The COMET-PCOS trial - Comparing the effects of Oral Contraceptive Pills versus Metformin in the medical management of overweight/obese women with Polycystic Ovary Syndrome

COMET-PCOS 试验 - 比较口服避孕药与二甲双胍在超重/肥胖多囊卵巢综合症女性医疗管理中的效果

• 批准号: 9286789
• 负责人: ANUJA DOKRAS
• 金额: $ 60.01万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9286789
• 关键词: Adipocytes; Affect; Aftercare; Age; Androgens; Apolipoproteins; Blood Pressure; Body Weight; Body Weight decreased; Body fat; Cardiovascular Diseases; Caucasians; Cholesterol; Chronic Disease; Clinical; Combined Modality Therapy; Conflict (Psychology); Consensus; Data; Development; Diabetes Mellitus; Dual-Energy X-Ray Absorptiometry; Dyslipidemias; Emotional; Endocrine System Diseases; Endocrinologist; Fatty acid glycerol esters; Functional disorder; Funding; Glucose; Guidelines; Gynecologist; Health; High Density Lipoproteins; High Prevalence; Hirsutism; Hyperandrogenism; Hypertriglyceridemia; IL6 gene; Individual; Inflammation; Inflammatory; Insulin; Insulin Resistance; International; Irregular Menstruation; Leptin; Lipids; Lipoproteins; Low Dose Oral Contraceptives; Measures; Medical; Metabolic; Metabolic syndrome; Metformin; Methods; Morbidity - disease rate; NMR Spectroscopy; National Institute of Child Health and Human Development; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Obesity; Oral Contraceptives; Overweight; Particle Size; Pathway interactions; Patients; Pattern; Periodicity; Pharmaceutical Preparations; Phenotype; Physicians; Polycystic Ovary Syndrome; Population; Pregnancy; Prevalence; Prevention strategy; Preventive treatment; Public Health; Race; Randomized; Randomized Clinical Trials; Risk; Risk Factors; Serum; Serum Markers; Surveys; System; TNF gene; Techniques; Testing; Triglycerides; Visceral; Weight; Woman; adipokines; adiponectin; arm; base; cardiometabolic risk; clinical practice; cytokine; design; evidence based guidelines; glucose tolerance; high risk population; improved; inflammatory marker; innovation; insulin sensitivity; intervention effect; metabolic profile; pediatrician; pill; preference; racial difference; reproductive; trial comparing; young woman

Background: Polycystic ovary syndrome (PCOS) is the commonest endocrine disorder in reproductive age women. Metabolic syndrome (MetS), a constellation of cardiometabolic risk factors, is a major health problem with a high prevalence in young women with PCOS (20-40%). Surprisingly, there is no consensus on the optimal treatment of overweight/obese women with PCOS not attempting pregnancy, resulting in conflicting clinical guidelines and prescribing patterns for the use of oral contraceptive pills (OCP) and metformin in the long term treatment of PCOS. Although OCP improve menstrual irregularity and lower androgens, they may be associated with increase in weight, serum triglycerides levels and blood pressure. In the OWL-PCOS study, we recently found that these adverse metabolic effects of OCP are exacerbated in overweight/obese women with PCOS. Metformin on the other hand, has a favorable metabolic profile but is less effective in improving menstrual regularity and reducing androgens. This conundrum highlights the need to identify comprehensive and safe treatments, whilst improving the metabolic profile in this high risk population. Specific Aims and Methods: In Specific Aim 1 we propose a pragmatic randomized clinical trial (COMET- PCOS) to compare the effects of OCP versus metformin versus OCP+metformin on change in prevalence of MetS after 6 months treatment in 240 overweight/obese women with PCOS. Based on our data from OWL- PCOS, we hypothesize that low dose OCP use will significantly increase the risk of MetS, while metformin alone or metformin+OCP use will result in a decrease or modest increase in MetS respectively. Our secondary aims will examine innovative mechanistic pathways associated with individual components of MetS. For example, to precisely understand the paradoxical effects of OCP on dyslipidemia (increased serum triglycerides and HDL-C levels), the commonest metabolic abnormality in PCOS, we will assess HDL-C function by measuring reverse cholesterol efflux, and lipoprotein particle size and number by NMR spectroscopy. In Specific Aim 2 we will precisely define the impact of OCP (by decreasing androgens) and metformin (by improving insulin sensitivity) or both on change in visceral fat distribution, glucose tolerance, inflammatory cytokines and adipokines. Summary: The presence of both PCOS and MetS adds significantly to long term morbidities, financial and emotional burden in young women. Our well-designed and adequately powered study will likely provide evidence favoring the use of OCP+metformin combination and avoiding use of OCP alone in management of overweight/obese women with PCOS. These findings will significantly change current clinical practice which is based on patient and physician preferences. Further, our secondary aims will be innovative as they are targeted at specifically comparing and understanding the pathophysiology of the metabolic alterations associated with use of OCP and metformin.

背景：多囊卵巢综合征（PCOS）是育龄期最常见的内分泌疾病 女性。代谢综合征 (MetS) 是一系列心脏代谢危险因素，是一个主要的健康问题 年轻女性 PCOS 患病率较高（20-40%）。令人惊讶的是，各方并没有达成共识 患有 PCOS 的超重/肥胖女性未尝试怀孕的最佳治疗方案，导致相互矛盾 使用口服避孕药 (OCP) 和二甲双胍的临床指南和处方模式 多囊卵巢综合症的长期治疗。尽管 OCP 可以改善月经不调并降低雄激素，但它们可能 与体重、血清甘油三酯水平和血压的增加有关。在 OWL-PCOS 研究中，我们 最近发现，OCP 的这些不良代谢影响在患有以下疾病的超重/肥胖女性中会加剧： 多囊卵巢综合症。另一方面，二甲双胍具有良好的代谢特征，但在改善代谢方面效果较差。 月经规律和减少雄激素。这个难题凸显了需要确定全面的 和安全的治疗，同时改善这一高危人群的代谢状况。 具体目标和方法：在具体目标 1 中，我们提出了一项实用的随机临床试验（COMET- PCOS）比较 OCP 与二甲双胍与 OCP+二甲双胍对患病率变化的影响 对 240 名患有 PCOS 的超重/肥胖女性进行 6 个月治疗后的 MetS。根据我们来自 OWL 的数据- PCOS，我们假设低剂量 OCP 使用会显着增加 MetS 的风险，而二甲双胍 单独使用或使用二甲双胍+OCP 将分别导致 MetS 减少或适度增加。我们的中学 目标将研究与 MetS 各个组成部分相关的创新机制途径。为了 例如，要准确了解 OCP 对血脂异常（血清浓度增加）的矛盾影响 甘油三酯和 HDL-C 水平），这是 PCOS 中最常见的代谢异常，我们将评估 HDL-C 通过测量反向胆固醇流出来发挥作用，并通过 NMR 测量脂蛋白颗粒大小和数量 光谱学。在具体目标 2 中，我们将精确定义 OCP 的影响（通过减少雄激素）和 二甲双胍（通过改善胰岛素敏感性）或两者都可以改变内脏脂肪分布、葡萄糖耐量、 炎症细胞因子和脂肪因子。 摘要：PCOS 和 MetS 的存在都会显着增加长期发病率、财务和健康风险。 年轻女性的精神负担。我们精心设计且动力充足的研究可能会提供 有证据支持使用 OCP+二甲双胍组合并避免单独使用 OCP 来治疗 患有多囊卵巢综合症的超重/肥胖女性。这些发现将显着改变当前的临床实践 根据患者和医生的喜好。此外，我们的次要目标将是创新的 旨在专门比较和了解代谢改变的病理生理学 与 OCP 和二甲双胍的使用有关。