Cost-Effectiveness of Canagliflozin versus Sitagliptin as Add-on to Metformin in Patients with Type 2 Diabetes Mellitus in Mexico

VALUE IN HEALTH REGIONAL ISSUES 8C (2015) 8–19

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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

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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.

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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

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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-

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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.

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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

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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].

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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.

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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

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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).

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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

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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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