TIRZEPATIDE (COAGONISTA GIP/GP1): DESARROLLO CLINICO SURPASS
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Ponencia Congreso Nacional SED (Sociedad Española Diabetes) 16 junio 2021: Mesa nuevos Ensayos Clínicos en Diabetes
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TIRZEPATIDE (COAGONISTA GIP/GP1): DESARROLLO CLINICO SURPASS
- 3. CONFLICTO DE INTERESES Ensayos clínicos Novonordisk, Sanofi, Astra Zeneca, Pzifer, Lilly, Merck, Lexicon, FPS,Hanmi, Janssen Boehringer, Takeda, Roche, Theracos, LeeGanz Advisory board Novonordisk, Lilly, MSD, Boehringuer, Astra, Sanofi, Abbot Ponente Sanofi, Novonordisk, Astra Zeneca, Roche, Lilly, Boehringher, MSD, Ferrer, Janssen, Abbot
- 4. Metabolic health: a priority for the post-pandemic era •The Lancet Diabetes & EndocrinologyPublished:March 04, 2021DOI:https://doi.org/10.1016/S2213-8587(21)00058-9 Avoiding the Coming Tsunami of Common, Chronic Disease: What the Lessons of the COVID-19 Pandemic Can Teach Us Robert M. Califf Originally published6 Apr 2021https://doi.org/10.1161/CIRCULATIONAHA.121.053461Circulation.
- 5. Pacientes jóvenes (DM1 <35 o DM2 <50 años) duración de DM <10 años sin otros factores de riesgo Duración DM>10 años Sin daño a órganos diana Sin factores de riesgo adicional @CristobMorales CATEGORIAS DE RIESGO CARDIOVASCULAR EN PACIENTES CON DIABETES(1) & The Contiuum CV Risk ECV Establecida Ó Daño órgano diana Proteinuria Insuficiencia Renal eGFR <30 ml/min/1.73 m2 Hipertrofia ventricular izquierda Retinopatía Ó 3 ó más Factores de Riesgo mayores Hipertensión Dislipidemia Tabaquismo Obesidad Edad >65 Ó DM de inicio temprano o DM de larga duración (>20 años) RIESGO MODERADO ALTO RIESGO MUY ALTO RIESGO
- 7. TIRZEPATIDE (coAgonista GLP1/GIP): Desarrollo clínico SURPASS en DM2 Cristóbal Morales INTRO: COAGONISTA GLP1/GIP RESULTADOS F2 F3: SURPASS CONCLUSIONES CLINICAS @CristobMorales
- 9. Los agonistas del receptor del GLP-1 tienen efectos multifactoriales más allá del control de la glucemia Contractilidad Función cardíaca Supervivencia de los miocitos Cardioprotección Utilización de glucosa Vasodilatación Recaptación de glucosa Función del ventrículo izquierdo Presión arterial Frecuencia cardíaca Producción de PNA Corazón Secreción de insulina Biosíntesis de insulina Secreción de glucagón Proliferación de células beta Supervivencia de las células beta Apoptosis Páncreas Osteogénesis Masa ósea Hueso Vaciamiento gástrico Motilidad digestiva Tubo digestivo Producción endógena de glucosa Esteatosis Hígado Diuresis Natriuresis Albuminuria Inflamación renal Riñón Ingesta de alimentos Ingesta de agua Memoria y capacidad de aprender Neuroprotección Inflamación Conducta de gratificación Palatabilidad Apoptosis Cerebro Sensibilidad a la insulina Recaptación de glucosa Músculo arGLP-1, agonista del receptor del péptido similar al glucagón 1; PNA, péptido natriurético auricular. 1. Müller TD, et al. Mol Metab. 2019;30:72-130; 2. Tsimihodimos V, et al. Eur J Pharmacol. 2018;818:103‐109. Efectos de los arGLP-1
- 11. Stomach • ↓ Gastric Emptying Skeletal Muscle • ↑ Insulin Sensitivity • ↑ Metabolic Flexibility • ↓ Ectopic Lipid Accumulation Subcutaneous White Adipose Tissue • ↑ Insulin Sensitivity • ↑ Lipid Buffering Capacity • ↑ Blood Flow • ↑ Storage Capacity • ↓ Proinflammatory Immune Cell Infiltration Liver • ↑ Insulin Sensitivity • ↓ Hepatic Glucose Production • ↓ Ectopic Lipid Accumulation Pancreas • ↑ Insulin • ↓ Glucagon Systemic • ↓ Hyperglycemia Systemic • ↓ Hyperglycemia, Dietary Triglyceride Pancreas • ↑ Insulin • ↑ Glucagon Central Nervous System Skeletal Muscle Liver Subcutaneous White Adipose Tissue Pancreas Stomach Central Nervous System • ↑ Satiety • ↓ Food Intake • ↑ Nausea • ↓ Body Weight Central Nervous System • ↓ Food intake • ↓ Nausea • ↓ Body weight GLP-1 Receptor Agonism GIP Receptor Agonism GIP Receptor Agonism GLP-1 Receptor Agonism Indirect Action Can next generation incretin therapies combine GLP-1R and GIPR-mediated actions? Adapted from: Samms RJ, et al. Trends Endocrinol Metab. 2020;31(6):410-421
- 12. GIP = glucose-dependent insulinotropic polypeptide; GLP-1 = glucagon-like peptide-1. Coskun T, et al. Mol Metab. 2018;18:3-14. Tirzepatide: Dual GIP/GLP-1 Receptor Agonist Company Confidential © 2021 Eli Lilly and Company Tirzepatide is a multi-functional peptide based on the native GIP peptide sequence, modified to bind to both GIP and GLP-1 receptors Tirzepatide is a 39 amino acid linear peptide and includes a C20 fatty diacid moiety In vitro, it has higher potency to native GIP and is less potent to native GLP-1 Tirzepatide has a mean half-life of ~5 days (116.7 h), enabling once-weekly dosing
- 13. In vitro, tirzepatide has a potency/affinity for the GIP receptor similar to native GIP Potency/affinity for the GLP-1 receptor is slightly weaker compared with native GLP-1 Tirzepatide potency and affinity for GIP and GLP-1 receptors Coskun T, et al. Mol Metab 2018;18:3-14 cAMP activation (%) 0 20 40 60 80 100 120 -14 -13 -12 -11 -10 -9 -8 -7 log [Treatment] M GIP TZP GIP-R cAMP activation (%) 0 20 40 60 80 100 120 -14 -13 -12 -11 -10 -9 -8 -7 log [Treatment] M GLP1-R GLP-1 TZP
- 14. TIRZEPATIDE (coAgonista GLP1/GIP): Desarrollo clínico SURPASS en DM2 Cristóbal Morales INTRO: COAGONISTA GLP1/GIP RESULTADOS F2 F3: SURPASS CONCLUSIONES CLINICAS @CristobMorales
- 18. -3 -2 -1 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 Week Study design Randomization: N=318 Primary endpoint End of treatment Screening Lead-in Follow-up Frias JP, et al. Lancet 2018;392(10160):2180-2193 Key objective: Explore the dose-response relationship of different doses of tirzepatide and collect initial efficacy and safety data in adults with T2D (HbA1c 7.0–10.5%) TZP 5 mg QW TZP 1 mg QW TZP 10 mg QW TZP 15 mg QW 5 mg 5 mg 10 mg PL QW DU 1.5 mg QW
- 20. TIRZEPATIDE (coAgonista GLP1/GIP): Desarrollo clínico SURPASS en DM2 Cristóbal Morales INTRO: COAGONISTA GLP1/GIP RESULTADOS F2 F3: SURPASS CONCLUSIONES CLINICAS @CristobMorales
- 22. SURPASS4 15RAND 7SF SURPASS5 12RAND 5SF SURPASS6 11 RANDO 3SF SURPASS CVOT 38 RAND +12SF UPDATE: 1 mayo21 @CristobMorales
- 23. 10 JUNIO 2019 PRIMERA DOSIS TIRZEPATIDE EN HUVM @CristobMorales
- 24. @CristobMorales
- 25. Phase 3 doses Tirzepatide: Dosing in Phase 3 clinical program Frias JP, et al. Diabetes Obes Metab 2020;22(6):938-946; Eli Lilly and Company. Diabetes – 2019 Business Update 5 mg Proportion of patients with nausea (%) 2.5 mg 7.5 mg 10 mg 12.5 mg 15 mg 0 5 10 15 20 0 4 8 12 16 20 24 28 32 Simulation of Dose Escalation Model predicts incidence of nausea with slow, step-wise titration and supports improved tolerability profile from Phase 2 to Phase 3 Weeks Step through doses (2.5 mg increments) allow gradual introduction and improved tolerability profile Informed by Phase 2 studies and exposure modeling 0 4 8 12 16 20 24 TZP 5 mg QW TZP 10 mg QW TZP 15 mg QW 2.5 mg 5 mg 7.5 mg 2.5 mg 2.5 mg 5 mg 7.5 mg 10 mg 12.5 mg Weeks 5 mg 10 mg 15 mg
- 26. The SURPASS Program: Studies of Tirzepatide in People With T2D Individual clinicaltrials.gov pages for each study are available in the slide notes. CVD = cardiovascular disease. Eli Lilly and Company. Diabetes – 2019 Business Update. Initiation: Dec 2018 Global submissions 2019 2022 2021 2020 SURPASS-4: vs glargine (increased CV risk) SURPASS-3: vs degludec SURPASS-1: monotherapy SURPASS-5: add-on to basal insulin SURPASS-2: vs semaglutide SURPASS-CVOT SURPASS-6: vs prandial insulin
- 27. SURPASS-1: Monotherapy A study to evaluate safety and efficacy of tirzepatide (5, 10, and 15 mg) in participants with T2D who are naïve to injectable therapy, not controlled with diet and exercise alone, and have not been treated with any oral antidiabetic medication during the 3 months preceding to the start of the study (HbA1c 7.0–9.5%) SURPASS-1. Available at: https://clinicaltrials.gov/ct2/show/NCT03954834. Accessed May 2020 0 4 8 12 16 20 24 28 32 36 40 44 Week -3 -2 -1 Randomization (Estimated enrolment: N=472) Screening Lead-in Follow-up TZP 5 mg QW PL QW TZP 10 mg QW TZP 15 mg QW Primary endpoint End of treatment 2.5 mg 5 mg 7.5 mg 2.5 mg 2.5 mg 5 mg 7.5 mg 10 mg 12.5 mg
- 28. SURPASS 1 Lilly's tirzepatide significantly reduced A1C and body weight in people with type 2 diabetes
- 29. SURPASS-2: H2H versus semaglutide 1 mg A study comparing the safety and efficacy of tirzepatide (5 mg, 10 mg, and 15 mg) versus semaglutide QW as add-on therapy to metformin in patients with T2D (HbA1c ≥7.0% and ≤10.5%) SURPASS-2. Available at: https://clinicaltrials.gov/ct2/show/NCT03987919. Accessed May 2020 0 4 8 12 16 20 24 28 32 36 40 44 Week -3 -2 -1 Screening Lead-in Follow-up TZP 5 mg QW Semaglutide 1 mg QW TZP 10 mg QW TZP 15 mg QW Randomization (Estimated enrolment: N=1872) Primary endpoint End of treatment 2.5 mg 5 mg 7.5 mg 2.5 mg 2.5 mg 5 mg 7.5 mg 10 mg 12.5 mg
- 30. SURPASS 2 (H2H SEMA) Tirzepatide achieved superior A1C and body weight reductions across all three doses compared to injectable semaglutide in adults with type 2 diabetes | Eli Lilly and Company
- 31. SURPASS-3: H2H versus insulin degludec Open-label study comparing the safety and efficacy of tirzepatide (5, 10, and 15 mg) vs insulin degludec in participants with T2D who have inadequate glycemic control on stable doses of metformin with or without an SGLT-2i (HbA1c ≥7.5% and ≤10.5%) SURPASS-3. Available at: https://clinicaltrials.gov/ct2/show/NCT03882970. Accessed May 2020 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 Week -3 -2 -1 Screening Lead-in Follow-up TZP 5 mg QW Insulin degludec QW TZP 10 mg QW TZP 15 mg QW 2.5 mg 5 mg 7.5 mg 2.5 mg 2.5 mg 5 mg 7.5 mg 10 mg 12.5 mg Randomization (Estimated enrolment: N=1420) Primary endpoint End of treatment Initial titration
- 32. SURPASS 3 (H2H IDEG) Tirzepatide achieved superior A1C and body weight reductions across all three doses compared to injectable semaglutide in adults with type 2 diabetes | Eli Lilly and Company
- 33. SURPASS-5: Tirzepatide add-on to insulin glargine A study to assess the safety and efficacy of tirzepatide (5, 10, and 15 mg) in participants with T2D receiving insulin glargine with or without metformin (HbA1c ≥7.0% and ≤10.5%) SURPASS-5. Available at: https://clinicaltrials.gov/ct2/show/NCT04039503. Accessed May 2020 0 4 8 12 16 20 24 28 32 36 40 44 Week -3 -2 -1 Randomization (Estimated enrolment: N=472) Screening Lead-in Follow-up TZP 5 mg QW PL QW TZP 10 mg QW TZP 15 mg QW Primary endpoint End of treatment 2.5 mg 5 mg 7.5 mg 2.5 mg 2.5 mg 5 mg 7.5 mg 10 mg 12.5 mg
- 34. SURPASS 5 (TRAS BASAL)
- 35. SURPASS-4: H2H versus insulin glargine Open-label study comparing safety and efficacy of tirzepatide (5, 10, and 15 mg) vs insulin glargine in participants with T2D on stable dose of at least 1 and no more than 3 OAMs (metformin, SGLT-2i, and/or SU) and increased cardiovascular risk (HbA1c ≥7.5% and ≤10.5%) SURPASS-4. Available at: https://clinicaltrials.gov/ct2/show/NCT03730662. Accessed May 2020 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 Week -3 -2 -1 108 104 52 Screening Lead-in Follow-up TZP 5 mg QW TZP 10 mg QW TZP 15 mg QW 2.5 mg 5 mg 7.5 mg 2.5 mg 2.5 mg 5 mg 7.5 mg 10 mg 12.5 mg Randomization (Estimated enrolment: N=1878) End of treatment Insulin glargine QD Primary endpoint
- 36. SURPASS-4: H2H versus insulin glargine SURPASS-4. Available at: https://clinicaltrials.gov/ct2/show/NCT03730662. Accessed May 2020
- 37. SURPASS CVOT: Versus dulaglutide 1.5 mg A study to compare the effect of tirzepatide (maximum tolerated dose) vs dulaglutide 1.5 mg on major cardiovascular events in participants with T2D with established CVD SURPASS-CVOT. Available at: https://clinicaltrials.gov/ct2/show/NCT04255433. Accessed May 2020 0 4 8 12 16 20 24 28 32 36 40 44 Week -2 -1 Screening Randomization (Estimated enrolment: N=12,500) (≥1615 events) DU 1.5 mg QW Up to TZP 15 mg QW 2.5 mg 5 mg 7.5 mg 10 mg 12.5 mg 15 mg Dose Escalation Period Maintenance Period
- 38. GPGN-SURPASS CVOT SCREENING ABIERTO 33+12 I8F-MC-GPGN -The Effect of Tirzepatide versus Dulaglutide on Major Adverse Cardiovascular Events in Patients with Type 2 Diabetes (SURPASS-CVOT) @CristobMorales
- 39. A Randomized, Phase 3, Open-label Trial Comparing the Effect of the Addition of Tirzepatide Once Weekly versus Insulin Lispro (U100) Three Times Daily in Participants with Type 2 Diabetes Inadequately Controlled on Insulin Glargine (U100) with or without Metformin (SURPASS-6)Protocol Number:I8F-MC-GPHD GPHD-SURPASS 6 VS LISPRO SCREENING ABIERTO 11+3 CUALQUIER INSULINA BASAL ESTABLES 3M (>30UI y >0,3 UI/KG/DÍA) CON O SIN ADOS: MET /SU /DPP4 (NO SGLT2) A1C 7,5-11% IMC ≥ 23 Kg/m2 NO RETINOPATÍA NO PROLIFERATIVA QUE REQUIERA TRATAMIENTO, NO RP PROLIFERATIVA O EDEMA MACULAR @CristobMorales
- 44. @CristobMorales
- 45. TIRZEPATIDE (coAgonista GLP1/GIP): Desarrollo clínico SURPASS en DM2 Cristóbal Morales INTRO: COAGONISTA GLP1/GIP RESULTADOS F2 F3: SURPASS CONCLUSIONES CLINICAS @CristobMorales
- 46. @CristobMorales F1 >>> F2>>> F3>>> APROBACIÓN
- 47. MédicoSAURIOS RESISTENTES A LA EVOLUCIÓN @CristobMorales
- 49. @CristobMorales
- 50. DESDE EL INICIO TRATAMIENTO DM2 PREVENCION COMPLICACIONES MICROVASCULARES PREVENCION OF ENFERMEDAD CARDIOVASCULAR Driven by A1c reduction irrespectively of tratment regimen Driven by drug strategy (agents) more than A1c reduction @CristobMorales “PIENSA EN MICRO, PIENSA EN MACRO… Y NO OLVIDES EL PESO “
- 52. CUIDAR
Editor's Notes
- Abbreviations GIP = glucose-dependent insulinotropic polypeptide; GLP-1 = glucagon-like peptide-1. Speaker notes This is the molecule now in phase 3 of development Tirzepatide (LY3298176) is a 39 amino acid linear peptide and includes a C20 fatty acid. This will allow the binding of the molecule to albumin and prolongation of its half-life The molecular weight is 4.8 kD It is a multi-functional peptide based on the native GIP peptide sequence that was modified to bind to both GIP and GLP-1 receptors In vitro, it has higher potency to native GIP and is less potent to native GLP-1 The mean half-life is of approximately 5 days (116.7 h), and this enables once-weekly dosing Now, let’s spend a few minutes with some of these characteristics References Coskun T, Sloop KW, Loghin C, et al. LY3298176, a novel dual GIP and GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus: from discovery to clinical proof of concept. Mol Metab. 2018;18:3-14. doi: 10.1016/j.molmet.2018.09.009. Epub October 3, 2018. PMID: 30473097; PMCID: PMC6308032.
- Abbreviations cAMP, cyclic adenosine monophosphate; GIP, glucose-dependent insulinotropic polypeptide; GIPR, glucose-dependent insulinotropic polypeptide receptor; GLP-1, glucagon-like peptide-1; GLP-1R, glucagon-like peptide-1 receptor; PoC, proof of concept; T2D, type 2 diabetes; TZP, tirzepatide Speaker notes Prior to administration to healthy volunteers and people with T2D in the Phase 1/1b PoC study, tirzepatide was characterised in vitro In signaling studies using cell lines recombinant for GIPR or GLP-1R, tirzepatide potently stimulated cAMP accumulation, an indirect way to measure binding to either receptor Reference Coskun T, et al. Mol Metab 2018;18:3-14
- Abbreviations BMI, body mass index; BP, blood pressure, CABG, coronary artery bypass graft; DU, dulaglutide; ECG, electrocardiogram; eGFR, estimated glomerular filtration rate; GLP-1, glucagon-like peptide-1; HbA1c, glycated hemoglobin; HF, heart failure; HIV, human immunodeficiency virus; HOMA2-B, homeostatic model assessment of β-cell function; HOMA2-IR, homeostatic model assessment of insulin resistance; MI, myocardial infarction; mITT, modified intention-to-treat; NYHA, New York Heart Association; PCI, percutaneous coronary intervention; PL, placebo; QW, once weekly; SMBG, self-monitored blood glucose; T2D, type 2 diabetes; TIA, transient ischemic attack; TZP, tirzepatide; ULN, upper limit of normal Speaker notes Study overview Study GPGB was a double-blind, placebo-controlled Phase 2b study in people with T2D and with an HbA1c 7.0-10.5%, who were inadequately controlled with diet and exercise alone or with stable metformin therapy The study investigated multiple doses of tirzepatide (1, 5, 10, 15 mg), compared with two control arms: placebo and dulaglutide (1.5 mg) Based on the rationale of maximizing the weight loss potential previously observed with tirzepatide, the study is designed with a longer duration compared with other Phase 2 trials, with a 26-week treatment period (plus a 4-week follow-up) versus a more typical duration of 12–16 weeks Study endpoints: Primary endpoint was change in HbA1c from baseline to 26 weeks in the mITT population, defined as all participants who took at least one dose of study drug and had at least one postbaseline measurement of any outcome Secondary endpoints: Change in HbA1c from baseline to 12 weeks Change in mean body weight, fasting plasma glucose, and waist circumference from baseline to weeks 12 and 26 Proportion of patients with ≥5% and 10% body weight loss from baseline to 26 weeks Proportion of patients reaching HbA1c target (≤6.5% and <7.0%) Change in lipid laboratory data from baseline to 26 weeks Safety endpoints: Overall adverse events; gastrointestinal tolerability; hypersensitivity; injection site reactions; anti-drug antibodies to tirzepatide; incidence of pancreatitis; rates of hypoglycemia; cardiovascular vital signs Key inclusion criteria: People 18–75 years old with T2D for ≥6 months HbA1c 7.0–10.5%, inadequately controlled with diet and exercise alone or with stable metformin therapy for ≥3 months before screening BMI 25–30 kg/m2 The 10mg and 15mg treatment arms included a 2-week and 6-week titration phase, respectively, in order to improve gastrointestinal tolerability Key exclusion criteria: ≥1 hypoglycemic episode in the 6 months prior to Visit 1, history of hypoglycemia unawareness or poor recognition of hypoglycemic symptoms History of acute or chronic pancreatitis Active proliferative diabetic retinopathy Liver disease, acute or chronic hepatitis MI, unstable angina, CABG, PCI, TIA, cerebrovascular accident, or NYHA III/IV HF ≤6 months prior to screening Reference Frias JP, et al. Lancet 2018;392(10160):2180-2193
- Abbreviations AE, adverse event; DU, dulaglutide; GLP-1 RA, glucagon-like peptide-1 receptor agonist; PL, placebo; TEAE, treatment-emergent adverse event; T2D, type 2 diabetes; TZP, tirzepatide Speaker notes In summary, Phase 2 and 2b studies evaluated a range of doses of tirzepatide in patients with type 2 diabetes1,2 Efficacy was shown to be dose-dependent, with the greatest improvements in glycemic variables observed for higher doses (TZP 10 mg and 15 mg)1 Tirzepatide showed clinically meaningful improvements in glycemic control and superior weight loss compared with DU 1.5 mg1 Safety and tolerability was comparable to DU 1.5 mg at doses of 5 mg and 10 mg. Gastrointestinal adverse events were the most commonly observed adverse event. Generally, they were mild to moderate in severity and transient1 TZP 15 mg was associated with an increased frequency of gastrointestinal adverse events and treatment discontinuation. However, they were mostly reported early in the up-titration phase1 A longer titration phase with more incremental dose escalations can potentially alleviate these symptomologies. The superior efficacy observed in the 15 mg group supports the rationale for carrying this dose forward to the Phase 3 program1 References Frias JP, et al. Lancet 2018;392(10160):2180-2193 Frias JP, et al. Diabetes Obes Metab 2020;22(6):938-946
- Abbreviations QW, once weekly; TZP, tirzepatide Speaker notes Based on the previous Phase 2 data and some exposure modeling, a more progressive approach to dose titration was chosen for the Phase 3 program Three maintenance doses will be tested in the Phase 3 studies (5, 10 and 15 mg). The starting dose will be 2.5 mg once weekly. Then, dose increases by 2.5 mg will happen every 4 weeks until the final maintenance dose (5, 10 or 15 mg) is achieved. This would mean that it would take 4 weeks to get to 5 mg, 12 weeks to get to 10 mg, and 20 weeks to get to 15 mg The modeling predicts a lower incidence of nausea, and we consider that this approach will translate into a better tolerability profile that will help patients achieve the final dose with less discontinuations due to this cause References Frias JP, et al. Diabetes Obes Metab 2020;22(6):938-946 Eli Lilly and Company. Diabetes – 2019 Business Update
- Note to speaker This is an interactive slide. Click on any trial name in the timeline above to view additional details. Navigate back to this slide by clicking the “Back” button in the lower right corner. Abbreviations CVD = cardiovascular disease; CVOT = cardiovascular outcomes trial; T2D = type 2 diabetes. References A Study of Tirzepatide (LY3298176) in Participants With Type 2 Diabetes Not Controlled With Diet and Exercise Alone (SURPASS-1). ClinicalTrials.gov. Accessed November 1, 2020. https://www.clinicaltrials.gov/ct2/show/NCT03954834 A Study of Tirzepatide (LY3298176) Versus Semaglutide Once Weekly as Add-on Therapy to Metformin in Participants With Type 2 Diabetes (SURPASS-2). ClinicalTrials.gov. Accessed November 1, 2020. https://clinicaltrials.gov/ct2/show/NCT03987919 A Study of Tirzepatide (LY3298176) Versus Insulin Degludec in Participants With Type 2 Diabetes (SURPASS-3). ClinicalTrials.gov. Accessed November 1, 2020. https://clinicaltrials.gov/ct2/show/NCT03882970 A Study of Tirzepatide (LY3298176) Once a Week Versus Insulin Glargine Once a Day in Participants With Type 2 Diabetes and Increased Cardiovascular Risk (SURPASS-4). ClinicalTrials.gov. Accessed November 1, 2020. https://clinicaltrials.gov/ct2/show/NCT03730662 A Study of Tirzepatide (LY3298176) Versus Placebo in Participants With Type 2 Diabetes Inadequately Controlled on Insulin Glargine With or Without Metformin (SURPASS-5). ClinicalTrials.gov. Accessed November 1, 2020. https://clinicaltrials.gov/ct2/show/NCT04039503 A Study of Tirzepatide (LY3298176) Versus Insulin Lispro (U100) in Participants With Type 2 Diabetes Inadequately Controlled on Insulin Glargine (U100) With or Without Metformin (SURPASS-6). ClinicalTrials.gov. Accessed November 1, 2020. https://clinicaltrials.gov/ct2/show/NCT04537923 A Study of Tirzepatide (LY3298176) Compared With Dulaglutide on Major Cardiovascular Events in Participants With Type 2 Diabetes (SURPASS-CVOT). ClinicalTrials.gov. Accessed November 1, 2020. https://clinicaltrials.gov/ct2/show/NCT04255433
- Abbreviations BMI, body mass index; HbA1c, glycated hemoglobin; PL, placebo; QW, once weekly; T2D, type 2 diabetes; TZP, tirzepatide; Speaker notes SURPASS-1 is a double-blind, placebo-controlled Phase 3 study in people with T2D not adequately controlled with diet and exercise alone The study is investigating multiple doses of TZP (5, 10, 15 mg), compared with a PL control arm To evaluate the efficacy and safety of tirzepatide, the study is designed to last 47 weeks with about 15 study visits Criteria Inclusion Criteria: Have been diagnosed with T2D. Naïve to diabetes injectable therapies and have not used any oral antihyperglycemic medications during the 3 months preceding screening. HbA1c between ≥7.0% and ≤9.5%. Be of stable weight (± 5%) for at least 3 months before screening. Have a BMI ≥23 kg/m² at screening. Exclusion Criteria: Have type 1 diabetes. Have had chronic or acute pancreatitis any time prior to study entry. Have proliferative diabetic retinopathy or diabetic maculopathy or nonproliferative diabetic retinopathy requiring acute treatment. Have disorders associated with slowed emptying of the stomach, or have had any stomach surgeries for the purpose of weight loss. Have an estimated glomerular filtration rate <30 mL/minute/1.73 m². Have had a heart attack, stroke, or hospitalization for congestive heart failure in the past 2 months. Have a personal or family history of medullary thyroid carcinoma or personal history of multiple endocrine neoplasia syndrome type 2. Have been taking weight loss drugs, including over-the-counter medications during the last 3 months. Reference SURPASS-1. Available at: https://clinicaltrials.gov/ct2/show/NCT03954834. Accessed May 2020
- Abbreviations ALT, alanine transaminase; BMI, body mass index; HbA1c, glycated hemoglobin; NAFLD, nonalcoholic fatty liver disease; QW, once weekly; T2D, type 2 diabetes; TZP, tirzepatide; ULN, upper limit of normal Study overview SURPASS-2 is an open-label Phase 3 study in people with T2D receiving metformin The study is investigating multiple doses of TZP (5, 10, 15 mg) as add-on therapy, compared with semaglutide as add-on To compare the effect of tirzepatide to semaglutide on blood sugar levels, the study is designed to last 47 weeks with about 12 study visits Criteria Inclusion Criteria: Have been diagnosed with T2D Have HbA1c between ≥7.0% and ≤10.5% Be on stable treatment with unchanged dose of metformin >1500 mg/day for at least 3 months prior to screening Be of stable weight (±5%) for at least 3 months before screening Have a BMI ≥25 kilograms per meter squared (kg/m²) at screening Exclusion Criteria: Have type 1 diabetes Have had chronic or acute pancreatitis any time prior to study entry Have proliferative diabetic retinopathy or diabetic maculopathy or nonproliferative diabetic retinopathy requiring acute treatment Have disorders associated with slowed emptying of the stomach, or have had any stomach surgeries for the purpose of weight loss Have acute or chronic hepatitis, signs and symptoms of any other liver disease, or blood ALT enzyme level >3.0 x ULN for the reference range, as determined by the central laboratory. Participants with NAFLD are eligible for participation in this trial only if their ALT level is ≤3.0 x ULN for the reference range Have an estimated glomerular filtration rate <45 mL/min/1.73 m² (or lower than the country specific threshold for using the protocol required dose of metformin per local label) Have had a heart attack, stroke, or hospitalization for congestive heart failure in the past 2 months Have a personal or family history of medullary thyroid carcinoma or personal history of multiple endocrine neoplasia syndrome type 2 Have been taking any other diabetes medicines other than metformin during the last 3 months Have been taking weight loss drugs, including over-the-counter medications during the last 3 months Reference SURPASS-2. Available at: https://clinicaltrials.gov/ct2/show/NCT03987919 . Accessed May 2020
- Abbreviations ALT, alanine transaminase; BMI, body mass index; HbA1c, glycated hemoglobin; NAFLD, nonalcoholic fatty liver disease; QW, once weekly; SGLT-2, sodium glucose transporter 2; T2D, type 2 diabetes; TZP, tirzepatide; ULN, upper limit of normal Speaker notes SURPASS-3 is an open-label Phase 3 study in people with T2D The study is investigating multiple doses of TZP (5, 10, 15 mg) compared with insulin degludec To compare the effect of tirzepatide to insulin degludec on blood sugar levels, the study is designed to last 56 weeks with up to 22 study visits Criteria Inclusion Criteria: Diagnosed with type 2 diabetes HbA1c between ≥7.0% and ≤10.5% On stable treatment with unchanged dose of metformin or metformin plus an SGLT-2 inhibitor for at least 3 months before screening Stable weight (± 5%) for at least 3 months before screening BMI ≥25 kg/m2 at screening Exclusion Criteria: Type 1 diabetes Chronic or acute pancreatitis any time prior to study entry Proliferative diabetic retinopathy or diabetic maculopathy or nonproliferative diabetic retinopathy requiring acute treatment Disorders associated with slowed emptying of the stomach, or have had any stomach surgeries for the purpose of weight loss Acute or chronic hepatitis, signs and symptoms of any other liver disease, or blood ALT enzyme level >3.0 x ULN for the reference range, as determined by the central laboratory. Participants with NAFLD are eligible for participation in this trial only if their ALT level is ≤3.0 x ULN for the reference range Have an estimated glomerular filtration rate <45 mL/minute/1.73 m2 (or lower than the country specific threshold for using the protocol required dose of metformin per local label) Have had a heart attack, stroke, or hospitalization for congestive heart failure in the past 2 months Have a personal or family history of medullary thyroid carcinoma or personal history of multiple endocrine neoplasia syndrome type 2 Have been taking any other diabetes medicines other than metformin, or metformin plus an SGLT-2 inhibitor during the last 3 months Have been taking weight loss drugs, including over-the-counter medications during the last 3 months Reference SURPASS-3. Available at: https://clinicaltrials.gov/ct2/show/NCT03882970. Accessed May 2020
- Abbreviations ALT, alanine transaminase; BMI, body mass index; HbA1c, glycated hemoglobin; PL, placebo; QW, once weekly; T2D, type 2 diabetes; TZP, tirzepatide Speaker notes SURPASS-5 is a double-blind placebo-controlled Phase 3 study in people with T2D treated with insulin glargine with or without metformin The study is investigating multiple doses of TZP (5, 10, 15 mg) compared with PL To compare the efficacy and safety of tirzepatide to PL, the study is designed to last 47 weeks with about 23 study visits Criteria Inclusion Criteria Have been diagnosed with T2D and have been treated with insulin glargine (U100), once daily with or without metformin ≥3 months prior to screening visit. Have HbA1c between ≥7.0% and ≤10.5%. Have a stable weight (± 5%) for at least 3 months before screening. Have a BMI ≥23 kg/m² at screening. Exclusion Criteria Have type 1 diabetes. Have had chronic or acute pancreatitis any time prior to study entry. Have proliferative diabetic retinopathy or diabetic maculopathy or nonproliferative diabetic retinopathy requiring acute treatment. Have disorders associated with slowed emptying of the stomach, or have had any stomach surgeries for the purpose of weight loss. Have an estimated glomerular filtration rate <30 mL/minute/1.73 m² [for participants on metformin, estimated glomerular filtration rate <45 mL/min/1.73 m2 (or lower than the country-specific threshold for using the protocol-required dose of metformin per local label)] Have had a heart attack, stroke, or hospitalization for congestive heart failure in the past 2 months. Have a personal or family history of medullary thyroid carcinoma or personal history of multiple endocrine neoplasia syndrome type 2. Have been taking weight loss drugs, including over-the-counter medications during the last 3 months. Reference SURPASS-5. Available at: https://clinicaltrials.gov/ct2/show/NCT04039503. Accessed May 2020
- Abbreviations ALT, alanine transaminase; BMI, body mass index; HbA1c, glycated hemoglobin; MACE, major adverse cardiovascular events; NAFLD, nonalcoholic fatty liver disease; OAM oral antihyperglycemic medication; QD, once daily; QW, once weekly; SGLT-2, sodium glucose transporter 2; SU, sulphonylurea; T2D, type 2 diabetes; TZP, tirzepatide; ULN, upper limit of normal Speaker notes SURPASS-4 is an open-label Phase 3 study in people with T2D The study is investigating multiple doses of TZP (5, 10, 15 mg) compared with insulin glargine To compare the efficacy and safety of tirzepatide to insulin glargine, the study is designed to last 107 weeks with up to 30 study visits The study includes 3 periods: Study Period 1 is a 3-week screening/lead-in phase, Study Period 2 is a 52-week treatment period that includes a 24-week dose escalation for tirzepatide and a 16-week initial, intensive insulin glargine titration. The primary and key secondary endpoints will be assessed at 52 weeks. Study Period 3 is a variable treatment period. Patients will be on treatment for at least 12, but no more than 24 months. This variable treatment period is designed to characterize the longer-term efficacy and safety of tirzepatide. This variable treatment period will also allow the tirzepatide development program to meet regulatory requirements for exposure and to collect sufficient MACE-4 events for a program wide meta-analysis designed to assess the cardiovascular safety of tirzepatide. The study will have a rolling duration and will be considered complete when each of these criteria have been met: at least 52 weeks after the last patient is randomized, at least 300 patients on tirzepatide reach 78 weeks of exposure, and approximately 110 patients experience a MACE-4 event. Criteria Inclusion Criteria: Have been diagnosed with T2D Have HbA1c between ≥7.5% and ≤10.5% Be on stable treatment with unchanged dose of at least 1 and no more than 3 types of oral antihyperglycemic drugs, which may only include metformin, SGLT-2 inhibitors, and/or sulfonylureas for at least 3 months before screening Have increased risk for CV events Be of stable weight (± 5%) Have a BMI ≥25 kg/m2 at screening Exclusion Criteria Have type 1 diabetes Have had chronic or acute pancreatitis any time prior to study entry Have proliferative diabetic retinopathy or diabetic maculopathy or nonproliferative diabetic retinopathy requiring immediate or urgent treatment Have disorders associated with slowed emptying of the stomach, or have had any stomach surgeries for the purpose of weight loss Have acute or chronic hepatitis, signs and symptoms of any other liver disease, or blood ALT enzyme level >3.0 x ULN for the reference range, as determined by the central laboratory. Participants with NAFLD are eligible for participation in this trial only if their ALT level is ≤3.0 x ULN for the reference range Have had a heart attack, stroke, or hospitalization for congestive heart failure in the past 2 months Have a personal or family history of medullary thyroid carcinoma or personal history of multiple endocrine neoplasia syndrome type 2 Have been taking any other diabetes medicines other than metformin, SGLT-2 inhibitors, and/or sulfonylureas during the last 3 months Have been taking weight loss drugs, including over-the-counter medications during the last 3 months Reference SURPASS-4. Available at: https://clinicaltrials.gov/ct2/show/NCT03730662. Accessed May 2020
- Abbreviations ALT, alanine transaminase; BMI, body mass index; HbA1c, glycated hemoglobin; MACE, major adverse cardiovascular events; NAFLD, nonalcoholic fatty liver disease; OAM oral antihyperglycemic medication; QD, once daily; QW, once weekly; SGLT-2, sodium glucose transporter 2; SU, sulphonylurea; T2D, type 2 diabetes; TZP, tirzepatide; ULN, upper limit of normal Speaker notes SURPASS-4 is an open-label Phase 3 study in people with T2D The study is investigating multiple doses of TZP (5, 10, 15 mg) compared with insulin glargine To compare the efficacy and safety of tirzepatide to insulin glargine, the study is designed to last 107 weeks with up to 30 study visits The study includes 3 periods: Study Period 1 is a 3-week screening/lead-in phase, Study Period 2 is a 52-week treatment period that includes a 24-week dose escalation for tirzepatide and a 16-week initial, intensive insulin glargine titration. The primary and key secondary endpoints will be assessed at 52 weeks. Study Period 3 is a variable treatment period. Patients will be on treatment for at least 12, but no more than 24 months. This variable treatment period is designed to characterize the longer-term efficacy and safety of tirzepatide. This variable treatment period will also allow the tirzepatide development program to meet regulatory requirements for exposure and to collect sufficient MACE-4 events for a program wide meta-analysis designed to assess the cardiovascular safety of tirzepatide. The study will have a rolling duration and will be considered complete when each of these criteria have been met: at least 52 weeks after the last patient is randomized, at least 300 patients on tirzepatide reach 78 weeks of exposure, and approximately 110 patients experience a MACE-4 event. Criteria Inclusion Criteria: Have been diagnosed with T2D Have HbA1c between ≥7.5% and ≤10.5% Be on stable treatment with unchanged dose of at least 1 and no more than 3 types of oral antihyperglycemic drugs, which may only include metformin, SGLT-2 inhibitors, and/or sulfonylureas for at least 3 months before screening Have increased risk for CV events Be of stable weight (± 5%) Have a BMI ≥25 kg/m2 at screening Exclusion Criteria Have type 1 diabetes Have had chronic or acute pancreatitis any time prior to study entry Have proliferative diabetic retinopathy or diabetic maculopathy or nonproliferative diabetic retinopathy requiring immediate or urgent treatment Have disorders associated with slowed emptying of the stomach, or have had any stomach surgeries for the purpose of weight loss Have acute or chronic hepatitis, signs and symptoms of any other liver disease, or blood ALT enzyme level >3.0 x ULN for the reference range, as determined by the central laboratory. Participants with NAFLD are eligible for participation in this trial only if their ALT level is ≤3.0 x ULN for the reference range Have had a heart attack, stroke, or hospitalization for congestive heart failure in the past 2 months Have a personal or family history of medullary thyroid carcinoma or personal history of multiple endocrine neoplasia syndrome type 2 Have been taking any other diabetes medicines other than metformin, SGLT-2 inhibitors, and/or sulfonylureas during the last 3 months Have been taking weight loss drugs, including over-the-counter medications during the last 3 months Reference SURPASS-4. Available at: https://clinicaltrials.gov/ct2/show/NCT03730662. Accessed May 2020
- Abbreviations BMI, body mass index; CV, cardiovascular; DU, dulaglutide; HbA1c, glycated hemoglobin; MACE, major adverse cardiovascular events; MTD, maximum tolerated dose; QW, once weekly; T2D, type 2 diabetes; TZP, tirzepatide; Speaker notes SURPASS-COVT is a Phase 3, event-driven, double-blind study in people with T2D and established CV disease at elevated risk for MACE The study is investigating TZP (up to 15 mg) QW compared with DU (1.5 mg) QW To compare the efficacy and safety of tirzepatide vs dulaglutide, the study is designed to last up 54 months, or until ≥1615 events are accrued Criteria Inclusion Criteria: Have a diagnosis of type 2 diabetes Have confirmed atherosclerotic cardiovascular disease HbA1c ≥7.0% to ≤10.5% BMI ≥25 kg/m² Exclusion Criteria: Have had a major cardiovascular event within the last 60 days Have type 1 diabetes Have a history of severe hypoglycemia and/or hypoglycemia unawareness within the last 6 months Have a history of proliferative diabetic retinopathy; or diabetic maculopathy; or non-proliferative diabetic retinopathy that requires acute treatment Currently planning a coronary, carotid, or peripheral artery revascularization Have a history of pancreatitis Have a history of ketoacidosis or hyperosmolar state/coma Have a known clinically significant gastric emptying abnormality, have undergone or plan to have during the course of the study, or chronically take drugs that directly affect gastrointestinal motility Have a history of an active or untreated malignancy or are in remission from a clinically significant malignancy for less than 5 years Have a family or personal history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2 Reference SURPASS-CVOT. Available at: https://clinicaltrials.gov/ct2/show/NCT04255433. Accessed May 2020