Metformin Alleviates Abnormal Glucose Metabolism Induced by Statins in Schizophrenia Patients

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.