Diabetes, Diabetes Mellitus, Type 2
Conditions
Brief summary
This trial is conducted in Asia, Europe and North America. The aim of the trial is to investigate the efficacy and safety of switching from sitagliptin to liraglutide in subjects with type 2 diabetes not achieving adequate glycaemic control on sitagliptin and metformin.
Interventions
DRUGliraglutide
Starting dose of 0.6 mg/day, with weekly dose escalations of 0.6 mg/day until the maintenance dose of 1.8 mg/day is reached. Administered subcutaneously (s.c., under the skin) once daily + metformin tablets (at least 1000 mg/day)
DRUGsitagliptin
100 mg/day sitagliptin tablets once-daily + metformin (at least 1000 mg/day)
DRUGplacebo
Sitagliptin placebo tablets once-daily
Sponsors
Novo Nordisk A/S
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
* \- Informed consent obtained before any trial-related activities. Trial-related activities are any procedures that are carried out as part of the trial, including activities to determine suitability for the trial * \- Subjects diagnosed with type 2 diabetes and treated with metformin equal to or above 1500 mg/day (or maximum tolerated dose equal to or above 1000 mg/day) and sitagliptin 100 mg/day, both at a stable dose for at least 90 days prior to screening. Stable is defined as unchanged medication and dose * \- HbA1c 7.5% - 9.5% (58 mmol/mol - 80 mmol/mol) (both inclusive) * \- Body mass index equal to or above 20 kg/m\^2
Exclusion criteria
* \- Any chronic disorder or severe disease which at the discretion of the investigator might jeopardise subject's safety or compliance with the protocol * \- Treatment with glucose lowering agent(s) other than stated in the inclusion criteria in a period of 90 days prior to screening. An exception is short-term treatment (equal to or less than 7 days in total) with insulin in connection with intercurrent illness * \- Female who is pregnant, breast-feeding, intends to become pregnant or of child-bearing potential not using adequate contraceptive methods (adequate contraceptive measures as required by local regulations or practice) * \- History of chronic pancreatitis or idiopathic acute pancreatitis * \- Screening calcitonin value equal to or above 50 ng/L * \- Personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2 * \- Diagnosis of malignant neoplasm in the previous 5 years (except basal cell skin cancer or squamous cell skin cancer) * \- Impaired liver function, defined as alanine aminotransferase equal to or above 2.5 times upper normal limit * \- Impaired renal function defined as estimated glomerular filtration rate 60 mL/min/1.73 m\^2 per modification of diet in renal disease formula * \- Any episode of unstable angina, acute coronary event, cerebral stroke/transient ischemic attack or other significant cardiovascular event as judged by the investigator within 90 days prior to screening * \- Heart failure, New York Heart Association class IV * \- Uncontrolled treated or untreated hypertension (systolic blood pressure equal to or above 180 mmHg and/or diastolic blood pressure equal to or above 100 mmHg)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in HbA1c (Glycosylated Haemoglobin) | From baseline to week 26 | Change from baseline in HbA1c was analysed after 26 weeks of treatment. Analysis population set: full analysis set (FAS); all randomised subjects receiving at least one dose of any of the trial products. Missing values were imputed using mixed model for repeated measurements (MMRM). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Fasting Plasma Glucose | From baseline to week 26 | Change from baseline in fasting plasma glucose was analysed after 26 weeks of treatment. Missing values were imputed using MMRM. |
| Change in Fasting Blood Lipids | From baseline to week 26 | Ratio to baseline in fasting blood lipids (total cholesterol, low density lipoprotein \[LDL\], very low density lipoprotein \[VLDL\], high density lipoprotein \[HDL\], triglycerides, and free fatty acids) were analysed after 26 weeks treatment. Missing values were imputed using MMRM. Here we are presenting ratio to baseline data. |
| Change in Body Weight | From baseline to week 26 | Change from baseline in body weight was analysed after 26 weeks of treatment. Analysis population set: FAS: all randomised subjects receiving at least one dose of any of the trial products. Missing values were imputed using MMRM. |
| Subjects Who Achieve HbA1c Below 7.0% (53 mmol/Mol) (American Diabetes Association Target) (y/n) | After 26 weeks of treatment | Number of subjects who achieve HbA1c \<7.0% were analysed after 26 weeks of treatment. Missing values were imputed using MMRM. |
| Number of Treatment Emergent Adverse Events (TEAEs) | During 26 weeks of treatment plus one week follow-up period. | A treatment emergent adverse event (TEAE) was defined as an event that had an onset date (or increase in severity) on or after the first day of exposure to randomised treatment and no later than seven days after the last day of randomised treatment. The number of TEAEs was recorded during 26 weeks of treatment plus one week follow-up period. |
| Change in Systolic Blood Pressure and Diastolic Blood Pressure | From baseline to week 26 | Change from baseline in systolic and diastolic blood pressure were analysed after 26 weeks of treatment. Missing values were imputed using MMRM. |
Countries
Canada, Hungary, India, Israel, Puerto Rico, Spain, United States
Participant flow
Recruitment details
The trial was conducted at 86 sites in 6 countries: Canada (14); Hungary (8); India (7); Israel (8); Spain (6); and United States (43).
Pre-assignment details
Screening details: Subjects were adult males or females with type 2 diabetes mellitus (T2DM) who had inadequate glycaemic control with stable doses of sitagliptin and metformin for 90 days prior to screening.
Participants by arm
| Arm | Count |
|---|---|
| Liraglutide Subjects in this arm received treatments for a duration of 26 weeks; once-daily (OD) liraglutide (s.c., \[under the skin\] injection 0.6 mg/day, with weekly dose escalations of 0.6 mg/day up to a maintenance dose of 1.8 mg/day) + metformin tablets (≥1500 mg/day \[or documented maximum tolerated dose
≥1000 mg/day\]) + OD sitagliptin placebo tablets. | 202 |
| Sitagliptin Subjects in this arm received treatments for a duration of 26 weeks; OD sitagliptin tablets (100 mg) + metformin tablets (≥1500 mg/day \[or documented maximum tolerated dose ≥1000 mg/day\]) + OD s.c., injection of liraglutide placebo. | 204 |
| Total | 406 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 2 | 2 |
| Overall Study | Protocol Violation | 1 | 1 |
| Overall Study | Unclassified | 4 | 3 |
| Overall Study | Withdrawal by Subject | 9 | 7 |
Baseline characteristics
| Characteristic | Sitagliptin | Total | Liraglutide |
|---|---|---|---|
| Age, Continuous | 56.5 years STANDARD_DEVIATION 9.7 | 56.4 years STANDARD_DEVIATION 10.2 | 56.3 years STANDARD_DEVIATION 10.6 |
| Body Weight | 91.2 kg STANDARD_DEVIATION 19.6 | 90.1 kg STANDARD_DEVIATION 19.7 | 88.9 kg STANDARD_DEVIATION 19.8 |
| Fasting Plasma Glucose | 9.7 mmol/L STANDARD_DEVIATION 2.5 | 9.9 mmol/L STANDARD_DEVIATION 2.6 | 10.0 mmol/L STANDARD_DEVIATION 2.7 |
| HbA1c | 8.2 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.6 | 8.3 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.6 | 8.3 percentage of glycosylated haemoglobin STANDARD_DEVIATION 0.6 |
| Sex: Female, Male Female | 79 Participants | 164 Participants | 85 Participants |
| Sex: Female, Male Male | 125 Participants | 242 Participants | 117 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 96 / 202 | 61 / 204 |
| serious Total, serious adverse events | 6 / 202 | 7 / 204 |
Outcome results
Primary
Change in HbA1c (Glycosylated Haemoglobin)
Change from baseline in HbA1c was analysed after 26 weeks of treatment. Analysis population set: full analysis set (FAS); all randomised subjects receiving at least one dose of any of the trial products. Missing values were imputed using mixed model for repeated measurements (MMRM).
Time frame: From baseline to week 26
Population: Full analysis set (FAS) -All randomised subjects receiving at least one dose of any of the trial product.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Liraglutide | Change in HbA1c (Glycosylated Haemoglobin) | -1.146 percentage of glycosylated haemoglobin | Standard Deviation 0.9748 |
| Sitagliptin | Change in HbA1c (Glycosylated Haemoglobin) | -0.529 percentage of glycosylated haemoglobin | Standard Deviation 1.0148 |
Comparison: Changes in HbA1c from baseline to the 26 weeks measurements were analysed using MMRM, with treatment, baseline HbA1c level (≤8.5% and \>8.5%), metformin dose (\<1500 mg/day and ≥1500 mg/day), the interaction between baseline HbA1c level and metformin dose, and country as factors and the HbA1c value at baseline as a covariate, all variables nested within week as a factor.p-value: <0.000195% CI: [-0.82, -0.4]Mixed Models Analysis
Secondary
Change in Body Weight
Change from baseline in body weight was analysed after 26 weeks of treatment. Analysis population set: FAS: all randomised subjects receiving at least one dose of any of the trial products. Missing values were imputed using MMRM.
Time frame: From baseline to week 26
Population: FAS - All randomised subjects receiving at least one dose of any of the trial product.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Liraglutide | Change in Body Weight | -3.32 kg | Standard Deviation 3.135 |
| Sitagliptin | Change in Body Weight | -1.80 kg | Standard Deviation 2.974 |
Comparison: Change in body weight from baseline to the 26 weeks measurements was analysed using MMRM, with treatment, baseline HbA1c level (≤8.5% and \>8.5%), metformin dose (\<1500 mg/day and ≥1500 mg/day), the interaction between baseline HbA1c level and metformin dose, and country as factors and the body weight at baseline as a covariate and all variables nested within week as a factor.p-value: <0.000195% CI: [-2.34, -0.99]Mixed Models Analysis
Secondary
Change in Fasting Blood Lipids
Ratio to baseline in fasting blood lipids (total cholesterol, low density lipoprotein \[LDL\], very low density lipoprotein \[VLDL\], high density lipoprotein \[HDL\], triglycerides, and free fatty acids) were analysed after 26 weeks treatment. Missing values were imputed using MMRM. Here we are presenting ratio to baseline data.
Time frame: From baseline to week 26
Population: FAS-All randomised subjects receiving at least one dose of any of the trial product. There were missing baseline values for free fatty acids in 1 subject in the liraglutide arm and 6 subjects in the sitagliptin arm.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Liraglutide | Change in Fasting Blood Lipids | Total cholesterol | 1.011 ratio | Standard Deviation 0.1906 |
| Liraglutide | Change in Fasting Blood Lipids | LDL cholesterol | 1.049 ratio | Standard Deviation 0.3899 |
| Liraglutide | Change in Fasting Blood Lipids | VLDL cholesterol | 1.062 ratio | Standard Deviation 0.4236 |
| Liraglutide | Change in Fasting Blood Lipids | HDL cholesterol | 1.004 ratio | Standard Deviation 0.1528 |
| Liraglutide | Change in Fasting Blood Lipids | Triglycerides | 1.089 ratio | Standard Deviation 0.4975 |
| Liraglutide | Change in Fasting Blood Lipids | Free Fatty acids | 1.086 ratio | Standard Deviation 0.774 |
| Sitagliptin | Change in Fasting Blood Lipids | Triglycerides | 1.099 ratio | Standard Deviation 0.4889 |
| Sitagliptin | Change in Fasting Blood Lipids | Total cholesterol | 1.045 ratio | Standard Deviation 0.2323 |
| Sitagliptin | Change in Fasting Blood Lipids | HDL cholesterol | 0.997 ratio | Standard Deviation 0.1548 |
| Sitagliptin | Change in Fasting Blood Lipids | LDL cholesterol | 1.121 ratio | Standard Deviation 0.4661 |
| Sitagliptin | Change in Fasting Blood Lipids | Free Fatty acids | 1.104 ratio | Standard Deviation 0.5839 |
| Sitagliptin | Change in Fasting Blood Lipids | VLDL cholesterol | 1.075 ratio | Standard Deviation 0.4625 |
Secondary
Change in Fasting Plasma Glucose
Change from baseline in fasting plasma glucose was analysed after 26 weeks of treatment. Missing values were imputed using MMRM.
Time frame: From baseline to week 26
Population: FAS - All randomised subjects receiving at least one dose of any of the trial product.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Liraglutide | Change in Fasting Plasma Glucose | -1.967 nmol/L | Standard Deviation 2.3585 |
| Sitagliptin | Change in Fasting Plasma Glucose | -0.588 nmol/L | Standard Deviation 2.1363 |
Secondary
Change in Systolic Blood Pressure and Diastolic Blood Pressure
Change from baseline in systolic and diastolic blood pressure were analysed after 26 weeks of treatment. Missing values were imputed using MMRM.
Time frame: From baseline to week 26
Population: FAS - All randomised subjects receiving at least one dose of any of the trial product
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Liraglutide | Change in Systolic Blood Pressure and Diastolic Blood Pressure | Systolic Blood Pressure | -3.6 mmHg | Standard Deviation 11.596 |
| Liraglutide | Change in Systolic Blood Pressure and Diastolic Blood Pressure | Diastolic Blood Pressure | -0.23 mmHg | Standard Deviation 7.085 |
| Sitagliptin | Change in Systolic Blood Pressure and Diastolic Blood Pressure | Systolic Blood Pressure | -2.57 mmHg | Standard Deviation 11.593 |
| Sitagliptin | Change in Systolic Blood Pressure and Diastolic Blood Pressure | Diastolic Blood Pressure | -0.81 mmHg | Standard Deviation 7.193 |
Secondary
Number of Treatment Emergent Adverse Events (TEAEs)
A treatment emergent adverse event (TEAE) was defined as an event that had an onset date (or increase in severity) on or after the first day of exposure to randomised treatment and no later than seven days after the last day of randomised treatment. The number of TEAEs was recorded during 26 weeks of treatment plus one week follow-up period.
Time frame: During 26 weeks of treatment plus one week follow-up period.
Population: Safety analysis set-All randomised subjects receiving at least one dose of any of the trial product.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Liraglutide | Number of Treatment Emergent Adverse Events (TEAEs) | 455 number of events |
| Sitagliptin | Number of Treatment Emergent Adverse Events (TEAEs) | 318 number of events |
Secondary
Subjects Who Achieve HbA1c Below 7.0% (53 mmol/Mol) (American Diabetes Association Target) (y/n)
Number of subjects who achieve HbA1c \<7.0% were analysed after 26 weeks of treatment. Missing values were imputed using MMRM.
Time frame: After 26 weeks of treatment
Population: FAS-All randomised subjects receiving at least one dose of any of the trial product.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Liraglutide | Subjects Who Achieve HbA1c Below 7.0% (53 mmol/Mol) (American Diabetes Association Target) (y/n) | Yes | 50.6 percentage (%) |
| Liraglutide | Subjects Who Achieve HbA1c Below 7.0% (53 mmol/Mol) (American Diabetes Association Target) (y/n) | No | 49.4 percentage (%) |
| Sitagliptin | Subjects Who Achieve HbA1c Below 7.0% (53 mmol/Mol) (American Diabetes Association Target) (y/n) | Yes | 26.9 percentage (%) |
| Sitagliptin | Subjects Who Achieve HbA1c Below 7.0% (53 mmol/Mol) (American Diabetes Association Target) (y/n) | No | 73.1 percentage (%) |