Metformin Alleviates Abnormal Glucose Metabolism Induced by Statins in Schizophrenia Patients

Not Applicable

Recruiting

• Conditions: Schizophrenia
• Interventions: Drug: Atorvastatin; Drug: Metformin; Drug: Placebo

• Registration Number: NCT07045142

Brief Summary

Schizophrenia is a severe mental illness associated with significant morbidity and disability. Patients often experience metabolic side effects from antipsychotic medications, including weight gain and dyslipidemia. Statins, commonly used to manage dyslipidemia, can lower cholesterol levels but may increase the risk of new-onset diabetes.

This study aims to investigate how atorvastatin affects glucose metabolism in schizophrenia patients and assess whether metformin can help improve these metabolic issues. The investigators will include 200 patients with dyslipidemia from the Second Xiangya Hospital and other sites, randomly assigning them to receive either atorvastatin with metformin or atorvastatin with placebo over six months.

Key goals include evaluating the impact of atorvastatin on insulin resistance and blood glucose levels and determining the effectiveness of metformin in mitigating glucose metabolism abnormalities while managing lipid levels.

Understanding these interactions will help improve treatment strategies for schizophrenia patients, potentially lowering their risk of cardiovascular diseases and diabetes and enhancing overall health outcomes.

Detailed Description

Research Background: Schizophrenia is a severe mental disorder characterized by high morbidity, significant disability, and substantial disease burden. Studies have shown that antipsychotic medications, particularly atypical antipsychotics, can lead to considerable metabolic side effects, including weight gain, hyperlipidemia, hyperglycemia, and insulin resistance. Statins are widely used for cardiovascular disease prevention and treatment in high-risk populations. Schizophrenia patients are at an increased risk of dyslipidemia due to long-term antipsychotic medication use, with research indicating that approximately 66% of chronic schizophrenia patients develop varying degrees of dyslipidemia following antipsychotic treatment. Dyslipidemia not only accelerates cardiovascular disease progression but may also lead to premature mortality, with schizophrenia patients facing double the risk of cardiovascular death compared to the general population, resulting in a reduction of lifespan by 9 to 12 years. As such, monitoring and intervening in dyslipidemia among these patients are crucial for improving long-term prognosis. However, while long-term statin use can mitigate myocardial infarction risk, it also raises the risk of new-onset diabetes, with evidence suggesting a 10% increase in diabetes risk attributable to statins-a factor that has not been thoroughly examined in the context of glucose metabolism in schizophrenia patients.

Research Objective: This study aims to explore the occurrence of glucose metabolism abnormalities in schizophrenia patients undergoing atorvastatin treatment for dyslipidemia and to evaluate the ameliorative effects of metformin. Specific objectives include: 1) Investigating the impact of atorvastatin on glucose metabolism by observing changes in insulin resistance, fasting blood glucose, and glycated hemoglobin levels to assess atorvastatin's potential effects on glucose metabolism; 2) Evaluating the adjunctive role of metformin by randomly assigning eligible patients to either a metformin treatment group or a placebo group to observe the auxiliary effect of metformin in atorvastatin therapy and assess its impact on glucose metabolism abnormalities and underlying mechanisms; and 3) Examining the metabolic effects of metformin on dyslipidemia by assessing its influence on lipid profiles (e.g., LDL-C, total cholesterol, triglycerides) during atorvastatin treatment while controlling for glucose metabolism abnormalities.

Research Plan: This study will recruit 200 schizophrenia patients from the Second Xiangya Hospital of Central South University and other partnering institutions. Eligible participants must be aged 18 to 65, meet the criteria for schizophrenia, have stable symptoms and medication regimens for over three months. Participants will provide informed consent prior to inclusion. For lipid levels, participants must meet at least one of the following criteria: 1) fasting total cholesterol (TC) ≥ 5.2 mmol/L; 2) fasting triglycerides (TG) ≥ 1.7 mmol/L; 3) fasting low-density lipoprotein cholesterol (LDL-C) ≥ 3.4 mmol/L. For blood glucose, participants must have two consecutive fasting blood glucose (FPG) tests \< 6.1 mmol/L, with an interval of 1-4 weeks between tests. Patients with a prior diagnosis of diabetes, diabetic ketoacidosis, or any other diabetes-related complications are excluded. Participants will provide informed consent prior to inclusion. The study employs a randomized controlled trial (RCT) design, with participants randomly assigned to two groups: one group receiving atorvastatin 20 mg/day combined with metformin 1000 mg/day and the other receiving atorvastatin 20 mg/day with a placebo. The study duration is six months, with follow-ups at 3 and 6 months, including baseline assessments and multiple blood tests to monitor glucose metabolism and other relevant indices.

Expected Outcomes: By evaluating the effects of atorvastatin on glucose metabolism in schizophrenia patients and the intervention effects of metformin, this study seeks to elucidate the risk of glucose metabolism abnormalities associated with statin therapy in this population and the mechanisms through which metformin improves these outcomes. This research will contribute to developing more effective treatment regimens for schizophrenia patients, thereby reducing cardiovascular disease and diabetes risks and improving patient prognosis. Additionally, results may facilitate the integration of management practices for both mental and metabolic disorders, reducing the healthcare burden from metabolic complications.

Study Timeline

• Study First Submitted: 2025-06-22
• Study First Submitted QC: 2025-06-22
• Status Verified: 2025-07
• Study Start: 2025-07-01
• Study First Posted: 2025-07-01
• Last Update Submitted: 2025-07-16
• Last Update Posted: 2025-07-17
• Primary Completion: 2027-12-31
• Study Completion: 2028-06-01

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 200

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Metformin group	Atorvastatin	To explore the impact of metformin on glucose metabolism abnormalities in schizophrenia patients undergoing atorvastatin treatment.
Metformin group	Metformin	To explore the impact of metformin on glucose metabolism abnormalities in schizophrenia patients undergoing atorvastatin treatment.
Placebo group	Atorvastatin	To serve as a placebo control for evaluating the effects of atorvastatin treatment on glucose metabolism in schizophrenia patients, isolating the impact of metformin from the effects of atorvastatin.
Placebo group	Placebo	To serve as a placebo control for evaluating the effects of atorvastatin treatment on glucose metabolism in schizophrenia patients, isolating the impact of metformin from the effects of atorvastatin.

Primary Outcome Measures

Name	Time	Method
Change from Baseline in Fasting Blood Glucose Concentration	Baseline, 3rd month, 6th month
Change from Baseline in Glycated Hemoglobin (HbA1c) Concentration	Baseline, 3rd month, 6th month
Oral Glucose Tolerance Test	Baseline, 3rd month, 6th month	The Oral Glucose Tolerance Test (OGTT) requires subjects to undergo an 8-hour fasting period, followed by an initial measurement of fasting blood glucose via a portable glucometer using a finger prick. Subsequently, subjects are instructed to consume a solution containing 75 grams of anhydrous glucose dissolved in 300 milliliters of water. Blood samples are then collected through finger pricking at 1 hour and 2 hours post-ingestion for further analysis of glucose levels.

Secondary Outcome Measures

Name	Time	Method
Change from Baseline in Fasting insulin Concentration	Baseline, 3rd month, 6th month
Homeostasis Model Assessment of Insulin Resistance (HOMA-IR)	Baseline, 3rd month, 6th month	HOMA-IR (Homeostasis Model Assessment of Insulin Resistance) is a recognized method for estimating insulin resistance, which plays a critical role in metabolic disorders such as type 2 diabetes and cardiovascular disease. This assessment requires fasting for at least eight hours, followed by the measurement of fasting insulin and fasting glucose levels from blood samples. The HOMA-IR value indicates the degree of insulin resistance; higher values suggest reduced cellular responsiveness to insulin, thereby correlating with increased risk for metabolic syndrome and type 2 diabetes.
Change from Baseline in Positive and Negative Syndrome Scale (PANSS) Total Score	Baseline, 3rd month, 6th month	Range: 30 to 210; Higher Scores Indicate Worse Symptoms.
Cytokines and Oxidative Stress Markers	Baseline, 3rd month, 6th month
Change from Baseline in Global Assessment of Functioning Scale (GAF) Total Score	Baseline, 3rd month, 6th month	Range: 0 to 100; Higher Scores Indicate Better Functioning.
Abdominal ultrasound examination.	baseline, 6 months	The abdominal ultrasound examination will focus on assessing the occurrence of metabolic associated fatty liver disease (MAFLD). Subjects are required to fast for at least 8 hours prior to the examination, and they will lie supine on the examination table. After applying a coupling agent, an ultrasound scan will be performed. The physician will measure the size of the liver, observe its echo characteristics, and assess the echo differences with surrounding organs to determine the presence of liver enlargement or fat deposition. MAFLD typically presents as increased hepatic echogenicity and blurred liver margins. Doppler ultrasound may also be used to evaluate hepatic blood flow if necessary. All examination results will be recorded on case report forms for comprehensive analysis to assess the metabolic status and the degree of MAFLD in the study subjects.
Gut Microbiota	Baseline, 3rd month, 6th month

Trial Locations

Locations (6)

Zhumadian Second People's Hospital; 🇨🇳 Zhumadian, Henan, China

Mental Health Institute of Second Xiangya Hospital, CSU; 🇨🇳 Changsha, Hunan, China

The Third Hospital of Changsha County; 🇨🇳 Changsha, Hunan, China

Loudi Rehabilitation Hospital, Loudi Mental Health Center; 🇨🇳 Loudi, Hunan, China

The Second People's Hospital of Dali Bai Autonomous Prefecture; 🇨🇳 Dali, Yunnan, China

Xiangshan County Traditional Chinese Medicine Hospital Medical and Health Group Three Hospitals District; 🇨🇳 Xiangshan, Zhejiang, China