Type 2 Diabetes Mellitus
Conditions
Brief summary
The main purpose of this study is to evaluate the efficacy and safety of the study drug known as dulaglutide when added to sodium-glucose co-transporter 2 (SGLT2) inhibitors in participants with type 2 diabetes mellitus.
Interventions
DRUGDulaglutide
Administered SC
DRUGPlacebo
Administered SC
DRUGSGLT2 inhibitor
Administered orally as standard of care for type 2 diabetes
DRUGMetformin
Administered orally as standard of care for type 2 diabetes
Sponsors
Eli Lilly and Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Have type 2 diabetes mellitus (based on the World Health Organization's \[WHO\] diagnostic criteria) * Have been treated with an SGLT2 inhibitor, with or without metformin, for at least 3 months prior to study entry (minimum required doses for that period for allowed SGLT2 inhibitors: empagliflozin 10 mg, dapagliflozin 5 or 10 mg \[per country-specific label\], canagliflozin 100 mg); minimum required dose for metformin, if used, is ≥1500 mg/day and must be reached (or highest tolerated dose which is acceptable with documented gastrointestinal \[GI\] intolerability) * Daily doses of all allowed oral antihyperglycemia agent (OAMs) must have been stable for at least 12 weeks (±3 days) prior to randomization (study enrollment); daily doses of SGLT2 inhibitor and metformin, if used, will be considered stable during this period if: * all prescribed daily doses were in the range between the minimum required dose and maximum-approved dose per country-specific label; and * \>90% of prescribed daily doses were equal to the dose at randomization * Have HbA1c ≥7.0% and ≤9.5% at study entry and approximately 1 week prior to randomization * Have body mass index (BMI) ≤45 kilograms per meter squared (kg/m\^2) and agree to not initiate a diet and/or exercise program during the study with the intent of reducing body weight other than the lifestyle and dietary measures for diabetes treatment
Exclusion criteria
* Have type 1 diabetes mellitus * Have been treated with any other OAMs (other than SGLT2 inhibitors and metformin), glucagon-like peptide-1 receptor agonist (GLP-1 RA), pramlintide or insulin 3 months prior to study entry, or between study entry and randomization; or initiate metformin between study entry and randomization; short-term use of insulin for acute care (≤14 days) during the 3-month period prior to entry is not exclusionary * Have any condition that is a contraindication for use of the GLP-1 RA class or the SGLT2 inhibitor class (per country-specific labels) at study entry or develop such condition between study entry and randomization * Have acute or chronic hepatitis, signs and symptoms of any other liver disease other than nonalcoholic fatty liver disease (NAFLD), or alanine transaminase (ALT) level \>2.5 times the upper limit of the reference range, as determined by the central laboratory at study entry; participants with NAFLD are eligible for participation in this trial * Had chronic or acute pancreatitis any time prior to study entry * Estimated glomerular filtration rate (eGFR) \<45 milliliters(mL)/minute/1.73m\^2, calculated by the Chronic Kidney Disease-Epidemiology (CKD-EPI) equation, as determined by the central laboratory at study entry and confirmed at lead in * Have any self or family history of type 2A or type 2B multiple endocrine neoplasia (MEN 2A or 2B) in the absence of known C-cell hyperplasia (this exclusion includes participants with a family history of MEN 2A or 2B, whose family history for the syndrome is rearranged during transfect \[RET\]-negative; the only exception for this exclusion will be for participants whose family members with MEN 2A or 2B have a known RET mutation and the potential participant for the study is negative for the RET mutation) * Have any self or family history of medullary C-cell hyperplasia, focal hyperplasia, carcinoma (including sporadic, familial, or part of MEN 2A or 2B syndrome) * Have a serum calcitonin ≥20 picograms/mL as determined by the central laboratory at study entry
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Hemoglobin A1c (HbA1c) at 24 Weeks (Treatment-regimen Estimand) | Baseline, Week 24 | Least Squares mean (LS) of the HbA1c change from baseline to primary endpoint at week 24 was adjusted by treatment, country, SGLT2 inhibitor dose, metformin use, treatment-by-visit interactions as fixed effects, and baseline HbA1c as a covariate and participant as a random effect, via a MMRM analysis. The treatment-regimen estimand used all data including post-rescue data and compared the benefit of treatment regimens as they were actually taken. |
| Change From Baseline in the HbA1c at 24 Weeks (Efficacy Estimand) | Baseline, Week 24 | LS mean of the HbA1c change from baseline to primary endpoint at week 24 was adjusted by treatment, country, SGLT2 inhibitor dose, metformin use, treatment-by-visit interactions as fixed effects, and baseline HbA1c as a covariate and participant as a random effect, via a MMRM analysis. The efficacy estimand excluded post-rescue data and compared the benefit of randomized treatments when taken as directed without rescue medication. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Fasting Serum Glucose (Central Laboratory) at 24 Weeks | Baseline, Week 24 | LS mean of change from baseline was calculated using last observation carried forward (LOCF) by treatment group, adjusted for treatment, country, SGLT2 inhibitor dose, metformin use, baseline HbA1c strata, and baseline fasting serum glucose using analysis of covariance (ANCOVA). |
| Change From Baseline in 6-Point Self-Monitored Plasma Glucose (SMPG) Profile at 24 Weeks | Baseline, Week 24 | The self-monitored plasma glucose (SMPG) data were collected at the following 6 time points: pre-morning meal; 2 hours post-morning meal; pre-midday meal; 2 hours post-midday meal; pre-evening meal; 2 hours post-evening meal. Least Squares (LS) means of change from baseline were calculated using a mixed-effects model for repeated measures (MMRM) with treatment, metformin use, SGLT2 inhibitor use, country, visit, baseline HbA1c strata, and treatment-by-visit interaction as fixed effects and baseline as a covariate. |
| Change From Baseline in Fasting Glucagon at 24 Weeks | Baseline, Week 24 | Change from baseline in fasting glucagon was analyzed using an ANCOVA model with last observation carried forward (LOCF) included in treatment, country, SGLT2i dose, metformin use, and baseline HbA1c strata as fixed effects and baseline fasting glucagon as a covariate (with and without post rescue data). |
| Percentage of Participants With HbA1c <7% | 24 Weeks | Number of participants with an HbA1c value of \<7% at Week 24 is measured using longitudinal logistic regression with repeated measurements. The model will include independent variables of treatment, country, SGLT2 inhibitor dose, metformin use, visit, treatment-by-visit interaction, and baseline HbA1c as a covariate. |
| Number of Participants Requiring Rescue Therapy Due to Severe Persistent Hyperglycemia | Baseline through 24 Weeks | Rescue therapy was defined as any additional therapeutic intervention in participants who developed persistent, severe hyperglycemia despite full compliance with the assigned therapeutic regimen, or initiation of an alternative antihyperglycemic medication following study drug discontinuation. |
| Number of Participants With Adjudicated Acute Pancreatitis Events | Baseline through 24 Weeks | The number of participants with events of pancreatitis confirmed by adjudication were summarized cumulatively at 24 weeks. Pancreatitis events were adjudicated by a committee of physicians external to the Sponsor. A summary of serious and other non-serious events regardless of causality is located in the Reported Adverse Events module. |
| Number of Participants With Adjudicated Cardiovascular (CV) Events | Baseline through 24 Weeks | Death and selected nonfatal CV adverse events (AEs) were adjudicated by an independent committee of physicians with cardiology expertise external to the Sponsor. Nonfatal CV events that were to be adjudicated were myocardial infarction (MI); hospitalization for unstable angina; hospitalization for heart failure; coronary interventions such as coronary artery bypass graft (CABG) or ( percutaneous coronary intervention (PCI); and cerebrovascular events, including cerebrovascular accident (stroke) and transient ischemic attack (TIA). |
| Rate of Hypoglycemic Events Adjusted Per 30 Days | Baseline through 24 Weeks | A hypoglycemic event is defined as any time a participant feels that he/she is experiencing symptoms and/or signs associated with hypoglycemia, and has a PG level of ≤70 mg/dL (≤3.9 mmol/L). |
| Change From Baseline in Body Weight at 24 Weeks | Baseline, Week 24 | LS mean of the body weight change from baseline to primary endpoint at week 24 was adjusted by treatment, country, SGLT2 inhibitor dose, metformin use, baseline HbA1c strata, treatment-by-visit interactions as fixed effects, and baseline body weight as a covariate and participant as a random effect, via a MMRM analysis |
Countries
Austria, Czechia, Germany, Hungary, Israel, Mexico, Puerto Rico, Spain, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 1.5 mg Dulaglutide Dulaglutide 1.5 milligrams (mg) given SC QW for 24 weeks. | 142 |
| 0.75 mg Dulaglutide Dulaglutide 0.75 mg given subcutaneously (SC) once a week (QW) for 24 weeks. | 141 |
| Placebo Placebo given SC QW for 24 weeks. | 140 |
| Total | 423 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 2 | 0 | 0 |
| Overall Study | Death | 2 | 0 | 0 |
| Overall Study | Lost to Follow-up | 0 | 3 | 2 |
| Overall Study | Noncompliant with Study Visits | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 2 | 2 | 1 |
Baseline characteristics
| Characteristic | Total | Placebo | 0.75 mg Dulaglutide | 1.5 mg Dulaglutide |
|---|---|---|---|---|
| Age, Continuous | 57.27 years STANDARD_DEVIATION 9.36 | 57.10 years STANDARD_DEVIATION 9.59 | 58.55 years STANDARD_DEVIATION 9.14 | 56.17 years STANDARD_DEVIATION 9.26 |
| Baseline Mean Hemoglobin A1c (HbA1c) Treatment-Regimen Estimand | 8.04 percentage of HbA1c STANDARD_DEVIATION 0.64 | 8.05 percentage of HbA1c STANDARD_DEVIATION 0.66 | 8.04 percentage of HbA1c STANDARD_DEVIATION 0.61 | 8.04 percentage of HbA1c STANDARD_DEVIATION 0.66 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 139 Participants | 44 Participants | 44 Participants | 51 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 281 Participants | 94 Participants | 97 Participants | 90 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants | 2 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 7 Participants | 4 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 12 Participants | 6 Participants | 3 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 25 Participants | 6 Participants | 8 Participants | 11 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 378 Participants | 124 Participants | 127 Participants | 127 Participants |
| Region of Enrollment Austria | 29 Participants | 9 Participants | 11 Participants | 9 Participants |
| Region of Enrollment Czechia | 73 Participants | 25 Participants | 23 Participants | 25 Participants |
| Region of Enrollment Germany | 33 Participants | 10 Participants | 11 Participants | 12 Participants |
| Region of Enrollment Hungary | 57 Participants | 19 Participants | 19 Participants | 19 Participants |
| Region of Enrollment Israel | 18 Participants | 6 Participants | 6 Participants | 6 Participants |
| Region of Enrollment Mexico | 83 Participants | 28 Participants | 28 Participants | 27 Participants |
| Region of Enrollment Spain | 42 Participants | 15 Participants | 13 Participants | 14 Participants |
| Region of Enrollment United States | 88 Participants | 28 Participants | 30 Participants | 30 Participants |
| Sex: Female, Male Female | 211 Participants | 74 Participants | 72 Participants | 65 Participants |
| Sex: Female, Male Male | 212 Participants | 66 Participants | 69 Participants | 77 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 142 | 0 / 141 | 0 / 140 |
| other Total, other adverse events | 43 / 142 | 34 / 141 | 29 / 140 |
| serious Total, serious adverse events | 5 / 142 | 3 / 141 | 5 / 140 |
Outcome results
Primary
Change From Baseline in Hemoglobin A1c (HbA1c) at 24 Weeks (Treatment-regimen Estimand)
Least Squares mean (LS) of the HbA1c change from baseline to primary endpoint at week 24 was adjusted by treatment, country, SGLT2 inhibitor dose, metformin use, treatment-by-visit interactions as fixed effects, and baseline HbA1c as a covariate and participant as a random effect, via a MMRM analysis. The treatment-regimen estimand used all data including post-rescue data and compared the benefit of treatment regimens as they were actually taken.
Time frame: Baseline, Week 24
Population: All randomized participants who received at least one dose of study medication and had evaluable data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 1.5 mg Dulaglutide | Change From Baseline in Hemoglobin A1c (HbA1c) at 24 Weeks (Treatment-regimen Estimand) | -1.34 percentage of HbA1c | Standard Error 0.064 |
| 0.75 mg Dulaglutide | Change From Baseline in Hemoglobin A1c (HbA1c) at 24 Weeks (Treatment-regimen Estimand) | -1.21 percentage of HbA1c | Standard Error 0.064 |
| Placebo | Change From Baseline in Hemoglobin A1c (HbA1c) at 24 Weeks (Treatment-regimen Estimand) | -0.54 percentage of HbA1c | Standard Error 0.064 |
p-value: <0.00195% CI: [-0.97, -0.61]Mixed Models Analysis
p-value: <0.00195% CI: [-0.84, -0.49]Mixed Models Analysis
Primary
Change From Baseline in the HbA1c at 24 Weeks (Efficacy Estimand)
LS mean of the HbA1c change from baseline to primary endpoint at week 24 was adjusted by treatment, country, SGLT2 inhibitor dose, metformin use, treatment-by-visit interactions as fixed effects, and baseline HbA1c as a covariate and participant as a random effect, via a MMRM analysis. The efficacy estimand excluded post-rescue data and compared the benefit of randomized treatments when taken as directed without rescue medication.
Time frame: Baseline, Week 24
Population: All randomized participants who received at least one dose of study drug and had a baseline and post-baseline value excluding values collected after rescue medication.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 1.5 mg Dulaglutide | Change From Baseline in the HbA1c at 24 Weeks (Efficacy Estimand) | -1.33 percentage of HbA1c | Standard Error 0.063 |
| 0.75 mg Dulaglutide | Change From Baseline in the HbA1c at 24 Weeks (Efficacy Estimand) | -1.19 percentage of HbA1c | Standard Error 0.063 |
| Placebo | Change From Baseline in the HbA1c at 24 Weeks (Efficacy Estimand) | -0.51 percentage of HbA1c | Standard Error 0.065 |
p-value: <0.00195% CI: [-1, -0.64]Mixed Models Analysis
p-value: <0.00195% CI: [-0.86, -0.51]Mixed Models Analysis
Secondary
Change From Baseline in 6-Point Self-Monitored Plasma Glucose (SMPG) Profile at 24 Weeks
The self-monitored plasma glucose (SMPG) data were collected at the following 6 time points: pre-morning meal; 2 hours post-morning meal; pre-midday meal; 2 hours post-midday meal; pre-evening meal; 2 hours post-evening meal. Least Squares (LS) means of change from baseline were calculated using a mixed-effects model for repeated measures (MMRM) with treatment, metformin use, SGLT2 inhibitor use, country, visit, baseline HbA1c strata, and treatment-by-visit interaction as fixed effects and baseline as a covariate.
Time frame: Baseline, Week 24
Population: All participants who received at least one dose of study drug and had baseline SMPG value and at least one post-baseline SMPG value.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| 1.5 mg Dulaglutide | Change From Baseline in 6-Point Self-Monitored Plasma Glucose (SMPG) Profile at 24 Weeks | Pre-morning Morning Meal | -27.8 mg/dL | Standard Error 2.13 |
| 1.5 mg Dulaglutide | Change From Baseline in 6-Point Self-Monitored Plasma Glucose (SMPG) Profile at 24 Weeks | 2-Hour Postprandial Morning Meal | -44.6 mg/dL | Standard Error 3.31 |
| 1.5 mg Dulaglutide | Change From Baseline in 6-Point Self-Monitored Plasma Glucose (SMPG) Profile at 24 Weeks | Pre-Mid Day Meal | -26.0 mg/dL | Standard Error 2.91 |
| 1.5 mg Dulaglutide | Change From Baseline in 6-Point Self-Monitored Plasma Glucose (SMPG) Profile at 24 Weeks | 2-Hour Postprandial Mid Day Meal | -31.8 mg/dL | Standard Error 3.47 |
| 1.5 mg Dulaglutide | Change From Baseline in 6-Point Self-Monitored Plasma Glucose (SMPG) Profile at 24 Weeks | Pre-Evening Meal | -30.3 mg/dL | Standard Error 2.85 |
| 1.5 mg Dulaglutide | Change From Baseline in 6-Point Self-Monitored Plasma Glucose (SMPG) Profile at 24 Weeks | 2-Hour Postprandial Evening Meal | -36.0 mg/dL | Standard Error 3.3 |
| 0.75 mg Dulaglutide | Change From Baseline in 6-Point Self-Monitored Plasma Glucose (SMPG) Profile at 24 Weeks | 2-Hour Postprandial Evening Meal | -30.6 mg/dL | Standard Error 3.31 |
| 0.75 mg Dulaglutide | Change From Baseline in 6-Point Self-Monitored Plasma Glucose (SMPG) Profile at 24 Weeks | Pre-morning Morning Meal | -23.2 mg/dL | Standard Error 2.17 |
| 0.75 mg Dulaglutide | Change From Baseline in 6-Point Self-Monitored Plasma Glucose (SMPG) Profile at 24 Weeks | 2-Hour Postprandial Mid Day Meal | -25.5 mg/dL | Standard Error 3.47 |
| 0.75 mg Dulaglutide | Change From Baseline in 6-Point Self-Monitored Plasma Glucose (SMPG) Profile at 24 Weeks | Pre-Evening Meal | -30.1 mg/dL | Standard Error 2.93 |
| 0.75 mg Dulaglutide | Change From Baseline in 6-Point Self-Monitored Plasma Glucose (SMPG) Profile at 24 Weeks | 2-Hour Postprandial Morning Meal | -41.1 mg/dL | Standard Error 3.3 |
| 0.75 mg Dulaglutide | Change From Baseline in 6-Point Self-Monitored Plasma Glucose (SMPG) Profile at 24 Weeks | Pre-Mid Day Meal | -22.0 mg/dL | Standard Error 2.94 |
| Placebo | Change From Baseline in 6-Point Self-Monitored Plasma Glucose (SMPG) Profile at 24 Weeks | 2-Hour Postprandial Morning Meal | -20.1 mg/dL | Standard Error 3.33 |
| Placebo | Change From Baseline in 6-Point Self-Monitored Plasma Glucose (SMPG) Profile at 24 Weeks | Pre-Mid Day Meal | -7.7 mg/dL | Standard Error 2.93 |
| Placebo | Change From Baseline in 6-Point Self-Monitored Plasma Glucose (SMPG) Profile at 24 Weeks | 2-Hour Postprandial Evening Meal | -13.9 mg/dL | Standard Error 3.38 |
| Placebo | Change From Baseline in 6-Point Self-Monitored Plasma Glucose (SMPG) Profile at 24 Weeks | 2-Hour Postprandial Mid Day Meal | -12.8 mg/dL | Standard Error 3.53 |
| Placebo | Change From Baseline in 6-Point Self-Monitored Plasma Glucose (SMPG) Profile at 24 Weeks | Pre-morning Morning Meal | -8.1 mg/dL | Standard Error 2.14 |
| Placebo | Change From Baseline in 6-Point Self-Monitored Plasma Glucose (SMPG) Profile at 24 Weeks | Pre-Evening Meal | -7.5 mg/dL | Standard Error 2.91 |
Comparison: Pre-morning meal.p-value: <0.00195% CI: [-25.7, -13.8]Mixed Models Analysis
Comparison: Pre-morning mealp-value: <0.00195% CI: [-21.2, -9.2]Mixed Models Analysis
Comparison: 2-hour postprandialp-value: <0.00195% CI: [-33.8, -15.3]Mixed Models Analysis
Comparison: 2-hour postprandialp-value: <0.00195% CI: [-30.3, -11.8]Mixed Models Analysis
Comparison: Pre-midday mealp-value: <0.00195% CI: [-26.4, -10.2]Mixed Models Analysis
Comparison: Pre-midday mealp-value: <0.00195% CI: [-22.5, -6.2]Mixed Models Analysis
Comparison: 2-hour postprandial after midday mealp-value: <0.00195% CI: [-28.8, -9.3]Mixed Models Analysis
Comparison: 2-hour postprandial after midday mealp-value: 0.0195% CI: [-22.5, -3.1]Mixed Models Analysis
Comparison: Pre-evening mealp-value: <0.00195% CI: [-30.7, -14.7]Mixed Models Analysis
Comparison: Pre-evening mealp-value: <0.00195% CI: [-30.7, -14.4]Mixed Models Analysis
Comparison: 2-hour postprandial after evening mealp-value: <0.00195% CI: [-31.4, -12.9]Mixed Models Analysis
Comparison: 2-hour postprandial after evening mealp-value: <0.00195% CI: [-26, -7.4]Mixed Models Analysis
Secondary
Change From Baseline in Body Weight at 24 Weeks
LS mean of the body weight change from baseline to primary endpoint at week 24 was adjusted by treatment, country, SGLT2 inhibitor dose, metformin use, baseline HbA1c strata, treatment-by-visit interactions as fixed effects, and baseline body weight as a covariate and participant as a random effect, via a MMRM analysis
Time frame: Baseline, Week 24
Population: All participants who received at least one dose of study drug.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| 1.5 mg Dulaglutide | Change From Baseline in Body Weight at 24 Weeks | Treatment-regimen Estimand | -3.1 kilograms (kg) | Standard Error 0.3 |
| 1.5 mg Dulaglutide | Change From Baseline in Body Weight at 24 Weeks | Efficacy Estimand | -3.1 kilograms (kg) | Standard Error 0.3 |
| 0.75 mg Dulaglutide | Change From Baseline in Body Weight at 24 Weeks | Treatment-regimen Estimand | -2.6 kilograms (kg) | Standard Error 0.3 |
| 0.75 mg Dulaglutide | Change From Baseline in Body Weight at 24 Weeks | Efficacy Estimand | -2.6 kilograms (kg) | Standard Error 0.3 |
| Placebo | Change From Baseline in Body Weight at 24 Weeks | Treatment-regimen Estimand | -2.1 kilograms (kg) | Standard Error 0.3 |
| Placebo | Change From Baseline in Body Weight at 24 Weeks | Efficacy Estimand | -2.3 kilograms (kg) | Standard Error 0.31 |
Comparison: Treatment-regimen Estimandp-value: 0.02795% CI: [-1.8, -0.1]Mixed Models Analysis
Comparison: Treatment-regimen Estimandp-value: 0.26495% CI: [-1.3, 0.4]Mixed Models Analysis
Comparison: Efficacy Estimandp-value: 0.05995% CI: [-1.7, 0]Mixed Models Analysis
Comparison: Efficacy Estimandp-value: 0.43595% CI: [-1.2, 0.5]Mixed Models Analysis
Secondary
Change From Baseline in Fasting Glucagon at 24 Weeks
Change from baseline in fasting glucagon was analyzed using an ANCOVA model with last observation carried forward (LOCF) included in treatment, country, SGLT2i dose, metformin use, and baseline HbA1c strata as fixed effects and baseline fasting glucagon as a covariate (with and without post rescue data).
Time frame: Baseline, Week 24
Population: All participants who received at least one dose of study drug and with non-missing baseline values and at least one post-baseline value at the specified time point.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| 1.5 mg Dulaglutide | Change From Baseline in Fasting Glucagon at 24 Weeks | Treatment-regimen Estimand | -2.1 picomole per liter (pmol/L) | Standard Error 0.39 |
| 1.5 mg Dulaglutide | Change From Baseline in Fasting Glucagon at 24 Weeks | Efficacy Estimand | -2.2 picomole per liter (pmol/L) | Standard Error 0.39 |
| 0.75 mg Dulaglutide | Change From Baseline in Fasting Glucagon at 24 Weeks | Treatment-regimen Estimand | -1.5 picomole per liter (pmol/L) | Standard Error 0.39 |
| 0.75 mg Dulaglutide | Change From Baseline in Fasting Glucagon at 24 Weeks | Efficacy Estimand | -1.4 picomole per liter (pmol/L) | Standard Error 0.39 |
| Placebo | Change From Baseline in Fasting Glucagon at 24 Weeks | Treatment-regimen Estimand | -0.9 picomole per liter (pmol/L) | Standard Error 0.4 |
| Placebo | Change From Baseline in Fasting Glucagon at 24 Weeks | Efficacy Estimand | -0.9 picomole per liter (pmol/L) | Standard Error 0.41 |
Comparison: Treatment-regimen Estimandp-value: 0.03295% CI: [-2.3, -0.1]ANCOVA
Comparison: Treatment-regimen Estimandp-value: 0.27395% CI: [-1.7, 0.5]ANCOVA
Comparison: Efficacy Estimandp-value: 0.02395% CI: [-2.4, -0.2]ANCOVA
Comparison: Efficacy Estimandp-value: 0.3295% CI: [-1.7, 0.6]ANCOVA
Secondary
Change From Baseline in Fasting Serum Glucose (Central Laboratory) at 24 Weeks
LS mean of change from baseline was calculated using last observation carried forward (LOCF) by treatment group, adjusted for treatment, country, SGLT2 inhibitor dose, metformin use, baseline HbA1c strata, and baseline fasting serum glucose using analysis of covariance (ANCOVA).
Time frame: Baseline, Week 24
Population: All participants who received at least one dose of study drug and had baseline and at least one post-baseline value.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| 1.5 mg Dulaglutide | Change From Baseline in Fasting Serum Glucose (Central Laboratory) at 24 Weeks | Treatment-regimen Estimand | -31.6 milligram/deciliter (mg/dL) | Standard Error 2.17 |
| 1.5 mg Dulaglutide | Change From Baseline in Fasting Serum Glucose (Central Laboratory) at 24 Weeks | Efficacy Estimand | -31.9 milligram/deciliter (mg/dL) | Standard Error 2.11 |
| 0.75 mg Dulaglutide | Change From Baseline in Fasting Serum Glucose (Central Laboratory) at 24 Weeks | Treatment-regimen Estimand | -26.5 milligram/deciliter (mg/dL) | Standard Error 2.18 |
| 0.75 mg Dulaglutide | Change From Baseline in Fasting Serum Glucose (Central Laboratory) at 24 Weeks | Efficacy Estimand | -26.0 milligram/deciliter (mg/dL) | Standard Error 2.12 |
| Placebo | Change From Baseline in Fasting Serum Glucose (Central Laboratory) at 24 Weeks | Treatment-regimen Estimand | -6.9 milligram/deciliter (mg/dL) | Standard Error 2.21 |
| Placebo | Change From Baseline in Fasting Serum Glucose (Central Laboratory) at 24 Weeks | Efficacy Estimand | -5.3 milligram/deciliter (mg/dL) | Standard Error 2.21 |
Comparison: Treatment-regimen Estimandp-value: <0.00195% CI: [-30.8, -18.6]ANCOVA
Comparison: Treatment-regimen Estimandp-value: <0.00195% CI: [-25.7, -13.5]ANCOVA
Comparison: Efficacy Estimandp-value: <0.00195% CI: [-32.7, -20.6]ANCOVA
Comparison: Efficacy Estimandp-value: <0.00195% CI: [-26.7, -14.6]ANCOVA
Secondary
Number of Participants Requiring Rescue Therapy Due to Severe Persistent Hyperglycemia
Rescue therapy was defined as any additional therapeutic intervention in participants who developed persistent, severe hyperglycemia despite full compliance with the assigned therapeutic regimen, or initiation of an alternative antihyperglycemic medication following study drug discontinuation.
Time frame: Baseline through 24 Weeks
Population: All participants who had at least one dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 1.5 mg Dulaglutide | Number of Participants Requiring Rescue Therapy Due to Severe Persistent Hyperglycemia | 0 Participants |
| 0.75 mg Dulaglutide | Number of Participants Requiring Rescue Therapy Due to Severe Persistent Hyperglycemia | 3 Participants |
| Placebo | Number of Participants Requiring Rescue Therapy Due to Severe Persistent Hyperglycemia | 2 Participants |
Secondary
Number of Participants With Adjudicated Acute Pancreatitis Events
The number of participants with events of pancreatitis confirmed by adjudication were summarized cumulatively at 24 weeks. Pancreatitis events were adjudicated by a committee of physicians external to the Sponsor. A summary of serious and other non-serious events regardless of causality is located in the Reported Adverse Events module.
Time frame: Baseline through 24 Weeks
Population: All participants who received at least one dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 1.5 mg Dulaglutide | Number of Participants With Adjudicated Acute Pancreatitis Events | 0 Participants |
| 0.75 mg Dulaglutide | Number of Participants With Adjudicated Acute Pancreatitis Events | 0 Participants |
| Placebo | Number of Participants With Adjudicated Acute Pancreatitis Events | 0 Participants |
Secondary
Number of Participants With Adjudicated Cardiovascular (CV) Events
Death and selected nonfatal CV adverse events (AEs) were adjudicated by an independent committee of physicians with cardiology expertise external to the Sponsor. Nonfatal CV events that were to be adjudicated were myocardial infarction (MI); hospitalization for unstable angina; hospitalization for heart failure; coronary interventions such as coronary artery bypass graft (CABG) or ( percutaneous coronary intervention (PCI); and cerebrovascular events, including cerebrovascular accident (stroke) and transient ischemic attack (TIA).
Time frame: Baseline through 24 Weeks
Population: All participants who received at least one dose of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| 1.5 mg Dulaglutide | Number of Participants With Adjudicated Cardiovascular (CV) Events | Fatal CV Event | 0 Participants |
| 1.5 mg Dulaglutide | Number of Participants With Adjudicated Cardiovascular (CV) Events | Any CV Event | 0 Participants |
| 1.5 mg Dulaglutide | Number of Participants With Adjudicated Cardiovascular (CV) Events | Non-fatal CV Event | 0 Participants |
| 0.75 mg Dulaglutide | Number of Participants With Adjudicated Cardiovascular (CV) Events | Fatal CV Event | 0 Participants |
| 0.75 mg Dulaglutide | Number of Participants With Adjudicated Cardiovascular (CV) Events | Any CV Event | 0 Participants |
| 0.75 mg Dulaglutide | Number of Participants With Adjudicated Cardiovascular (CV) Events | Non-fatal CV Event | 0 Participants |
| Placebo | Number of Participants With Adjudicated Cardiovascular (CV) Events | Any CV Event | 3 Participants |
| Placebo | Number of Participants With Adjudicated Cardiovascular (CV) Events | Non-fatal CV Event | 3 Participants |
| Placebo | Number of Participants With Adjudicated Cardiovascular (CV) Events | Fatal CV Event | 0 Participants |
Secondary
Percentage of Participants With HbA1c <7%
Number of participants with an HbA1c value of \<7% at Week 24 is measured using longitudinal logistic regression with repeated measurements. The model will include independent variables of treatment, country, SGLT2 inhibitor dose, metformin use, visit, treatment-by-visit interaction, and baseline HbA1c as a covariate.
Time frame: 24 Weeks
Population: All participants who received at least one dose of Dulaglutide with HbA1c \<7% at Week 24.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 1.5 mg Dulaglutide | Percentage of Participants With HbA1c <7% | Efficacy Estimand | 71.54 percentage of participants |
| 1.5 mg Dulaglutide | Percentage of Participants With HbA1c <7% | Treatment-regimen Estimand | 71.21 percentage of participants |
| 0.75 mg Dulaglutide | Percentage of Participants With HbA1c <7% | Efficacy Estimand | 61.83 percentage of participants |
| 0.75 mg Dulaglutide | Percentage of Participants With HbA1c <7% | Treatment-regimen Estimand | 60.45 percentage of participants |
| Placebo | Percentage of Participants With HbA1c <7% | Efficacy Estimand | 32.52 percentage of participants |
| Placebo | Percentage of Participants With HbA1c <7% | Treatment-regimen Estimand | 31.58 percentage of participants |
Comparison: Treatment-regimen Estimandp-value: <0.001Regression, Logistic
Comparison: Treatment-regimen Estimandp-value: <0.001Regression, Logistic
Comparison: Efficacy Estimandp-value: <0.001Regression, Logistic
Comparison: Efficacy Estimandp-value: <0.001Regression, Logistic
Secondary
Rate of Hypoglycemic Events Adjusted Per 30 Days
A hypoglycemic event is defined as any time a participant feels that he/she is experiencing symptoms and/or signs associated with hypoglycemia, and has a PG level of ≤70 mg/dL (≤3.9 mmol/L).
Time frame: Baseline through 24 Weeks
Population: All participants who received at least one dose of study drug.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 1.5 mg Dulaglutide | Rate of Hypoglycemic Events Adjusted Per 30 Days | Total Hypoglycemia | 0.026 Number of events/participant/30 days | Standard Deviation 0.1827 |
| 1.5 mg Dulaglutide | Rate of Hypoglycemic Events Adjusted Per 30 Days | Documented Symptomatic Hypoglycemia | 0.013 Number of events/participant/30 days | Standard Deviation 0.1406 |
| 1.5 mg Dulaglutide | Rate of Hypoglycemic Events Adjusted Per 30 Days | Asymptomatic Hypoglycemia | 0.013 Number of events/participant/30 days | Standard Deviation 0.118 |
| 1.5 mg Dulaglutide | Rate of Hypoglycemic Events Adjusted Per 30 Days | Probable Symptomatic | 0.000 Number of events/participant/30 days | Standard Deviation 0 |
| 1.5 mg Dulaglutide | Rate of Hypoglycemic Events Adjusted Per 30 Days | Relative Hypoglycemia | 0.003 Number of events/participant/30 days | Standard Deviation 0.0311 |
| 1.5 mg Dulaglutide | Rate of Hypoglycemic Events Adjusted Per 30 Days | Nocturnal Hypoglycemia | 0.002 Number of events/participant/30 days | Standard Deviation 0.0288 |
| 0.75 mg Dulaglutide | Rate of Hypoglycemic Events Adjusted Per 30 Days | Nocturnal Hypoglycemia | 0.009 Number of events/participant/30 days | Standard Deviation 0.0821 |
| 0.75 mg Dulaglutide | Rate of Hypoglycemic Events Adjusted Per 30 Days | Total Hypoglycemia | 0.022 Number of events/participant/30 days | Standard Deviation 0.1375 |
| 0.75 mg Dulaglutide | Rate of Hypoglycemic Events Adjusted Per 30 Days | Probable Symptomatic | 0.001 Number of events/participant/30 days | Standard Deviation 0.0152 |
| 0.75 mg Dulaglutide | Rate of Hypoglycemic Events Adjusted Per 30 Days | Relative Hypoglycemia | 0.001 Number of events/participant/30 days | Standard Deviation 0.015 |
| 0.75 mg Dulaglutide | Rate of Hypoglycemic Events Adjusted Per 30 Days | Documented Symptomatic Hypoglycemia | 0.013 Number of events/participant/30 days | Standard Deviation 0.103 |
| 0.75 mg Dulaglutide | Rate of Hypoglycemic Events Adjusted Per 30 Days | Asymptomatic Hypoglycemia | 0.008 Number of events/participant/30 days | Standard Deviation 0.0639 |
| Placebo | Rate of Hypoglycemic Events Adjusted Per 30 Days | Documented Symptomatic Hypoglycemia | 0.010 Number of events/participant/30 days | Standard Deviation 0.0893 |
| Placebo | Rate of Hypoglycemic Events Adjusted Per 30 Days | Asymptomatic Hypoglycemia | 0.006 Number of events/participant/30 days | Standard Deviation 0.054 |
| Placebo | Rate of Hypoglycemic Events Adjusted Per 30 Days | Nocturnal Hypoglycemia | 0.000 Number of events/participant/30 days | Standard Deviation 0 |
| Placebo | Rate of Hypoglycemic Events Adjusted Per 30 Days | Probable Symptomatic | 0.001 Number of events/participant/30 days | Standard Deviation 0.0147 |
| Placebo | Rate of Hypoglycemic Events Adjusted Per 30 Days | Total Hypoglycemia | 0.017 Number of events/participant/30 days | Standard Deviation 0.132 |
| Placebo | Rate of Hypoglycemic Events Adjusted Per 30 Days | Relative Hypoglycemia | 0.005 Number of events/participant/30 days | Standard Deviation 0.0493 |