Type 2 Diabetes Mellitus
Conditions
Keywords
Diabetes Mellitus, Diabetes Mellitus, Type 2, Glucose Metabolism Disorders, Metabolic Diseases, Endocrine System Diseases, Hypoglycemic Agents, Physiological Effects of Drugs, Tirzepatide, Incretins, Glucagon-Like Peptide 1, Gastric Inhibitory Polypeptide, Hormones, Hormones, Hormone Substitutes, and Hormone Antagonists
Brief summary
The purpose of the trial is to assess the efficacy and safety of tirzepatide to dulaglutide in participants with type 2 diabetes and increased cardiovascular risk.
Interventions
DRUGTirzepatide
Administered SC
DRUGDulaglutide
Administered SC
Sponsors
Eli Lilly and Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Men or women at least 40 years old with a diagnosis of type 2 diabetes * Established cardiovascular disease, including at least 1 of the following: * Coronary artery disease (CAD) with any of the following: * Documented history of spontaneous myocardial infarction (MI) * ≥50% stenosis in 1 or more major coronary arteries, determined by invasive angiography * ≥50% stenosis in 2 or more major coronary arteries, determined by computed tomography coronary angiography (CTCA) * History of surgical or percutaneous coronary revascularization procedure * Cerebrovascular disease - any of the following: * Documented history of ischemic stroke * Carotid arterial disease with ≥50% stenosis, documented by carotid ultrasound, magnetic resonance imaging (MRI), or angiography * Carotid stenting or surgical revascularization * Peripheral arterial disease with either of the following: * Intermittent claudication and ankle-brachial index \<0.9 * Prior nontraumatic amputation or peripheral vascular procedure (eg, stenting or surgical revascularization), due to peripheral arterial ischemia * Note: Supporting medical documentation is required in all instances * HbA1c ≥7% (≥53 mmol/mol) and ≤10.5% (≤91.3 mmol/mol) based on central laboratory assessment at screening * Body mass index (BMI) ≥25 kg/m2 * At the time of signing the informed consent: Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical trials. * Male patients: Men, regardless of their fertility status, with nonpregnant women of childbearing potential (WOCBP) partners must agree to either remain abstinent (if this is their preferred and usual lifestyle) or use condoms, as well as 1 additional highly effective (less than 1% failure rate) method of contraception (such as combination oral contraceptives, implanted contraceptives, or intrauterine devices) or effective method of contraception (such as diaphragms with spermicide or cervical sponges) for the duration of the study and until their plasma concentrations are below the level that could result in a relevant potential exposure to a possible fetus, predicted to be 90 days following the last dose of study drug. * Men and their partners may choose to use a double-barrier method of contraception. (Barrier protection methods without concomitant use of a spermicide are not an effective or acceptable method of contraception. Thus, each barrier method must include use of a spermicide. It should be noted, however, that the use of male and female condoms as a double barrier method is not considered acceptable due to the high failure rate when these barrier methods are combined). * Periodic abstinence (eg, calendar, ovulation, symptothermal, or postovulation methods), declaration of abstinence just for the duration of a trial, and withdrawal are not acceptable methods of contraception. * Men with pregnant partners should use condoms during intercourse for the duration of the study and until the end of the estimated relevant potential exposure in WOCBP (90 days). Men should refrain from sperm donation for the duration of the study and until their plasma concentrations are below the level that could result in a relevant potential exposure to a possible fetus, predicted to be 90 days following the last dose of study drug. Men who are in exclusively same-sex relationships (as their preferred and usual lifestyle) are not required to use contraception. * Female patients: Women of childbearing potential who are abstinent (if this is complete abstinence, as their preferred and usual lifestyle) or in a same-sex relationship (as part of their preferred and usual lifestyle) must agree to either remain abstinent or stay in a same-sex relationship without sexual relationships with males. Periodic abstinence (eg, calendar, ovulation, symptothermal, or postovulation methods), declaration of abstinence just for the duration of a trial, and withdrawal are not acceptable methods of contraception. Otherwise, WOCBP participating must agree to use 2 forms of effective contraception, where at least 1 form is highly effective (less than 1% failure rate), for the entirety of the study. Contraception must continue following completion of study drug administration for the entirety of the study and for 30 days thereafter. * WOCBP participating must test negative for pregnancy prior to initiation of treatment as indicated by a negative serum pregnancy test at the screening visit followed by a negative urine pregnancy test within 24 hours prior to exposure. * Two forms of effective contraception, where at least 1 form is highly effective, (such as combination oral contraceptives, implanted contraceptives, or intrauterine devices) will be used. Effective contraception (such as male or female condoms with spermicide, diaphragms with spermicide, or cervical sponges) may be used as the second therapy. Barrier protection methods without concomitant use of a spermicide are not a reliable or acceptable method. Thus, each barrier method must include use of a spermicide (ie, condom with spermicide, diaphragm with spermicide, or female condom with spermicide). It should be noted that the use of male and female condoms as a double barrier method is not considered acceptable due to the high failure rate when these methods are combined. * Women not of childbearing potential may participate and include those who are: * infertile due to surgical sterilization (hysterectomy, bilateral oophorectomy, or tubal ligation), congenital anomaly such as mullerian agenesis, or * postmenopausal - defined as either: A woman at least 40 years of age with an intact uterus, not on hormone therapy, who has cessation of menses for at least 1 year without an alternative medical cause, AND a follicle-stimulating hormone \>40 mIU/mL; or ii. A woman 55 or older not on hormone therapy, who has had at least 12 months of spontaneous amenorrhea; or A woman at least 55 years of age with a diagnosis of menopause prior to starting hormone replacement therapy. * In the investigator's opinion, are well motivated, capable, and willing to: * learn how to self-inject treatment (tirzepatide or dulaglutide), as required for this protocol (visually impaired persons who are not able to perform the injections must have the assistance of a sighted individual trained to inject the study drug; persons with physical limitations who are not able to perform the injections must have the assistance of an individual trained to inject the study drug), * inject study drug weekly, * have a sufficient understanding of 1 of the provided languages of the country such that they will be able to complete the patient questionnaires, and * make themselves available for the duration of the study, and who will comply with the required study visits. * Capable of giving signed informed consent
Exclusion criteria
* Have type 1 diabetes mellitus * Have uncontrolled diabetes requiring immediate therapy (such as diabetic ketoacidosis) at screening or randomization, in the judgment of the physician * Have had 1 or more events of severe hypoglycemia and/or 1 or more events of hypoglycemia unawareness within 6 months prior to screening * Are currently planning treatment for diabetic retinopathy and/or macular edema. * Have been hospitalized for congestive heart failure (CHF) within 2 months prior to screening * Have chronic New York Heart Association Functional Classification IV CHF * Are currently planning a coronary, carotid, or peripheral artery revascularization * Had chronic or acute pancreatitis any time prior to screening, irrespective of etiology * Have a known clinically significant gastric emptying abnormality such as severe gastroparesis or gastric outlet obstruction, or have undergone or currently planning any gastric bypass (bariatric) surgery or restrictive bariatric surgery * Have acute or chronic hepatitis, signs or symptoms of any other liver disease, an alanine aminotransferase (ALT) level ≥3 times the upper limit of normal (ULN) for the reference range, as determined by the central laboratory (Note: Patients with nonalcoholic fatty liver disease are eligible to participate if their ALT level is \<3 times the ULN for the reference range) * Have known chronic severe renal failure (defined as a known estimated glomerular filtration rate (eGFR) \<15 mL/minute/1.73 m2) or are on chronic dialysis * Have evidence of a significant, uncontrolled endocrine abnormality (eg, thyrotoxicosis or adrenal crises) * Have a family or personal history of multiple endocrine neoplasia type 2 (MEN2) or familial medullary thyroid carcinoma (MTC) or personal history of nonfamilial MTC * Have a serum calcitonin level at screening of: (based on central laboratory results) * ≥20 ng/L at Visit 1, if eGFR ≥60 mL/min/1.73 m2, or * ≥35 ng/L at Visit 1, if eGFR \<60 mL/min/1.73 m2 * Have a history of an active or untreated malignancy or are in remission from a clinically significant malignancy for less than 5 years. An exception for this criterion is basal or squamous cell skin cancer, in situ carcinomas of the cervix, or in situ prostate cancer * Have a history of any other condition (such as known drug or alcohol abuse or psychiatric disorder) that, in the opinion of the investigator, may preclude the patient from following and completing the protocol * Have had a transplanted organ (corneal transplants \[keratoplasty\] allowed) or awaiting an organ transplant * Have any other condition (eg, hypersensitivity) that is a contraindication to any incretin or glucagon-like peptide-1 (GLP-1) receptor agonist (RA) * Have had an MI, percutaneous coronary revascularization procedure, ischemic stroke, carotid stenting or surgical revascularization, nontraumatic amputation, or peripheral vascular procedure (eg, stenting or surgical revascularization) less than 60 days prior to screening * Have had coronary artery bypass graft surgery less than 5 years prior to screening * Have had a blood transfusion or severe blood loss within 90 days prior to screening or have known hematological conditions that may interfere with HbA1c measurement * Treatment with GLP-1 RA or pramlintide, in a period of 3 months prior to Visit 1 * Discontinuation of GLP-1 RA or pramlintide, due to intolerability any time prior to Visit 1 * Are currently enrolled in any other clinical study involving an investigational product or any other type of medical research judged not to be scientifically or medically compatible with this study * Have participated within the last 30 days in a clinical trial involving an investigational product. If the previous investigational product has a long half-life, 3 months or 5 half-lives (whichever is longer) should have passed * Have previously completed or withdrawn from this study or randomized into any other study investigating tirzepatide
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants From Randomization to First Occurrence of Death From MACE-3 [Composite Endpoint of Major Adverse Cardiovascular Events Death From Cardiovascular Causes, Myocardial Infarction (MI) or Stroke] | From randomization (week 0) up to week 259 | Number of participants with first occurrence of Clinical Endpoint Committee (CEC), a composite endpoint i.e., from time of randomization to first occurrence of cardiovascular (CV) death, myocardial infarction and stroke combined data was reported. Time to event was defined as the number of days from the date of randomization to the first occurrence of any of these events during the study follow-up period. Participants without an event were censored at their last known contact or end of follow-up. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants From Randomization to Time to Occurrence of All-Cause Death | From randomization (week 0) up to week 259 | The number of participants from randomization to time to occurrence of Clinical Endpoint Committee (CEC) confirmed all-cause death was reported. Time to event was defined as the number of days from the date of randomization to the first occurrence of all-cause death during the study follow-up period. Participants without an event were censored at their last known contact or end of follow-up. |
| Number of Participants From Randomization to Time of Occurrence of CV Death | From randomization (week 0) up to week 259 | Number of participants from time of randomization to time to occurrence of CEC confirmed CV death was reported. Time to event was defined as the number of days from the date of randomization to the first occurrence of CV death during the study follow-up period. Participants without an event were censored at their last known contact or end of follow-up. |
| Number of Participants From Randomization to Time to First Occurrence of Myocardial Infarction (MI) | From randomization (week 0) up to week 259 | The number of participants from randomization to first occurrence of CEC confirmed MI was reported. Time to event was defined as the number of days from the date of randomization to the first occurrence of nonfatal MI during the study follow-up period. Participants without an event were censored at their last known contact or end of follow-up. |
| Number of Participants From Randomization toTime to First Occurrence of Stroke | From randomization (week 0) up to week 259 | The number of participants from randomization to first occurrence of CEC confirmed stroke was reported. Time to event was defined as the number of days from the date of randomization to the first occurrence of nonfatal stroke during the study follow-up period. Participants without an event were censored at their last known contact or end of follow-up. |
| Number of Participants From Randomization to Time to First Occurrence of the Expanded Composite of CV Death, MI, Stroke or Coronary Revascularization (MACE-4) | From randomization (week 0) up to week 259 | The number of participants from randomization to first occurrence of MACE-4 was reported. Time to event was defined as the number of days from the date of randomization to the first occurrence of any of these events during the study follow-up period. Participants without an event were censored at their last known contact or end of follow-up. |
| Number of Participants From Randomization to Time to First Occurrence of CV Deaths or Heart Failure Events Requiring Hospitalization and/or Urgent Heart Failure Visits | From randomization (week 0) up to week 259 | The number of participants from randomization to first occurrence of Clinical Endpoint Committee (CEC) confirmed heart failure requiring hospitalisation or urgent heart failure was reported. Time to event was defined as the number of days from the date of randomization to the first occurrence of any of these events during the study follow-up period. Participants without an event were censored at their last known contact or end of follow-up. |
| Number of Participants From Randomization to Time to First Occurrence of Revascularization | From randomization (week 0) up to week 259 | The number of participants from randomization to first occurrence of coronary revascularization was reported. Time to event was defined as the number of days from the date of randomization to the first occurrence of revascularization during the study follow-up period. Participants without an event were censored at their last known contact or end of follow-up. |
| Number of Participants From Randomization to Time to First Occurrence of New or Worsening Nephropathy | From randomization (week 0) up to week 259 | New or worsening nephropathy (Composite Endpoint 1) was defined as the first occurrence of any of the following events: persistent macroalbuminuria (urine albumin-to-creatinine ratio \>300 mg/g), persistent doubling of serum creatinine with eGFR \<45 mL/min/1.73 m², onset of end-stage renal disease (including initiation of chronic dialysis or kidney transplantation), or death due to renal disease. Time to event was defined as the number of days from the date of randomization to the first occurrence any of these events. during the study follow-up period. Participants without an event were censored at their last known contact or end of follow-up. |
| Change From Baseline to 36 Months in Estimated Glomerular Filtration Rate (eGFR) in Patients With High or Very-high Risk Chronic Kidney Disease (CKD) | Baseline, 36 Months | Change from baseline in eGFR calculated as difference between value at 36 months and baseline value. Participants included in this analysis were classified as having high or very high risk of chronic kidney disease at baseline based on their kidney function (eGFR) and urine albumin-to-creatinine ratio (UACR). High risk included participants with eGFR 45 to less than 60 milliliters/minutes/1.73 square metres (mL/min/1.73 m²) and UACR greater than 30 mg/g, or eGFR 60 mL/min/1.73 m² or higher with UACR greater than 300 mg/g. Very high risk included participants with eGFR less than 45 mL/min/1.73 m² or severely increased UACR (greater than 300 mg/g). These criteria are associated with an increased risk of worsening kidney function. Least squares (LS) mean was calculated using analysis of covariance (ANCOVA) model for endpoint measures: Variable = Baseline + Treatment + Analysis Country + Baseline sodium-glucose cotransporter-2 (SGLT-2) Use Flag. |
| Change From Baseline to 36 Months in Hemoglobin A1c (HbA1c) | Baseline, 36 Months | HbA1c is the glycosylated fraction of hemoglobin A. HbA1c is measured primarily to identify average plasma glucose concentration over prolonged periods of time. Change in HbA1c from baseline up to 36 months during in-trial period were reported. In-trial observation period was defined as the period from date of randomization to the first of (both inclusive): date of follow-up visit, date when participant withdrew consent, date of last contact with participant (for participant lost to follow-up), and date of death. LS mean was calculated using ANCOVA model for endpoint measures: Variable = Baseline + Treatment + Analysis Country + Baseline SGLT-2i Use Flag (Type III sum of squares). |
| Percent Change From Baseline to 36 Months in Body Weight | Baseline, 36 Months | LS mean was calculated using ANCOVA model for endpoint measures: Variable = Baseline + Treatment + Analysis Country + Baseline SGLT-2i Use Flag (Type III sum of squares) |
| Percent Change From Baseline to 36 Months in Urinary Albumin to Creatinine Ratio (UACR) | Baseline, 36 Months | Urine samples were collected for the analysis of UACR. UACR (gram per kilograms \[g/kg\]) was calculated as urine albumin (gram per liter \[g/L\])/urine creatinine (kg/L). Percent change from baseline at 36 months was calculated as: \[(UACR at 36 months - baseline UACR) / baseline UACR\] × 100. LS mean was calculated using ANCOVA model for endpoint measures: log(Actual Measurement/Baseline) = log(Baseline) + Treatment + Analysis Country + Baseline SGLT-2i Use Flag (Type III sum of squares). |
| Percent Change From Baseline to 24 Months in Blood Lipids (Total Cholesterol (TC), Low-Density Lipoprotein Cholesterol (LDL-C), High-Density Lipoprotein Cholesterol (HDL-C), and Triglycerides (TG)) | Baseline, 24 Months | Blood samples of participants who had fasted for 12 to 14 hours were collected for lipid profile (TC, LDL-C, HDL-C, TG) assessment. The lipid profile asesses the risk of heart disease. Percent change from baseline = 100\*(post-baseline assessment - baseline assessment)/baseline assessment. LS mean was calculated using ANCOVA model for endpoint measures: log(Actual Measurement/Baseline) = log(Baseline) + Treatment + Analysis Country + Baseline SGLT-2i Use Flag. |
Countries
Argentina, Australia, Austria, Belgium, Brazil, Canada, China, Czechia, France, Germany, Greece, Hungary, India, Israel, Italy, Japan, Mexico, Netherlands, Poland, Puerto Rico, Romania, Russia, Slovakia, South Korea, Spain, Sweden, Taiwan, Turkey (Türkiye), Ukraine, United Kingdom, United States
Contacts
STUDY_DIRECTORCall 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST)
Eli Lilly and Company
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 64.10 years STANDARD_DEVIATION 8.77 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2003 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4316 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 647 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 489 Participants |
| Race (NIH/OMB) Asian | 1170 Participants |
| Race (NIH/OMB) Black or African American | 111 Participants |
| Race (NIH/OMB) More than one race | 26 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 18 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 176 Participants |
| Race (NIH/OMB) White | 10697 Participants |
| Region of Enrollment Argentina | 812 Participants |
| Region of Enrollment Australia | 388 Participants |
| Region of Enrollment Austria | 41 Participants |
| Region of Enrollment Belgium | 131 Participants |
| Region of Enrollment Brazil | 622 Participants |
| Region of Enrollment Canada | 454 Participants |
| Region of Enrollment China | 175 Participants |
| Region of Enrollment Czechia | 227 Participants |
| Region of Enrollment France | 150 Participants |
| Region of Enrollment Germany | 488 Participants |
| Region of Enrollment Greece | 160 Participants |
| Region of Enrollment Hungary | 375 Participants |
| Region of Enrollment India | 118 Participants |
| Region of Enrollment Israel | 428 Participants |
| Region of Enrollment Italy | 217 Participants |
| Region of Enrollment Japan | 50 Participants |
| Region of Enrollment Mexico | 1584 Participants |
| Region of Enrollment Netherlands | 128 Participants |
| Region of Enrollment Poland | 447 Participants |
| Region of Enrollment Romania | 283 Participants |
| Region of Enrollment Russia | 178 Participants |
| Region of Enrollment Slovakia | 82 Participants |
| Region of Enrollment South Korea | 130 Participants |
| Region of Enrollment Spain | 205 Participants |
| Region of Enrollment Sweden | 97 Participants |
| Region of Enrollment Taiwan | 160 Participants |
| Region of Enrollment Turkey (Türkiye) | 124 Participants |
| Region of Enrollment Ukraine | 750 Participants |
| Region of Enrollment United Kingdom | 78 Participants |
| Region of Enrollment United States | 1501 Participants |
| Sex: Female, Male Female | 1903 Participants |
| Sex: Female, Male Male | 4745 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 568 / 6,648 | 670 / 6,651 |
| other Total, other adverse events | 4,718 / 6,647 | 4,297 / 6,647 |
| serious Total, serious adverse events | 2,117 / 6,647 | 2,121 / 6,647 |
Outcome results
None listed