Introduction: The Growing Need for Effective Weight Management Strategies
The increasing prevalence of obesity and related metabolic disorders has fueled the search for effective weight management strategies. Polycystic ovary syndrome (PCOS), a common endocrine disorder affecting women of reproductive age, is often associated with obesity, insulin resistance, and dyslipidemia, further complicating the picture. These metabolic abnormalities elevate the risk of type 2 diabetes mellitus, cardiovascular diseases, and endometrial cancer, while ovulatory dysfunction contributes to female infertility. Given that a weight loss of just 5-10% can significantly improve the pathological features and long-term outcomes for patients with PCOS, effective interventions are crucial. However, first-line lifestyle interventions often yield unsatisfactory results, necessitating the exploration of pharmacological approaches.
Metformin (MET), a well-established drug for improving insulin resistance and reproductive outcomes in PCOS, has limited effectiveness in promoting weight loss among obese individuals. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have emerged as a promising treatment option, not only facilitating weight loss but also addressing mechanisms associated with insulin resistance. Semaglutide, a GLP-1 RA administered weekly, has demonstrated consistent weight reduction in obese patients. This article delves into the potential of combining semaglutide and metformin for enhanced weight loss and metabolic benefits, drawing on recent research and clinical trials.
The Promise of GLP-1 RAs in Weight Management
GLP-1 RAs offer a multifaceted approach to weight management by not only facilitating body weight loss but also addressing mechanisms associated with insulin resistance. They enhance the expression of glucose transporters in insulin-sensitive tissues, reduce inflammation and oxidative stress, and regulate lipid metabolism, and may improve fertility through mitigating hypothalamic-pituitary suppression and lowering elevated LH levels associated with hyperinsulinemia and obesity.
The combination of MET with GLP-1 RAs, such as liraglutide or exenatide, offers several benefits in treating obese patients with PCOS. These include significant reductions in body weight and fat, improved insulin resistance, enhanced menstrual cycle regularity and ovulation rates, reduced inflammation and oxidative stress, and increased treatment efficacy, particularly in patients with limited responses to lifestyle interventions combined with MET therapy.
Semaglutide offers superior weight reduction efficacy and a lower risk of gastrointestinal side effects compared to liraglutide, resulting in higher patient adherence rates.
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Semaglutide and Metformin Combination Therapy: A Clinical Evaluation
A recent study aimed to evaluate the impact of combined semaglutide and MET therapy on metabolic, endocrine, reproductive disorders and inflammatory markers in overweight/obese women with PCOS.
Study Design and Methodology
In a randomized, prospective, open-label, parallel, controlled study, 100 overweight/obese women with PCOS were enrolled and randomly assigned to two groups: MET monotherapy (1000 mg twice daily [BID] for 16 weeks) and combination therapy (COM) (1000 mg MET BID plus 1-mg semaglutide once weekly [QW] for 16 weeks). The study was conducted at the Second Affiliated Hospital of Chongqing Medical University and adhered to the Declaration of Helsinki guidelines, with ethics committee approval.
PCOS was diagnosed based on the Rotterdam criteria, requiring at least two of the following: oligo-anovulation and/or anovulation, clinical and/or biochemical signs of hyperandrogenism, and polycystic ovaries. Inclusion criteria included age between 18 and 40 years, a BMI ≥ 24 kg/m², fulfillment of the PCOS diagnostic criteria, lack of response to lifestyle interventions, and voluntary participation with informed consent. Exclusion criteria encompassed allergies to GLP-1 RAs or MET, pre-existing diabetes, comorbid conditions, abnormal liver or kidney function, use of certain medications affecting reproduction, other gynecological conditions causing severe infertility, inability to comply with follow-up, and planned pregnancy within 16 weeks.
After baseline assessments, including anthropometric measurements and biochemical parameters, patients were randomly assigned to either the MET or COM group. MET treatment started at 500 mg daily (QD) and was gradually increased to 1000 mg BID. Semaglutide was initiated at 0.25 mg and increased to 0.5 mg at 4 weeks and 1 mg at 8 weeks, contingent on tolerability. Barrier contraception was recommended throughout the study. At Week 16, semaglutide was discontinued in the COM group, while MET was continued in both groups at 1000 mg BID for an additional 24 weeks, focusing on pregnancy outcomes.
Anthropometric measurements, including height, weight, WC, HC, and WHR, were collected at baseline and Week 16. Biochemical parameters, including glucose, insulin, HbA1c, sex hormones, lipid profile, UA, CRP, and AMH levels, were assessed via blood samples collected after an overnight fast. Insulin resistance was assessed using HOMA-IR, and the FAI and CVAI were calculated. Menstrual cycle and pregnancy outcomes were monitored throughout the study.
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Key Findings and Observations
After 16 weeks of intervention, the COM group exhibited significantly greater reductions in body weight, BMI, and WHR compared to the MET group (all P < 0.01). The COM group experienced an average weight loss of 6.09 ± 3.34 kg, while the MET group lost only 2.25 ± 4.27 kg. The COM group also demonstrated greater improvements in TEST, CVAI, and CRP levels compared to the MET group. Additionally, the COM group showed higher rates of menstrual cycle recovery than the MET group. From weeks 16 to 40, the COM group demonstrated a significantly higher natural pregnancy rate than the MET group (35% vs.).
Compared to the control group, the PCOS group showed significantly higher levels of BMI, WHR, UA, ALT, TG, TC, HDL, LDL, WBCs, CRP, HbA1c, FBG, FINS, HOMA-IR, DHEA-S, TEST, FAI, PRL, LH/FSH, and AMH, while SHBG levels were lower.
Meta-Analysis of Semaglutide and Metformin in Type 2 Diabetes
Another study conducted a meta-analysis to assess the efficacy of semaglutide combined with metformin in patients with type 2 diabetes mellitus (T2DM) while being overweight or obese. Ten studies, involving 962 patients, were included in this meta-analysis. The results demonstrated that semaglutide combined with metformin exhibited a more pronounced reduction in FBG compared with metformin alone. Semaglutide combined with metformin resulted in a more significantly reduced 2-hour postprandial glucose level. The combined treatment resulted in a lower BMI compared to metformin alone. Meta-analysis of data showed that homeostatic model assessment of insulin resistance (HOMA-IR) were significantly improved in T2DM patients who are overweight or obese.
The meta-analysis study showed that semaglutide combined with metformin demonstrated a better hypoglycemic effect, with significant reductions in FPG and HbA1c.
In terms of BMI, the meta-analysis studies showed that the combination of semaglutide and metformin significantly reduced BMI compared to the control arm.
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The results of this meta-analysis suggest that patients in the semaglutide and metformin group showed a more significant decrease in TC and TG compared to the control arm. This effect may be linked to the higher baseline lipid levels typically seen in overweight or obese patients and the influence of semaglutide and metformin on dietary habits.
Studies have shown a significant positive correlation and causal relationship between blood glucose, lipid levels, and blood pressure, all of which are factors affecting insulin resistance. Other studies have shown that if blood lipids and blood pressure are well controlled in patients with T2DM, it not only significantly delays the occurrence of microvascular complications of diabetes but also significantly reduces the risk of cardiovascular and cerebrovascular accidents related to diabetes. Therefore, semaglutide, through its good regulation of lipid levels, increases insulin sensitivity in patients, effectively controls blood glucose, and slows down the progression of acute and chronic complications in patients with T2DM and issues with being overweight/obese.
Semaglutide for Antipsychotic-Induced Weight Gain (AIWG)
Antipsychotic-induced weight gain (AIWG) represents a significant clinical challenge for both patients and clinicians, requiring appropriate interventions to prevent or reverse weight gain in patients using antipsychotics. Glucagon-like peptide 1 (GLP-1) agonists represent a novel approach to the management of obesity that has recently attracted considerable attention. Semaglutide (a GLP-1 agonist) has been demonstrated to result in notable weight loss.
A prospective, non-randomised cohort study was conducted with the objective of evaluating the efficacy and safety of oral semaglutide for the treatment of AIWG in routine outpatient clinical practice. Subsequently, the results were compared with those of a control group of AIWG patients taking metformin. After 16 weeks, the mean body weight loss was 4.5 kg (95% confidence interval (CI), -6.7 to -2.3 kg; p < 0.001) in the semaglutide group (n = 10) versus 2.9 kg (95% CI, -4.5 to -1.4 kg; p < 0.001) in the metformin group (n = 26). This corresponds to an average body weight loss of 4% for semaglutide, and 2.5% for metformin. The respective reductions in body mass index (BMI) and waist circumference were -1.7 kg/m2 (95% CI, -2.4 to -1.0 kg/m2; p < 0.001) and -6.8 cm (95% CI, -9.7 to -3.8 cm; p < 0.001) for semaglutide. The observed reductions for metformin were -0.8 kg/m2 (95% CI, -1.4 to -0.3 kg/m2; p = 0.001) and -3.4 cm (95% CI, -5.4 to -1.3 cm; p = 0.001). The differences between the two groups were not statistically significant. In both groups, adverse effects were typically mild and transient, predominantly nausea.
Oral semaglutide represents a viable, effective, and safe treatment option for psychiatric patients.
The Role of Lac-Phe in Metformin-Induced Weight Loss
An "anti-hunger" molecule produced after vigorous exercise is responsible for the moderate weight loss caused by the diabetes medication metformin, according to a new study in mice and humans. The finding, made jointly by researchers at Stanford Medicine and at Harvard Medical School, further cements the critical role the molecule, called lac-phe, plays in metabolism, exercise and appetite. Obese laboratory mice given metformin had increased levels of lac-phe in their blood. The researchers also analyzed stored blood plasma samples from people with Type 2 diabetes before and 12 weeks after they had begun taking metformin to control their blood sugar. They saw significant increases in the levels of lac-phe in people after metformin compared with their levels before treatment.
Practical Considerations and Personalized Approaches
Given the complexities of weight management and the potential for individual variability in treatment response, a personalized approach is crucial. Factors such as dietary habits, lifestyle, and underlying metabolic conditions should be carefully considered when designing a treatment plan.