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. 2024 Feb 3;30(2):153–162. doi: 10.18553/jmcp.2024.30.2.153

Tirzepatide 10 and 15 mg vs semaglutide 2.0 mg: A long-term cost-effectiveness analysis in patients with type 2 diabetes in the United States

Reema Mody 1,*, William J Valentine 2, Meredith Hoog 1, Helen Sharland 2, Mark Belger 3
PMCID: PMC10839462  PMID: 38308628

Abstract

BACKGROUND:

Tirzepatide is a novel glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist approved for type 2 diabetes (T2D) treatment.

OBJECTIVE:

To compare the long-term cost-effectiveness of tirzepatide 10 mg and 15 mg vs semaglutide 2.0 mg, an injectable glucagon-like peptide-1 receptor agonist, in patients with T2D from a US health care payer perspective.

METHODS:

The PRIME T2D Model was used to project clinical and cost outcomes over a 50-year time horizon. Baseline cohort characteristics and treatment effects were sourced from a published adjusted indirect treatment comparison that used data from the SURPASS-2 and SUSTAIN FORTE trials. Patients were assumed to intensify to insulin therapy at a hemoglobin A1c of greater than 7.5%. Costs and health state utilities were derived from published sources. Future costs and clinical benefits were discounted at 3% annually.

RESULTS:

Tirzepatide 10 mg and 15 mg were associated with improved quality-adjusted life-expectancy (10 mg: 0.085 quality-adjusted life-years [QALYs], 15 mg: 0.121 QALYs), higher direct costs (10 mg: USD 5,990, 15 mg: USD 6,617), and incremental cost-effectiveness ratios of USD 70,147 and 54,699 per QALY gained, respectively, vs semaglutide 2.0 mg. Both doses of tirzepatide remained cost-effective vs semaglutide 2.0 mg over a range of sensitivity analyses.

CONCLUSIONS:

Long-term projections using the PRIME T2D model and based on treatment effects from an adjusted indirect treatment comparison indicate that tirzepatide 10 mg and 15 mg are likely to be cost-effective vs semaglutide 2.0 mg for the treatment of T2D in the United States.

Plain language summary

Tirzepatide is a novel therapy for the treatment of type 2 diabetes (T2D). In this long-term modeling study, based on published clinical evidence, tirzepatide 10 and 15 mg were associated with improved clinical outcomes in patients with T2D compared with semaglutide 2.0 mg in the United States. The analysis also showed that tirzepatide 10 and 15 mg are likely to be cost-effective vs semaglutide 2.0 mg, making tirzepatide an attractive choice for formulary decision-makers.

Implications for managed care pharmacy

This is the first published study to evaluate the long-term cost-effectiveness of tirzepatide vs semaglutide 2.0 mg for the management of T2D. The analysis showed that tirzepatide 10 mg and 15 mg doses were likely to be cost-effective vs semaglutide 2.0 mg with incremental cost-effectiveness ratios of less than USD 100,000 per quality-adjusted life-year gained, which may help guide formulary decision-making for the management of T2D in the United States.

Type 2 diabetes (T2D) is a condition characterized by progressive loss of insulin secretion, often in conjunction with insulin resistance.1 More than 25 million people in the United States are estimated to have been diagnosed with T2D, and an additional 7 million are estimated to have undiagnosed T2D.2 It is projected that by 2060, 18% of the US population will be diagnosed with diabetes.3 T2D is associated with a high economic and humanistic burden.4-8 In 2017, the cost of diagnosed diabetes was estimated to be USD 327 billion.9 Despite advances in treatment, more than half of patients with T2D do not meet glycemic control targets, with estimates suggesting as much as 54.2% failing to meet a glycated hemoglobin (A1c) of less than 7.0%.10 Poor glycemic control, typically defined as an A1c of 7% or greater, is associated with increased prevalence of diabetes-related complications.11 Of those with T2D, 90% have overweight or obesity, and patients with T2D and obesity are more likely to have an A1c greater than or equal to 7% than individuals with T2D and normal weight.12,13 As the prevalence of T2D is expected to increase, improving glycemic control in people with T2D will be essential to manage the overall socioeconomic disease burden.14

Tirzepatide is a first-in-class once weekly glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 (GLP-1) receptor agonist (RA) that has been approved in many countries, including the United States, European Union, and Japan for treatment of people with T2D and in the United States and the United Kingdom for the treatment of obesity (≥30 kg/m2) and for overweight (≥27 kg/m2) with at least 1 weight-related comorbid condition.15-18 The safety and efficacy of tirzepatide was investigated in the SURPASS clinical trial program. The SURPASS clinical trials demonstrated the efficacy and safety of tirzepatide in people with T2D and showed that patients experienced reductions in A1c and body weight when treated with tirzepatide.19-22 In the SURPASS-2 clinical trial comparing tirzepatide 5 mg, 10 mg, and 15 mg with injectable semaglutide among patients with T2D on background therapy of metformin, all 3 doses of tirzepatide were shown to reduce A1c by 2.01%, 2.24%, and 2.30%, respectively, compared with a 1.86% decrease experienced by patients treated with semaglutide 1.0 mg.20

Higher doses of GLP-1 RAs, a class of antihyperglycemic drug that reduce plasma glucose through effects on insulin and glucagon secretion and by the deceleration of gastric emptying, have recently been approved for the treatment of T2D in the United States.23,24 One such agent, semaglutide 2.0 mg, has been shown to be more efficacious and have a comparable safety profile to the lower dose of semaglutide 1.0 mg in the SUSTAIN FORTE trial.25 In SUSTAIN FORTE, a significantly higher proportion of patients reached an A1c of less than 7.0% on semaglutide 2.0 mg than 1.0 mg (67.6% vs 57.5%, respectively).25

Tirzepatide has already been shown to be cost-effective vs semaglutide 1.0 mg for the treatment of T2D in the United States.26 Although there is no head-to-head trial comparing tirzepatide with semaglutide 2.0 mg, a recently published adjusted indirect treatment comparison (aITC) by Vadher et al has provided a comparison of tirzepatide 5 mg, 10 mg, and 15 mg with semaglutide 2.0 mg on the key clinical endpoints of change in A1c and change in weight from baseline to end of study period.27 The aITC showed that tirzepatide 10 mg and 15 mg were associated with significantly greater reductions in A1c and body weight at week 40 compared with semaglutide 2.0 mg. Vadher et al reported that tirzepatide 10 and 15 mg significantly reduced A1c vs semaglutide 2 mg with estimated treatment differences of -0.36% (95% CI = -0.63 to -0.09) and -0.4% (95% CI = -0.67 to -0.13), respectively. Estimated treatment differences for body weight were -3.15 kg (95% CI = -4.84 to -1.46) and -5.15 kg (95% CI = -6.85 to –3.45) for tirzepatide 10 and 15 mg vs semaglutide 2.0 mg, respectively. There was no significant difference in the outcomes between tirzepatide 5 mg and semaglutide 2.0 mg. The aim of the present analysis was therefore to compare the long-term cost-effectiveness of tirzepatide 10 mg and 15 mg vs semaglutide 2.0 mg from a US health care payer perspective.

Methods

MODELING APPROACH

Long-term projections of clinical and cost outcomes were made using the previously published and validated PRIME Type 2 Diabetes Model (PRIME T2D Model).28 The PRIME T2D Model is a patient-level simulation capable of modeling treatment algorithms, simulating risk-factor progression, and projecting the cumulative incidence of macrovascular and microvascular complications, as well as hypoglycemic events. The model and validation analysis that compared model projections with outcomes from real-life studies spanning a range of time frames, interventions, and country settings, including 4 cardiovascular outcomes studies, was published in 2022. The validation analysis reported that all root-mean-square deviation values for external validations were 3.7% or less and for internal validations (against published studies used to develop the model) were 1.1% or less. In the present analysis, the PRIME T2D Model was used to project outcomes for patients treated with tirzepatide 10 or 15 mg or with semaglutide 2.0 mg over a 50-year time horizon, with shorter time horizons (5-year and 10-year) investigated in sensitivity analyses. A summary and rationale for key assumptions in the modeling analysis is provided in the Supplementary Table 1 (556.1KB, pdf) , available in online article.

BASELINE COHORT CHARACTERISTICS AND TREATMENT EFFECTS

In the base-case analysis, cohort characteristics were based on a weighted average calculated from the SURPASS-2 refined cohort presented in Vadher et al, and supplemented with data from the clinical study report and Centers for Disease Control and Prevention (Table 1).27,29 The effects associated with tirzepatide therapy on A1c and body weight were taken from the aITC by Vadher et al, whereas the effects associated with semaglutide 2.0 mg on A1c and body weight were sourced from SUSTAIN FORTE.25,27 Treatment effects associated with tirzepatide 10 and 15 mg and semaglutide 2.0 mg on blood pressure, lipids, and estimated glomerular filtration rate (eGFR) were supplemented with data from the SURPASS-2 clinical study report (Table 2). As there were no significant differences between tirzepatide 5 mg and semaglutide 2.0 mg in the published aITC analysis (see Supplementary Table 2 (556.1KB, pdf) for details), no long-term modeling of this comparison was performed. Treatment effects on blood pressure, lipids, and eGFR associated with semaglutide 2.0 mg were not available from the aITC and were assumed to be the same as tirzepatide 5 mg (in SURPASS-2), as these treatments were broadly equivalent in the aITC analysis.

TABLE 1.

Cohort Characteristics for the Base-Case Analysis

Characteristics Mean (SD) Reference
Demographics
    Age at baseline, years 56.0 (10.2) 27
    Duration of diabetes, years 9.5 (6.9) 27
    Male/female/other, % 45.0 / 55.0 / 0.0 27
    Smokers, % 13.7 29
    Race, %
      Black 4.2 SURPASS-2 CSR
      Other 11.9 SURPASS-2 CSR
      Southeast Asian 1.3 SURPASS-2 CSR
      White 82.6 SURPASS-2 CSR
Baseline risk factors
    HbA1c, % 8.8 (0.6) 27
    Systolic blood pressure, mm Hg 131.3 (13.7) 27
    Total cholesterol, mmol/L 4.41 (0.44) SURPASS-2 CSR
    Low-density lipoprotein cholesterol, mmol/L 2.27 (0.23) SURPASS-2 CSR
    High-density lipoprotein cholesterol, mmol/L 1.11 (0.11) SURPASS-2 CSR
    eGFR, mL/min/1.73 m2 98.1 (16.5) 26
    BMI 34.1 (7.1) 27
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BMI = body mass index; CSR = clinical study report; eGFR = estimated glomerular filtration rate; HbA1c = glycated hemoglobin.

TABLE 2.

Treatment Effects Used in the Base-Case Analysis

Mean change from baseline (SD) Source
TZP 10 mg TZP 15 mg SEMA 2.0 mg
HbA1c, % −2.66 (0.27) −2.70 (0.27) −2.30 (0.23) TZP,27 SEMA25
Systolic blood pressure, mm Hg −5.30 (0.53) −6.50 (0.65) −4.80 (0.48) SURPASS-2 CSR (SEMA 2.0 mg value assumed to match TZP 5 mg)
Low-density lipoprotein cholesterol, mmol/L −0.13 (0.01) −0.12 (0.01) −0.17 (0.02) SURPASS-2 CSR (SEMA 2.0 mg value assumed to match TZP 5 mg)
High-density lipoprotein cholesterol, mmol/L 0.09 (0.01) 0.08 (0.01) 0.07 (0.01) SURPASS-2 CSR (SEMA 2.0 mg value assumed to match TZP 5 mg)
eGFR, mL/min/1.73 m2 −4.80 (0.48) −5.00 (0.50) −4.60 (0.46) SURPASS-2 CSR (SEMA 2.0 mg value assumed to match TZP 5 mg)
BMI −3.94 (0.39) −4.66 (0.47) −2.79 (0.28) TZP,27 SEMA25
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BMI = body mass index; CSR = clinical study report; eGFR = estimated glomerular filtration rate; HbA1c = glycated hemoglobin; SEMA = semaglutide; TZP = tirzepatide; USD = US dollars.

Simulated patients in the modeling analysis were assumed to intensify therapy when A1c levels rose above 7.5%, in line with American Diabetes Association guidance (the impact of intensification at other A1c thresholds is investigated in sensitivity analyses, see below).30 On intensification, simulated patients stopped tirzepatide or semaglutide treatment and initiated basal insulin therapy. No further intensification steps were modeled as these would be the same in both treatment arms and have little effect on cost-effectiveness. On intensification, A1c was assumed to decrease by a mean (SD) of 0.8% (1.0%) for both the tirzepatide and semaglutide treatment arms, based on 12-month follow up observations from the 4T trial.31 All other risk factors, specifically body mass index (BMI), systolic blood pressure, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol, were assumed to return to baseline, with the exception of eGFR in which no change was applied upon insulin intensification. Long-term A1c progression was based on the published equation from the original UK Prospective Diabetes Study Outcomes Model 1 (UKPDS OM1) published by Clarke et al in 2003.32 Long-term eGFR progression was based on data published by Zoppini et al showing a progressive decrease in renal function over time, while all other risk factors were assumed to remain constant.33

In the modeling analysis, nausea rates associated with treatment initiation were applied in the first year of the simulation and were sourced from the SURPASS-2 and SUSTAIN FORTE trials.20,25 The percentages of patients experiencing nausea on tirzepatide were 19.2% (10 mg) and 22.1% (15 mg), vs 14.0% for patients on semaglutide 2.0 mg.20,25 Hypoglycemia rates were not included in the aITC and, in line with the very low rates of hypoglycemia reported in the SURPASS-2 and SUSTAIN FORTE trials, it was conservatively assumed the rates of nonsevere and severe hypoglycemia associated with tirzepatide and semaglutide treatments were zero for the modeling analysis. For basal insulin therapy, hypoglycemia event rates were taken from the baseline period of the REFLECT real-world study (Supplementary Table 3 (556.1KB, pdf) ).34

COST AND QUALITY-OF-LIFE UTILITIES

Pharmacy costs associated with tirzepatide and semaglutide treatment were based on 2022 wholesale acquisition cost values in the IBM Micromedex Red Book (May 2022). In addition, patients were assumed to receive 1,500 mg of metformin per day based on the minimum dose permitted by the SURPASS-2 trial protocol. Basal insulin usage was assumed to be 40 IU per day in line with the World Health Organization–defined daily dose estimate for insulin glargine.35 No self-monitoring of blood glucose costs were included in the base-case analysis. The annual costs for tirzepatide and semaglutide therapy were assumed to be USD 12,768 and USD 11,694, respectively (Supplementary Table 4 (556.1KB, pdf) ).

Costs associated with diabetes-related complications and adverse events were sourced primarily from Yang et al, in line with the approach used by Institute for Clinical and Economic Review in the 2022 review of tirzepatide, and supplemented with costs from published sources (Supplementary Table 5 (556.1KB, pdf) ).36-38 Costs were inflated to 2021 USD values using Medical Care inflation indices from the Bureau of Labor and Statistics.39 Quality-of-life utilities were sourced from the analysis of the ACCORD population published by Shao et al, in line with the Institute for Clinical and Economic Review analysis of tirzepatide.40,41 Additional utilities were taken from published sources (Supplementary Table 6 (556.1KB, pdf) ).42-46 These included utilities associated with nausea, the treatment administration device, weight loss, and BMI health state. Published utilities were combined using an additive approach to evaluate quality-adjusted life expectancy.

OTHER SETTINGS AND SENSITIVITY ANALYSES

Mortality risk was estimated using a hybrid approach with equations from the UKPDS Outcomes Model 2 (UKPDS OM2) to evaluate risk of death after diabetes-related complications and cause-subtracted US life tables for mortality from other causes.28 Future costs and clinical benefits were discounted at 3% annually.47 For the base-case analysis, 300,000 simulated patients were run through the model in each treatment arm in a first-order Monte Carlo simulation with sampling from distributions around patient characteristics and treatment effects. This number was established by stability analysis, which showed that for patient numbers above 200,000, total costs and quality-adjusted life-expectancy estimates in both treatment arms were within 0.15% of the median (indicating that random variation had a very modest impact on outcomes). Probabilistic sensitivity analyses were conducted using a nonparametric bootstrapping approach, in which samples from 1% of the simulated population (comprising 3,000 patients) were drawn 1,000 times from the full patient dataset at the end of the simulation. Sampling was performed with replacement and samples were drawn from distributions with a variable-specific mean and SD, bounded by clinically plausible limits, for cohort characteristics, probabilities, costs associated with diabetes-related complications, quality-of-life utilities, and regression equation parameters (coefficients). Subsequently, the population mean and CIs were calculated by rerunning the cost and quality-of-life estimators on each sampled population and generating a set of descriptive statistics.

A series of sensitivity analyses were performed to identify key drivers of outcomes in the base-case modeling analysis. Model inputs were changed around time horizon, discount rate, cohort characteristics, treatment effects, treatment intensification, and weight-loss or BMI utilities. In the Vadher et al aITC analysis, sensitivity analyses were conducted to test the robustness of the primary analysis.27 The outcomes of 2 of these sensitivity analyses were used to conduct sensitivity analyses in the present cost-effectiveness evaluation. In the aITC “Sensitivity analysis 2,” the results from the efficacy estimand of the full SURPASS-2 and SUSTAIN FORTE cohorts were used to project outcomes, whereas in “Sensitivity analysis 3,” the treatment estimand from the same cohorts was used.27

Results

BASE-CASE ANALYSIS

Tirzepatide 10 mg and 15 mg were associated with increased quality-adjusted life-expectancy compared with semaglutide 2.0 mg. In patients receiving tirzepatide 10 mg, quality-adjusted life-expectancy was projected to increase by 0.085 quality-adjusted life-years (QALYs) vs semaglutide 2.0 mg. In patients receiving tirzepatide 15 mg, quality-adjusted life-expectancy was 0.121 QALYs higher compared with semaglutide 2.0 mg. Direct medical costs associated with semaglutide 2.0 mg were projected to be USD 138,046 and were USD 5,990 and USD 6,617 higher in patients receiving tirzepatide 10 mg and 15 mg, respectively. Therefore, the incremental cost-effectiveness ratio (ICER) was USD 70,147 (tirzepatide 10 mg) and USD 54,699 (tirzepatide 15 mg) per QALY gained vs semaglutide 2.0 mg (Table 3). One of the reasons for increased costs on tirzepatide treatment was a longer duration of therapy, as improved A1c levels delayed the intensification to insulin therapy (at a threshold of 7.5%). For example, at the end of year 3, approximately 53.6% and 55.7% of patients remained on tirzepatide 10 mg and 15 mg prior to intensification, respectively, compared with 35.7% on semaglutide 2.0 mg.

TABLE 3.

Base-Case Results

TZP SEMA 2.0 mg Difference
TZP 10 mg vs SEMA 2.0 mg
    QALY 10.32 10.24 +0.085
    Costs, USD 144,036 138,046 +5,990
    ICER, USD per QALY gained 70,147
TZP 15 mg vs SEMA 2.0 mg
    QALY 10.36 10.24 +0.121
    Costs, USD 144,663 138,046 +6,617
    ICER, USD per QALY gained 54,699
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ICER = incremental cost-effectiveness ratio; QALY = quality-adjusted life year; SEMA = semaglutide; TZP = tirzepatide; USD = US dollars.

SENSITIVITY ANALYSES

One-way and multiway sensitivity analyses showed that tirzepatide remained cost-effective when most model input parameters were varied (Table 4, Supplementary Figures 1 and 2 (556.1KB, pdf) , and Supplementary Tables 7 and 8 (556.1KB, pdf) ). In almost all sensitivity analyses, the projected ICER remains below the USD 100,000 per QALY gained threshold. Varying risk-factor inputs showed A1c and BMI to be key drivers of cost-effectiveness. Applying only the difference in A1c between tirzepatide and semaglutide led to decreased incremental quality-adjusted life-expectancy gains for tirzepatide and resulted in increased ICERs of USD 99,301 (tirzepatide 10 mg) and USD 80,759 (tirzepatide 15 mg) per QALY gained. When the only BMI difference between tirzepatide and semaglutide was applied, and the treatment effects applied to all other risk factors were the same, the incremental quality-adjusted life-expectancy and incremental direct costs associated with tirzepatide decreased. The ICER associated with tirzepatide 10 mg increased to USD 147,783 per QALY gained vs semaglutide 2.0 mg, but the ICER associated with tirzepatide 15 mg decreased to USD 49,835 per QALY gained vs semaglutide 2.0 mg. Multiple treatment-switching and intensification scenarios were tested in sensitivity analyses to evaluate against the base case in which patients intensified to insulin therapy at an A1c threshold of 7.5%, but all produced ICERs in the range considered to be cost-effective. Using no weight-loss utilities in year 1 of the simulation with or without BMI utilities throughout the simulation resulted in increased ICERs for both tirzepatide 10 mg and 15 mg vs semaglutide 2.0 mg.

TABLE 4.

Selected Sensitivity Analysis Results

QALY Costs (USD) ICER (USD per QALY gained)
TZP SEMA 2.0 mg Difference TZP SEMA 2.0 mg Difference
TZP 10 mg vs SEMA 2.0 mg
    Base case 10.325 10.240 +0.085 144,036 138,046 +5,990 70,147
    5-year time horizon 3.397 3.332 +0.065 50,324 44,355 +5,969 91,835
    10-year time horizon 5.730 5.655 +0.074 76,091 70,211 +5,880 78,958
    Only HbA1c difference 10.303 10.240 +0.063 144,306 138,046 +6,261 99,301
    Only BMI difference 10.254 10.240 +0.014 140,175 138,046 +2,130 147,783
    Only HbA1c and BMI difference 10.342 10.240 +0.102 144,073 138,046 +6,027 58,821
    Continue TZP/SEMA with basal insulin therapy before basal-bolus insulin intensification 10.707 10.616 +0.091 211,435 205,564 +5,871 64,174
    Treatment intensification at 3 years 10.362 10.322 +0.040 147,249 144,568 +2,680 66,707
    Treatment intensification at 5 years 10.549 10.482 +0.066 163,484 158,966 +4,518 67,995
TZP 15 mg vs SEMA 2.0 mg
    Base case 10.360 10.240 +0.121 144,663 138,046 +6,617 54,699
    5-year time horizon 3.414 3.332 +0.082 50,642 44,355 +6,287 76,482
    10-year time horizon 5.751 5.655 +0.096 76,435 70,211 +6,224 64,974
    Only HbA1c difference 10.322 10.240 +0.082 144,696 138,046 +6,651 80,759
    Only BMI difference 10.279 10.240 +0.039 140,014 138 046 +1,968 49,835
    Only HbA1c and BMI difference 10.349 10.240 +0.110 144,384 138,046 +6,338 57,723
    Continue TZP/SEMA with basal insulin therapy before basal-bolus insulin intensification 10.737 10.616 +0.122 211,598 205,564 +6,034 49,631
    Treatment intensification at 3 years 10.378 10.322 +0.056 147,118 144,568 +2,549 45,606
    Treatment intensification at 5 years 10.579 10.482 +0.096 163,135 158,966 +4,169 43,204
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BMI = body mass index; HbA1c = glycated hemoglobin; ICER = incremental cost-effectiveness ratio; QALY = quality-adjusted life year; SEMA = semaglutide; TZP = tirzepatide; USD = US dollars.

Probabilistic sensitivity analyses showed that, at a willingness-to-pay threshold of USD 100,000 per QALY gained, tirzepatide 10 mg and 15 mg were likely to be cost-effective vs semaglutide 2.0 mg (Figure 1 and Supplementary Figures 3 and 4 (556.1KB, pdf) ). Acceptability curve analysis showed that there was an 81.1% likelihood that tirzepatide 10 mg would be cost-effective vs semaglutide 2.0 mg, whereas tirzepatide 15 mg was associated with an 82.6% likelihood at the same threshold.

FIGURE 1.

FIGURE 1

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Probabilistic Sensitivity Analysis Acceptability Curves for Tirzepatide 10 mg and 15 mg vs Semaglutide 2.0 mg

Discussion

The current study represents one of the few analyses evaluating the long-term cost-effectiveness of tirzepatide and the first to compare with the higher dose of semaglutide (2.0 mg). Long-term projections using the PRIME T2D model and based on treatment effects from an aITC indicate that tirzepatide 10 mg and 15 mg are projected to be cost-effective vs semaglutide 2.0 mg for the treatment of T2D from a health care payer perspective in the United States at the generally accepted threshold of USD 100,000 per QALY gained. In sensitivity analyses, key drivers of cost-effectiveness were determined to be the A1c and BMI benefits associated with tirzepatide. Tirzepatide 15 mg remained cost-effective vs semaglutide 2.0 mg over a broad range of one-way and multiway sensitivity analyses, whereas the 10 mg dose remained cost-effective in most sensitivity analyses, with the exception of when only the BMI difference between tirzepatide 10 mg and semaglutide 2.0 mg was applied (all other risk factors including A1c were identical), and when no weight-loss utilities in year 1 or BMI utilities were applied.

The higher direct costs projected in the present analysis are in part a result of the effectiveness of tirzepatide. In the base-case analysis, intensification to basal insulin was initiated when A1c increased to above 7.5%. Patients remained on tirzepatide for longer than patients treated with semaglutide 2.0 mg before intensification to insulin, resulting in increased costs due to a longer time receiving the higher-priced tirzepatide and a shorter time receiving the lower-priced basal insulin. In sensitivity analyses in which the treatment intensification threshold was increased to 8.5% or 9.5%, both the incremental quality-adjusted life-expectancy and incremental costs increased, further demonstrating this phenomenon. By contrast, in sensitivity analyses in which treatment intensification occurred at 3 or 5 years, relative to the base case, incremental quality-adjusted life-expectancy and incremental costs decreased. Whether treatment intensification was initiated due to reaching a specified A1c threshold or at a specific time, the ICER associated with tirzepatide 10 mg and 15 mg remained below the willingness-to-pay threshold of USD 100,000 per QALY gained. Additional sensitivity analyses explored the effects of patients continuing with tirzepatide or semaglutide treatment in conjunction with insulin therapy until intensification to basal-bolus insulin, and the ICER associated with tirzepatide 10 mg and 15 mg remained below the USD 100,000 per QALY gained willingness-to-pay threshold and was less than the ICER projected in the respective base cases.

Sensitivity analyses also showed A1c and BMI benefits associated with tirzepatide to be key drivers of clinical outcomes and cost-effectiveness. Projecting cost-effectiveness outcomes of tirzepatide vs the higher dose of semaglutide 2.0 mg is key to understanding the value of tirzepatide within the entire class of antihyperglycemic agents. Although there are no published cost-effectiveness data comparing the newly approved semaglutide 2.0 mg against other available antihyperglycemic treatments, semaglutide 0.5 mg and 1.0 mg have been shown to be cost-effective against numerous other GLP-1 RAs, highlighting semaglutide as an important comparator for which the cost-effectiveness of tirzepatide should be measured against.48 This study further adds to the body of published evidence regarding long-term cost-effectiveness of tirzepatide vs semaglutide for which tirzepatide was also found to be cost-effective compared with semaglutide 1.0 mg.26 Based on the results of the aITC showing the lowest dose of tirzepatide (5 mg) and the highest dose of semaglutide (2.0 mg) were not significantly different, tirzepatide 5 mg was not included in the evaluation as a nonsignificant low-dose vs high-dose comparison would have provided little meaningful information for formulary decision-makers.

The present analysis reported incremental quality-adjusted life-expectancy benefits of 0.085 QALYs and 0.121 QALYs for tirzepatide 10 and 15 mg, respectively, over semaglutide 2.0 mg. In the context of a large health plan, these could translate to meaningful benefits. For example, based on the Centers for Disease Control and Prevention diabetes prevalence estimates, it would be expected that there are around 1.28 million patients with diabetes among Kaiser Permanente’s 12.6 million members. Adding 0.085 QALYs for each patient would add around 109,000 QALYs to the population. This estimate goes up to an additional 155,000 QALYs, assuming a benefit of 0.121 QALYs per patient with T2D, representing a potentially significant health benefit at the population level.

This cost-effectiveness evaluation has a long-term (50 year) time horizon for the base-case analysis, in line with American Diabetes Association’s guidelines to capture changes in end-stage complication risk associated with earlier changes in risk factors, such as A1c.49 The analysis takes the perspective of a health care payer in general, rather than that of an individual health plan. In this context, it is important to note that if all health plans ascribed to the same willingness-to-pay thresholds and supported treatment to manage risk factors, such as A1c and BMI, then the long-term benefits would also be shared across all health plans in the US setting.

The present analysis included numerous sensitivity analyses in which a wide range of model inputs were varied to show the cost-effectiveness of tirzepatide compared with semaglutide 2.0 mg. Shortening the time horizons to 5 and 10 years increased the ICER associated with tirzepatide 10 mg or 15 mg vs semaglutide 2.0 mg, but for both doses of tirzepatide and both time horizons the ICER remained cost-effective and under the USD 100,000 per QALY gained willingness-to-pay threshold. This is despite the differences in the proportion of patients that remained on initial therapy (tirzepatide 10 mg or 15 mg or semaglutide 2.0 mg) over the first 5 years of the analysis, which would be expected to have a greater impact on outcomes over the shorter time horizon.

Any long-term modeling analysis is inherently associated with a degree of uncertainty. However, every effort was made to minimize that uncertainty in the present analysis. The model used (the PRIME T2D Model) was recently published and has been internally and externally validated.28 Numerous sensitivity analyses were performed around key model inputs and assumptions, and tirzepatide remained cost-effective under the majority of scenarios. The treatment effects applied in the modeling analysis were sourced from an aITC.27 An indirect treatment comparison was required, as no head-to-head comparison of tirzepatide with semaglutide 2.0 mg has been published. In the base-case analysis cohort, characteristics were sourced from the SURPASS-2 refined population that consisted of patients from the SURPASS-2 population that fulfilled the inclusion criterion of A1c in the SUSTAIN FORTE trial. To mitigate the uncertainty that these inputs may introduce, sensitivity analyses were conducted using the full SURPASS-2 cohort with or without the implementation of treatment effects derived from sensitivity analyses presented in the indirect treatment comparison. Compared with the SURPASS refined cohort, the full SURPASS-2 cohort had a lower mean baseline A1c (8.80% vs 8.28%, respectively). Analyses using the full SURPASS-2 cohort showed that both doses of tirzepatide remained cost-effective vs semaglutide 2.0 mg in all analyses in which the full SURPASS-2 cohort was used, showing the projected outcomes not to be reliant on the use of the refined population or on the treatment effects calculated from only the refined population. In particular, in the comparison of tirzepatide 10 mg vs semaglutide 2.0 mg, using the full SURPASS-2 cohort resulted in a reduced ICER compared with the base case (USD 60,240 vs USD 70,147 per QALY gained, respectively).

LIMITATIONS

A potential limitation of the present analysis is that risk adjustments based on data from cardiovascular outcomes trials (CVOTs) were not integrated for tirzepatide or semaglutide treatments. Semaglutide 0.5 mg and 1.0 mg have been associated with cardio-protective effects in SUSTAIN 6, whereas the CVOT for tirzepatide is still ongoing.50,51 In a safety meta-analysis of the SURPASS 1-5 trials, tirzepatide did not show cardiovascular harm and a trend toward cardiovascular benefit was reported in SURPASS-4.52,53 In the present analysis, cardiovascular outcomes were modeled based on conventional risk factors (eg, A1c, BMI) and risk equations, and no cardiovascular risk from CVOTs were applied. To conduct a cost-effectiveness evaluation using cardiovascular risk adjustment for 1 comparator but not the other would run a risk of biasing the analysis. It may be an interesting avenue for future research to revisit the cost-effectiveness analysis by incorporating SURPASS-CVOT findings, once available, and SUSTAIN 6 results.

Conclusions

The present analysis is the first published study to evaluate the long-term cost-effectiveness of tirzepatide 10 mg and 15 mg vs semaglutide 2.0 mg for the management of T2D. Based on long-term projections with the PRIME T2D Model using the treatment estimates from a published aITC, tirzepatide 10 mg and 15 mg were shown to be associated with higher quality-adjusted life-expectancy and increased direct costs vs semaglutide 2.0 mg. In the United States, for the treatment of patients with T2D, tirzepatide 10 mg and 15 mg doses were likely to be cost-effective vs semaglutide 2.0 mg with ICERs of less than USD 100,000 per QALY gained. This economic analysis may serve as valuable evidence to guide formulary decision-making for new treatments, such as tirzepatide, for the management of T2D in the United States.

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