5.5 Metabolic Changes
Atypical antipsychotic drugs have been associated with metabolic changes that include hyperglycemia/diabetes mellitus, dyslipidemia, and body weight gain. While all of the drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile. In some patients, a worsening of more than one of the metabolic parameters of weight, blood glucose, and lipids was observed in clinical studies. Changes in these metabolic profiles should be managed as clinically appropriate.
Hyperglycemia and Diabetes Mellitus
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Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics, including quetiapine. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse reactions is not completely understood. However, epidemiological studies suggest an increased risk of hyperglycemia-related adverse reactions in patients treated with the atypical antipsychotics. Precise risk estimates for hyperglycemia-related adverse reactions in patients treated with atypical antipsychotics are not available.
Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug.
Adults:
Table 3: Fasting Glucose – Proportion of Patients Shifting to ≥ 126 mg/dL in Short-Term (≤12 weeks) Placebo-Controlled Studies1
1. Includes quetiapine tablets and SEROQUEL XR data.
In a 24-week trial (active-controlled, 115 patients treated with quetiapine) designed to evaluate glycemic status with oral glucose tolerance testing of all patients, at week 24 the incidence of a post-glucose challenge glucose level ≥ 200 mg/dL was 1.7% and the incidence of a fasting blood glucose level ≥126 mg/dL was 2.6%. The mean change in fasting glucose from baseline was 3.2 mg/dL and mean change in 2-hour glucose from baseline was -1.8 mg/dL for quetiapine.
In 2 long-term placebo-controlled randomized withdrawal clinical trials for bipolar I disorder maintenance, mean exposure of 213 days for quetiapine (646 patients) and 152 days for placebo (680 patients), the mean change in glucose from baseline was +5.0 mg/dL for quetiapine and -0.05 mg/dL for placebo. The exposure-adjusted rate of any increased blood glucose level (≥ 126 mg/dL) for patients more than 8 hours since a meal (however, some patients may not have been precluded from calorie intake from fluids during fasting period) was 18.0 per 100 patient years for quetiapine (10.7% of patients; n=556) and 9.5 for placebo per 100 patient years (4.6% of patients; n=581).
Children and Adolescents:
In a placebo-controlled quetiapine monotherapy study of adolescent patients (13 to 17 years of age) with schizophrenia (6 weeks duration), the mean change in fasting glucose levels for quetiapine (n=138) compared to placebo (n=67) was – 0.75 mg/dL versus -1.70 mg/dL. In a placebo-controlled quetiapine monotherapy study of children and adolescent patients (10-17 years of age) with bipolar mania (3 weeks duration), the mean change in fasting glucose level for quetiapine (n=170) compared to placebo (n=81) was 3.62 mg/dL versus -1.17 mg/dL. No patient in either study with a baseline normal fasting glucose level (<100 mg/dL) or a baseline borderline fasting glucose level (≥ 100 mg/dL and <126mg/dL) had a blood glucose level of ≥ 126mg/dL.
In a placebo-controlled SEROQUEL XR monotherapy study (8 weeks duration) of children and adolescent patients (10 to 17 years of age) with bipolar depression, in which efficacy was not established, the mean change in fasting glucose levels for SEROQUEL XR (n = 60) compared to placebo (n = 62) was 1.8 mg/dL versus 1.6 mg/dL. In this study, there were no patients in the SEROQUEL XR or placebo-treated groups with a baseline normal fasting glucose level (< 100 mg/dL) that had an increase in blood glucose level > 126 mg/dL. There was one patient in the SEROQUEL XR group with a baseline borderline fasting glucose level (> 100 mg/dL) and (< 126 mg/dL) who had an increase in blood glucose level of > 126 mg/dL compared to zero patients in the placebo group.
Dyslipidemia
Adults:
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Table 4 shows the percentage of adult patients with changes in total cholesterol, triglycerides, LDL-cholesterol and HDL- cholesterol from baseline by indication in clinical trials with Quetiapine.
Table 4: Percentage of Adult Patients with Shifts in Total Cholesterol, Triglycerides, LDL-Cholesterol and HDL-Cholesterol from Baseline to Clinically Significant Levels by Indication
1. 6 weeks duration
2. 8 weeks duration
3. Parameters not measured in the quetiapine registration studies for schizophrenia. Children and Adolescents:
Table 5 shows the percentage of children and adolescents with changes in total cholesterol, triglycerides, LDL-cholesterol and HDL-cholesterol from baseline in clinical trials with quetiapine.
Table 5: Percentage of Children and Adolescents with Shifts in Total Cholesterol, Triglycerides, LDL- Cholesterol and HDL-Cholesterol from Baseline to Clinically Significant Levels
1. 13 to 17 years, 6 weeks duration
2. 10 to 17 years, 3 weeks duration
In a placebo-controlled SEROQUEL XR monotherapy study (8 weeks duration) of children and adolescent patients (10 to 17 years of age) with bipolar depression, in which efficacy was not established, the percentage of children and adolescents with shifts in total cholesterol (≥200 mg/dL), triglycerides (≥150 mg/dL), LDL-cholesterol (≥130 mg/dL) and HDL-cholesterol (≤ 40 mg/dL) from baseline to clinically significant levels were: total cholesterol 8% (7/83) for SEROQUEL XR vs. 6% (5/84) for placebo; triglycerides 28% (22/80) for SEROQUEL XR vs. 9% (7/82) for placebo; LDL-cholesterol 2% (2/86) for SEROQUEL XR vs. 4% (3/85) for placebo and HDL-cholesterol 20% (13/65) for SEROQUEL XR vs. 15% (11/74) for placebo.
Weight Gain
Increases in weight have been observed in clinical trials. Patients receiving quetiapine should receive regular monitoring of weight.
Adults:
In clinical trials with quetiapine the following increases in weight have been reported.
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Table 6:Proportion of Patients with Weight Gain ≥ 7% of Body Weight (Adults)
1. up to 6 weeks duration
2. up to 12 weeks duration
3. up to 3 weeks duration
4. up to 8 weeks duration
Children and Adolescents:
In two clinical trials with quetiapine, one in bipolar mania and one in schizophrenia, reported increases in weight are included in Table 7.
Table 7: Proportion of Patients with Weight Gain ≥ 7% of Body Weight (Children and Adolescents)
1. 6 weeks duration
2. 3 weeks duration
The mean change in body weight in the schizophrenia trial was 2.0 kg in the quetiapine group and -0.4 kg in the placebo group and in the bipolar mania trial, it was 1.7 kg in the quetiapine group and 0.4 kg in the placebo group.
In an open-label study that enrolled patients from the above two pediatric trials, 63% of patients (241/380) completed 26 weeks of therapy with quetiapine. After 26 weeks of treatment, the mean increase in body weight was 4.4 kg. Forty-five percent of the patients gained ≥ 7% of their body weight, not adjusted for normal growth. In order to adjust for normal growth over 26 weeks, an increase of at least 0.5 standard deviation from baseline in BMI was used as a measure of a clinically significant change; 18.3% of patients on quetiapine met this criterion after 26 weeks of treatment.
In a clinical trials for SEROQUEL XR in children and adolescents (10 to 17 years of age) with bipolar depression, in which efficacy was not established, the percentage of patients with weight gain ≥ 7% of body weight at any time was 15% (14/92) for SEROQUEL XR vs. 10% (10/100) for placebo. The mean change in body weight was 1.4 kg in the SEROQUEL XR group vs. 0.6 kg in the placeo group.
When treating pediatric patients with quetiapine for any indication, weight gain should be assessed against that expected for normal growth.
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