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Tirzepatide versus insulin glargine as second-line or third-line therapy in type 2 diabetes in the Asia-Pacific region: the SURPASS-AP-Combo trial

Nature Medicine volume 29, pages 1500–1510 (2023)Cite this article

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Abstract

Tirzepatide is a once-weekly GIP/GLP-1 receptor agonist. In this phase 3, randomized, open-label trial, insulin-naive adults (≥18 years of age) with type 2 diabetes (T2D) uncontrolled on metformin (with or without a sulphonylurea) were randomized 1:1:1:1 to weekly tirzepatide 5 mg, 10 mg or 15 mg or daily insulin glargine at 66 hospitals in China, South Korea, Australia and India. The primary endpoint was non-inferiority of mean change in hemoglobin A1c (HbA1c) from baseline to week 40 after treatment with 10 mg and 15 mg of tirzepatide. Key secondary endpoints included non-inferiority and superiority of all tirzepatide doses in HbA1c reduction, proportions of patients achieving HbA1c < 7.0% and weight loss at week 40. A total of 917 patients (763 (83.2%) in China) were randomized to tirzepatide 5 mg (n = 230), 10 mg (n = 228) or 15 mg (n = 229) or insulin glargine (n = 230). All doses of tirzepatide were non-inferior and superior to insulin glargine for least squares mean (s.e.) reduction in HbA1c from baseline to week 40: tirzepatide 5 mg, 10 mg and 15 mg, −2.24% (0.07), −2.44% (0.07) and −2.49% (0.07), respectively, and insulin glargine, −0.95% (0.07), with a treatment difference ranging from −1.29% to −1.54% (all P < 0.001). Proportions of patients achieving HbA1c < 7.0% at week 40 were greater in tirzepatide 5-mg (75.4%), 10-mg (86.0%) and 15-mg (84.4%) groups compared to insulin glargine (23.7%) (all P < 0.001). All tirzepatide doses led to superior body weight reduction at week 40: tirzepatide 5 mg, 10 mg and 15 mg, −5.0 kg (−6.5%), −7.0 kg (−9.3%) and −7.2 kg (−9.4%), respectively, compared to insulin glargine, 1.5 kg (+2.1%) (all P < 0.001). The most common adverse events with tirzepatide were mild to moderate decreased appetite, diarrhea and nausea. No severe hypoglycemia was reported. Tirzepatide demonstrated superior reductions in HbA1c versus insulin glargine in an Asia-Pacific, predominately Chinese, population with T2D and was generally well tolerated. ClinicalTrials.gov registration: NCT04093752.

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Fig. 1: Trial profile.
Fig. 2: HbA1c, HbA1c target attainment, FSG and seven-point SMBG in the mITT population.
Fig. 3: Body weight, weight loss target attainment, BMI and fasting lipid profile in the mITT population.

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Data availability

Data from the analyses in this study cannot be publicly available due to the sponsor’s (Eli Lilly and Company) contractual obligations. Eli Lilly provides access to all individual participant data collected during the trial, after anonymization, with the exception of pharmacokinetic or genetic data. Data are available to request 6 months after the indication studied has been approved in the United States and the European Union and after primary publication acceptance, whichever is later. No expiration date of data requests is currently set once data are made available. Access is provided after a proposal has been approved by an independent review committee identified for this purpose and after receipt of a signed data sharing agreement. Data and documents, including the study protocol, statistical analysis plan, clinical study report and blank or annotated case report forms, will be provided in a secure data sharing environment. For details on submitting a request, see the instructions provided at https://vivli.org/.

Code availability

No customer code was used for data analysis in this study.

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Acknowledgements

This study was funded by Eli Lilly and Company. The study sponsor had a role in the study design, data collection, data analysis, interpretation of data, writing of the report and in the decision to submit the paper for publication. Medical writing assistance in the preparation of this article was provided by M. Dyson on behalf of Rude Health Consulting, J. Burrell (Rude Health Consulting) and C. Zeng (Eli Lilly and Company) and was funded by Eli Lilly and Company.

Author information

Authors and Affiliations

  1. Peking University People’s Hospital, Beijing, China

    Leili Gao & Linong Ji

  2. Severance Hospital, Yonsei University Health System, Seoul, South Korea

    Byung Wan Lee

  3. BSES Municipal General Hospital, Mumbai, India

    Manoj Chawla

  4. Paratus Clinical Research Western Sydney, Sydney, New South Wales, Australia

    Joshua Kim

  5. Eli Lilly Suzhou Pharmaceutical Co. Ltd., Shanghai, China

    Li Huo, Liying Du & Yan Huang

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Contributions

L.J. led the design, conduct and analysis of the clinical study. L.G., B.L., M.C. and J.K. contributed to the acquisition of data. L.D. led the data analysis, and all authors participated in data interpretation. All authors confirm that they had full access to the complete study data, took part in the development of the manuscript and accept responsibility to submit for publication.

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Correspondence to Linong Ji.

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Competing interests

L.H., L.D. and Y.H. are employees of Eli Lilly and Company. L.J. reports receiving consulting and lecture fees from Eli Lilly and Company, Novo Nordisk, Merck, Bayer, Sanofi-Aventis, Roche, Merck Sharp & Dohme, Metronics, AstraZeneca, Boehinger Ingelheim and Abbott. L.J. and L.G. received a research grant for this study from Eli Lilly and Company. M.C. reports having speaker contracts with Novo Nordisk, Sanofi, Biocon, Cipla, USV Ltd. and Abbott. The other authors declare no competing interests.

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Extended data

Extended Data Fig. 1 Change from baseline in HbA1c (a) and proportion of patients achieving HbA1c < 7.0% (b) at week 40 in the full analysis set.

LSMean changes from baseline in HbA1c were estimated using an ANCOVA with return-to-baseline multiple imputation for missing values at week 40 in patients who received at least 1 dose of study drug (5 mg, N = 230; 10 mg, N = 228; 15 mg, N = 229; insulin glargine, N = 220); statistical tests for 10 mg and 15 mg were two sided at a significance level of 0.025, statistical tests for 5 mg were two sided at a significance level of 0.05. Proportion of patients achieving HbA1c < 7.0% was estimated using logistic regression analysis with return-to-baseline multiple imputation for missing values at week 40 in patients who received at least 1 dose of study drug (5 mg, n = 230; 10 mg, n = 228; 15 mg, n = 229; insulin glargine, n = 220); all statistical tests were two sided at a significance level of 0.05. Error bars indicate SE. ANCOVA, analysis of covariance; HbA1c, glycated hemoglobin; LSMean, least-square mean; n, number of patients achieving target with missing value imputed by return-to-baseline multiple imputation; N, number of patients who were randomized and received at least 1 dose of study drug; SE, standard error.

Extended Data Fig. 2 Change from baseline in bodyweight at week 40 in the full analysis set.

Changes from baseline in bodyweight were estimated using an ANCOVA with return-to-baseline multiple imputation for missing values at week 40 in patients who received at least 1 dose of study drug (5 mg, N = 230; 10 mg, N = 228; 15 mg, N = 229; insulin glargine, N = 220); statistical tests for 10 mg and 15 mg were two sided at a significance level of 0.025, statistical tests for 5 mg were two sided at a significance level of 0.05. Data presented are LSMean (SE). Error bars indicate SE. ANCOVA, analysis of covariance; LSMean, least-square mean; N, number of patients who were randomized and received at least 1 dose of study drug; SE, standard error.

Extended Data Fig. 3 Incidence and severity of nausea, vomiting, diarrhea and decreased appetite over time.

Notes: dotted areas indicate the tirzepatide dose escalation period. Severity is indicated by color: green (mild); orange (moderate); red (severe). TZP, tirzepatide.

Extended Data Fig. 4 P-amylase (a) and lipase (b) levels over time.

Data presented are estimate mean (SE). Error bars indicate SE. Baseline values were calculated using an ANOVA, post-baseline measures were calculated from an MMRM, all statistical tests were two sided at a significance level of 0.05. Normal reference values: p-amylase (13–53 IU/L); lipase (13–60 IU/L). ANOVA, analysis of variance; MMRM, mixed model for repeated measures; No., number of patients with baseline and post-baseline value at the specified time point; p-amylase, pancreatic amylase; TZP, tirzepatide; SE, standard error; SFU, safety follow up.

Extended Data Fig. 5 Change in waist circumference over time.

Data presented are LSMean (SE). Error bars indicate SE. LSMean, least-square mean; No., number of patients with baseline and post-baseline value at the specified time point; SE, standard error.

Extended Data Fig. 6 Percent changes in ALT (a) and AST (b) over time.

Data presented are estimate mean (SE). Error bars indicate SE. Baseline values were calculated using an ANOVA, post-baseline measures were calculated from an MMRM, all statistical tests were two sided at a significance level of 0.05. ANOVA, analysis of variance; ALT, alanine aminotransferase; AST, aspartate aminotransferase; MMRM, mixed model for repeated measures; No., number of patients with baseline and post-baseline value at the specified time point; TZP, tirzepatide; SE, standard error; SFU, safety follow up.

Extended Data Fig. 7 Subgroup analysis of change in HbA1c from baseline to week 40 according to baseline oral anti-hyperglycemic medication use and enrolment in China versus out of China.

ETD and CIs in HbA1c at week 40 were estimated using an MMRM without missing-value imputation in the patients who received at least 1 dose of study drug (5 mg, N = 230; 10 mg, N = 228; 15 mg, N = 229; insulin glargine, N = 220); all statistical tests were two sided at a significance level of 0.05 and no adjustments were made for multiplicity. Data presented are LSMean. Error bars indicate 95% CI. P values represent treatment-by-subgroup interaction at week 40. ETD, estimated treatment difference; CI, confidence interval; CHN, China; HbA1c, glycated hemoglobin; LSMean, least-square mean; MMRM, mixed model for repeated measures; N, number of patients who were randomized and received at least 1 dose of study drug; OAM, oral anti-hyperglycemic medication; OCHN, out of China; SU, sulphonylurea; TZP, tirzepatide.

Extended Data Fig. 8 Subgroup analysis of change in bodyweight from baseline to week 40 according to baseline oral anti-hyperglycemic medication use and enrolment in China versus out of China.

ETD and CIs in bodyweight at week 40 were estimated using an MMRM without missing-value imputation in the in patients who received at least 1 dose of study drug (5 mg, N = 230; 10 mg, N = 228; 15 mg, N = 229; insulin glargine, N = 220); all statistical tests were two sided at a significance level of 0.05 and no adjustments were made for multiplicity. Data presented are LSMean. Error bars indicate 95% CI. P values represent treatment-by-subgroup interaction at week 40. ETD, estimated treatment difference; CI, confidence interval; CHN, China; LSMean, least-square mean; MMRM, mixed model for repeated measures; N, number of patients who were randomized and received at least 1 dose of study drug; OAM, oral anti-hyperglycemic medication; OCHN, out of China; SU, sulphonylurea; TZP, tirzepatide.

Extended Data Fig. 9 SURPASS-AP-Combo trial design.

FBG, fasting blood glucose; QW, once weekly; QD, once daily; SU, sulfonylurea. a Stable doses of metformin (metformin ≥1000 mg/day and no more than the maximum approved dose per country-specific label) and/or a sulfonylurea for 2 months prior to Visit 1, and during the screening/lead-in Period. b The initial dose of insulin glargine was 6 IU/day for patients who had an average FBG concentration of ≥7.8 mmol/L (140 mg/dL). The initial dose of insulin glargine for patients with an average FBG concentration of <7.8 mmol/L (<140 mg/dL) might be reduced by 1-2 IU/day at the investigator’s discretion. Note: Patients titrated insulin glargine dose in a weekly manner and made the dose decision with the investigator for the first 8 weeks (phone or clinic visit). From week 8 to week 16 patients continued the titration by a phone consultation or clinic visit every other week. It was expected that the insulin dose stayed relatively stable from week 16 onwards.

Extended Data Fig. 10 Graphical multiple-testing procedure for the primary and key secondary efficacy endpoints.

HbA1c, glycated hemoglobin; TZP, tirzepatide.

Supplementary information

Supplementary Information

The file contains Supplementary Tables 1–10; criteria for severe, persistent hyperglycemia; and a complete list of eligibility criteria from the protocol.

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Gao, L., Lee, B.W., Chawla, M. et al. Tirzepatide versus insulin glargine as second-line or third-line therapy in type 2 diabetes in the Asia-Pacific region: the SURPASS-AP-Combo trial. Nat Med 29, 1500–1510 (2023). https://doi.org/10.1038/s41591-023-02344-1

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