Metabolic Complications
Conditions
Keywords
Olanzapine, Zyprexa, Weight Gain, Antipsychotics, Metformin, Glucophage, Bipolar Disorder, Schizophrenia, Depression, Diabetes, Side effects, Metabolic complications, Prevention, Treatment, Metabolic side effects of olanzapine
Brief summary
We hypothesize that metformin co-administered with olanzapine will be well tolerated and associated with significantly less insulin resistance, weight gain and dyslipidemia as compared to olanzapine plus placebo.
Detailed description
Increased risk of metabolic complications with olanzapine therapy, relative to other antipsychotics, may lead clinicians to avoid its use, despite evidence of greater efficacy. These problems may also pose a therapeutic dilemma for patients who respond well to olanzapine. Metabolic complications negatively impact on morbidity and mortality, impair quality of life and increase illness relapse secondary to medication non-compliance. Thus far, no pharmacologic agent co-administered with olanzapine has proven effective at preventing these untoward effects. The present study proposes to examine the efficacy and safety of metformin to attenuate the metabolic side effects associated with olanzapine.
Interventions
DRUGMetformin
Drug: Metformin 500 mg po daily titrated up to but no greater than 2000 mg based upon fasting blood glucose during study visits over six months.
DRUGPlacebo
Drug: Placebo. Subjects will remain on placebo for 6 months.
Sponsors
Eli Lilly and Company
Rush University Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Diagnosis of: Schizophrenia, Schizoaffective Disorder, Bipolar I or II or major depression with psychotic features who will be started on or who have just started taking Olanzapine (Zyprexa).
Exclusion criteria
* Patients with either a history of diabetes mellitus or a baseline FBG\>126 or two random blood sugars of \> 200 or during a OGTT glucose level of \> 200 two hours after a glucose load of 50 grams. (All American Diabetes Association criteria for diabetes mellitus). * Baseline liver function tests (SGOT, SGPT, AP) greater than 3X normal. * Chronic alcoholism * MDRD less than 60 ml/1.73 m2. Modification of Diet in Renal Disease (MDRD) Equation estimates the glomerular filtration rate as a measure of kidney function. This equation takes into account the plasma creatinine, age, race and gender, and is a more accurate estimation of glomerular filtration rate than serum creatinine alone. * Patients with unstable medical problems, including cardiovascular instability or significant congestive heart failure (as determined by study investigators). * Prolonged QTc greater than 430 ms on baseline EKG. * History of lactic acidosis. * History of hypoglycemia. * Current treatment with metformin or other antidiabetic agents. * Treatment with any antihyperlipidemic medication within 3 months of randomization. * Treatment with olanzapine or clozapine within 3 months of randomization. * Concurrent treatment with ziprasidone, risperidone, quetiapine or aripiprazole or any other neuroleptic medication. * Concurrent use of OTC chromium, gymnema or cimetidine will be prohibited. Patient may discontinue these medications up to one day prior to randomization. * Current treatment with corticosteroids.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Weight Gain | Baseline and 6 months | Change from Baseline in weight |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Hemoglobin A1C | Baseline and 6 months | change from baseline in hemoglobin AIC |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Metformin Olanzapine plus metformin: olanzapine plus metformin 500 mg titrated up to but no greater than 2,000 mg based upon fasting blood glucose during study visits over six months.
Metformin: Drug: Metformin 500 mg po daily titrated up to but no greater than 2000 mg based upon fasting blood glucose during study visits over six months. | 12 |
| Placebo Olanzapine plus Drug: Placebo. Subjects will remain on olanzapine plus placebo for 6 months.
Placebo: Drug: Placebo. Subjects will remain on placebo for 6 months. | 13 |
| Total | 25 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 2 |
| Overall Study | Lack of Efficacy | 1 | 0 |
| Overall Study | Lost to Follow-up | 1 | 3 |
| Overall Study | Pregnancy | 0 | 1 |
| Overall Study | Withdrawal by Subject | 2 | 0 |
Baseline characteristics
| Characteristic | Total | Placebo | Metformin |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 25 Participants | 13 Participants | 12 Participants |
| Age, Continuous | 36.4 years STANDARD_DEVIATION 9.6 | 39.08 years STANDARD_DEVIATION 8.62 | 33.5 years STANDARD_DEVIATION 10.12 |
| Race/Ethnicity, Customized African American | 12 participants | 8 participants | 4 participants |
| Race/Ethnicity, Customized Other | 3 participants | 2 participants | 1 participants |
| Race/Ethnicity, Customized White | 12 participants | 3 participants | 7 participants |
| Region of Enrollment United States | 27 participants | 13 participants | 12 participants |
| Sex: Female, Male Female | 13 Participants | 8 Participants | 5 Participants |
| Sex: Female, Male Male | 12 Participants | 5 Participants | 7 Participants |
| weight | 90.33 kilogram STANDARD_DEVIATION 27.39 | 95.59 kilogram STANDARD_DEVIATION 34.44 | 84.51 kilogram STANDARD_DEVIATION 16.56 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 3 / 12 | 6 / 13 |
| serious Total, serious adverse events | 1 / 12 | 2 / 13 |
Outcome results
Primary
Weight Gain
Change from Baseline in weight
Time frame: Baseline and 6 months
Population: intent to treat using last observation carried forward. Only subjects with one observation post-baseline were included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Metformin | Weight Gain | 2.54 kilogram | Standard Deviation 2.35 |
| Placebo | Weight Gain | 5.88 kilogram | Standard Deviation 5.23 |
Secondary
Hemoglobin A1C
change from baseline in hemoglobin AIC
Time frame: Baseline and 6 months
Population: total of 18 participants reflects the number of participants with available data at 6 months.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Metformin | Hemoglobin A1C | 0.05 % HbAIC | Standard Deviation 0.28 |
| Placebo | Hemoglobin A1C | 0.1 % HbAIC | Standard Deviation 0.26 |