Diabetes Mellitus, Type 2, Obesity
Conditions
Keywords
Post-Bariatric Surgery, hemoglobin A1c protein, human
Brief summary
This is a prospective, randomized clinical trial for patients with recurrent type 2 diabetes post-gastric bypass surgery that will compare a 6 month course of canagliflozin monotherapy vs. placebo on clinical outcomes of type 2 diabetes.
Detailed description
Following consent and a screening visit to assess eligibility and clinical status (i.e. historical, physical and biochemical parameters including glycemic control and a pregnancy test in females), a baseline visit with diabetes educator will take place to provide standard diabetes education, nutrition and exercise prescription. Nutritional assessment for vitamin/mineral deficiency will be performed per clinical care guidelines at the screening visit. Subjects will be asked to take nutritional supplements (i.e. vitamins and minerals) per current clinical guidelines for post-bariatric patients. Stable doses of supplements will be established for at least 2 weeks prior to randomization. Thirty-six subjects with recurrent diabetes that are naïve to hypoglycemic agents with HbA1c greater than or equal to 6.5% and less than 10% will be randomly assigned to a six month course of a) canagliflozin 100mg for 2 weeks titrated up to 300 mg daily (N = 24) vs. placebo (n= 12) at the randomization. Patients taking an anti-diabetic medication will be asked to wash out for 8 weeks prior to the randomization visit. At randomization, biochemical assessment of glycemic parameters (fasting glucose, HbA1c), lipid panel, complete metabolic panel, uric acid, leptin, total and HMW adiponectin, C-reactive protein and urine for albumin/creatinine ratio will be performed. Dual-energy x-ray absorptiometry (DXA) scan will be performed for body fat composition. Following randomization, subjects will be clinically evaluated at three office visits at 6 weeks, 3 and 6 months by PI and/or the research staff. The primary outcome measures at 6 months post-randomization include HbA1c followed by the change in HbA1c from randomization. Secondary measures include fasting glucose, BMI, change in body weight, blood pressure, lipid profile. Symptomatic hypoglycemia (blood glucose \< 70) and drug related side effects (i.e. mycotic genital infections, urinary tract infection) will be monitored with adverse event reporting. Metabolic testing in all subjects at randomization and at 6 months will include a DXA scan for body fat composition and blood for leptin and adiponectin levels. Rescue glucose lowering therapy will be provided for the control group for blood glucose \>250 mg/dl. If chronic uncontrolled hyperglycemia (HbA1c \>10%) occurs then basal bolus insulin will be implemented.
Interventions
DRUGcanagliflozin
encapsulated (gelatin capsule).
DRUGPlacebo (for canagliflozin)
encapsulated (gelatin capsule). The placebo capsule filler is called micro-crystalline cellulose.
Sponsors
Janssen Scientific Affairs, LLC
The Cleveland Clinic
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
20 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Post Roux-n-Y gastric bypass (RYGB) surgery and sleeve gastrectomy (SG) patients who underwent surgery \>1 and \<15 years ago in the Cleveland surrounding area * Age 20-75 years of age * Type II Diabetes Mellitus (D2M) diagnosis (history, medication usage, biochemical criteria) prior to and after surgery; after surgery, defined by a single HbA1c of greater or equal to 6.5% at consent and screening. * Metformin patients must have an HbA1c greater than or equal to 6.5% but less than or equal to 10% at randomization; for diet controlled patients (i.e. not on any T2D medication), HbA1c must be greater than or equal to 6.5% at randomization. * Patient reporting of improvement in T2D status or objective improvements in T2D status at any time post-surgery. * estimated glomerular filtration rate (eGFR) ≥ 60mL/min prior to randomization * Has the ability and willingness to provide informed consent. * Is able to understand the options and to comply with the requirements of each program * Female subject agrees to have a serum pregnancy test at screening. A negative serum pregnancy test result is required prior to randomization. * Female patients must agree to use a reliable method of contraception for 6 months or duration of intervention * Patients taking an anti-diabetic medication, except insulin, are eligible and must agree to washout for 8 weeks prior to the randomization visit.
Exclusion criteria
* Type 1 diabetes indicated by history of diabetic ketoacidosis and lack of remission in response to bariatric surgery * Other post bariatric procedures (banding, duodenal switch, biliopancreatic diversion) * Current use of insulin. * End organ diabetic complications (renal failure, cardiomyopathy, severe neuropathy/foot ulcers) * Documented severe or unstable depression/anxiety or eating disorder that would not enable patient to adhere to anti-diabetic treatment * Clinical contraindications to use canagliflozin, i.e., history of bladder cancer, Child-Pugh class C
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change at Six Months Versus Baseline in Hemoglobin A1c Value (%) | 6 months | The change in hemoglobin A1c from randomization following the 6 month administration of canagliflozin vs. placebo in patients with type 2 diabetes post-bariatric surgery |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Body Weight at Six Months Compared to Baseline | 6 months | The change in body weight from randomization following the 6 month administration of canagliflozin vs. placebo in patients with type 2 diabetes post-bariatric surgery. |
| Change in Total Cholesterol | 6 months | The change in total cholesterol from randomization following the 6 month administration of canagliflozin vs. placebo in patients with type 2 diabetes post-bariatric surgery |
| Change in Diastolic Blood Pressure at Six Months Compared to Baseline | 6 months | The change in diastolic blood pressure from randomization following the 6 month administration of canagliflozin vs. placebo in patients with type 2 diabetes post-bariatric surgery |
| Change in Adiponectin Levels at 6 Months Compared to Randomization | 6 months | The change in adiponectin levels from randomization following the 6 month administration of canagliflozin vs. placebo in patients with type 2 diabetes post-bariatric surgery. |
| Change in Leptin Levels at 6 Months Compared to Baseline | 6 months | Change in leptin levels at 6 months compared to baseline The change in leptin levels from randomization following the 6 month administration of canagliflozin vs. placebo in patients with type 2 diabetes post-bariatric surgery. |
| Change in CRP Levels at 6 Months Compared to Baseline | 6 months | The change in C-reactive protein levels from randomization following the 6 month administration of canagliflozin vs. placebo in patients with type 2 diabetes post-bariatric surgery. |
| Number of Participants Who Reported Hypoglycemia From Each Group (at a Frequency of 1 Episode) | 6 months | The number of participants who reported symptomatic hypoglycemia episodes from randomization following the 6 month administration of canagliflozin vs. placebo in patients with type 2 diabetes post-bariatric surgery. |
| Change in Fasting Glucose From Randomization | 6 months | The change in fasting glucose from randomization following the 6 month administration of canagliflozin vs. placebo in patients with type 2 diabetes post-bariatric surgery. |
| Change in Systolic Blood Pressure at 6 Months Compared to Baseline | 6 months | The Change in Systolic Blood Pressure From Randomization Following the 6 Month Administration of Canagliflozin vs. Placebo in Patients With Type 2 Diabetes Post-bariatric Surgery |
| Change in Percentage of Lean Mass | 6 months | Change in percentage of lean body mass as measured by DEXA scan at 6 months compared to randomization |
| Change in Percentage of Truncal Fat | 6 months | Change in percentage of truncal fat as measured by DEXA scan at 6 months compared to randomization |
| Change in Percentage of Android Fat | 6 months | Change in percentage of android fat as measured by DEXA scan at 6 months compared to randomization |
| Change in Percentage of Gynoid Fat | 6 months | Change in percentage of gynoid fat as measured by DEXA scan at 6 months compared to randomization |
| Change in Spine Bone Mineral Density | 6 months | Change in spine bone marrow density as measured by DEXA scan at 6 months compared to randomization |
| Change in Leg Bone Mineral Density | 6 months | Change in leg bone marrow density as measured by DEXA scan at 6 months compared to randomization |
| Change in Percent Body Fat as Measured by DEXA Scan at 6 Months Compared to Randomization | 6 months | The change in body fat from randomization following the 6 month administration of canagliflozin vs. placebo in patients with type 2 diabetes post-bariatric surgery. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Study Drug (Canagliflozin) Subjects randomized to study drug will be assigned a six month course starting on canagliflozin 100 mg for two weeks titrated up to 300 mg daily.
canagliflozin: encapsulated (gelatin capsule). | 11 |
| Placebo Drug: Placebo (for canagliflozin)
encapsulated (gelatin capsule). The placebo capsule filler is called micro-crystalline cellulose. | 5 |
| Total | 16 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lack of Efficacy | 0 | 1 |
| Overall Study | Lost to Follow-up | 2 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Placebo | Study Drug (Canagliflozin) | Total |
|---|---|---|---|
| Adiponectin | 5 ug/mL | 4.2 ug/mL | 4.6 ug/mL |
| Age, Continuous | 44.0 years | 58 years | 54.0 years |
| Android fat | 51.3 percentage of android fat | 55.6 percentage of android fat | 53.9 percentage of android fat |
| BMI | 37.9 kg/m^2 | 39.6 kg/m^2 | 39.2 kg/m^2 |
| Body fat % | 44.1 percentage of body fat | 49.3 percentage of body fat | 48.6 percentage of body fat |
| CRP | 0.45 mg/L | 4.1 mg/L | 3.7 mg/L |
| Diastolic blood pressure (mm/Hg) | 77.0 mmHg | 73.0 mmHg | 76.5 mmHg |
| Fasting glucose (mg/dL) | 164.0 mg/dL | 163.0 mg/dL | 163.5 mg/dL |
| Gynoid fat | 47.3 percentage of gynoid fat | 48.1 percentage of gynoid fat | 47.7 percentage of gynoid fat |
| HDL (mg/dL) | 51.0 mg/dL | 47.0 mg/dL | 49.0 mg/dL |
| Height (m) | 1.7 meters | 1.7 meters | 1.7 meters |
| Hemoglobin A1c (%) | 8.2 percent | 7.2 percent | 7.4 percent |
| HMW adiponectin | 3.3 ug/mL | 2.9 ug/mL | 3.1 ug/mL |
| LDL (mg/dL) | 108.0 mg/dL | 87.0 mg/dL | 92.0 mg/dL |
| Lean mass % | 55.9 percentage of lean mass | 50.7 percentage of lean mass | 51.5 percentage of lean mass |
| Leg BMD | 1.2 g/cm^2 | 1.2 g/cm^2 | 1.2 g/cm^2 |
| Leptin | 29 ng/mL | 28 ng/mL | 28.5 ng/mL |
| Race and Ethnicity Not Collected | — | — | 0 Participants |
| Region of Enrollment United States | 5 participants | 11 participants | 16 participants |
| Sex: Female, Male Female | 4 Participants | 7 Participants | 11 Participants |
| Sex: Female, Male Male | 1 Participants | 4 Participants | 5 Participants |
| Spine BMD | 1.3 g/cm^2 | 1.2 g/cm^2 | 1.2 g/cm^2 |
| Systolic blood pressure (mm/Hg) | 133.0 mmHg | 137.0 mmHg | 134.5 mmHg |
| Total cholesterol (mg/dL) | 167.0 mg/dL | 160.0 mg/dL | 162.0 mg/dL |
| Triglycerides (mg/dL) | 107.0 mg/dL | 130.0 mg/dL | 109.5 mg/dL |
| Truncal fat | 47.8 percentage of truncal fat | 53.5 percentage of truncal fat | 50.9 percentage of truncal fat |
| Uric acid (mg/dL) | 3.9 mg/dL | 4.9 mg/dL | 4.3 mg/dL |
| Weight (kg) | 117.5 kg | 108.6 kg | 108.9 kg |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 11 | 0 / 5 |
| other Total, other adverse events | 7 / 11 | 3 / 5 |
| serious Total, serious adverse events | 0 / 11 | 0 / 5 |
Outcome results
Primary
Change at Six Months Versus Baseline in Hemoglobin A1c Value (%)
The change in hemoglobin A1c from randomization following the 6 month administration of canagliflozin vs. placebo in patients with type 2 diabetes post-bariatric surgery
Time frame: 6 months
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Study Drug (Canagliflozin) | Change at Six Months Versus Baseline in Hemoglobin A1c Value (%) | -0.31 percentage |
| Placebo | Change at Six Months Versus Baseline in Hemoglobin A1c Value (%) | 0.11 percentage |
Secondary
Change in Adiponectin Levels at 6 Months Compared to Randomization
The change in adiponectin levels from randomization following the 6 month administration of canagliflozin vs. placebo in patients with type 2 diabetes post-bariatric surgery.
Time frame: 6 months
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Study Drug (Canagliflozin) | Change in Adiponectin Levels at 6 Months Compared to Randomization | 0.7 ug/mL |
| Placebo | Change in Adiponectin Levels at 6 Months Compared to Randomization | -3.4 ug/mL |
Secondary
Change in Body Weight at Six Months Compared to Baseline
The change in body weight from randomization following the 6 month administration of canagliflozin vs. placebo in patients with type 2 diabetes post-bariatric surgery.
Time frame: 6 months
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Study Drug (Canagliflozin) | Change in Body Weight at Six Months Compared to Baseline | -3.77 kilograms |
| Placebo | Change in Body Weight at Six Months Compared to Baseline | 6.33 kilograms |
Secondary
Change in CRP Levels at 6 Months Compared to Baseline
The change in C-reactive protein levels from randomization following the 6 month administration of canagliflozin vs. placebo in patients with type 2 diabetes post-bariatric surgery.
Time frame: 6 months
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Study Drug (Canagliflozin) | Change in CRP Levels at 6 Months Compared to Baseline | -5.35 mg/L |
| Placebo | Change in CRP Levels at 6 Months Compared to Baseline | 3.34 mg/L |
Secondary
Change in Diastolic Blood Pressure at Six Months Compared to Baseline
The change in diastolic blood pressure from randomization following the 6 month administration of canagliflozin vs. placebo in patients with type 2 diabetes post-bariatric surgery
Time frame: 6 months
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Study Drug (Canagliflozin) | Change in Diastolic Blood Pressure at Six Months Compared to Baseline | -1.18 mmHg |
| Placebo | Change in Diastolic Blood Pressure at Six Months Compared to Baseline | 2.95 mmHg |
Secondary
Change in Fasting Glucose From Randomization
The change in fasting glucose from randomization following the 6 month administration of canagliflozin vs. placebo in patients with type 2 diabetes post-bariatric surgery.
Time frame: 6 months
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Study Drug (Canagliflozin) | Change in Fasting Glucose From Randomization | -32.90 mg/dL |
| Placebo | Change in Fasting Glucose From Randomization | -44.61 mg/dL |
Secondary
Change in Leg Bone Mineral Density
Change in leg bone marrow density as measured by DEXA scan at 6 months compared to randomization
Time frame: 6 months
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Study Drug (Canagliflozin) | Change in Leg Bone Mineral Density | 0.01 grams per square centimeter |
| Placebo | Change in Leg Bone Mineral Density | -0.04 grams per square centimeter |
Secondary
Change in Leptin Levels at 6 Months Compared to Baseline
Change in leptin levels at 6 months compared to baseline The change in leptin levels from randomization following the 6 month administration of canagliflozin vs. placebo in patients with type 2 diabetes post-bariatric surgery.
Time frame: 6 months
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Study Drug (Canagliflozin) | Change in Leptin Levels at 6 Months Compared to Baseline | -8.1 ng/mL |
| Placebo | Change in Leptin Levels at 6 Months Compared to Baseline | -11 ng/mL |
Secondary
Change in Percentage of Android Fat
Change in percentage of android fat as measured by DEXA scan at 6 months compared to randomization
Time frame: 6 months
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Study Drug (Canagliflozin) | Change in Percentage of Android Fat | -3.00 percent change |
| Placebo | Change in Percentage of Android Fat | 3.33 percent change |
Secondary
Change in Percentage of Gynoid Fat
Change in percentage of gynoid fat as measured by DEXA scan at 6 months compared to randomization
Time frame: 6 months
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Study Drug (Canagliflozin) | Change in Percentage of Gynoid Fat | -1.69 percent change |
| Placebo | Change in Percentage of Gynoid Fat | 2.17 percent change |
Secondary
Change in Percentage of Lean Mass
Change in percentage of lean body mass as measured by DEXA scan at 6 months compared to randomization
Time frame: 6 months
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Study Drug (Canagliflozin) | Change in Percentage of Lean Mass | 1.82 percent change |
| Placebo | Change in Percentage of Lean Mass | -2.65 percent change |
Secondary
Change in Percentage of Truncal Fat
Change in percentage of truncal fat as measured by DEXA scan at 6 months compared to randomization
Time frame: 6 months
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Study Drug (Canagliflozin) | Change in Percentage of Truncal Fat | -2.67 percent change |
| Placebo | Change in Percentage of Truncal Fat | 2.74 percent change |
Secondary
Change in Percent Body Fat as Measured by DEXA Scan at 6 Months Compared to Randomization
The change in body fat from randomization following the 6 month administration of canagliflozin vs. placebo in patients with type 2 diabetes post-bariatric surgery.
Time frame: 6 months
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Study Drug (Canagliflozin) | Change in Percent Body Fat as Measured by DEXA Scan at 6 Months Compared to Randomization | -1.82 percent change |
| Placebo | Change in Percent Body Fat as Measured by DEXA Scan at 6 Months Compared to Randomization | 2.65 percent change |
Secondary
Change in Spine Bone Mineral Density
Change in spine bone marrow density as measured by DEXA scan at 6 months compared to randomization
Time frame: 6 months
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Study Drug (Canagliflozin) | Change in Spine Bone Mineral Density | -0.02 grams per square centimeter |
| Placebo | Change in Spine Bone Mineral Density | 0.14 grams per square centimeter |
Secondary
Change in Systolic Blood Pressure at 6 Months Compared to Baseline
The Change in Systolic Blood Pressure From Randomization Following the 6 Month Administration of Canagliflozin vs. Placebo in Patients With Type 2 Diabetes Post-bariatric Surgery
Time frame: 6 months
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Study Drug (Canagliflozin) | Change in Systolic Blood Pressure at 6 Months Compared to Baseline | 4.62 mmHg |
| Placebo | Change in Systolic Blood Pressure at 6 Months Compared to Baseline | 12.63 mmHg |
Secondary
Change in Total Cholesterol
The change in total cholesterol from randomization following the 6 month administration of canagliflozin vs. placebo in patients with type 2 diabetes post-bariatric surgery
Time frame: 6 months
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Study Drug (Canagliflozin) | Change in Total Cholesterol | -0.87 mg/dL |
| Placebo | Change in Total Cholesterol | 3.69 mg/dL |
Secondary
Number of Participants Who Reported Hypoglycemia From Each Group (at a Frequency of 1 Episode)
The number of participants who reported symptomatic hypoglycemia episodes from randomization following the 6 month administration of canagliflozin vs. placebo in patients with type 2 diabetes post-bariatric surgery.
Time frame: 6 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Study Drug (Canagliflozin) | Number of Participants Who Reported Hypoglycemia From Each Group (at a Frequency of 1 Episode) | 2 participants |
| Placebo | Number of Participants Who Reported Hypoglycemia From Each Group (at a Frequency of 1 Episode) | 0 participants |