clinical trial; both canagliflozin and sitagliptin have mechanisms
of action that have been shown to not independently increase the
risk of hypoglycemia [16,46]. The disutilities associated with AEs
15
VALUE IN HEALTH REGIONAL ISSUES 8C (2015) 8–19
Table 4 – Base case, costs of complications and AEs, average costs, and benefits per person, over 20 y (modeled).
Outcome parameter
Costs (MXP), discounted
Macrovascular
Myocardial infarction
Ischemic heart disease
Congestive heart failure
Stroke
Microvascular
Retinopathy
Nephropathy
Neuropathy
AHA
Oral agents
Insulin
Prescription treatment
Hypoglycemia
AEs
Hypertension
Dyslipidemia
Total costs (MXP)
Health indicators, discounted
Life-years
QALYs
Survival (%)*
Cost per QALY (MXP)
CANA
300 mg
SITA
100 mg
Difference
CANA
100 mg
SITA
100 mg
Difference
24,951
13,111
3,720
4,220
26,906
13,611
3,915
4,436
–955
–500
–195
–215
24,428
12,924
3,738
4,121
24,787
13,306
3,884
4,285
–540
–382
–146
–163
9,455
1,528
35,054
9,461
1,539
35,111
–5
–12
–58
9,461
1,528
35,116
9,449
1,535
35,021
13
–7
94
155,433
56,242
150,781
58,927
4,652
–2,686
152,916
60,499
150,573
58,837
2,343
1,662
357
3,675
3,495
18,846
330,087
428
2,439
4,649
17,086
328,290
–71
1,236
–1,154
1,760
1,797
464
5,657
3,699
19,215
333,587
445
2,439
4,645
17,117
326,324
19
3,218
–947
2,099
7,262
10.66
6.35
56.8
–
10.64
6.19
56.4
–
0.02
0.16
0.4
11,210
10.64
6.23
56.5
–
10.63
6.18
56.2
–
0.02
0.06
0.3
128,883
AE, adverse event; AHA, antihyperglycemic agent; CANA, canagliflozin; MXP, Mexican peso; QALY, quality-adjusted life-year; SITA, sitagliptin.
* Percentage alive at simulation end.
potentially related to the SGLT2 mechanism of action favored
sitagliptin, but their impact was small in magnitude (0.003 and
0.006 for canagliflozin 300 and 100 mg vs. sitagliptin 100 mg,
respectively).
The effect of parameter uncertainty on outcomes is illustrated
in the scatterplot of the incremental costs and QALYs from each
of the 1000 cohorts. Canagliflozin 300 mg was associated with
greater QALYs in all 1000 simulations (northeast and southeast
quadrants; Fig. 2A), and nearly half of the cohort replications had
lower costs as well (southeast quadrant; Fig. 2A). Canagliflozin
100 mg was associated with more QALYs than sitagliptin 100 mg
in all but 1 of the 1000 cohort replications (Fig. 2B). Canagliflozin
100 mg was also associated with greater costs in most of the
replications, though in a minority of cases it was associated with
greater QALYs and lower costs (Fig. 2B). These scatterplots
indicate a high degree of confidence that canagliflozin 300 mg
is very cost-effective versus sitagliptin 100 mg, which is depicted
graphically in Fig. 2C. The likelihood that canagliflozin is costeffective versus sitagliptin 100 mg naturally increases as the WTP
increases (i.e., gains in QALYs become increasingly rewarded),
reaching approximately 95% for canagliflozin 300 mg at both
specified WTP thresholds. Canagliflozin 100 mg has an approximately 65% probability of being cost-effective versus sitagliptin
100 mg at the 3 times the GDP per-capita threshold versus
approximately 50% probability of being very cost-effective at
the more conservative WTP threshold (Fig. 2C). The probability
that canagliflozin is cost saving is indicated by the probability at a
WTP of 0 (the Y axis), and is approximately 37% for the 300-mg
dose and approximately 10% for the 100-mg dose.
Sensitivity Analyses
Findings from the sensitivity analyses generally support the findings
of the base case that canagliflozin is cost-effective versus sitagliptin.
In fact, QALY gains for canagliflozin 300 and 100 mg versus
sitagliptin 100 mg increased to 0.19 and 0.27, respectively, from
0.16 and 0.06 in the base case, respectively, in the case in which the
Latin American subsample data from the clinical study were used to
define clinical characteristics, efficacy, and AE rates. Total cost
offsets were MXP –2256 and –8088 with canagliflozin 300 and
100 mg, respectively. Both canagliflozin doses dominated sitagliptin
100 mg (i.e., lower costs and higher QALYs) in this scenario (Table 5).
Using the less stringent HbA1c treatment target of less than 8.0%,
QALY gains for canagliflozin 300 and 100 mg versus sitagliptin 100
mg were 0.14 and 0.08, respectively, with total cost increases of MXP
3477 and 6521, respectively. In this scenario, both canagliflozin 300
and 100 mg were very cost-effective (Table 5).
When the time horizon was shortened to 10 years, QALY gains
were 0.11 and 0.06 for canagliflozin 300 and 100 mg versus
sitagliptin 100 mg, respectively, with total cost increases of MXP
1592 and 4582, respectively. QALY gains were 0.17 and 0.04 for
canagliflozin 300 and 100 mg versus sitagliptin 100 mg, respectively, over 30 years, and 0.18 and 0.05, respectively, over 40 years.
Cost increases were seen with canagliflozin 300 and 100 mg
versus sitagliptin 100 mg of MXP 2076 and 9084, respectively, over
30 years, and MXP 2483 and 9508, respectively, over 40 years. In
each of these analyses, canagliflozin 300 mg was very costeffective and canagliflozin 100 mg was cost-effective at the
WTP threshold of 3 times the GDP per capita (Table 5).
Using a more conservative disutility for overweight/obesity,
treatment with canagliflozin 300 mg versus sitagliptin 100 mg
resulted in a QALY gain of 0.08 (smaller compared with the base
case) and a cost increase of MXP 1797 for canagliflozin 300 mg,
compared with a small decrease in QALYs of –0.01 and a cost
increase of MXP 7262 with canagliflozin 100 mg versus sitagliptin
100 mg. Thus, in this conservative scenario, canagliflozin 100 mg
was dominated by sitagliptin 100 mg, but canagliflozin 300 mg
remained very cost-effective (Table 5).
16
VALUE IN HEALTH REGIONAL ISSUES 8C (2015) 8–19
cost-effective when either costs or quality of life associated with
SGLT2-related AEs was doubled; canagliflozin 100 mg was costeffective at the WTP threshold of 3 times the GDP per capita in
these analyses (Table 5).
Incremental cost (MXP)
25,000
20,000
15,000
10,000
Discussion and Conclusions
5,000
0
–5,000
–10,000
–15,000
–0.2
–0.1
0
0.1
0.2
0.3
0.4
0.2
0.3
0.4
QALY
Incremental cost (MXP)
25,000
20,000
15,000
10,000
5,000
0
–5,000
–10,000
–15,000
–0.2
–0.1
0
0.1
QALY
Probability of cost-effectiveness
CANA 300 mg
CANA 100 mg
1.0
0.8
0.6
0.4
0.2
0
0
50,000 100,000 150,000 200,000 250,000 300,000 350,000 400,000 450,000 500,000
Threshold WTP per QALY (MXP)
Fig. 2 – Cost-effectiveness planes for (A) CANA 300 mg and
(B) CANA 100 mg* and (C) cost-effectiveness acceptability
curves for CANA 300 and 100 mg over time. CANA,
canagliflozin; MXP, Mexican peso; QALY, quality-adjusted
life-year; WTP, willingness to pay. *Open circles represent
the mean value across cohorts.
In the sensitivity analysis that doubled costs of AEs potentially related to the SGLT2 mechanism of action, canagliflozin 300
and 100 mg showed QALY gains of 0.16 and 0.05, respectively,
relative to sitagliptin 100 mg; costs were higher by MXP 2964 and
10,353, respectively. When the QALYs associated with AEs potentially related to the SGLT2 mechanism of action were doubled,
canagliflozin 300 and 100 mg versus sitagliptin 100 mg resulted in
QALY gains of 0.16 and 0.05, respectively, and cost increases of
MXP 1729 and 7138, respectively. Canagliflozin 300 mg was very
Economic simulations in the Mexican setting based on the
52-week clinical study data of patients with T2DM on background
metformin suggest that the use of canagliflozin 300 and 100 mg is
associated with improved health outcomes, associated QALY
gains, and a relatively marginal increase in total costs relative
to sitagliptin 100 mg. Both canagliflozin doses were found to be
cost-effective for patients with T2DM in Mexico, even when
considering the most conservative WTP threshold suggested by
the Mexican government. The base-case cost-effectiveness estimates of MXP 11,210/QALY gained (US $834) and MXP 128,883/
QALY gained (US $9590) for canagliflozin 300 and 100 mg,
respectively, fell below this conservative threshold, suggesting
that both doses were very cost-effective.
Note that the ICER for canagliflozin 100 mg versus sitagliptin
100 mg is influenced by the difference observed in the incidence of nonsevere symptomatic hypoglycemia with canagliflozin 100 mg versus sitagliptin 100 mg in the clinical trial. As
noted above, however, both agents have a low inherent risk of
hypoglycemia [16,46] and the observed difference is likely
spurious. Sensitivity analyses modeling equal rates of nonsevere symptomatic hypoglycemia with canagliflozin 100 mg
and sitagliptin 100 mg were performed in various scenarios,
and, indeed, lower ICERs for canagliflozin 100 mg were estimated (data on file).
All ICERs generated for canagliflozin 300 mg in the sensitivity
analyses fell below the very cost-effective WTP threshold. ICERs
generated for canagliflozin 100 mg were very cost-effective,
except in the sensitivity analyses related to the unlikely scenarios
of a doubling of costs or QALYs for AEs potentially associated
with the SGLT2 mechanism of action or analyses over longer time
horizons (30 and 40 years); however, these were cost-effective at
the WTP threshold of 3 times the GDP per capita. The increase in
ICERs seen over longer time horizons with canagliflozin 100 mg is
likely related to the fact that the simulations accounted for the
observed changes in the efficacy of agents with SGLT2 inhibition
activity (such as canagliflozin) in patients with lower eGFR values
[45]. As a result, additional costs for insulin were incurred and
more hypoglycemic events occurred over time. In a sensitivity
analysis using the Latin American subsample data, both canagliflozin doses dominated sitagliptin, likely because of the greater
efficacy associated with canagliflozin 300 and 100 mg versus
sitagliptin 100 mg in Latin American patients enrolled in the
clinical study, suggesting that canagliflozin may be especially
favorable in the Latin American setting. Future analyses based on
a larger Latin American or Mexican population would be of value
given the relatively smaller sample size of this subsample
compared with the total trial population. In the scenario more
likely mimicking the real-world setting in Mexico (therapy intensification threshold of HbA1c Z8.0%), where only a minority of
patients achieve the generally recommended HbA1c target of less
than 7.0% [11], canagliflozin was again very cost-effective.
There were several challenges in performing this analysis in
the Mexican health care setting. The evidence base on T2DM
outcomes in Mexico is limited (e.g., the most recent data on
goal attainment were from 2006). Enhanced data collection
in Mexico and Latin America, including detailed studies on
disutility weights for the complications associated with T2DM in
the Mexican population, would be beneficial in terms of understanding the true burden of T2DM in this region and assessing
17
VALUE IN HEALTH REGIONAL ISSUES 8C (2015) 8–19
Table 5 – Sensitivity analyses: ICERs.
Scenario
Base case
Baseline characteristics
SA1: Latin American subsample
Treatment rules
SA2: 8.0% HbA1c intensification trigger
Time horizon
SA3: 10-y time horizon
SA4: 30-y time horizon
SA5: 40-y time horizon
Disutility associated with weight change
SA6: Alternative disutility estimate for weight loss per
BMI unit 425 kg/m2
AEs potentially related to SGLT2 inhibition
SA7: Double costs
SA8: Double QALYs
ICERs (LY), MXP
ICERs (QALY), MXP
CANA
300 mg
CANA
100 mg
CANA
300 mg
CANA
100 mg
82,647
468,069
11,210
128,883
Dominating
Dominating
Dominating
Dominating
148,801
670,144
24,859
80,450
166,014
63,896
64,579
1,192,916
462,865
392,635
14,839
12,158
13,931
81,149
205,500
186,313
82,647
468,069
23,301
Dominated
137,627
80,267
1,166,370
804,182
18,361
10,921
195,928
154,759
BMI, body mass index; CANA, canagliflozin; HbA1c, glycated hemoglobin; ICER, incremental cost-effectiveness ratio; LY, life-year; MXP,
Mexican peso; QALY, quality-adjusted life-year; SA, sensitivity analysis; SGLT2, sodium glucose co-transporter 2.
the effectiveness of alternative treatment strategies. Obtaining
accurate costs in Mexico is complicated given the fragmented
health care system. Better unit cost data at the micro-level for the
Mexican context would improve estimation of the true economic
consequences of treatment intervention in T2DM.
This article described economic modeling of T2DM using
results from a clinical trial of canagliflozin versus sitagliptin with
local costs sourced from Mexican sources and a well-validated
model, ECHO-T2DM [47,48]. Findings suggest that canagliflozin is
likely to be cost-effective versus sitagliptin as an add-on therapy
to metformin in patients with T2DM from the perspective of the
Mexican health care system, owing to the differential benefits of
improved control of hyperglycemia, hypertension, and weight
with canagliflozin versus sitagliptin.
Source of financial support: This analysis was sponsored by
Janssen Global Services, LLC, and was based on data from a study
supported by Janssen Research & Development, LLC. Editorial
support was provided by Cherie Koch, PhD, of MedErgy, and was
funded by Janssen Global Services, LLC. Canagliflozin has been
developed by Janssen Research & Development, LLC, in collaboration with Mitsubishi Tanabe Pharma Corporation.
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jval.2014.12.017 or, if a hard copy of article, at www.valueinhealth
journal.com/issues (select volume, issue, and article).
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