OBJECTIVES: To compare the effects of metformin and orlistat in terms of reduction in weight or BMI, and improvement of ovulation rates, endocrinologic and lipid profiles, and occurrence of adverse events among overweight or obese women diagnosed with PCOS.

SEARCH METHODS: We searched Medline, OVID, HERDIN, EMBASE, Cochrane Library and ClinicalTrials.gov for head to head clinical trials of metformin versus orlistat for the treatment of overweight and obese women with PCOS. We also contacted the pharmaceutical companies and did hand-searching to look for related studies.

SELECTION CRITERIA: Only randomized controlled trials comparing metformin and orlistat as treatment for overweight and obese PCOS women were included. Other inclusion criteria included: trial period of at least 3 months duration, participants, of any ethnicity, 18-40 years old, who are overweight or obese, and studies with or without non-pharmacologic interventions as part of the treatment regimen.

DATA COLLECTION AND ANALYSIS: Titles and abstracts identified through the search strategies were screened by two reviewers. Two authors extracted data on publication characteristics, inclusion and exclusion criteria, intervention and co-intervention, primary and secondary outcomes, and details of study design. Two authors assessed the quality and risk bias of each RCT based on random sequence generation, allocation concealment, blinding of participants, caregivers, and assessors, attrition bias, incomplete outcome data, selective reporting, and publication bias.

MAIN RESULTS: We included 5 RCTs (n=221). Overall, treatment effects of orlistat and metformin showed no significant difference in the following outcomes: ovulation rates (RR 0.78; 95% CI 0.41, 1.49), reduction of BMI (MD -0.47; 95%CI:-1.53,0.59), serum testosterone levels (MD -2.15;95% CI -9.64, 5.33), free androgen index MD 3.26; 95% CI -7.91, 14.43), homeostatic model assessment-insulin resistance (3.70; 95% CI -6.74, 14.15), fasting insulin (MD 7.86; 95% CI -3.09, 18.81), HDL-C (MD -1.19 ; 95% CI -4.78, 7.16) and triglycerides (MD -1.95; 95% CI -8.81, 4.90). Orlistat was significantly better than metformin in reducing total cholesterol (MD -6.60; 95% CI -10.79, -2.41), and LDL (MD -5.04; 95% CI -9.64, 5.33), free androgen index (MD 3.26; 95% CI -7.91, 14.43), homeostaic model assessment-insulin resistance (3.70; 95% CI -6.74, 14.15), fasting insulin (MD 7.86; 95% CI -3.09, 18.81), HDL-C (MD -1.19 ; 95% CI -4.78, 7.16) and triglycerides (MD -1.95; 95% CI -8.81, 4.90). Orlistat was significantly better than metformin in reducing total cholesterol (MD -6.60; 95% CI -10.79, -2.41), and LDL (MD -5.04); 95% CI  -9.99, -0.09), and had less adverse events (RR 0.37, 95% CI 0.14, 0.96).

AUTHORS' CONCLUSIONS: Metformin and Orlistat have similar effects on weight loss, ovulation rates, and endocrinologic profiles of obese women with PCOS. Orlistat is more effective than metformin in decreasing total cholesterol and LDL -C levels, and has less adverse events than metformin. Therefore, we may recommend orlistat to overweight or obese women with PCOS who also have dyslipidemia. However, caution is given to our interpretations since small sample size, low quality of RCTs, and wide confidence intervals of pooled estimates significantly influence interpretation and recommendations. RCTs with adequately powered study populations are recommended to confirm findings of this review.

Human ; Female ; Polycystic Ovary Syndrome ; Ovarian Cysts ; Metformin ; orlistat ;

Aberrant de novo lipid synthesis is involved in the progression and treatment resistance of many types of cancers, including lung cancer; however, targeting the lipogenetic pathways for cancer therapy remains an unmet clinical need. In this study, we tested the anticancer activity of orlistat, an FDA-approved anti-obesity drug, in human and mouse cancer cells in vitro and in vivo, and we found that orlistat, as a single agent, inhibited the proliferation and viabilities of lung cancer cells and induced ferroptosis-like cell death in vitro. Mechanistically, we found that orlistat reduced the expression of GPX4, a central ferroptosis regulator, and induced lipid peroxidation. In addition, we systemically analyzed the genome-wide gene expression changes affected by orlistat treatment using RNA-seq and identified FAF2, a molecule regulating the lipid droplet homeostasis, as a novel target of orlistat. Moreover, in a mouse xenograft model, orlistat significantly inhibited tumor growth and reduced the tumor volumes compared with vehicle control (P < 0.05). Our study showed a novel mechanism of the anticancer activity of orlistat and provided the rationale for repurposing this drug for the treatment of lung cancer and other types of cancer.
Animals ; Cell Death ; Cell Line, Tumor ; Ferroptosis ; Lung Neoplasms/drug therapy* ; Mice ; Orlistat

OBJECTIVE: To investigate the expression of pyruvate kinase M2 (PKM2) in bone marrow mesenchymal stem cells (BMSCs) in myeloma bone disease (MBD) and its effect on osteogenic and adipogenic differentiation of BMSCs. METHODS: BMSCs were isolated from bone marrow of five patients with multiple myeloma (MM) (MM group) and five with iron deficiency anemia (control group) for culture and identification. The expression of PKM2 protein were compared between the two groups. The differences between osteogenic and adipogenic differentiation of BMSCs were assessed by using alkaline phosphatase (ALP) and oil red O staining, and detecting marker genes of osteogenesis and adipogenesis. The effect of MM cell line (RPMI-8226) and BMSCs co-culture on the expression of PKM2 was explored. Functional analysis was performed to investigate the correlations of PKM2 expression of MM-derived BMSCs with osteogenic and adipogenic differentiation by employing PKM2 activator and inhibitor. The role of orlistat was explored in regulating PKM2 expression, osteogenic and adipogenic differentiation of MM-derived BMSCs. RESULTS: Compared with control, MM-originated BMSCs possessed the ability of increased adipogenic and decreased osteogenic differentiation, and higher level of PKM2 protein. Co-culture of MM cells with BMSCs markedly up-regulated the expression of PKM2 of BMSCs. Up-regulation of PKM2 expression could promote adipogenic differentiation and inhibit osteogenic differentiation of MM-derived BMSCs, while down-regulation of PKM2 showed opposite effect. Orlistat significantly promoted osteogenic differentiation in MM-derived BMSCs via inhibiting the expression of PKM2. CONCLUSION The overexpression of PKM2 can induce the inhibition of osteogenic differentiation of BMSCs in MBD. Orlistat can promote the osteogenic differentiation of BMSCs via inhibiting the expression of PKM2, indicating a potential novel agent of anti-MBD therapy.
Humans ; Adipogenesis ; Bone Diseases/metabolism* ; Bone Marrow Cells ; Cell Differentiation ; Cells, Cultured ; Mesenchymal Stem Cells/physiology* ; Multiple Myeloma/metabolism* ; Orlistat/pharmacology* ; Osteogenesis/genetics*