Clinical Therapeutics/Volume ], Number ], 2014

Cost-Effectiveness of Insulin Glargine Versus Sitagliptin in Insulin-Naïve Patients With Type 2 Diabetes Mellitus Stephen T. Brown, PhD1; Daniel Grima Grima, MSc1; and Luc Sauriol, MSc2 1

Cornerstone Research Group Inc., Burlington, Ontario, Canada; and 2Sanofi Canada, Laval, Quebec, Canada

ABSTRACT Purpose: In the EASIE (Evaluation of Insulin Glargine Versus Sitagliptin in Insulin-Naïve Patients) trial, insulin glargine found a significant reduction in glycosylated hemoglobin compared with sitagliptin in patients with type 2 diabetes who are inadequately controlled with metformin. The objective of this study was to assess the cost-effectiveness of insulin glargine compared with sitagliptin in type 2 diabetes patients, from the perspective of the publicly funded Canadian health care system. Methods: The IMS CORE Diabetes Model, a standard Markov structure and Monte Carlo simulation model, was used. The model used a lifetime horizon to capture the long-term complications associated with type 2 diabetes. The efficacy of insulin glargine and sitagliptin in terms of glycosylated hemoglobin reduction and corresponding rates of hypoglycemia were obtained from the EASIE trial. Health utility and cost data were obtained from recently published Canadian publications. Univariate and probabilistic sensitivity analyses were conducted. Findings: In the lifetime base-case analysis, treatment with insulin glargine resulted in cost savings of $1434 CAD in 2012 and a gain of 0.08 qualityadjusted life years per patient. A probabilistic sensitivity analysis found the robustness of the base-case analysis, with 88% probability of insulin glargine being dominant (ie, cost savings and more qualityadjusted life years). Implications: Insulin glargine is a clinically superior and cost-effective alternative to sitagliptin in patients with type 2 diabetes who are inadequately controlled with metformin. (Clin Ther. 2014;]:]]]–]]]) & 2014 Elsevier HS Journals, Inc. All rights reserved. Key words: cost-effectiveness, insulin glargine, sitagliptin, type 2 diabetes.

INTRODUCTION In 2008 and 2009, an estimated 2.4 million Canadians, roughly 6.8% of the population, had either type 1 or type 2 diabetes, which represented an increase in prevalence of 70% from the previous decade.1 This growing prevalence has significant implications for health care spending, with health care costs in Canada for treatment of patients with diabetes estimated to be $13.7 billion CAD in 2012.2 These expenditures include the cost of diabetes treatment in addition to the management of long-term diabetes consequences, which can have substantial short- and long-term costs. Long-term consequences of type 2 diabetes include macrovascular complications, such as myocardial infarction (MI), stroke, and congestive heart failure, and microvascular complications, such as neuropathy, retinopathy, and nephropathy.3 Diabetes has a substantial mortality impact, with up to 80% of diabetic patients estimated to die from a cardiovascular complication.4 Currently, the Canadian Agency for Drugs and Technologies in Health (CADTH) has issued an optimal therapy report and cost-effectiveness analysis examining second- and third-line therapies for patients with type 2 diabetes.5 These reports recommend the use of sulfonylurea as second-line therapy for the majority of patients who are inadequately controlled on metformin alone. For patients who fail to achieve or maintain glycemic control with dual therapy, basal insulin (insulin neutral protamine Hagedorn) was recommended as third-line therapy. Recently, the Evaluation of Insulin Glargine Versus Sitagliptin in Insulin-Naïve Patients (EASIE) trial

Accepted for publication July 24, 2014. http://dx.doi.org/10.1016/j.clinthera.2014.07.019 0149-2918/$ - see front matter & 2014 Elsevier HS Journals, Inc. All rights reserved.

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Clinical Therapeutics compared the efficacy, safety profile, and tolerability of basal insulin (insulin glargine) versus the dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin in type 2 diabetes who are inadequately controlled with metformin.6 In this randomized, open-label trial, patients aged 35 to 70 years with glycosylated hemoglobin (HbA1c) of 7% to 11%, diagnosis of type 2 diabetes for at least 6 months, and body mass index (BMI; calculated as kg/m2) of 25 to 45 were randomly assigned to 24week treatment with insulin glargine (titrated to attain fasting plasma glucose of 4.05.5 mmol/L) or sitagliptin (oral dosage of 100 mg daily).6 The study found a greater adjusted mean reduction in HbA1c with insulin glargine (n ¼ 227; mean [SE], 1.72% [0.06%]) compared with sitagliptin (n ¼ 253; mean [SE], 1.13% [0.06%]), with a mean difference of 0.59% (95% CI, 0.77 to 0.42; P o 0.0001). Rates of symptomatic hypoglycemia were greater with insulin glargine than with sitagliptin (mean [SE], 4.21 [0.54] vs 0.50 [0.09] events per patient year; P o 0.0001). Overall, the results supported the option for the addition of basal insulin in patients with type 2 diabetes inadequately controlled on metformin. In light of the results from the EASIE trial, the objective of this study was to examine the long-term cost-effectiveness of insulin glargine compared with sitagliptin.

METHODS Model Overview The economic analysis was based on the IMS CORE Diabetes Model.7,8 The structure and input parameters for this model are described elsewhere.7,8 In brief, the model consisted of a number of submodels that simulate diabetes-related complications and both diabetes-related and nonrelated mortality. The model included a range of complications, including angina, MI, congestive heart failure, stroke, peripheral vascular disease, retinopathy, macular edema, cataract, nephropathy, foot ulcers and amputation, hypoglycemia, ketoacidosis, and lactic acidosis. The model used a standard Markov structure and Monte Carlo simulation, which allowed individual patients to progress and experience multiple complications during their lifetime. Costs and outcomes were discounted at a rate of 5% per year, as per Canadian guidelines.9 The base-case analysis used a lifetime

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(50-year) time horizon to capture the long-term impact of HbA1c reduction on diabetes-related events and mortality.

Patient Population and Treatment Inputs The model was populated with data from the EASIE trial, which included patients with type 2 diabetes with HbA1c levels between 7% and 11%, aged 35 to 70 years. Baseline patient characteristics included mean age of 54 years, predominantly male sex (51%), mean duration of diabetes of 4.5 years, mean HbA1c of 8.5%, mean BMI of 31.1.6 Some patients (28%) had a history of diabetes-related complications, such as MI, angina, coronary artery disease, heart failure, stroke, transient ischemic attack, peripheral vascular disease, diabetic neuropathy, nephropathy and retinopathy. A more detailed description of patient characteristics can be found in the published EASIE trial.6 Treatment effects considered in this analysis are HbA1c reduction, BMI variation, and hypoglycemia episodes. As reported in the EASIE trial, a mean (SE) reduction of 1.72% (0.06%) in HbA1c was used in the analyses for insulin glargine and a mean (SE) reduction of 1.13% (0.06%) in HbA1c was used in the analyses for sitagliptin.6 HbA1c was assumed to drift upward over time based on the United Kingdom Prospective Diabetes Study Outcomes model equations.10 BMI variation was different in both treatment groups. There was a small increase in BMI in the glargine group (0.164), and a decrease in BMI in the sitagliptin group (0.402). Rates for mild hypoglycemia for insulin glargine and sitagliptin were 4.21 and 0.5 events per patient year, respectively, as reported in the EASIE trial. Rates for severe hypoglycemia were 0.03 and 0.01 events per patient year for insulin glargine and sitagliptin, respectively, as reported in the EASIE trial. In the base case, we assumed there was no difference in weight between treatments, however, a sensitivity analysis was performed based on data reported in EASIE.

Health-Related Utility Values Patients with type 2 diabetes and no complications were assumed to have a utility score of 0.80.11 Disutilities for diabetes-related complications were obtained from the literature (Table I). It was assumed that disutilities for events were additive, therefore, a patient experiencing multiple events in a given year would also receive all corresponding

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S.T. Brown et al.

Table I. Health-related quality of life values. Utility or Disutility

First Year or Per Event

Subsequent Years

Utility for type 2 diabetes patient with no complications Myocardial infarction event (disutility per event) Angina

0.80



0.0409

0.0120

0.0412

0.0240

Congestive heart failure

0.0635

0.0180

Stroke event (disutility per event)

0.0524

0.0400

Peripheral vascular disease Microalbuminuria Gross proteinuria Dialysis Renal transplantation Diabetic retinopathy Macular edema Severe vision loss or blindness

0.0210 0.012 0.017 0.160 0.030 0.0156 0.0171 0.0498

       

Cataract Neuropathy Active ulcer (infected) Amputation (disutility per event)

0.0171 0.0243 0.1400 0.280

   0.280

Severe hypoglycemia (disutility per event)

0.01



Minor hypoglycemia (disutility per event)

4.767E-06



disutilities for that year. In addition, it was assumed that after certain events, like stroke or MI, patients would receive a permanent decrease in their healthrelated utility. Mild-to-moderate hypoglycemia was assumed to reduce health utility by 0.167 per event, with each event assumed to last 15 minutes.11,12 This was applied as a yearly decrement by converting 15 minutes to a proportion of a year and multiplying it by the health utility (Table I). There is evidence to suggest that the fear of severe hypoglycemia can have a chronic effect on a patient’s quality of life. To captures this impact, we applied an annual health utility decrement of 0.01 for each severe hypoglycemic

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References Cameron and Bennett, 200911 Canadian Agency for Drugs and Technologies in Health, 20135 Canadian Agency for Drugs and Technologies in Health, 201312 Canadian Agency for Drugs and Technologies in Health, 20135 Canadian Agency for Drugs and Technologies in Health, 201312 Cameron and Bennett, 200911 Cameron and Bennett, 200911 Cameron and Bennett, 200911 Cameron and Bennett, 200911 Cameron and Bennett, 200911 Cameron and Bennett, 200911 Cameron and Bennett, 200911 Canadian Agency for Drugs and Technologies in Health, 201312 Cameron and Bennett, 200911 Cameron and Bennett, 200911 Cameron and Bennett, 200911 Canadian Agency for Drugs and Technologies in Health, 201312 Canadian Agency for Drugs and Technologies in Health, 201312 Canadian Agency for Drugs and Technologies in Health, 201312

event.12,13 This decrement represents the decrease in health-related quality of life caused by the event itself and the fear of future events the patient might experience.

Resource Use and Costs The perspective of the analysis was that of the publically funded, Canadian health care system, therefore, only direct health care costs were used in the model (Table II). Drug prices were based on the prices in the Quebec drug formulary; sitagliptin was assumed to be $2.62 per 100 mg and insulin glargine was assumed to be $88.12 per 1500 IU.14

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Clinical Therapeutics

Table II. Resource costs and references. Costs, $CAD (2012) Description of Event or State Annual cost of statins (assume atorvastatin) Annual cost of aspirin Annual cost of ACE inhibitors (assume Apo-Ramipril) Annual cost of microalbuminuria screening Annual cost for gross proteinuria screening Nonstandard ulcer treatment Myocardial infarction Angina Congestive heart failure Stroke Fatal stroke Peripheral vascular disease Hemodialysis Peritoneal dialysis Renal transplantation Major hypoglycemic event Lactic acidosis event Edema onset Retinal photocoagulation Cataract extraction Severe vision loss or blindness, first year Neuropathy, onset Amputation, year of event Gangrene Infected ulcer Uninfected ulcer

Year 1

Year 2 or Later

Reference

189.80



54.38



92.45



30.40



Regie de l'assurance maladie du Quebec (RAMQ), 201314 Canadian Agency for Drugs and Technologies in Health, 201028 Regie de l'assurance maladie du Quebec (RAMQ), 201314 Guillermin et al, 201118

30.40



Guillermin et al, 201118

180.33 19,103.93 4099.68 17,476.22 26,021.11 8123.33 6168.53

 2987.26 1912.67 4899.52 3610.24  

78,545.59 55,632.22 100,042.42 142.97 10,919.63

78,545.59 55,632.22 42,067.72  

3590.92 637.56 4226.19 3196.87 190.62 40,364.87 10,048.91 2811.69 1342.09

  2660.54 2277.62  5528.36   

Guillermin et al, 201118 O'Reilly et al, 200616 O'Brien et al, 200321 O'Reilly et al, 200616 O'Reilly et al, 200616 O'Reilly et al, 200616 Alberta Health and Wellness, 200629 Manns et al, 200317 Manns et al, 200317 Guillermin et al, 201118 O'Brien et al, 200321 Ontario Case Costing Initiative (OCCI), 201019 (Guillermin et al, 2011) O'Brien et al, 200321 O'Reilly et al, 200616 O'Reilly et al, 200616 O'Brien et al, 200321 O'Reilly et al, 200616 O'Brien et al, 200321 O'Brien et al, 200321 O'Brien et al, 200321

ACE ¼ angiotensin-converting-enzyme.

Blood glucose testing strips were assumed to cost $0.80 per strip, which includes the cost of $0.729 per strip and a pharmacy fee of $7.00 per 100 strips.11,12,15 For the base case, we assumed that both insulin glargine and sitagliptin would require the use

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of one test strip per day. However, alternative blood glucose test strip use was assessed in sensitivity analysis. Dosages of insulin glargine and sitagliptin were based on the EASIE trial. Sitagliptin was assumed to

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S.T. Brown et al. be administered as 100 mg/d. Patients on insulin glargine were assumed to receive 41.4 U/d, which was the mean dosage from the EASIE trial at the conclusion of the study. These dosages were assumed to remain constant throughout a patient’s lifetime. A sensitivity analysis was done in which patients switched to a new treatment when their HbA1c increased to >9%. The costs of diabetes-related complications were obtained from the Ontario Ministry of Health and LongTerm Care and from the literature (Table II).16–19 All costs were inflated to 2012 prices using the health care component of the Canadian Consumer Price index.20 It was assumed that mild-to-moderate hypoglycemic events required no health care resource use and, therefore, had no associated costs.11,12 The cost of severe hypoglycemia was based on a report by O’Brien et al21 that examined the cost of managing complications from type 2 diabetes in Canada. In that study, the authors reported that the cost of a severe hypoglycemic event was $111 (CAD 2000). This value was derived from the percent of patients requiring glucagon injection with no medical assistance, patients requiring ambulatory care or emergency room consultation, and patients requiring hospitalization (only 1% of patients were assigned inpatient costs), as reported in O’Brien et al. The costs reported by O’Brien et al were inflated to 2012 prices ($143). It was noted that, the cost of severe hypoglycemia varies in the literature, with a recent 2013 draft from the CADTH Health Technology Assessment reporting a cost of $2030.92 per event.12 However, this value was based on a UK study that only examined hypoglycemic events that required emergency treatment by health care personnel. Even though the majority of hypoglycemic events do not require intervention by a health care worker, this value was tested in a sensitivity analysis.13,21

Sensitivity Analyses A number of sensitivity analyses were performed around the assumptions of blood glucose testing strip usage (Table III). Currently, self-monitoring blood glucose is recommended for all patients with type 2 diabetes.22,23 However, as sitagliptin is an oral medication and insulin glargine is an injectable medication, it is possible that patients might require different testing regimens. A 2009 study in Ontario found that patients using insulin required, on average, 2.08 test

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strips per day, and patients on nonhypoglycemiainducing oral antidiabetic drugs only required 0.94 test strips per day.24 However, this study grouped all insulin types together; biphasic, basal, and long lasting. As insulin glargine is only a once-a-day injectable insulin as opposed to a twice-daily injectable insulin, it would likely require less frequent blood glucose testing. However, for sensitivity analysis, the values of 2.08 and 0.94 were used. Also, a sensitivity analysis was conducted where the requirement for sitagliptin blood glucose testing was reduced from once per day to once per week or no testing. Alternative assumptions around the cost of severe hypoglycemia were also examined. Analyses were also performed on the efficacy of both insulin glargine and sitagliptin using the upper and lower 95% CIs for HbA1c reduction reported in the EASIE trial. An additional analysis was performed that included changes in BMI as reported in the EASIE trial. The disutility for severe hypoglycemia was also tested in a sensitivity analysis using a value reported by Currie et al.25 An additional sensitivity analysis was performed to assess the impact of treatment switching on the results. In this analysis, patients whose HbA1c increased to >9% were assumed to change treatments. Patients on insulin glargine were assumed to add prandial insulin to their regimen, making it a basal-bolus therapy (assumed cost of the prandial insulin is $1471/year in addition to the basal treatment, and it is assumed that 2.08 tests per day are used with basal-bolus therapy). Patients on sitagliptin were assumed to add basal insulin once daily to their treatment (assumed to be the cost of insulin glargine plus one extra test strip per day). If a patient’s HbA1c again went to >9%, they would switch treatment to insulin glargine plus bolus (cease sitagliptin therapy). The HbA1c reduction of adding basal insulin was assumed to be 1.08%, and a reduction of 1.51% when prandial insulin was added to basal therapy.26 The increase in BMI was assumed to be 0.708 with basal insulin, and an additional 1.86 when prandial insulin was added to basal insulin. Parameter uncertainty was tested by performing a probabilistic sensitivity analysis in which individual parameters were randomly chosen from a distribution based on their SE, as reported in the EASIE trial. For cost parameters that lacked an SE value, values were randomly chosen from a distribution based on the mean ⫾ 25%.

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Clinical Therapeutics

Table III. Summary of inputs for sensitivity analyses. Sensitivity Analysis Parameter Tested

Treatment

Base-Case Value*

Sensitivity Analysis Value*

Reference or Comments Exclude the cost of glucose test strips Assumes no testing for sitagliptin Assumes 2 tests per day for insulin glargine

Cost of testing strips excluded

Annual cost of treatment

Insulin Glargine Sitagliptin

$1179.72 $1248.30

$887.72 $956.30

No testing for sitagliptin

Annual cost of treatment

Insulin Glargine Sitagliptin

$1179.72 $1248.30

$1179.72 $956.30

Testing based on Ontario test usage (0.94 vs 2.08) Decreased testing for sitagliptin (1 per week) Increased HbA1c reduction efficacy

Annual cost of treatment

Insulin Glargine Sitagliptin

$1179.72 $1248.30

$1495.08 $1230.78

Annual cost of treatment

Insulin Glargine Sitagliptin

$1179.72 $1248.30

$1179.72 $998.01

Decreased HbA1c reduction efficacy Treatment switching No BMI effects

Increase decrement of severe hypoglycemia Increase cost of severe hypoglycemia

Assumes only 1 test per week for sitagliptin Insulin Glargine 1.72% 1.84% HbA1c reduction Reduction in Sitagliptin 1.13% 1.25% base on upper HbA1c 95%CI reported in EASIE trial Reduction in Insulin Glargine 1.72% 1.60% HbA1c reduction HbA1c Sitagliptin 1.13% 1.01% base on lower 95%CI reported in EASIE trial Costs and efficacy Insulin Glargine No switching IG - IG þ bolus Treatment switching at 9% Sitagliptin No switching Sita - Sita þ IG HbA1c - IG þ Bolus Change in BMI Insulin Glargine 0.164 0 Assumes treatment Sitagliptin 0.401 0 does not affect weight Utility decrement Both Severe ¼ 0.01 Severe ¼ 0.047 Based on values of hypoglycemia reported by Currie et al, 200625 Cost of severe Both $142.97 $2030.92 Based on severe hypoglycemia hypoglycemia costs reported in Canadian Agency for Drugs and Technologies in Health, 201326

BMI ¼ body mass index (calculated as kg/m2); HbA1c ¼ glycosylated hemoglobin; IG ¼ insulin glargine; Sita ¼ sitagliptin. * Dollar values are CAD.

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Table IV. Summary of base-case results. Insulin Glargine (95% CI) Life years (discounted) Life years (undiscounted) QALYs (discounted) QALYs (undiscounted) Costs, $CAD in 2012 (discounted) Incremental life years (discounted) Incremental QALYs (discounted) Incremental costs, $CAD in 2012 (discounted) Cost, $CAD in 2012, per life year gained (Insulin glargine vs sitagliptin) Cost, $CAD in 2012, per QALY gained Insulin glargine vs sitagliptin

Sitagliptin (95% CI)

11.465 19.784 8.815 15.006 45,556

(11.457 to 11.473) 11.376 (11.367 to 11.384) (19.764 to 19.803) 19.567 (19.547 to 19.587) (8.809 to 8.821) 8.739 (8.733 to 8.745) (14.992 to 15.021) 14.83 (14.815 to 14.845) (45,474 to 45,638) 45,638 (46,903 to 47,077) 0.089 (0.078 to 0.100) 0.076 (0.068 to 0.084) 1434 (1553 to 1314) Dominant (insulin glargine is more effective and less costly) 16,076 ($22,797 to 22,860) Dominant (insulin glargine is more effective and less costly) 18,882 (52,158 to 33)

QALY ¼ quality-adjusted life year.

RESULTS Base Case The base-case analysis found that insulin glargine was dominant versus sitagliptin, with a cost savings of $1434 and a gain of 0.08 quality-adjusted life years (QALYs) per patient during a period of 50 years (Table IV). This result was driven by the greater reduction in HbA1c and lower acquisition cost with insulin glargine. The larger reduction in HbA1c achieved with insulin glargine results in a decrease in diabetes-related complications compared with sitagliptin. Insulin glargine delayed the onset of all diabetes-related complications (Figure 1). This delay in complications resulted in increased life expectancy (19.784 years vs 19.567 years, undiscounted) and quality of life (15.006 vs 14.830, undiscounted). Insulin glargine also resulted in a cost savings of 1% for cardiovascular disease related complications, 5% in renal-related complications, 3% in neuropathy-related complications, and 2% in retinopathy-related complications (Figure 2). However, because of the higher rates of hypoglycemia, the cost to treat hypoglycemia was greater with insulin glargine; $50 per patient for insulin glargine versus $17 for sitagliptin.

Sensitivity Analyses Results from the probabilistic sensitivity analysis (1000 simulations) indicated that the deterministic

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results were robust, with the 95% CI for the cost per QALY ranging between $23,815 (dominant) and $2044 (Table V). The probabilistic sensitivity analysis results found that the majority of the simulations fell within the southeast quadrant of the scatter plot, which corresponds to insulin glargine being dominant (Figure 3). The probability of being cost-effective for insulin glargine ranged from 74% to 88% at willingness to pay threshold of $0 to $100,000 (Figure 4). Univariate and multivariate sensitivity analyses also supported the robustness of the base-case results. Changes to the number of testing strips used for sitagliptin and insulin glargine resulted in the largest impact on the incremental cost-effectiveness ratio. Depending on the number of test strips used, the incremental cost-effectiveness ratio varied from $18,670 to $39,091 (Table VI). Changes in the efficacy (HbA1c and BMI) for sitagliptin and insulin glargine produced results similar to the base case. Increasing the cost of severe hypoglycemia (from $143 to $2030) also did not affect the results of the analysis, as severe hypoglycemia was a relative rare event, as reported by the EASIE trial. Increasing the disutility also did not have a significant impact on the results. However, it should be noted that this disutility for severe hypoglycemia reported by Currie et al25 is quite extreme and is of the same magnitude of the disutility of an MI. The incremental QALYs gained

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Clinical Therapeutics

Severe Vision Loss Macular Edema Cataract Stroke Myocardial Infarction Angina Congestive Heart Failure Peripheral Vascular Disease Neuropathy Amputation First Ulcer End-Stage Renal Disease Gross Proteinuria Microalbuminuria Proliferative Retinopathy Background Retinopathy 5

10 15 Time to First Event (Years) Sitagliptin

20

Insulin Glargine

Figure 1. Time to first diabetes-related complication. Insulin glargine delayed the onset of all diabetes-related complications. Illustration of the mean time in years to the first diabetes-related complication in insulin glargine versus sitagliptin.

decreased to 0.07, but did not alter the conclusion of the analysis. Assuming treatment switching when patients reach an HbA1c threshold of 9% did have a significant impact on the results. The results went from being dominant to producing a cost-effectiveness

$50,000 Insulin glargine

$40,000 Costs (CAD)

Sitagliptin $30,000 $20,000 $10,000

ia

e Ey

lyc em

og H yp

n tio

na l Ul

ce r/

Am

pu ta

Re

CV D

en t ge

m

m an a M

ea t Tr

To

ta lC

os

ts

en t

$0

Figure 2. Breakdown of costs. Costs (in CAD) associated with insulin glargine versus sitagliptin treatment.

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ratio of $3179 per QALY. However, insulin glargine would still be considered a cost-effective therapy at this incremental cost-effectiveness ratio.

DISCUSSION The EASIE trial reported a significantly larger reduction in HbA1c with insulin glargine compared with sitagliptin. The results of the cost-effectiveness analysis and the sensitivity analyses demonstrate that insulin glargine can produce cost savings compared with sitagliptin in patients with type 2 diabetes who are inadequately controlled on metformin. The results support the use of insulin glargine as a viable alternative to sitagliptin in patients with inadequate control of HBA1c on metformin. The model contained a number of simplifying assumptions concerning diabetes treatment. The model assumed that treatment with either sitagliptin or insulin glargine was fixed for the lifetime of the patient, with no dosage increases for both patient groups. The model assumed HbA1c will drift upward over time. This drifting resulted in convergence of HbA1c levels such that at approximately 10 years after Volume ] Number ]

S.T. Brown et al.

Table V. Summary of probabilistic sensitivity analysis results. Insulin Glargine (95% CI) Life years (discounted) Life years (undiscounted) QALYs (discounted) QALYs (undiscounted) Costs, $CAD in 2012 (discounted) Incremental life years (discounted) Incremental QALYs (discounted) Incremental costs, $CAD in 2012 (discounted) Cost, $CAD in 2012, per life year gained Insulin glargine vs sitagliptin) Cost, $CAD in 2012, per QALY gained Insulin glargine vs sitagliptin

Sitagliptin (95% CI)

11.15 19.377 8.575 14.689 45,560

(11.056 to 11.244) 11.062 (10.967 to 11.157) (19.127 to 19.628) 19.161 (18.911 to 19.411) (8.503 to 8.646) 8.501 (8.428 to 8.573) (14.503 to 14.875) 14.514 (14.328 to 14.699) (44,939 to 46,181) 46,978 (46,338 to 47,619) 0.088 (0.077 to 0.099) 0.074 (0.066 to 0.082) 1418 ($1540 to 1295) Dominant (insulin glargine is more effective and less costly) 16,109 (55,867 to 74,115) Dominant (insulin glargine is more effective and less costly) 19,155 (23,815 to 2044)

QALY ¼ quality-adjusted life year.

HbA1c would be controlled by increasing the dosage of insulin. These adjustments in treatment in response to HbA1c were not included in the model. The impact of such adjustments on the cost-effectiveness results are unknown and would depend on numerous factors concerning the selection, cost, and efficacy of subsequent treatments.

initiation, there was no difference in HbA1c levels between treatment groups. In clinical practice, increases in a patient’s HbA1c would be treated with dosage increases of existing drug or the addition of a new drug. In the case of sitagliptin, it is likely that patients would eventually be treated with insulin to control their HbA1c. In the case of insulin glargine,

$4,000

Incremental Costs (CAD)

$2,000 $0 –$2,000 –$4,000 –$6,000 –$8,000 –$10,000 –0.5

–0.4

–0.3

–0.2

–0.1

0

0.1

0.2

0.3

0.4

0.5

0.6

Incremental QALYs

Figure 3. Scatter Plot of incremental costs versus incremental quality-adjusted life years (QALYs). Scatter plot of incremental costs in CAD against incremental QALYs. The probabilistic sensitivity analysis results demonstrated that the majority of the simulations fell within the southwest quadrant of the scatter plot, which corresponds to insulin glargine being dominant.

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Clinical Therapeutics

Probability of Being Cost-Effective

100% 80% 60% 40% 20% 0% $0

$20,000

$40,000

$60,000

$80,000

$100,000

Cost-Effectiveness Threshold

Figure 4. Cost-effectiveness acceptability curve. Illustration of the probability of being cost-effective over a range of costeffectiveness thresholds. The cost-effectiveness of insulin glargine ranged from 74% to 88% at willingness to pay thresholds of $0 to $100,000 CAD.

A recent draft CADTH publication12 on second-line pharmacotherapy (after first-line metformin) for type 2 diabetes found that basal insulins, such are insulin glargine, are dominated by DPP-4 inhibitors, such as sitagliptin. This is in direct contrast to the results of the EASIE trial and this cost-effectiveness analysis, which found that insulin glargine was dominant over sitagliptin. There are a number of differences between the 2 cost-effectiveness models and parameters that can explain these diametrically opposite conclusions. First, the analyses are based on 2 different models. The CADTH report uses a model based on the United Kingdom Prospective Diabetes Study Outcomes model, and the analysis presented here is based on the IMS CORE model. Second, the CADTH report pooled individual diabetes drugs into classes such that basal insulin included insulin neutral protamine Hagedorn, insulin detemir, and insulin glargine. The class of DPP4 inhibitors included linagliptin, saxagliptin, and sitagliptin. The efficacy of each class of drugs was determined using a network meta-analysis across a wide number of studies (approximately 23 DPP-4 inhibitor studies [vildagliptin, sitagliptin, linagliptin, and saxagliptin] and approximately 7 studies of basal insulin [glargine and neutral protamine Hagedorn]). The network meta-analysis found that DPP-4 inhibitors and basal insulins produced reductions of 0.69 and 0.91 in HbA1c, respectively, which represents a difference of 0.22 between the 2 classes of drugs in favor of insulin.12 In contrast, the EASIE trial, which is a direct head-to-head randomized trial comparing insulin

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glargine with sitagliptin, found a significant mean difference of 0.59 in reduction of HBA1c in favor of insulin glargine, which is more than double that in the CADTH analysis.6 Although the use of network meta-analysis, such as that used within the CADTH study, allows multiple data sources to be included in the analysis, it does also introduce heterogeneity, as patient populations can differ widely between trials. In contrast, a head-tohead randomized trial minimizes heterogeneity between patients in each treatment group. When conducting a meta-analysis of multiple trials, the heterogeneity among the trials is assessed to determine if the trials contain differences in population or treatment protocols that would preclude pooling the findings. If the trials are deemed to be similar, the results are pooled. The impact of individual studies on the pooled results can be tested through sensitivity analyses in which individual studies are excluded to determine the change in the pooled results. When comparing the results from the CADTH study and the EASIE trial, it is clear that the inclusion of additional studies to the EASIE trial data substantially changed the magnitude of the differences in HBA1c between treatment arms. This might be a result of the design of the trials included or differences in patient populations between studies. The most likely source of heterogeneity is the inclusion of different basal insulins and DPP-4 inhibitors within each arm of the CADTH analysis. This assumes that individual drugs in each class have the same efficacy. In the CADTH report, the reduction in HbA1c for the individual DPP-4 inhibitors varied widely from 0.56 to 0.74 (0.56 for saxagliptin, 0.66 for linagliptin, 0.67 for sitagliptin, and 0.74 for vildagliptin). The overall class effect for the DPP-4 inhibitors was determined to be 0.69, however, vildagliptin is not currently approved for use in Canada, therefore, 0.69 might overestimate the efficacy of the DPP-4 inhibitors available in Canada.27 Overall, the CADTH methodology includes a number of substantial assumptions about pooling of studies and might not represent a better indication for relative effectiveness of insulin glargine to sitagliptin than that provided by the EASIE trial. Finally, the CORE model used does not allow for treatment switch through time. Therefore, it limits the capacity to analyze a dynamic treatment evolution and account for future therapy changes and their potential effects on results.

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S.T. Brown et al. Table VI. Summary of sensitivity analyses results.* Scenario Cost of testing strips excluded No testing for sitagliptin Testing based on Ontario test usage (0.94 vs 2.08) Decreased testing for sitagliptin (1 per week) Increased HbA1c reduction efficacy Decreased HbA1c reduction efficacy Treatment switching No BMI effects Increase decrement of severe hypoglycemia Increase cost of severe hypoglycemia

Treatment

Costs, $CAD

LYs

QALYs

Insulin Glargine Sitagliptin Insulin Glargine Sitagliptin Insulin Glargine Sitagliptin

42,127 43,462 45,556 43,462 49,343 46,695

11.47 11.37 11.47 11.37 11.47 11.37

8.82 8.74 8.82 8.74 8.82 8.74

Insulin Glargine Sitagliptin Insulin Glargine Sitagliptin Insulin Glargine Sitagliptin Insulin Glargine Sitagliptin Insulin Glargine Sitagliptin Insulin Glargine Sitagliptin Insulin Glargine Sitagliptin

45,596 43,953 45,586 46,861 45,655 46,887 49,390 49,177 45,596 46,902 45,556 46,990 46,251 47,121

11.47 11.37 11.48 11.39 11.46 11.34 11.51 11.43 11.48 11.38 11.47 11.37 11.47 11.37

8.82 8.74 8.83 8.75 8.80 8.71 8.85 8.78 8.82 8.73 8.81 8.74 8.82 8.74

ΔCosts, $CAD

ΔLYs

ΔQALYs

Cost per LY, $CAD

Cost per QALY, $CAD

1335

0.10

0.08

Dominant

Dominant

2094

0.10

0.08

21,813

26,175

2648

0.10

0.08

24,981

30,091

1643

0.10

0.08

15,500

18,670

1275

0.09

0.08

Dominant

Dominant

1232

0.11

0.09

Dominant

Dominant

213

0.08

0.07

2730

3179

1306

0.11

0.09

Dominant

Dominant

1434

0.09

0.07

Dominant

Dominant

870

0.10

0.08

Dominant

Dominant

BMI ¼ body mass index (calculated as kg/m2); HbA1c ¼ glycosylated hemoglobin; LY ¼ life year; QALY ¼ quality-adjusted life year. * Values rounded for display purposes.

CONCLUSIONS The EASIE trial reported a significantly larger reduction in HbA1c in patients using insulin glargine versus sitagliptin. This cost-effectiveness analysis provides evidence that using insulin glargine as an alternative treatment to sitagliptin provides better reduction in HbA1c and results in cost savings.

ACKNOWLEDGMENTS Dr. Brown conducted analyses and interpreted the results. Mr. Grima and Mr. Sauriol designed the analyses, collected input data for the analysis, and interpreted the results. Dr. Brown and Mr. Grima wrote the manuscript, and L. Sauriol reviewed and revised the manuscript.

CONFLICTS OF INTEREST Dr. Brown and Mr. Grima are representatives of Cornerstone Research Group, which received payment from Sanofi Pharma Canada to run the analyses contained in this report and prepare the manuscript. Mr. Sauriol is an employee of Sanofi Pharma Canada.

] 2014

The authors have indicated that they have no other conflicts of interest regarding the content of this article.

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23. American Diabetes Association, Standards of medical care in diabetes—2009. Diabetes Care. 2009;32(Suppl 1):S13–S61. 24. Gomes T, et al. Blood Glucose Test Strip Use: Patterns, Costs and Potential Cost Reduction Associated with Reduced Testing. Ottawa: ICES; 2009. 25. Currie CJ, et al. Multivariate models of health-related utility and the fear of hypoglycaemia in people with diabetes. Curr Med Res Opin. 2006;22:1523–1534. 26. Canadian Agency for Drugs and Technologies in Health. Third-Line Pharmacotherapy for Type 2 Diabetes (Update). Ottawa: Canadian Agency for Drugs and Technologies in Health; 2013. 27. Canadian Agency for Drugs and Technologies in Health. CADTH Optimal Use Report: Combination Use of Insulin and Incretins in Type 2 Diabetes. Ottawa: Canadian Agency for Drugs and Technologies in Health; 2013. 28. CADTH, Clopidogrel compared with other antiplatelet agents for secondary prevention of vascular events in adults undergoing percutaneous coronary intervention: clinical and cost-effectiveness analyses, 2010. http://www.cadth.ca/ media/pdf/H2481_Clopidogrel_ Percutaneous_Coronary_Interven tion_tr_e.pdf. 29. Edmonton (AB): Alberta Health and Wellness. Health costing in Alberta: 2006 annual report. Edmonton (AB): Alberta Health and Wellness, 2010.

Address correspondence to: Stephen T. Brown, PhD, Cornerstone Research Group Inc., 204-3228 South Service Road, Burlington, Ontario, Canada, L7N 3H8. E-mail: [email protected]

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Cost-effectiveness of insulin glargine versus sitagliptin in insulin-naïve patients with type 2 diabetes mellitus.

In the EASIE (Evaluation of Insulin Glargine Versus Sitagliptin in Insulin-Naïve Patients) trial, insulin glargine found a significant reduction in gl...
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