Rosiglitazone-Induced Weight Gain
| Status: | Recruiting |
|---|---|
| Conditions: | Obesity Weight Loss, Diabetes |
| Therapuetic Areas: | Endocrinology |
| Healthy: | No |
| Age Range: | 20 - 75 |
| Updated: | 4/2/2016 |
Given the high prevalence of type 2 diabetes and the 2- to 4-fold increased risk of fatal
and non-fatal coronary heart disease events in these patients, long-term glycemic control is
of great importance. TZDs improves glycemic control in patients with type 2 DM as well as
enhances their insulin-mediated glucose disposal. However, the improvement of glycemic
control seen with TZDs may be blunted in the long run by weight gain.
Previous data on weight gain during TZD therapy in patients with type 2 DM is very sparse.
It is generally assumed that an increase in adipocyte differentiation is the cause of weight
gain in association with TZD treatment which may limit their use. Increased body weight
assumed to compromise the positive effects of treatment. There is also a theoretical concern
that, with the development of new adipocytes, future weight loss may be difficult.
However, if weight gain is primarily due to failure to adjust caloric intake in proportion
to the decrease in urinary glucose loss, it is totally preventable. It has been previously
shown that improvement of glycemia favored weight gain by decreasing the energy loss in the
urine as glucose. Severity of weight gain appears to be proportional to the level of
glycemic control achieved.
The overall goal of the proposed research is to provide the experimental evidence for the
later alternative by showing that the modest weight gain that takes place in association
with effective rosiglitazone treatment of hyperglycemic patients with type 2 DM is primarily
due to its therapeutic efficacy. More specifically, by decreasing the caloric intake in
proportion to a decrease in urinary glucose loss associated with improved glycemic control,
we will be able to prevent significant weight gain following Rosiglitazone treatment. In
order to provide an optimal dietary modification that can be universally applied to
TZD-treated patients in clinical practice, we will have a group with a fixed amount of
caloric restriction per day. It will be the first randomized controlled trial of a potential
strategy for prevention of weight gain associated with thiazolidinediones.
and non-fatal coronary heart disease events in these patients, long-term glycemic control is
of great importance. TZDs improves glycemic control in patients with type 2 DM as well as
enhances their insulin-mediated glucose disposal. However, the improvement of glycemic
control seen with TZDs may be blunted in the long run by weight gain.
Previous data on weight gain during TZD therapy in patients with type 2 DM is very sparse.
It is generally assumed that an increase in adipocyte differentiation is the cause of weight
gain in association with TZD treatment which may limit their use. Increased body weight
assumed to compromise the positive effects of treatment. There is also a theoretical concern
that, with the development of new adipocytes, future weight loss may be difficult.
However, if weight gain is primarily due to failure to adjust caloric intake in proportion
to the decrease in urinary glucose loss, it is totally preventable. It has been previously
shown that improvement of glycemia favored weight gain by decreasing the energy loss in the
urine as glucose. Severity of weight gain appears to be proportional to the level of
glycemic control achieved.
The overall goal of the proposed research is to provide the experimental evidence for the
later alternative by showing that the modest weight gain that takes place in association
with effective rosiglitazone treatment of hyperglycemic patients with type 2 DM is primarily
due to its therapeutic efficacy. More specifically, by decreasing the caloric intake in
proportion to a decrease in urinary glucose loss associated with improved glycemic control,
we will be able to prevent significant weight gain following Rosiglitazone treatment. In
order to provide an optimal dietary modification that can be universally applied to
TZD-treated patients in clinical practice, we will have a group with a fixed amount of
caloric restriction per day. It will be the first randomized controlled trial of a potential
strategy for prevention of weight gain associated with thiazolidinediones.
Study Design Randomized, controlled trial. Volunteers for the study will be recruited by
advertisements in the local newspapers as well as through Stanford University e-mail. All
studies will occur at Stanford General Clinical Research Center (GCRC).
At baseline, enrolled candidates will be required to keep a daily food and beverage record
for 2 weeks as well as blood sugar log of at least 2 measurements a day (fasting and
pre-dinner). Candidates will have an initial nutrition/diabetes consult with dietitian. They
also will be asked to do a 24-hour urine collection once a week (2 times during the 2 week
period) for quantitative assessment of glucosuria. During those 2 weeks individuals will
come for GCRC outpatient visit once a week for weight, blood pressure, and blood sugar
check.
After the initial two weeks, all individuals will undergo a meal profile test, after a
12-hour overnight fast, which consists of measurement of daylong plasma glucose, free fatty
acids, and insulin responses to standard meals. Food for the test will be prepared by GCRC
Metabolic kitchen. In order to assess the degree of postprandial and day-long
hyperinsulinemia and the benefits of rosiglitazone on the metabolic abnormalities in
patients with poor glycemic control, we plan to measure plasma glucose, free fatty acids,
and insulin concentrations before 8 am and at hourly intervals for four hours after
breakfast at 8 am and four hours after lunch at noon in response to identical test meals
containing (as percentage of calories) 15% protein, 40% fat, and 45% carbohydrate. Baseline
blood samples for fasting lipid and lipoprotein concentrations will be obtained after an
overnight fast on the day of the meal profile. Cholesterol and lipoprotein subclasses will
be analyzed by VAP-II method which is based on continuous enzymatic analysis of cholesterol
and lipoprotein classes separated by a single vertical spin centrifugation using a
controlled-dispersion flow analyzer. Hemoglobin A1C will be measured by an affinity
chromography assay at baseline and at the end of the study.
Randomization protocol. After completion of the Meal Profile test all subjects will be
started on Rosiglitazone for improvement of their glycemic control and randomized to one of
the three groups (15 subjects in each group):
1. Continuation of the current diet.
2. Reduced calorie diet. Amount of reduced calories will be calculated proportionally to
the calories lost via glucosuria.
3. Fixed calorie reduction diet. Reduction of daily caloric intake by 500 kcal.
Rosiglitazone will be given at 4 mg for the first 4 weeks, and if tolerated, increased
to 8 mg for the duration of the study. All candidates will have counseling on general
meal plan with the nutritionist.
Follow-up. Subjects will be followed for 4 months. They will come to the GCRC twice a month
for weight, blood pressure, blood sugar checks, and for nutrition follow-up.
End of the study measurements and clinical procedures: meal profile, lipid panel, 24-hour
urine collection will be done at the end of 4 month follow-up period. Liver function tests
will be done at the baseline, 4, 8, 12, and 16 weeks while on Rosiglitazone.
Outcomes: we expect to demonstrate at the end of the study that modification of the diet
prevents weight gain in Rosiglitazone treated patients and to offer the optimal dietary
interventions that could be applied in TZD-treated patients to minimize weight gain while
effectively treating DM and insulin resistance.
Inclusion / Exclusion Inclusion criteria: 1) age between 30 and 70 years old, 2) normal
chemical screening battery, 2) BMI less than 36 kg/M2, 3) non-controlled type 2 DM, defined
by a fasting plasma glucose between 160 and 220 mg/dl, 4) individuals should be on a stable
dose of sulfonylurea for at least one month prior to the enrollment.
Exclusion criteria: 1) liver enzymes 2.5 times above normal values, 2) chronic inflammatory,
neoplastic disease, 3) subjects with clinical evidence of congestive heart failure.
advertisements in the local newspapers as well as through Stanford University e-mail. All
studies will occur at Stanford General Clinical Research Center (GCRC).
At baseline, enrolled candidates will be required to keep a daily food and beverage record
for 2 weeks as well as blood sugar log of at least 2 measurements a day (fasting and
pre-dinner). Candidates will have an initial nutrition/diabetes consult with dietitian. They
also will be asked to do a 24-hour urine collection once a week (2 times during the 2 week
period) for quantitative assessment of glucosuria. During those 2 weeks individuals will
come for GCRC outpatient visit once a week for weight, blood pressure, and blood sugar
check.
After the initial two weeks, all individuals will undergo a meal profile test, after a
12-hour overnight fast, which consists of measurement of daylong plasma glucose, free fatty
acids, and insulin responses to standard meals. Food for the test will be prepared by GCRC
Metabolic kitchen. In order to assess the degree of postprandial and day-long
hyperinsulinemia and the benefits of rosiglitazone on the metabolic abnormalities in
patients with poor glycemic control, we plan to measure plasma glucose, free fatty acids,
and insulin concentrations before 8 am and at hourly intervals for four hours after
breakfast at 8 am and four hours after lunch at noon in response to identical test meals
containing (as percentage of calories) 15% protein, 40% fat, and 45% carbohydrate. Baseline
blood samples for fasting lipid and lipoprotein concentrations will be obtained after an
overnight fast on the day of the meal profile. Cholesterol and lipoprotein subclasses will
be analyzed by VAP-II method which is based on continuous enzymatic analysis of cholesterol
and lipoprotein classes separated by a single vertical spin centrifugation using a
controlled-dispersion flow analyzer. Hemoglobin A1C will be measured by an affinity
chromography assay at baseline and at the end of the study.
Randomization protocol. After completion of the Meal Profile test all subjects will be
started on Rosiglitazone for improvement of their glycemic control and randomized to one of
the three groups (15 subjects in each group):
1. Continuation of the current diet.
2. Reduced calorie diet. Amount of reduced calories will be calculated proportionally to
the calories lost via glucosuria.
3. Fixed calorie reduction diet. Reduction of daily caloric intake by 500 kcal.
Rosiglitazone will be given at 4 mg for the first 4 weeks, and if tolerated, increased
to 8 mg for the duration of the study. All candidates will have counseling on general
meal plan with the nutritionist.
Follow-up. Subjects will be followed for 4 months. They will come to the GCRC twice a month
for weight, blood pressure, blood sugar checks, and for nutrition follow-up.
End of the study measurements and clinical procedures: meal profile, lipid panel, 24-hour
urine collection will be done at the end of 4 month follow-up period. Liver function tests
will be done at the baseline, 4, 8, 12, and 16 weeks while on Rosiglitazone.
Outcomes: we expect to demonstrate at the end of the study that modification of the diet
prevents weight gain in Rosiglitazone treated patients and to offer the optimal dietary
interventions that could be applied in TZD-treated patients to minimize weight gain while
effectively treating DM and insulin resistance.
Inclusion / Exclusion Inclusion criteria: 1) age between 30 and 70 years old, 2) normal
chemical screening battery, 2) BMI less than 36 kg/M2, 3) non-controlled type 2 DM, defined
by a fasting plasma glucose between 160 and 220 mg/dl, 4) individuals should be on a stable
dose of sulfonylurea for at least one month prior to the enrollment.
Exclusion criteria: 1) liver enzymes 2.5 times above normal values, 2) chronic inflammatory,
neoplastic disease, 3) subjects with clinical evidence of congestive heart failure.
Inclusion Criteria:- 1) age between 30 and 70 years old, 2) normal chemical screening
battery, 2) BMI less than 36 kg/M2, 3) non-controlled type 2 DM, defined by a fasting
plasma glucose between 160 and 220 mg/dl, 4) individuals should be on a stable dose of
sulfonylurea for at least one month prior to the enrollment. Exclusion Criteria:- 1) liver
enzymes 2.5 times above normal values, 2) chronic inflammatory, neoplastic disease, 3)
subjects with clinical evidence of congestive heart failure.
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