Summary

• Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and body weight gain. While all of the drugs in this class have been shown to produce some metabolic changes, each drug has its own specific risk profile.¹
• Hyperglycemia and diabetes mellitus, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, have been reported in patients treated with all atypical antipsychotics.² Hyperglycemia and diabetes have been reported in trial subjects treated with INVEGA HAFYERA.³
• Hyperglycemia, diabetes mellitus, and exacerbation of pre-existing diabetes have been reported during treatment with antipsychotic drugs. 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 events is not completely understood. Any patient treated with atypical antipsychotics, including INVEGA HAFYERA should be monitored for symptoms of hyperglycemia and diabetes mellitus.⁴
• Consensus panel guidelines recommend that fasting plasma glucose be monitored at baseline, 3 months post-treatment, and every year thereafter (if glucose levels are normal) or more often if clinically indicated (high risk for diabetes or rapid weight gain).^5,6
• 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.⁷
• A phase 3, 12-month, randomized, double-blind (DB), active-controlled, parallel-group, noninferiority trial was conducted to evaluate the efficacy and safety of INVEGA HAFYERA (n=478) relative to INVEGA TRINZA (n=224) in adults with schizophrenia.³ During the DB phase, 15 patients (3.1%) in the INVEGA HAFYERA and 6 (2.7%) in the INVEGA TRINZA groups had diabetes mellitus and hyperglycemia-related TEAEs. The majority of patients with normal fasting glucose at baseline (DB) remained normal during treatment; however, some patients shifted from normal or impaired glucose tolerance to higher fasting glucose levels.⁸ None of these TEAEs were serious or led to study discontinuation.³
  • In a post hoc subgroup analysis of the Asian population, diabetes mellitus was reported in zero patients in the INVEGA TRINZA group and 2 (3.2%) patients in the INVEGA HAFYERA group during the DB phase.⁹
• In a 2-year, single-arm, open-label extension (OLE) of the phase 3, DB, noninferiority study, diabetes mellitus and hyperglycemia-related TEAEs were reported in 4 (2.2%) patients, of which 1 event was reported as new-onset diabetes.¹⁰

BACKGROUND

The use of second-generation antipsychotics (SGAs) has been associated with weight gain and metabolic abnormalities, including diabetes and reports of acute metabolic decompensation (eg, diabetic ketoacidosis).⁵ Metabolic abnormalities such as diabetes observed in these patients may result in increased cardiovascular risk. Because there are limited data in drug-naïve patients, it is unclear whether these metabolic abnormalities are due to the drug treatment or to the psychiatric disease itself. The prevalence of diabetes in patients with schizophrenia has been estimated to be approximately 1.5- to 2-fold higher than the prevalence in the general population; however, lifestyle changes such as sedentary behavior may contribute to the higher prevalence of metabolic abnormalities. Changes in body composition and weight gain may be contributing factors to metabolic abnormalities such as insulin resistance, pre-diabetes, and diabetes. Another possible mechanism for drug-associated hyperglycemia may be associated with direct effects on insulin-sensitive tissue targets. Treatment selection must be individualized on the basis of specific patient risk factors to ensure the benefits outweigh the risks. Consensus panel guidelines recommend that fasting plasma glucose be monitored at baseline, 3 months post-treatment, and every year thereafter (if glucose levels are normal) or more often if clinically indicated (high risk for diabetes or rapid weight gain).^5,6 Hemoglobin A_1C may be an acceptable alternative if fasting blood glucose is not attainable.⁶ Glucose values indicative of diabetes are ≥126 mg/dL (fasting blood glucose), >200 mg/dL (random blood glucose), or hemoglobin A_1C >6.1%; any of these values should prompt follow-up with a primary health care provider or internist. Immediate care is recommended for patients with symptomatic or severe hyperglycemia (glucose level ≥300 mg/dL) or symptomatic hypoglycemia or for patients with glucose readings ≤60 mg/dL, regardless of symptom status.⁵

DOSAGE STRENGTH INFORMATION

Doses of paliperidone palmitate extended-release injectable suspension may be expressed in milligram equivalents of paliperidone (active moiety) or milligrams of paliperidone palmitate. Dosage information in this response has been converted to mg of paliperidone palmitate to reflect the commercially available INVEGA SUSTENNA, INVEGA TRINZA, AND INVEGA HAFYERA dosage strengths. The conversion factor from mg eq. to mg is 1.56.

• INVEGA SUSTENNA doses expressed as 50, 100 and 150 mg eq. are equal to 78, 156 and 234 mg of paliperidone palmitate, respectively.
• INVEGA TRINZA doses expressed as 350 and 525 mg eq. are equal to 546 and 819 mg of paliperidone palmitate, respectively.
• INVEGA HAFYERA doses expressed as 700 and 1,000 mg eq. are equal to 1,092 and 1,560 mg of paliperidone palmitate, respectively.

CLINICAL Data

Noninferiority Trial³

A phase 3, randomized, DB, active-controlled, parallel-group, multicenter, noninferiority trial was conducted to evaluate the efficacy and safety of INVEGA HAFYERA relative to INVEGA TRINZA on time to first relapse in adults with schizophrenia who were previously stabilized on corresponding doses of INVEGA SUSTENNA or INVEGA TRINZA. See FIGURE: Study Design^3,11

Results

During the OL phase, 1 patient (0.1%) reported a hyperglycemia-related treatment-emergent adverse event (TEAE) of diabetes mellitus. During the DB phase, 15 patients (3.1%) in the INVEGA HAFYERA and 6 (2.7%) in the INVEGA TRINZA groups had diabetes mellitus and hyperglycemia-related TEAEs.³

The majority of patients with normal fasting glucose at baseline (DB) remained normal during treatment.⁸ The percent of patients with a shift in fasting glucose levels from baseline (DB) to maximum DB post-baseline value are listed. See Table: Change in Fasting Glucose from the randomized double-blind active-controlled study with INVEGA HAFYERA in patients with schizophrenia

^a The number of patients with paired fasting data (baseline and any post baseline assessment).Using the conversion factor (1 mg/dL=0.05551 mmol/L) the ADA specified limits are as follows:Normal: <100 mg/dL (<5.551 mmol/L)Impaired: ≥100 mg/dL (≥5.551 mmol/L) to <126 mg/dL (<6.994 mmol/L)High: ≥126 mg/dL (≥6.994 mmol/L)126 mg/dL=6.994 mmol/L; 140 mg/dL=7.771 mmol/L; 200 mg/dL=11.102 mmol/L; 300 mg/dL=16.653 mmol/L

None of the diabetes mellitus and hyperglycemia-related TEAEs were reported as a serious adverse event or led to study drug discontinuation during the open-label and DB phases of the study.³

Post Hoc Subgroup Analysis of the DB Phase of the Noninferiority Study

Richarz et al (2023)⁹ reported the results of a post hoc analysis of the Asian subgroup enrolled in the noninferiority study. Ninety patients were evaluated in this subgroup (INVEGA TRINZA, n=28; INVEGA HAFYERA, n=62). In the DB phase, diabetes mellitus was reported in zero patients in the INVEGA TRINZA group and 2 (3.2%) patients in the INVEGA HAFYERA group.

OLE Phase of the Noninferiority Study

Najarian et al (2023)¹⁰ conducted a 2-year, single-arm, OLE study to evaluate the long-term safety, efficacy, and tolerability of INVEGA HAFYERA in 178 patients who remained relapse-free in the DB study and continued treatment with INVEGA HAFYERA in the OLE phase. Diabetes mellitus and hyperglycemia-related TEAEs were reported in 4 (2.2%) patients in the OLE phase, including increased blood glucose (n=2) and new onset of diabetes (n=1).

LITERATURE SEARCH

A literature search of Ovid MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File databases (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 12 September 2024.