GENDER DIFFERENCES IN THYROIDECTOMY-INDUCED WEIGHT LOSS AND IMPAIRED GLUCOSE LEVELS: ROLE OF L-THYROXINE.

Thyroxine, a key regulator of metabolic pathways, plays a pivotal role in glucose metabolism and the maintenance of glucose homeostasis. In clinical practice, L-thyroxine replacement therapy is commonly prescribed for patients with hypothyroidism. However, the specific effects of L-thyroxine and thyroidectomy (TX) on glucose levels remain an area of interest and investigation. In this study, 20 rats were divided into two groups (n=10 per group). The TX group (male and female rats) underwent thyroidectomy for 4 weeks. After 4 weeks, male and female thyroidectomized rats received L-thyroxine (10 µg/100 g/day, intraperitoneally) for 4 weeks. The rats' weights were monitored weekly post-surgery. Compared to the initial level, thyroidectomy resulted in weight loss, whereas L-thyroxine replacement therapy normalized the weight loss induced by thyroidectomy. Additionally, thyroidectomy led to impaired glucose levels, which were restored to normal levels with L-thyroxine treatment. These findings underscore the impact of thyroid function on glucose metabolism and highlight the potential therapeutic role of L-thyroxine.

Bone Health After Exercise Alone, GLP-1 Receptor Agonist Treatment, or Combination Treatment: A Secondary Analysis of a Randomized Clinical Trial.

Importance: A major concern with weight loss is concomitant bone loss. Exercise and glucagon-like peptide-1 receptor agonists (GLP-1RAs) represent weight loss strategies that may protect bone mass despite weight loss. Objective: To investigate bone health at clinically relevant sites (hip, spine, and forearm) after diet-induced weight loss followed by a 1-year intervention with exercise, liraglutide, or both combined. Design, Setting, and Participants: This study was a predefined secondary analysis of a randomized clinical trial conducted between August 2016 and November 2019 at the University of Copenhagen and Hvidovre Hospital in Denmark. Eligible participants included adults aged 18 to 65 years with obesity (body mass index of 32-43) and without diabetes. Data analysis was conducted from March to April 2023, with additional analysis in February 2024 during revision. Interventions: After an 8-week low-calorie diet (800 kcal/day), participants were randomized to 1 of 4 groups for 52 weeks: a moderate- to vigorous-intensity exercise program (exercise alone), 3.0 mg daily of the GLP-1 RA liraglutide (liraglutide alone), the combination, or placebo. Main Outcomes and Measures: The primary outcome was change in site-specific bone mineral density (BMD) at the hip, lumbar spine, and distal forearm from before the low-calorie diet to the end of treatment, measured by dual-energy x-ray absorptiometry in the intention-to-treat population. Results: In total, 195 participants (mean [SD] age, 42.84 [11.87] years; 124 female [64%] and 71 male [36%]; mean [SD] BMI, 37.00 [2.92]) were randomized, with 48 participants in the exercise group, 49 participants in the liraglutide group, 49 participants in the combination group, and 49 participants in the placebo group. The total estimated mean change in weight losses during the study was 7.03 kg (95% CI, 4.25-9.80 kg) in the placebo group, 11.19 kg (95% CI, 8.40-13.99 kg) in the exercise group, 13.74 kg (95% CI, 11.04-16.44 kg) in the liraglutide group, and 16.88 kg (95% CI, 14.23-19.54 kg) in the combination group. In the combination group, BMD was unchanged compared with the placebo group at the hip (mean change, -0.006 g/cm2; 95% CI, -0.017 to 0.004 g/cm2; P = .24) and lumbar spine (-0.010 g/cm2; 95% CI, -0.025 to 0.005 g/cm2; P = .20). Compared with the exercise group, BMD decreased for the liraglutide group at the hip (mean change, -0.013 g/cm2; 95% CI, -0.024 to -0.001 g/cm2; P = .03) and spine (mean change, -0.016 g/cm2; 95% CI, -0.032 to -0.001 g/cm2; P = .04). Conclusions and Relevance: In this randomized clinical trial, the combination of exercise and GLP-1RA (liraglutide) was the most effective weight loss strategy while preserving bone health. Liraglutide treatment alone reduced BMD at clinically relevant sites more than exercise alone despite similar weight loss. Trial Registration: EudraCT: 2015-005585-32.

Obesity management for the treatment of type 2 diabetes: emerging evidence and therapeutic approaches.

Excess adiposity can contribute to metabolic complications, such as type 2 diabetes mellitus (T2DM), which poses a significant global health burden. Traditionally viewed as a chronic and irreversible condition, T2DM management has evolved and new approaches emphasizing reversal and remission are emerging. Bariatric surgery demonstrates significant improvements in body weight and glucose homeostasis. However, its complexity limits widespread implementation as a population-wide intervention. The identification of glucagon-like peptide 1 (GLP-1) and the development of GLP-1 receptor agonists (GLP-1RAs) have improved T2DM management and offer promising outcomes in terms of weight loss. Innovative treatment approaches combining GLP-1RA with other gut and pancreatic-derived hormone receptor agonists, such as glucose-dependant insulinotropic peptide (GIP) and glucagon (GCG) receptor agonists, or coadministered with amylin analogues, are demonstrating enhanced efficacy in both weight loss and glycemic control. This review aims to explore the benefits of bariatric surgery and emerging pharmacological therapies such as GLP-1RAs, and dual and triple agonists in managing obesity and T2DM while highlighting the caveats and evolving landscape of treatment options.

Association between clinical and laboratory factors and response to sodium-glucose cotransporter 2 inhibitors in patients with type 2 diabetes: a retrospective observational study.

BACKGROUND: This study aimed to investigate the association between clinical and laboratory parameters and response to therapy with sodium-glucose cotransporter 2 inhibitors (SGLT2i) in patients with type 2 diabetes mellitus (T2D). RESEARCH DESIGN AND METHODS: We retrospectively analyzed the medical records of people with T2D in whom SGLT2i was started. Clinical and laboratory parameters were recorded before, 3 and 6 months after starting treatment. Specific criteria were applied to classify participants into good and poor responders in terms of weight loss (primary outcome) and glycemic control (secondary outcome), separately. RESULTS: Fifty individuals (64% men) with a mean age of 65.8 ± 8.5 years were included in the analysis. 86% and 64% of the participants were classified into good response categories for glycemic control and weight loss, respectively. Good responders in terms of glycemic control had lower high-density lipoprotein cholesterol levels at baseline compared to poor responders (43.3 vs 57.4 mg/dl, p = 0.044). In the logistic regression analysis, a higher baseline weight was associated with a better response to therapy in terms of weight loss (p = 0.04). CONCLUSIONS: Our findings suggest that specific clinical and laboratory parameters are associated with response to SGLT2i treatment and can contribute to a more personalized approach to T2D care.

Targeting obesity for therapeutic intervention in heart failure patients.

INTRODUCTION: Heart failure with preserved ejection fraction (HFpEF) is a highly heterogeneous syndrome, making it challenging to improve prognosis with pharmacotherapy. Obesity is one of the leading phenotypes of HFpEF, and its prevalence continues to grow worldwide. Consequently, obesity-targeted interventions have attracted attention as a novel treatment strategy for HFpEF. AREAS COVERED: The authors review the association between the pathogenesis of obesity and HFpEF and the potential for obesity-targeted pharmacotherapeutic strategies in HFpEF, together with the latest evidence. The literature search was conducted in PubMed up to April 2024. EXPERT OPINION: The STEP HFpEF (Semaglutide Treatment Effect in People with obesity and HFpEF) and SELECT (Semaglutide Effects on Cardiovascular Outcomes in People with Overweight or Obesity) trials recently demonstrated that the glucagon-like peptide 1 analogue, semaglutide, improves various aspects of clinical outcomes in obese HFpEF patients and significantly reduces cardiovascular and heart failure events in non-diabetic obese patients, along with a substantial weight loss. Future clinical trials with other incretin mimetics with more potent weight loss and sub-analyses of the SELECT trial may further emphasize the importance of the obesity phenotype-based approach in the treatment of HFpEF.

Transforming body composition with semaglutide in adults with obesity and type 2 diabetes mellitus.

Background: Glucagon-like peptide-1 receptor-agonists (GLP-1ra), such as semaglutide, have emerged as promising treatments, demonstrating sustained weight reduction and metabolic benefits. This study aims to assess the impact of oral and subcutaneous semaglutide on body composition and metabolic parameters in patients with T2DM and obesity. Methods: A 24-week quasi-experimental retrospective study including adults with T2DM and obesity (BMI ≥ 30 kg/m²) who were treated with either daily-oral or weekly-subcutaneous semaglutide. Body composition was measured using bioelectrical impedance analysis, evaluating fat mass, fat-free mass, total body water, skeletal muscle mass, and whole-body phase angle. Analytical parameters included lipid profile and glycaemic control. Statistical analyses were performed using SPSS v.26. Results: Participants (n=88) experienced significant weight loss after treatment with semaglutide (9.5% in subcutaneous, 9.4% in oral, P<0.001). Weight reduction primarily resulted from fat mass reduction without substantial lean mass compromise. Visceral fat area decreased, whiles phase-angle remained stable. Improvements in lipid profiles and glycaemic control were observed, with a decrease in both HbA1c and insulin requirements. Multivariate analysis demonstrated comparable impacts of oral and subcutaneous semaglutide on body composition. Conclusion: Semaglutide, administered orally or subcutaneously, demonstrated positive effects on body composition, metabolic and glycaemic control in patients with T2DM and obesity. This real-world study highlights the potential of bioelectrical impedance analysis in assessing antidiabetic drugs' impact on body composition, providing valuable insights for future research and clinical applications.

Adverse effects of methylphenidate for apathy in patients with Alzheimer's disease (ADMET2 trial).

OBJECTIVES: To examine clinically important adverse events (AEs) associated with methylphenidate (MPH) treatment of apathy in Alzheimer's Disease (AD) versus placebo, including weight loss, vital signs, falls, and insomnia. METHODS: The Apathy in Dementia Methylphenidate Trial 2 (ADMET2) trial was a multicenter randomized, placebo-controlled trial of MPH to treat apathy in individuals with apathy and AD. Participants in ADMET2 had vital signs and weight measured at monthly visits through 6 months. AEs, including insomnia, falls, and cardiovascular events, were reported at every visit by participants and families using a symptom checklist. RESULTS: The study included 98 participants in the MPH group and 101 in the placebo group. Participants in the MPH group experienced greater weight loss on average than the placebo through the 6-month follow-up, with a difference in change between MPH and placebo of 2.8 lb (95% confidence interval, CI: 0.7, 4.9 lb). No treatment group differences in change during the trial were found in systolic and diastolic blood pressure. More participants in the MPH group reported falls during the follow-up, 10 versus 6 in MPH and placebo groups, respectively. No differences in post-baseline insomnia were observed between the treatment groups. No participants reported instances of myocardial infarction, congestive heart failure, arrhythmia, stroke, or cardiomyopathy throughout the study period. CONCLUSIONS: MPH use in AD patients for treating apathy is relatively safe, particularly notable given the many medical comorbidities in this population. There was a statistically significant but modest weight loss associated with MPH use, and clinicians are thus advised to monitor weight during MPH treatment.

Proprietary alpha-amylase inhibitor formulation from white kidney bean (Phaseolus vulgaris L.) promotes weight and fat loss: a 12-week, double-blind, placebo-controlled, randomized trial.

White kidney bean (Phaseolus vulgaris L.) extracts can aid weight management by reducing calorie intake from complex carbohydrates through alpha-amylase inhibition. We examined the impact of a proprietary aqueous extract from whole dried white kidney beans standardized by its alpha-amylase inhibitor activity (Phase 2 white kidney bean extract (WKBE)) on weight management in subjects with overweight and moderate obesity. In a randomized, double-blind, placebo-controlled fashion, 81 participants completed the study and ingested either a high dose of Phase 2 (1000 mg, WKBE HIGH), a low dose (700 mg, WKBE LOW), or a matching placebo (microcrystalline cellulose, PLA) three times a day, 30 min before meals, for 12 weeks during a calorie restricted diet. In a dose-dependent manner, Phase 2 significantly reduced body weight, fat mass, BMI, waist, hip and in the WKBE HIGH group thigh circumference. Phase 2 is an effective and safe supplement aiding weight and fat loss. ClinicalTrials.gov identifier NCT02930668.

Association of different doses of antenatal corticosteroids exposure with early major outcomes and early weight loss percentage in extremely preterm infants or extremely low birthweight infants: a multicentre cohort study.

OBJECTIVES: To determine the dose-dependent associations between antenatal corticosteroids (ANS) exposure and the rates of major morbidities, and the early weight loss percentage (EWLP) in hospital among extremely preterm infants (EPI) or extremely low birthweight infants (ELBWI). METHODS: A multicentre, retrospective cohort study of EPI or ELBWI born between 2017 and 2018 was conducted. Infants were classified into no ANS, partial ANS and complete ANS exposure group; three subgroups were generated by gestational age and birth weight. Multiple logistic regression and multiple linear regression were performed. RESULTS: There were 725 infants included from 32 centres. Among no ANS, partial ANS and complete ANS exposure, there were significant differences in the proportions of bronchopulmonary dysplasia (BPD) (24.5%, 25.4% and 16.1%), necrotising enterocolitis (NEC) (6.7%, 2.0% and 2.0%) and death (29.6%, 18.5% and 13.5%), and insignificant differences in the proportions of intraventricular haemorrhage (IVH) (12.5%, 13.2% and 12.2%), and extrauterine growth restriction (EUGR) (50.0%, 56.6% and 59.5%). In the logistic regression, compared with no ANS exposure, complete ANS reduced the risk of BPD (OR 0.58, 95% CI 0.37 to 0.91), NEC (OR 0.21, 95% CI 0.08 to 0.57) and death (OR 0.36, 95% CI 0.23 to 0.56), and partial ANS reduced the risk of NEC (OR 0.23, 95% CI 0.07 to 0.72) and death (OR 0.54, 95% CI 0.34 to 0.87). Compared with partial ANS exposure, complete ANS decreased the risk of BPD (OR 0.58, 95% CI 0.37 to 0.91). There were insignificant associations between ANS exposure and IVH, EUGR. In the multiple linear regression, partial and complete ANS exposure increased EWLP only in the ≥28 weeks (w) and <1000 g subgroup (p<0.05). CONCLUSIONS: Different doses of ANS (dexamethasone) exposure were protectively associated with BPD, NEC, death in hospital, but not EUGR at discharge among EPI or ELBWI. Beneficial dose-dependent associations between ANS (dexamethasone) exposure and BPD existed. ANS exposure increased EWLP only in the ≥28 w and<1000 g subgroup. ANS administration, especially complete ANS, is encouraged before preterm birth. TRIAL REGISTRATION NUMBER: NCT06082414.

Reductions of food intake and body weight in diet-induced obese rats following chronic treatment with a monomeric peptide multiagonist.

INTRODUCTION: While therapies based on endogenous gut peptides such as glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) have been compelling therapeutic agents for obesity and type 2 diabetes (T2D), only a few have achieved long-term weight loss and all have shown significant side-effects, including nausea/malaise and gastrointestinal ailments. OBJECTIVE: As the pathophysiology of obesity is driven by dysregulation of multiple, inter-related, pathways, we tested a novel peptide targeting multiple receptors of complementary neurocircuits regulating the controls of energy balance. METHODS: Response to daily injections of GEP44, a GLP-1R and neuropeptide Y1R and Y2R receptor (Y1R/Y2R) triple agonist was tested vs. the GLP-1R agonist liraglutide (LIRA) in diet-induced obese (DIO) male and female rats. Glucose tolerance tests after intraperitoneal injection of glucose (IPGTT) were performed at baseline and after 14-d of treatment in GEP44 treated rats. Other metabolic parameters were assessed in blood at the end of a 28-d intervention. RESULTS: Upon conclusion at 28-d, body weight reduction compared to vehicle was -15.6%/-11.9% in response to GEP44, vs. -9.7%/-5.1% after LIRA, males, and females, respectively. Significant reductions of cumulative food intake occurred over 28-d in female rats treated with GEP44 (-30%; p < 0.0001), vs. LIRA (-10%), and in male rats GEP44 (-39%; p < 0.0001), vs. LIRA (-20%; p = 0.003). In IPGTTs, a similar stimulation glucose induced insulin secretion was noted in rats treated with GEP44 and LIRA. CONCLUSION: The strong reductions of body weight in response to long-term applications of the triple agonist GEP44 confirms the therapeutic potential of targeting multiple receptors for achieving more robust and potentially more sustained improvement of energy balance.

Efficacy and safety of semaglutide 2.4 mg by race and ethnicity: A post hoc analysis of three randomized controlled trials.

OBJECTIVE: The objective of this study was to evaluate the efficacy and safety of semaglutide 2.4 mg, a glucagon-like peptide-1 receptor agonist, by race and ethnicity, across three phase 3 trials. METHODS: The Semaglutide Treatment Effect in People with Obesity (STEP) clinical trials evaluated the efficacy and safety of once-weekly subcutaneous semaglutide 2.4 mg. Here, STEP 1 and 3 data were pooled for analysis; STEP 2 data were examined separately. All analyses were conducted using data from racial and ethnic subgroups. The primary outcome was the estimated treatment difference in percent body weight change for semaglutide 2.4 mg versus placebo. RESULTS: Participants reported race as White (STEP 1 and 3, 75.3%; STEP 2, 59.4%), Black (8.8%; 8.9%), Asian (10.6%; 27.3%), or other racial group (5.3%; 4.4%); and ethnicity as Hispanic or Latino (13.9%; 11.9%) or not Hispanic or Latino (83.9%; 88.1%). There were no significant interactions between treatment effect and race (STEP 1 and 3: p ≥ 0.07; STEP 2: p ≥ 0.15) or ethnicity (p ≥ 0.40; p ≥ 0.85). The safety of semaglutide 2.4 mg was consistent across subgroups. CONCLUSIONS: The treatment effect of semaglutide was statistically significant versus placebo and clinically relevant across all racial and ethnic subgroups in STEP 1 and 3 and STEP 2. All subgroups across both samples demonstrated good tolerability.

Chronic treatment with glucagon-like peptide-1 and glucagon receptor co-agonist causes weight loss-independent improvements in hepatic steatosis in mice with diet-induced obesity.

OBJECTIVES: Co-agonists at the glucagon-like peptide-1 and glucagon receptors (GLP1R/GCGR) show promise as treatments for metabolic dysfunction-associated steatotic liver disease (MASLD). Although most co-agonists to date have been heavily GLP1R-biased, glucagon directly acts on the liver to reduce fat content. The aims of this study were to investigate a GCGR-biased co-agonist as treatment for hepatic steatosis in mice. METHODS: Mice with diet-induced obesity (DIO) were treated with Dicretin, a GLP1/GCGR co-agonist with high potency at the GCGR, Semaglutide (GLP1R monoagonist) or food restriction over 24 days, such that their weight loss was matched. Hepatic steatosis, glucose tolerance, hepatic transcriptomics, metabolomics and lipidomics at the end of the study were compared with Vehicle-treated mice. RESULTS: Dicretin lead to superior reduction of hepatic lipid content when compared to Semaglutide or equivalent weight loss by calorie restriction. Markers of glucose tolerance and insulin resistance improved in all treatment groups. Hepatic transcriptomic and metabolomic profiling demonstrated many changes that were unique to Dicretin-treated mice. These include some known targets of glucagon signaling and others with as yet unclear physiological significance. CONCLUSIONS: Our study supports the development of GCGR-biased GLP1/GCGR co-agonists for treatment of MASLD and related conditions.

The association between weight loss medications and cardiovascular complications.

OBJECTIVE: Obesity and its cardiovascular complications are major causes of morbidity and mortality. Little is known in real-world settings about the effect of newly approved antiobesity medications (AOMs) on cardiovascular complications among patients with obesity. METHODS: This retrospective cohort study examined the association between newly approved AOM use and cardiovascular events among Medicare patients with obesity using data from 2020 to 2022. Patient age, gender, comorbidity scores, socioeconomic status, and baseline cardiovascular comorbidities were compared descriptively. Subgroup analysis compared variables by medication type. Relative risk and absolute risk of cardiovascular disease (CVD) events were estimated using Cox and Aalen regression models. RESULTS: The analysis included 5926 patients treated with semaglutide and tirzepatide, including Ozempic (5404 patients), Wegovy (375 patients), or Mounjaro (147 patients). Hypertension, type 2 diabetes, and hyperlipidemia were the most common comorbidities. For patients with AOMs, less incidence of heart failure (4.89% vs. 6.13%, p < 0.0001), atrial fibrillation (3.83% vs. 5.17%, p < 0.0001), arrhythmia (3.59% vs. 4.14%, p < 0.0153), and peripheral vascular disease (3.44% vs. 2.94%, p < 0.0395) was found versus patients without AOMs. Patients receiving AOMs showed an 8% risk reduction in any CVD. Protective effect on CVD was apparent over the first 375 days. CONCLUSIONS: Results suggest that utilization of AOMs effectively alleviates the high prevalence of CVD.

The impact of flaxseed oil on lipid profiles, weight loss, and inflammatory markers in hemodialysis patients: A systematic review and meta-analysis of randomized controlled trials.

Studies investigating the effects of flaxseed oil on lipid profiles, weight loss, and inflammatory markers have produced inconsistent results. This systematic review and meta-analysis of randomized controlled trials (RCTs) aimed to explore the impact of flaxseed oil on these parameters in hemodialysis patients. The study protocol was registered online (PROSPERO number: CRD42023484076). The meta-analyses showed a significant decrease in triglyceride (TG) levels (WMD = -85.78 mg/dL, 95% CI: -155.24 to -16.32, I2 = 98.32%) and C-reactive protein (CRP) levels (WMD = -2.66 mg/L, 95% CI: -4.07 to -1.24, I2 = 92.26%) following consumption of flaxseed oil. Subgroup analyses revealed significant changes in LDL-C, HDL-C, and TC levels only in trials utilizing a dosage higher than 10 g per day and using ground flaxseed oil. Based on the results, flaxseed oil improves CRP and TG levels, and higher doses positively affect lipid profiles. However, it has no significant effect on anthropometric measures.

Semaglutide for management of obesity in adolescents: efficacy, safety, and considerations for clinical practice.

PURPOSE OF REVIEW: The purpose of this review is to describe the existing limited data related to the use of semaglutide in adolescents with obesity, supplementing with findings from adult studies of semaglutide use. RECENT FINDINGS: Semaglutide, as a once weekly subcutaneous injection for weight management, effectively reduces body mass index (BMI) while improving hyperglycemia, elevated alanine aminotransferase levels, hyperlipidemia, and quality of life in youth with obesity. As of this review, only one large randomized clinical trial of semaglutide in youth has been completed, with a follow-up duration of 68 weeks. Thus, long-term data on the safety in adolescents is limited, particularly regarding the risks of cholelithiasis, pancreatitis, suicidal ideation, and disordered eating. Due to the cost of semaglutide, particularly in the United States, limited cost effectiveness analyses have demonstrated unfavorable incremental cost-effectiveness ratios for semaglutide relative to phentermine-topiramate as an alternative antiobesity medication in adolescents. SUMMARY: Semaglutide represents an important advance in the pediatric obesity management, with clear short-term reductions in BMI and improvement in metabolic parameters. However, its long-term safety and efficacy for youth with obesity remain to be demonstrated. Additional research is needed to assess trends in utilization and adherence to minimize the risk of worsening socioeconomic disparities in pediatric obesity.