Metformin, a synthetic biguanide, is widely used to manage type 2 diabetes, and is commonly prescribed in polycystic ovary syndrome (PCOS) to address insulin resistance and associated metabolic and reproductive disturbances. PCOS is characterised by hormonal imbalances such as hyperandrogenism and anovulation, metabolic abnormalities including insulin resistance and increased cardiometabolic risk, and higher rates of pregnancy complications. However, the role of metformin in the multifaceted nature of PCOS remains debated. This review synthesises the mechanisms of action of metformin and its effects on metabolic, hormonal, reproductive, and pregnancy-related outcomes in PCOS. In non-pregnant women, metformin improves insulin resistance, menstrual regularity, and androgen levels, particularly in those with obesity or insulin resistance, and may enhance fertility when combined with other treatments. However, it is not effective as a first-line therapy for weight loss, ovulation induction, or treatment of clinical hyperandrogenic features, including hirsutism or acne. In pregnancy, metformin may reduce early pregnancy loss, miscarriage, and preterm birth, though findings for gestational diabetes and preeclampsia are inconsistent. Evidence is limited by study heterogeneity, varying diagnostic criteria, and the use of aggregate data in meta-analyses, all of which make interpretation challenging. Future research should prioritise well-powered clinical trials, individual patient data meta-analyses, and longer-term follow-up studies, particularly in pregnancy, to better define the populations most likely to benefit from metformin use across the PCOS spectrum. PLAIN LANGUAGE SUMMARY: Polycystic ovary syndrome (PCOS) is a common condition that affects up to 1 in 10 women of reproductive age. It is characterised by irregular or absent periods, signs of elevated male hormones (high androgens or excess hair growth), and/or polycystic ovaries seen on ultrasound. These features can lead to fertility problems, acne, psychological distress, and an increased risk of various disorders such as depression, type 2 diabetes and heart disease. Many women with PCOS also experience challenges during pregnancy, including a higher risk of miscarriage, preterm birth, and gestational diabetes. Metformin is a medication most often used to manage diabetes. In women with PCOS, it can help improve how the body responds to insulin, which may also reduce male hormone levels, improve menstrual cycles, and support fertility. This review examines the role of metformin in treating PCOS-both before and during pregnancy-by summarising key findings from the available evidence. In women who are not pregnant, metformin can help improve insulin resistance, hormone levels, and menstrual regularity, particularly among those who are overweight or have signs of insulin resistance. However, metformin alone is not a first-choice treatment for weight loss, ovulation problems, or symptoms such as acne and unwanted hair growth. When combined with other treatments, such as hormone therapy or fertility medications, it may offer additional benefits. During pregnancy, metformin is considered safe for use in women with PCOS and may lower the risk of early pregnancy loss and preterm birth. However, its effects on preventing gestational diabetes or high blood pressure are less clear, with mixed results across studies. Some research suggests that babies exposed to metformin in the womb may have slightly larger head sizes or a higher risk of being overweight in early childhood, but the long-term health effects remain unknown. Overall, metformin can be a helpful part of treatment for some women with PCOS, especially those with insulin resistance or certain pregnancy risks. Still, it is not a one-size-fits-all solution. More high-quality research is needed to better understand which women benefit most and to assess any long-term effects on children exposed to metformin during pregnancy.

This study compared the efficacy and safety of glucogan-like peptide-1 receptor agonists (GLP1RAs) combined with metformin versus metformin alone in women with polycystic ovary syndrome (PCOS). A systematic search of "PubMed", "EMBASE", "Cochrane Library", and "Web of Science", "Google Scholar" was conducted up to September 2024. Studies were included if they were RCTs investigating the combination of GLP1RAs and metformin in women diagnosed with PCOS. Eligible studies compared this combination therapy to metformin alone. Primary outcomes included changes in body weight, BMI, waist circumference, fasting glucose, HOMA-IR, androgen levels, and sex hormone-binding globulin (SHBG). Meta-analysis was performed using RevMan 5.4 software. Eight RCTs with a total of 337 participants were included. The combination of GLP1RAs and metformin resulted in significant reductions in body weight (mean difference [MD]=-1.37 kg, 95% CI [-2.07, -0.67]; P = 0.0001), BMI (MD= -0.88 kg/m², 95% CI [-1.37, -0.39]; P = 0.0005), waist circumference (MD= -2.46 cm, 95% CI [-3.59,-1.33]; P < 0.0001), fasting glucose level (MD= -0.30, 95% CI [-0.42,-0.17]; P < 0.0001), and glucose level at 2 h after OGTT (MD= -1.58, 95% CI [-2.10,-1.06]; P < 0.0001) compared to metformin alone. Improvements in insulin sensitivity (HOMA-IR) in GLP1RA + Met group were also observed (MD=-1.58, 95% CI [-2.10, -1.06]; P < 0.0001) comparing to Met group. Hormonal outcomes demonstrated an increase in SHBG (MD = 10.04, 95% CI [7.06, 13.01]; P < 0.0001). Adverse events were not different between GLP1RA + Met and Met groups. Collectivley, combination of GLP1RAs and metformin provides superior benefits over metformin alone in reducing body weight, improving insulin sensitivity, and regulating hormonal imbalances in women with PCOS.

Considering the important role of obesity and related factors in different societies on increasing the burden of non-communicable diseases, in this review we will investigate the possible effects of Beinaglutide on these risk factors.

In order to identify all randomized controlled trials that investigated the effects of Beinaglutide on cardiometabolic factors, a systematic search was conducted in the original databases using predefined keywords until July 2024. The pooled weighted mean difference (WMD) and 95% confidence intervals were computed using the random-effects model.

   A quantitative meta-analysis results from seven studies with 872 participants showed that Beinaglutide has a significant lowering effect on weight (WMD: -3.74 kg; 95% CI: -5.03, -2.45), body mass index (BMI) (WMD:-1.64 kg/m2; 95% CI: -2.10, -1.17), waist circumference (WC) (WMD: -3.19 cm; 95% CI: -4.65 to -1.73), triglyceride (TG) levels (WMD: -0.14 mmol/l with; 95% CI: -0.25, -0.04), and systolic blood pressure (SBP) (WMD: -1.76 mm/Hg; 95% CI: -2.61, -0.91). In addition, body weight loss was greater in doses < 0.4 mg compared to doses ≥ 0.4 mg.

The results of this meta-analysis show that Beinaglutide is effective in reducing parameters related to obesity, TG as well as SBP.

Polycystic ovary syndrome (PCOS) poses a multifaceted challenge, affecting women through genetic susceptibility, obesity, and insulin resistance. This narrative review explores the potential therapeutic role of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in PCOS treatment, with a focus on weight loss and associated metabolic changes. The off-label use of GLP-1 RAs in this population helps to treat comorbid obesity. By thoroughly examining PCOS diagnostic criteria, current treatments, and clinical trial outcomes involving GLP-1 RAs, this research reveals encouraging results. However, concerns about the long-term safety of GLP-1 RAs, including serious adverse events, warrant further investigation. While GLP-1 RAs hold promise for treating obesity in PCOS, safety issues may limit their utility.

This study aimed to provide evidence-based support and a reference for the efficacy and safety of seven glucagon-like peptide-1 (GLP-1) receptor agonists and polyagonists for weight loss in patients with obesity or overweight through a network meta-analysis.

Relevant randomized controlled trials (RCTs) with an intervention duration of at least 16 weeks assessing seven GLP-1 receptor agonists and polyagonists (mazdutide, 6 or 4.5 mg; retatrutide, 12 or 8 mg; tirzepatide, 15 or 10 mg; liraglutide, 3.0 mg; semaglutide, 2.4 mg; orforglipron, 45 or 36 mg; and beinaglutide, 0.2 mg) in patient with obesity or overweight was searched using three databases (Cochrane Library, PubMed, and Embase) from creation to August 30, 2024. The primary outcome was the percentage change in body weight from baseline. Secondary outcomes included changes in waist circumference, hemoglobin A1c, and fasting plasma glucose level from baseline; adverse events, serious adverse events, adverse event withdrawal, and hypoglycemic events. We conducted a frequentist random-effects network meta-analysis to analyze the data extracted from the RCTs using Stata 16.1 software.

Twenty-seven RCTs of seven GLP-1 receptor agonists and polyagonists and 15,584 patients were included in the network meta-analysis. In terms of efficacy, compared with placebo, retatrutide 12 mg (-22.10 % in body weight and - 17.00 cm in waist circumference), retatrutide 8 mg (-20.70 % and - 15.90 cm), and tirzepatide 15 mg (-16.53 % and - 13.23 cm) were the three most efficacious treatments for reducing body weight and waist circumference. However, these treatments were less effective in patients with type 2 diabetes mellitus (T2DM). In addition, patients with a high body mass index (BMI) or longer treatment cycles exhibited significantly greater weight loss than those with a low BMI or shorter treatment cycles. In terms of safety, patients without T2DM had a higher incidence of adverse events than those with T2DM. None of the interventions increased the incidence of serious adverse or hypoglycemic events (˂54 mg/dL). There was no significant difference in the incidence of adverse event withdrawal for all interventions in head-to-head comparisons. In addition, disparities in race, BMI, and treatment cycles did not significantly increase the incidence of adverse events. Finally, the sensitivity and publication bias analyses indicated that the basic analysis results were reliable.

Retatrutide (both doses) and tirzepatide exhibited superior efficacy compared to other GLP-1 receptor agonists and polyagonists in reducing body weight and waist circumference. Patients without T2DM, those with a high BMI, and individuals undergoing longer treatment cycles demonstrated significantly greater weight loss and reductions in waist circumference. Dual or triple receptor agonists (GLP-1 plus glucose-dependent insulinotropic polypeptide and/or Glucagon receptor) are more effective for weight loss than GLP-1 receptor agonists.

Polycystic ovary syndrome (PCOS) is common in women of reproductive age and is associated with obesity. Clinical guidelines recommend weight loss, but the impact on the clinical manifestations of PCOS is unclear.

To quantify the effect of weight loss interventions on clinical features of PCOS, compared with usual care.

MEDLINE, Embase, PsycINFO, CINAHL, Cochrane, Web of Science, and trial registries were searched from inception through June 2024.

Randomized controlled trials comparing interventions aiming to reduce weight against usual care, including lower-intensity weight loss interventions in people with PCOS. Conversations with people with PCOS informed the outcomes.

Pairs of independent reviewers screened studies, extracted data, and assessed risk of bias (RoB). Outcomes included glycemic control (Homeostasis Model Assessment for Insulin Resistance [HOMA-IR], fasting insulin and glucose), hormonal markers (free androgen index [FAI] and other sex hormones), menstrual frequency, hirsutism, and PCOS-related quality of life (QoL). Pooled mean differences were obtained from random-effects meta-analysis with Knapp-Hartung adjustment.

Primary analyses included 29 comparisons with 1529 participants: 13, 12, and 4 comparisons were judged as high, some, or low RoB, respectively. Twelve used behavioral interventions, 9 used glucagon-like peptide-1 (GLP1) agonists, and 8 used other weight loss medications. Weight loss interventions were associated with significantly greater improvements in HOMA-IR (mean difference, -0.45 [-0.75 to -0.15]; I 2 = 24%), FAI (mean difference, -2.03 [-3.0 to -1.07]; I 2 = 48%), and menstrual frequency (mean difference, 2.64 [0.65 to 4.63]; I2  = 43%). There was no evidence that weight loss interventions were associated with clinically or statistically significant improvements in hirsutism, QoL, or other sex hormones, which may be due to the limited power of the available data.

There was high statistical heterogeneity in the interventions, comparators, and outcomes, largely unexplained by sensitivity and subgroup analyses.

Weight loss interventions were associated with improvements in some important features of PCOS and should be considered as a routine treatment option for people with PCOS.

National Institute for Health and Care Research School for Primary Care Research. (PROSPERO: CRD42022367488).

Diabetes is a global disease that can lead to a range of complications. Currently, the treatment of type 2 diabetes focuses on oral hypoglycemic drugs and insulin analogues. Studies have shown that drugs such as oral metformin are useful in the treatment of diabetes but can limit the liver's ability to release sugar. The development of glucose-lowering peptides has provided new options for the treatment of type 2 diabetes. Peptide drugs have low oral utilization due to their easy degradation, short half-life, and difficulty passing through the intestinal mucosa. Therefore, improving the oral utilization of peptide drugs remains an urgent problem. This paper reviews the research progress of peptide drugs in the treatment of diabetes mellitus and proposes that different types of nano-formulation carriers, such as liposomes, self-emulsifying drug delivery systems, and polymer particles, should be combined with peptide drugs for oral administration to improve their absorption in the gastrointestinal tract.

Glucagon-like peptide-1 (GLP-1), secreted by L cells in the small intestine, assumes a central role in managing type 2 diabetes mellitus (T2DM) and obesity. Its influence on insulin secretion and gastric emptying positions it as a therapeutic linchpin. However, the limited applicability of native GLP-1 stems from its short half-life, primarily due to glomerular filtration and the inactivating effect of dipeptidyl peptidase-IV (DPP-IV). To address this, various structural modification strategies have been developed to extend GLP-1's half-life. Despite the commendable efficacy displayed by current GLP-1 receptor agonists, inherent limitations persist. A paradigm shift emerges with the advent of unimolecular multi-agonists, such as the recently introduced tirzepatide, wherein GLP-1 is ingeniously combined with other gastrointestinal hormones. This novel approach has captured the spotlight within the diabetes and obesity research community. This review summarizes the physiological functions of GLP-1, systematically explores diverse structural modifications, delves into the realm of unimolecular multi-agonists, and provides a nuanced portrayal of the developmental prospects that lie ahead for GLP-1 analogs.

Metformin is commonly prescribed to treat polycystic ovary syndrome (PCOS) patients, but in some cases, it may not be effective even at high doses or may cause intolerable side effects. Therefore, recent studies have examined the impact of combining metformin with other antidiabetic medications.

A systematic search was performed in Scopus, PubMed, Web of Science, and Embase up to 30 June 2023. All interventional studies that assessed the efficacy of different antidiabetic agents were included.

Among the 3488 records found in the primary search, 16 papers were included. Our study showed that dipeptidyl peptidase-4 inhibitors (DPP4i) had the most significant impact on glycemic profile, while thiazolidinediones (TZDs) had the most influence on lipid levels. However, it was observed that patients taking only metformin experienced a greater increase in high-density lipoprotein cholesterol (HDL-C) levels. Glucagon-like peptide-1 receptor agonists (GLP1RAs) effectively modified various anthropometric measurements, such as weight, body mass index, waist circumference, and waist-to-hip ratio. The effects of different antidiabetic drugs on hormone levels were inconclusive, although testosterone levels were more affected by GLP1RA, sodium-glucose cotransporter-2 inhibitors (SGLT2i), and TZDs. None of the combined therapies showed a significant change in blood pressure.

Since PCOS is a metabolic disorder, choosing the best combination of antidiabetic drugs in the clinical course of PCOS patients will be very important. Today, it seems that we need a new metabolic approach for better treatment of the metabolic aspects of these patients.

This prospective study aimed to evaluate the effect of beinaglutide combined with metformin versus aspart 30 with metformin on metabolic profiles and antidrug antibodies (ADAs) in patients with type 2 diabetes (T2D).

A total of 134 eligible participants were randomly assigned to the test group and the control group. Patients in the test group were treated with beinaglutide and metformin, whereas patients in the control group were randomly treated with aspart 30 and metformin, with a follow-up period of 6 months. The metabolic profiles and ADAs over 6 months were evaluated.

After 6 months, 101 (75.37%) patients completed the study. Compared with the control group, the beinaglutide group had significant reductions in 2-h postprandial blood glucose (2hBG) and low blood glucose index (LBGI). Glycated hemoglobin (HbA1c) decreased in both groups relative to baseline. In the test group, one had treatment-emergent beinaglutide ADAs. Significant reductions in triglycerides (TG), non-fasting TG, weight, waist circumference (WC), and body mass index (BMI) were observed. The values of insulin sensitivity index (HOMA-IR) were decreased to a statistically higher degree with beinaglutide treatment.

Beinaglutide reduces metabolic dysfunction, LBGI, and weight in patients of T2D with a low risk of ADAs. Beinaglutide may offer the potential for a disease-modifying intervention in cardiovascular disease (CVD).

www.chictr.org.cn, identifier ChiCTR2200061003.

Polycystic ovary syndrome (PCOS) is the most common cause of anovulatory infertility in women of childbearing age. Randomized controlled trials (RCTs) have reported that exenatide and metformin are effective in the treatment of PCOS. In this meta-analysis, we aimed to compare the effectiveness and safety of exenatide alone or in combination with metformin versus metformin in patients suffering from PCOS.

RCTs of exenatide therapy were identified through a search of electronic databases in November 2022 and updated in October 2023. Eligible studies were identified independently by the reviewers. Outcomes were analysed with Revman 5.4.

Nine RCTs among 214 studies on 1059 women with PCOS were included in the analysis, and among the nine RCTs, eight studies compared exenatide with metformin. Our meta-analysis demonstrated that exenatide was more effective than metformin in terms of pregnancy rate (RR 1.85 [95% CI 1.19,2.86] P = 0.006), sex hormone-binding globulin (SHBG) (MD 5 [95% CI 3.82,6.18] P < 0.001), and follicle-stimulating hormone (FSH) (MD 0.82 [95% 0.41,1.24] P < 0.001). The reductions in total testosterone (TT) (SMD -0.43 [95% CI -0.84, -0.03] P = 0.04) was more significant after treatment with exenatide than after treatment with metformin. In terms of safety, exenatide had a lower diarrhea rate (RR 0.11 [95% CI 0.01, 0.84]) than metformin. In the other three studies, exenatide plus metformin was compared with metformin. Exenatide combined with metformin was more effective in improving SHBG (MD 10.38[95%CI 6.7,14.06] P < 0.001), Matsuda index (MD 0.21[95%CI 0.05,0.37]) and reducing free androgen index (FAI) (MD -3.34 [-4.84, -1.83] P < 0.001), Weight (MD -2.32 [95%CI -3.89, -0.66]) and WC (MD-5.61[95%CI -8.4, -2.82] P < 0.001). The incidence of side effects between exenatide plus metformin and metformin was not statistically significant.

Exenatide alone or in combination with metformin is more effective than metformin for women with PCOS. Considering the evidence on effectiveness and safety, exenatide alone or in combination with metformin may be a better treatment approach than metformin for women with PCOS.

INPLASY https://inplasy.com/inplasy-protocols/ ID: 10.37766/inplasy2022.11.0055.