Cost-effectiveness of insulin glargine/lixisenatide titratable fixed-ratio combination for patients with basal insulin-treated type 2 diabetes in South Korea Park HY1, An S1, Park S1, Kim DH1, Jeon SM1, Kwon JM2, and Kwon JW1 1 Kyungpook National University, Daegu, South Korea 2 Sanofi-Aventis Korea Co. Ltd., Seoul, South Korea

BACKGROUND RESULT TABLE & FIGURE

Table 1. Characteristics of target cohort  Growing body of evidence supports the importance of early combined intensification treatment for glycemic control of type 2 diabetes (T2DM) management, but insulin intensification has been shown to Characteristic Base Cohort LixiLan-L Cohort HbA1c (%) 8.6 ± 1.3 8.1 ± 0.7 have a high start barrier related to side-effects of insulin therapy such as weight gain and hypoglycemia, Age (years) 64.4 ± 11.4 60.0 ± 9.1 1-2 complexity of the regimen, injection pain, and insulin resistance. Duration of diabetes (years) 18.0 ± 9.5 12.1 ± 6.7  A new preparation for insulin therapy, a 2:1 or 3:1 fixed-ratio co-formulation of insulin glargine and Male (%) 46.9 46.7 lixisenatide (iGlarLixi) launched in South Korea, showed superior HbA1c reduction than insulin glargine Baseline total cholesterol (mg/dL) 164.0 ± 39.0 180.5 ± 44.8 Baseline HDL-C (mg/dL) 45.9 ± 11.6 50.6 ± 13.2 alone in basal insulin-uncontrolled adult T2DM patients in a phase III trial of the LixiLan-L study, Baseline LDL-C (mg/dL) 93.6 ± 30.2 100.6 ± 37.8 considered to be a suitable option for patients who are required to start insulin therapy or insulin Baseline triglycerides (mg/dL) 146.9 ± 93.7 149.1 ± 98.4 intensification.3-4 Body weight (kg) 64.6 ± 11.2 87.4 ± 14.5 Body mass index (kg/m2) 24.4 ± 3.3 31.2 ± 4.2 HbA1c: glycated hemoglobin, HDL: high-density lipoprotein, LDL: low-density lipoprotein

OBJECTIVES Table 2. Efficacy and cost assumption by treatment arm

Base Analysis Sensitivity Analysis  The aim of this study was to assess the cost-effectiveness of insulin glargine/lixisenatide (iGlarLixi), a Rescue therapy fixed-ratio co-formulation of insulin glargine and lixisenatide, compared with that of premixed insulin Comparator: iGlarLixi Premixed insulin BIAsp30 iDegAsp Insulin glargine (comparator) for patients with basal insulin-uncontrolled type 2 diabetes (defined by a glycated Efficacy

hemoglobin [HbA1c] ≥7%) in South Korea. HbA1c (%) -1.15 (0.06) -0.65 (0.06)b -0.67 (0.06) b -0.64 (0.06)b -0.61 (0.06) b -0.84 (0.05)

Systolic blood pressure (mmHg) 0.02 (0.80) 0.02 (0.80)c 0.02 (0.80)c 0.02 (0.80)c 0.68 (0.78) 1.55 (0.84)

METHODS Total cholesterol (mg/dL) 1.53 (3.16) 1.53 (3.16)c 1.53 (3.16)c 1.53 (3.16)c 6.67 (2.98) -1.37 (2.25)

LDL-C (mg/dL) 1.01 (2.75) 1.01 (2.75)c 1.01 (2.75)c 1.01 (2.75)c 5.50 (2.59) -1.35 (1.84)  The CORE Diabetes Model (CDM) version 9.0, a generic diabetes decision analytic model developed by

c c c IQVIA, composed of 17 interconnected Markov sub-models were used. HDL-C (mg/dL) 0.11 (1.04) 0.11 (1.04) 0.11 (1.04) 0.11 (1.04) -0.73 (0.98) -0.44 (0.52)  Settings: horizon of 30 years, a payer perspective, and 3% discount rate for health outcomes and Triglycerides (mg/dL) -0.86 (7.79) -0.86 (7.79)c -0.86 (7.79)c -0.86 (7.79)c 8.58 (7.35) 0.92 (6.22)

treatment costs. Body mass index (kg/m2) -0.27 (0.07) 0.53 (0.07)d 0.79 (0.07)d 0.31 (0.07)d 0.21 (0.06) 0.51 (0.09)

Minor hypoglycemia  It was assumed that each treatment was administered for the first 3 years, and the effects were 303.0 303.0 454.0 303.0 422.0 410.4 (event per 100 patient year) maintained over that period. The treatments were then switched to rescue regimen (basal insulin + 3 Major hypoglycemiaa 2.5 2.5 2.5 2.5 0.5 0.0 (event per 100 patient year) times short acting insulin) from the 4th year and on. Insulin dose (IU/Kg/day)

 The HbA1c effects were modeled according to the United Kingdom Prospective Diabetes Study 0.52 (Basal) maintenance 0.53 0.84e 1.19 0.69 0.53 (UKPDS) model 68 regressions from the 4th year onwards. Sensitivity analyses were conducted with 0.39 (Bolus) Yearly treatment cost (USD)f

varying key inputs. Maintenance phase 1,614 1,005e 1,132 950 582 997  The treatment effects were sourced from an indirect treatment comparison via the common comparator iGlarLixi: Insulin glargine/lixisenatide, BIAsp30: Biphasic insulin aspart 30/70, iDegAsp: Insulin degludec/Aspart, LDL: low density lipoprotein, HDL: high density of insulin glargine and on a meta-analysis of two studies concerning premixed insulin versus insulin lipoprotein, Pt yr: Patient years., USD: US dollar (1USD=1100 Korea Won ). glargine by Ligthelm (2011)5 and by Kumar (2017).6 All data are means (standard error), unless otherwise specified. a Severe hypoglycemia requiring medical assistance; b Assumed mean values with the equation of ‘(mean value of iGlarLxi)-(mean difference between iGlarLixi  A meta-analysis and an ITC were conducted using the Revman Review Manager 5.3 and the Canadian and comparator in the ITC)’, and same standard errors as iGlarLixi were used due to limited data for comparators; ITC program, respectively. c Assumed same effectiveness as comparison data were not available for the ITC; d Assumed with the equation of ‘body weight / 1.7^2’; e Assumed as BIAsp30: iDegAsp=3:7; f Included the costs of metformin and disposable injection needles.  Cost data were derived from a real-world claims data analysis.  Sensitivity analyses were conducted with varying key inputs. Table 3. Results of base analysis

QALYS (YEAR) COSTS (USD) ICER Premixed i Premixed in iGlarLixi Difference iGlarLixi Difference (USD/QALY) Figure 1. Simplified structure of CORE Diabetes Model (CDM) nsulin sulin

Mean 8.251 8.171 0.079 106,225 106,453 -228 -2,872

95% CI low 8.243 8.164 0.069 106,060 106,282 -464 -5,155

95% CI high 8.258 8.179 0.090 106,389 106,623 8 113

iGlarLixi: Insulin glargine/lixisenatide, ICER: incremental cost–effectiveness ratio, QALY: quality adjusted life year

Figure 2. Tornado diagram for deterministic sensitivity analysis

Cohort-BMI 20% up Cohort-Lixilan-L study Horizon 15 years Horizon 20 years Switch at HbA1c 8% Switch at HbA1c 7.5% Switch after 5Yrs, HbA1c maintained Comparator-Novomix Comparator-Ryzodeg Comparator efficacy 20% up Comparator efficacy 20% down CV risk-UKPDS82 mode No BMI and hypoglycemia disutility adjustment Premix cost 20% up Premix cost 20% down Complication cost 20% up Complication cost 20% down Discount 0% Discount 5% Comparator: Insulin glargine ICER (USD/QALY) -15,000 -10,000 -5,000 0 5,000 10,000

RESULTS LIMITATIONS

 Effectiveness in the base analysis was derived from an indirect treatment comparison.  Indirect treatment comparisons showed that iGlarLixi resulted in significantly greater reduction from  Uncertainty arose related to the parameters in the CDM because the model required inputting various baselines for HbA1c and BMI compared with premixed insulin; mean difference of -0.50% (95% parameters on setting, cost, cohort, complications, and cost-effectiveness. confidence interval : -0.68, -0.32) for HbA1c and -0.80 kg/m2 (95% confidence interval : -1.29, -0.31) for BMI. CONCLUSIONS  In the base analysis, iGlarLixi was found to be dominant (more effective and less costly) over premixed insulin with 0.079 additional quality-adjusted life-years and lowered cost by approximately 230 USD.  iGlarLixi showed dominance or acceptable incremental cost-effectiveness over premixed insulin.  The incremental cost–utility ratios from sensitivity analyses also remained dominant or below 10,000  These outcomes suggest that iGlarLixi could be a suitable alternative to insulin intensification, which is USD. related to poor glycemic control and concerns about hypoglycemia and weight gain.

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