Diabetes Mellitus, Type 2
Conditions
Brief summary
In this study, the researchers hope to learn about SGLT2 inhibition on EGP (endogenous glucose production) and plasma glucose concentration in diabetic subjects. Researchers will examine diabetes and the role of increased plasma glucagon, decline in plasma insulin, and fall in plasma glucose concentration.
Detailed description
This study will examine whether the coadministration of exenatide plus dapagliflozin will prevent the increase in EGP and result in an additive or even synergistic decrease in plasma glucose concentration compared to each agent alone.
Interventions
DRUGDapagliflozin
10mg
DRUGExenatide
Byetta 5 to 10 ug (twice daily) Bydureon 2mg (once weekly)
DRUGPlacebo
Placebo for Dapagliflozin
Sponsors
AstraZeneca
The University of Texas Health Science Center at San Antonio
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
1. BMI = 25-35 kg/m\^2 2. must be drug naïve and/or on a stable dose (more than 3 months) of metformin and/or sulfonylurea 3. HbA1c \>7.0% and \<10.0% 4. Other than diabetes, subjects must be in good general health as determined by physical exam, medical history, blood chemistries, CBC, TSH, T4, EKG and urinanalysis. 5. Only subjects whose body weight has been stable (± 3 lbs) over the preceding three months and who do not participate in an excessively heavy exercise program will be included.
Exclusion criteria
1. Presence of significant systemic disease, heart problems including congestive heart failure, unstable angina or acute myocardial infarction, current infectious liver disease, acute stroke or transient ischemic attacks, history of pancreatitis, urosepsis and pyelonephritis, genital mycotic infections, or Type 1 diabetes mellitus 2. Any hepatic diseases in the past (infectious liver disease, viral hepatitis, toxic hepatic damage, jaundice of unknown etiology) or severe hepatic insufficiency and/or significant abnormal liver function tests defined as aspartate aminotransferase (AST) \>3x upper limit of normal (ULN) and/or alanine aminotransferase (ALT) \>3x ULN 3. Renal impairment (e.g., serum creatinine levels ≥1.4 mg/dL for women or ≥1.5 mg/dl for men, or eGFR \<60 mL/min/1.73 m2) or history of unstable or rapidly progressing renal disease or end stage renal disease. 4. Uncontrolled thyroid disease , Cushing's syndrome, congenital adrenal hyperplasia or hyperprolactinemia 5. Significantly elevated triglyceride levels (fasting triglyceride \> 400 mg/dl), uncontrolled increased LDL-C 6. Untreated or poorly controlled hypertension (sitting blood pressure \> 160/95 mm Hg) 7. Use of anti-obesity drugs or weight loss medications (prescription or OTC) and medications known to exacerbate glucose tolerance (such as isotretinoin, , GnRH agonists, glucocorticoids, anabolic steroids, C-19 progestins) stopped for at least 8 weeks. Use of anti-androgens that act peripherally to reduce hirsutism such as 5-alpha reductase inhibitors (finesteride, spironolactone, flutamide) stopped for at least 4 weeks 8. Prior history of a malignant disease requiring chemotherapy, prior history of bladder cancer regardless treatment 9. Patients at risk for volume depletion due to co-existing conditions or concomitant medications, such as loop diuretics should have careful monitoring of their volume status 10. History of unexplained microscopic or gross hematuria, or microscopic hematuria at visit 1, confirmed by a follow-up sample at next scheduled visit. 11. Presence of hypersensitivity to dapagliflozin or other SGLT2 inhibitors (e.g. anaphylaxis, angioedema, exfoliative skin conditions 12. Known hypersensitivity or contraindications to use GLP1 receptor agonists (exenatide, liraglutide) 13. Use of , thiazolidinediones, GLP-1 receptor agonists, DPP-4 inhibitors, SGLT2 inhibitors stopped for at least 8 weeks. 14. Eating disorders (anorexia, bulimia) or gastrointestinal disorders 15. Suspected pregnancy (documented negative serum β-hCG test), desiring pregnancy in next 6 months, breastfeeding, or known pregnancy in last 2 months 16. Active history of illicit substance abuse or significant intake of alcohol 17. Having a history of bariatric surgery 18. Patient not willing to use two barrier method contraception during study period (unless sterilized or have an IUD) 19. Debilitating uncontrolled psychiatric disorder such as psychosis or neurological condition that might confound outcome variables 20. Inability or refusal to comply with protocol 21. Current participation or participation in an experimental drug study in previous three months
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Endogenous Glucose Production (EGP) After Acute Exposure to a Single Dose and Again After 16 Weeks of Treatment | ACUTE [after a single dose of each study drug or placebo] | After screening, eligible subjects will receive a measurement of endogenous glucose production (EGP) with a prime-continuous infusion of 3-3H-glucose. The EGP measurement will be performed in the morning after a 10-12 hour overnight fast and will last 8.5 hours (from 6 AM to 2:30 PM). After a 3.5-hour tracer equilibration period, subjects (20 per group) will receive one of the following medications: (i) placebo; (ii) exenatide 5 ug subcutaneously; (iii) dapagliflozin (10 mg); and (iv) dapagliflozin 10 mg + exenatide 5 ug \[ACUTE STUDY\]. |
| Change in Endogenous Glucose Production (EGP) After 16 Weeks of Treatment With Each Study Drug. | 16 weeks | After screening, eligible subjects will receive a measurement of endogenous glucose production (EGP) with a prime-continuous infusion of 3-3H-glucose. The EGP measurement will be performed in the morning after a 10-12 hour overnight fast and will last 8.5 hours (from 6 AM to 2:30 PM). After a 3.5-hour tracer equilibration period, subjects (20 per group) will receive one of the following medications: (i) exenatide 5 ug subcutaneously; (ii) dapagliflozin (10 mg); and (iii) dapagliflozin 10 mg + exenatide 5 ug. Only three groups will be followed for 16 weeks since subjects are diabetic and placebo is not appropriate to use for this period. Again, subjects will be randomized to treatment with either exenatide, dapagliflozin or both drugs in combination. Repeat EGP will be measured again at 16 weeks as described above and data will be compared to respective acute studies. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Fasting Plasma Glucose (FPG) Concentration | 16 weeks | The change in (FPG) above baseline following administration of study interventions after 16 weeks of treatment with each study drug(s) compared to data obtained during the acute exposure. Placebo arm was not included in this 16 week portion of the study, since subjects are diabetic. Only 3 arms of the study were conducted: (i) Byetta/Bydureon, (ii) Dapagliflozin (iii) Byetta/Bydureon plus Dapagliflozin. |
| Change in Plasma Glucagon Concentration | Baseline to 16 weeks | Measurement of change in plasma glucagon concentration after 16 weeks of treatment with each study drug(s) compared to acute exposure at baseline. Placebo arm was not included in this 16 week portion of the study, since subjects are diabetic. Only 3 arms of the study were conducted: (i) Byetta/Bydureon, (ii) Dapagliflozin (iii) Byetta/Bydureon plus Dapagliflozin. |
| Change in Plasma Insulin Concentration | Baseline to 16 weeks | Measurement of change in plasma insulin concentration from baseline to 16 weeks following treatment with each study drug(s). Placebo arm was not included in this 16 week portion of the study, since subjects are diabetic. Only 3 arms of the study were conducted: (i) Byetta/Bydureon, (ii) Dapagliflozin (iii) Byetta/Bydureon plus Dapagliflozin. |
Countries
United States
Participant flow
Pre-assignment details
Type 2 diabetes with significant clinical complications were excluded
Participants by arm
| Arm | Count |
|---|---|
| Byetta / Bydureon Exenatide:
4 weeks Byetta, 5 to 10ug sc (daily) 12 weeks Bydureon 2mg sc
Exenatide: Byetta 5 to 10 ug (twice daily) Bydureon 2mg (once weekly) | 25 |
| Dapagliflozin 4 weeks Dapagliflozin, Farxiga, 10mg 12 weeks Dapagliflozin, Farxiga, 10mg
Dapagliflozin: 10mg | 25 |
| Byetta/Bydureon Plus Dapagliflozin Exenatide:
4 weeks Byetta, 5 to 10ug sc (daily) 12 weeks Bydureon 2mg sc PLUS
Dapagliflozin:
4 weeks Dapagliflozin, Farxiga, 10mg 12 weeks Dapagliflozin, Farxiga, 10mg
Dapagliflozin: 10mg
Exenatide: Byetta 5 to 10 ug (twice daily) Bydureon 2mg (once weekly) | 25 |
| Placebo Placebo group (4 weeks and 12 weeks)
Placebo: Placebo for Dapagliflozin | 15 |
| Total | 90 |
Baseline characteristics
| Characteristic | Byetta / Bydureon | Dapagliflozin | Byetta/Bydureon Plus Dapagliflozin | Placebo | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 2 Participants | 1 Participants | 3 Participants |
| Age, Categorical Between 18 and 65 years | 25 Participants | 25 Participants | 23 Participants | 14 Participants | 87 Participants |
| Age, Continuous | 52 years STANDARD_DEVIATION 3 | 51 years STANDARD_DEVIATION 2 | 49 years STANDARD_DEVIATION 4 | 54 years STANDARD_DEVIATION 3 | 52 years STANDARD_DEVIATION 3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 16 Participants | 19 Participants | 21 Participants | 11 Participants | 67 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 9 Participants | 6 Participants | 3 Participants | 2 Participants | 20 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 1 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 8 Participants | 7 Participants | 6 Participants | 5 Participants | 26 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 17 Participants | 17 Participants | 19 Participants | 8 Participants | 61 Participants |
| Region of Enrollment United States | 25 participants | 25 participants | 25 participants | 15 participants | 90 participants |
| Sex: Female, Male Female | 15 Participants | 12 Participants | 16 Participants | 8 Participants | 51 Participants |
| Sex: Female, Male Male | 10 Participants | 13 Participants | 9 Participants | 7 Participants | 39 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 25 | 0 / 25 | 0 / 25 | 0 / 15 |
| other Total, other adverse events | 6 / 25 | 4 / 25 | 7 / 25 | 0 / 15 |
| serious Total, serious adverse events | 0 / 25 | 0 / 25 | 0 / 25 | 0 / 15 |
Outcome results
Primary
Change in Endogenous Glucose Production (EGP) After 16 Weeks of Treatment With Each Study Drug.
After screening, eligible subjects will receive a measurement of endogenous glucose production (EGP) with a prime-continuous infusion of 3-3H-glucose. The EGP measurement will be performed in the morning after a 10-12 hour overnight fast and will last 8.5 hours (from 6 AM to 2:30 PM). After a 3.5-hour tracer equilibration period, subjects (20 per group) will receive one of the following medications: (i) exenatide 5 ug subcutaneously; (ii) dapagliflozin (10 mg); and (iii) dapagliflozin 10 mg + exenatide 5 ug. Only three groups will be followed for 16 weeks since subjects are diabetic and placebo is not appropriate to use for this period. Again, subjects will be randomized to treatment with either exenatide, dapagliflozin or both drugs in combination. Repeat EGP will be measured again at 16 weeks as described above and data will be compared to respective acute studies.
Time frame: 16 weeks
Population: Type 2 diabetes
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| EXENATIDE | Change in Endogenous Glucose Production (EGP) After 16 Weeks of Treatment With Each Study Drug. | -0.23 mg/kg.min | Standard Error 0.02 |
| Dapagliflozin | Change in Endogenous Glucose Production (EGP) After 16 Weeks of Treatment With Each Study Drug. | 0.20 mg/kg.min | Standard Error 0.03 |
| Exenatide Plus Dapagliflozin | Change in Endogenous Glucose Production (EGP) After 16 Weeks of Treatment With Each Study Drug. | -0.12 mg/kg.min | Standard Error 0.03 |
Primary
Change in Endogenous Glucose Production (EGP) After Acute Exposure to a Single Dose and Again After 16 Weeks of Treatment
After screening, eligible subjects will receive a measurement of endogenous glucose production (EGP) with a prime-continuous infusion of 3-3H-glucose. The EGP measurement will be performed in the morning after a 10-12 hour overnight fast and will last 8.5 hours (from 6 AM to 2:30 PM). After a 3.5-hour tracer equilibration period, subjects (20 per group) will receive one of the following medications: (i) placebo; (ii) exenatide 5 ug subcutaneously; (iii) dapagliflozin (10 mg); and (iv) dapagliflozin 10 mg + exenatide 5 ug \[ACUTE STUDY\].
Time frame: ACUTE [after a single dose of each study drug or placebo]
Population: Type 2 diabetes
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| EXENATIDE | Change in Endogenous Glucose Production (EGP) After Acute Exposure to a Single Dose and Again After 16 Weeks of Treatment | -0.18 mg/kg.min | Standard Error 0.02 |
| Dapagliflozin | Change in Endogenous Glucose Production (EGP) After Acute Exposure to a Single Dose and Again After 16 Weeks of Treatment | 0.14 mg/kg.min | Standard Error 0.03 |
| Exenatide Plus Dapagliflozin | Change in Endogenous Glucose Production (EGP) After Acute Exposure to a Single Dose and Again After 16 Weeks of Treatment | -0.08 mg/kg.min | Standard Error 0.03 |
| Placebo | Change in Endogenous Glucose Production (EGP) After Acute Exposure to a Single Dose and Again After 16 Weeks of Treatment | -0.03 mg/kg.min | Standard Error 0.02 |
Secondary
Change in Fasting Plasma Glucose (FPG) Concentration
The change in (FPG) above baseline following administration of study interventions after 16 weeks of treatment with each study drug(s) compared to data obtained during the acute exposure. Placebo arm was not included in this 16 week portion of the study, since subjects are diabetic. Only 3 arms of the study were conducted: (i) Byetta/Bydureon, (ii) Dapagliflozin (iii) Byetta/Bydureon plus Dapagliflozin.
Time frame: 16 weeks
Population: type 2 diabetes
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| EXENATIDE | Change in Fasting Plasma Glucose (FPG) Concentration | 42 mg/dl | Standard Error 1 |
| Dapagliflozin | Change in Fasting Plasma Glucose (FPG) Concentration | 72 mg/dl | Standard Error 3 |
| Exenatide Plus Dapagliflozin | Change in Fasting Plasma Glucose (FPG) Concentration | 11 mg/dl | Standard Error 3 |
Secondary
Change in Plasma Glucagon Concentration
Measurement of change in plasma glucagon concentration after 16 weeks of treatment with each study drug(s) compared to acute exposure at baseline. Placebo arm was not included in this 16 week portion of the study, since subjects are diabetic. Only 3 arms of the study were conducted: (i) Byetta/Bydureon, (ii) Dapagliflozin (iii) Byetta/Bydureon plus Dapagliflozin.
Time frame: Baseline to 16 weeks
Population: type 2 diabetes
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| EXENATIDE | Change in Plasma Glucagon Concentration | 4 pg/ml | Standard Error 2 |
| Dapagliflozin | Change in Plasma Glucagon Concentration | 5 pg/ml | Standard Error 2 |
| Exenatide Plus Dapagliflozin | Change in Plasma Glucagon Concentration | -6 pg/ml | Standard Error 2 |
Secondary
Change in Plasma Insulin Concentration
Measurement of change in plasma insulin concentration from baseline to 16 weeks following treatment with each study drug(s). Placebo arm was not included in this 16 week portion of the study, since subjects are diabetic. Only 3 arms of the study were conducted: (i) Byetta/Bydureon, (ii) Dapagliflozin (iii) Byetta/Bydureon plus Dapagliflozin.
Time frame: Baseline to 16 weeks
Population: Type 2 diabetes
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| EXENATIDE | Change in Plasma Insulin Concentration | -2 microUnits/ml | Standard Error 1 |
| Dapagliflozin | Change in Plasma Insulin Concentration | -2 microUnits/ml | Standard Error 2 |
| Exenatide Plus Dapagliflozin | Change in Plasma Insulin Concentration | 3 microUnits/ml | Standard Error 2 |