GLP-1R-positive neurons in the lateral septum mediate the anorectic and weight-lowering effects of liraglutide in mice.

Liraglutide, a glucagon-like peptide-1 (GLP-1) analog, is approved for obesity treatment, but the specific neuronal sites that contribute to its therapeutic effects remain elusive. Here, we show that GLP-1 receptor-positive (GLP-1R-positive) neurons in the lateral septum (LSGLP-1R) play a critical role in mediating the anorectic and weight-loss effects of liraglutide. LSGLP-1R neurons were robustly activated by liraglutide, and chemogenetic activation of these neurons dramatically suppressed feeding. Targeted knockdown of GLP-1 receptors within the LS, but not in the hypothalamus, substantially attenuated liraglutide's ability to inhibit feeding and lower body weight. The activity of LSGLP-1R neurons rapidly decreased during naturalistic feeding episodes, while synaptic inactivation of LSGLP-1R neurons diminished the anorexic effects triggered by liraglutide. Together, these findings offer critical insights into the functional role of LSGLP-1R neurons in the physiological regulation of energy homeostasis and delineate their instrumental role in mediating the pharmacological efficacy of liraglutide.

Use of glucagon-like-peptide 1 receptor agonist in the treatment of childhood obesity.

PURPOSE OF REVIEW: Pediatric obesity is a growing epidemic. Lifestyle modifications remain central to obesity treatment, however pharmacologic options have gained traction, particularly glucagon-like peptide-1 receptor agonists (GLP-1RA). This review aims to summarize evidence on the use of GLP-1RAs in the management of pediatric obesity, physiological mechanisms of action of GLP-1RAs and their role in appetite regulation and glucose homeostasis and address the challenges and special considerations surrounding GLP-1RA use. RECENT FINDINGS: Recent studies have highlighted the efficacy of GLP-1RAs, such as exenatide, liraglutide, and semaglutide, in promoting weight loss and improving metabolic parameters in children and adolescents. GLP-1RA's efficacy extends beyond glycemic control to include weight loss mechanisms such as delayed gastric emptying (gastroparesis), and appetite suppression. Semaglutide, the newest GLP-1RA, holds potential for substantial weight loss in adolescents and demonstrates a similar safety and efficacy as seen in adults. SUMMARY: GLP-1RAs may offer a promising adjunct therapy for pediatric obesity, particularly in cases where lifestyle interventions alone are insufficient. However, further research is needed to elucidate long-term safety and efficacy outcomes and to address potential disparities in access to care. Overall, this review highlights the relevance and timeliness of incorporating GLP-1RAs into the comprehensive management of pediatric obesity.

Open-label placebos reduce weight in obesity: a randomized controlled trial.

Obesity is a major public health problem worldwide. Different approaches are known to face this problem, for example, dieting, surgery, or drug interventions. It has also been shown that placebos may help to reduce weight and hunger feelings, but the use of placebos is linked to problems with respect to the patient-healthcare-provider relationship. However, recent studies demonstrated that even placebos without deception (open-label placebos) affect symptoms such as pain, anxiety, or emotional distress. Here we aimed to examine whether an open-label placebo may help to lose weight in obesity. Our study included fifty-seven overweight and obese patients who aimed to lose weight using a combination of diet and sports. Patients were randomly divided into two groups. Participants in the open-label placebo group received two placebos each day. A treatment-as-usual group received no pills. Primary outcome included changes of body weight. Secondary outcomes were change of eating behavior and self-management abilities. After 4 weeks we found that participants in the open-label placebo condition lost more weight than the treatment-as-usual group. Furthermore, OLP treatment affected eating behavior. No effects for self-management abilities were found. Although further research is necessary, open-label placebos might help individuals to lose weight.

One-Year Weight Reduction With Semaglutide or Liraglutide in Clinical Practice.

Importance: Limited data are available on long-term weight loss achieved with semaglutide or liraglutide for type 2 diabetes (T2D) or obesity in clinical practice. Objective: To document weight loss achieved with injectable forms of semaglutide or liraglutide and identify factors associated with weight reduction of 10% or greater at 1 year. Design, Setting, and Participants: This retrospective cohort study used electronic health records from a large, integrated health system in Ohio and Florida. Participants included adults with a body mass index (calculated as the weight in kilograms divided by the height in meters squared) of at least 30.0 who initiated treatment with semaglutide or liraglutide between July 1, 2015, and June 30, 2022. Follow-up was completed July 28, 2023. Exposure: Injectable forms of semaglutide or liraglutide approved for T2D or obesity. Main Outcomes and Measures: Percentage weight change and categorical weight reduction of 10% or greater at 1 year. Results: A total of 3389 patients (mean [SD] age, 50.4 [12.2] years; 1835 [54.7%] female) were identified. Of these, 1341 patients received semaglutide for T2D; 1444, liraglutide for T2D; 227, liraglutide for obesity; and 377, semaglutide for obesity. Mean (SD) percentage weight change at 1 year was -5.1% (7.8%) with semaglutide vs -2.2% (6.4%) with liraglutide (P < .001); -3.2% (6.8%) for T2D as a treatment indication vs -5.9% (9.0%) for obesity (P < .001); and -5.5% (7.5%) with persistent medication coverage (ie, a cumulative gap of less than 90 days) at 1 year vs -2.8% (7.0%) with 90 to 275 medication coverage days and -1.8% (6.7%) with fewer than 90 medication coverage days (P < .001). In the multivariable model, semaglutide vs liraglutide (adjusted odds ratio [AOR], 2.19 [95% CI, 1.77-2.72]), obesity as a treatment indication vs T2D (AOR, 2.46 [95% CI, 1.83-3.30]), persistent medication coverage vs 90 medication coverage days (AOR, 3.36 [95% CI, 2.52-4.54]) or 90 to 275 medication coverage days within the first year (AOR, 1.50 [95% CI, 1.10-2.06]), high dosage of the medication vs low (AOR, 1.58 [95% CI, 1.11-2.25]), and female sex (AOR, 1.57 [95% CI, 1.27-1.94]) were associated with achieving a 10% or greater weight reduction at year 1. Conclusions and Relevance: In this retrospective cohort study of 3389 patients with obesity, weight reduction at 1 year was associated with the medication's active agent, its dosage, treatment indication, persistent medication coverage, and patient sex. Future research should focus on identifying the reasons for discontinuation of medication use and interventions aimed at improving long-term persistent coverage.

The effectiveness of 0.5 mg and 1mg of semaglutide in patients with type two diabetes and predictors of response: a retrospective cohort study.

Background: Semaglutide is a glucagon-like peptide-1 receptor agonists (GLP-1-RAs) approved for the treatment of type 2 diabetes mellitus (T2DM) at doses up to 1 mg. The results from randomized control trials and real-world studies revealed that weekly semaglutide was associated with significant improvements in HbA1c and body weight. To our knowledge, no study assessed the effectiveness of using semaglutide for patients with T2DM in the Saudi population. We aim to assess the effectiveness of once weekly SC 0.5 and 1 mg of semaglutide on HbA1c and weight reduction in patients with T2DM in the Saudi population within 12 months of use, evaluate the predictors of response, and compare the effect of the two doses. Method: This is a retrospective cohort study conducted at Security Force Hospital in Riyadh, Saudi Arabia. Using electronic medical records of patients with type two diabetes who received semaglutide 0.5 or 1 mg for a total duration of at least 12 months of use. Results: Within the study period of semaglutide use, HbA1c significantly decreased from baseline by -2.1% (-2.3 to -1.91, 95% CI) (P <0.001). While the mean change in weight was -6.19 kg (-6.66 to -5.72, 95% CI) (P<0.001). Moreover, BMI, FBG, total cholesterol, LDL, and TG all decreased significantly from baseline (p<0.001). When comparing the sub-groups of 0.5 and 1 mg doses, although results were numerically favorable of 1 mg, there were no statistically significant differences in HbA1c % (-2.1 ± 1.8 vs. -2.1 ± 1.9, p-value= 0.934, respectively), and weight (-6.1 ± 5 vs. -6.2 ± 4.4 kg, p-value=0.837, respectively). Significant predictors of HbA1c reduction were the duration of DM, baseline HbA1c, and insulin therapy. While the significant predictor for weight reduction was insulin therapy. Conclusion: This study is document the effectiveness of once-weekly SC semaglutide on glycemic control and weight loss in real-world practice. We recommend a starting goal dose of 0.5 mg and gradual increase of dose based individual patient response. further studies are needed to assess the effectiveness and tolerability of various semagltude doses.

Sympathetic innervation of interscapular brown adipose tissue is not a predominant mediator of oxytocin-elicited reductions of body weight and adiposity in male diet-induced obese mice.

Previous studies indicate that CNS administration of oxytocin (OT) reduces body weight in high fat diet-induced obese (DIO) rodents by reducing food intake and increasing energy expenditure (EE). We recently demonstrated that hindbrain (fourth ventricular [4V]) administration of OT elicits weight loss and elevates interscapular brown adipose tissue temperature (TIBAT, a surrogate measure of increased EE) in DIO mice. What remains unclear is whether OT-elicited weight loss requires increased sympathetic nervous system (SNS) outflow to IBAT. We hypothesized that OT-induced stimulation of SNS outflow to IBAT contributes to its ability to activate BAT and elicit weight loss in DIO mice. To test this hypothesis, we determined the effect of disrupting SNS activation of IBAT on the ability of 4V OT administration to increase TIBAT and elicit weight loss in DIO mice. We first determined whether bilateral surgical SNS denervation to IBAT was successful as noted by ≥ 60% reduction in IBAT norepinephrine (NE) content in DIO mice. NE content was selectively reduced in IBAT at 1-, 6- and 7-weeks post-denervation by 95.9 ± 2.0, 77.4 ± 12.7 and 93.6 ± 4.6% (P<0.05), respectively and was unchanged in inguinal white adipose tissue, pancreas or liver. We subsequently measured the effects of acute 4V OT (1, 5 µg ≈ 0.99, 4.96 nmol) on TIBAT in DIO mice following sham or bilateral surgical SNS denervation to IBAT. We found that the high dose of 4V OT (5 µg ≈ 4.96 nmol) elevated TIBAT similarly in sham mice as in denervated mice. We subsequently measured the effects of chronic 4V OT (16 nmol/day over 29 days) or vehicle infusions on body weight, adiposity and food intake in DIO mice following sham or bilateral surgical denervation of IBAT. Chronic 4V OT reduced body weight by 5.7 ± 2.23% and 6.6 ± 1.4% in sham and denervated mice (P<0.05), respectively, and this effect was similar between groups (P=NS). OT produced corresponding reductions in whole body fat mass (P<0.05). Together, these findings support the hypothesis that sympathetic innervation of IBAT is not necessary for OT-elicited increases in BAT thermogenesis and reductions of body weight and adiposity in male DIO mice.

Real-World Evaluation of Once-Weekly Subcutaneous Semaglutide in Patients with Type 2 Diabetes Mellitus in Spain (SEMA-RW Study).

Although, in randomized clinical trials, once-weekly subcutaneous semaglutide (OW s.c.) has demonstrated superior efficacy in comparison with placebo and active controls in terms of glycemic control and body weight reduction in patients with type 2 diabetes mellitus (T2DM), these results need to be confirmed in a real-world (RW) setting. An RW ambispective study (6 months retrospective and 6 months prospective) was conducted in 10 tertiary hospitals in Spain. We evaluated changes in HbA1c and body weight in patients with T2DM treated with semaglutide OW s.c. Additionally, we analyzed different subgroups of patients treated with semaglutide OW s.c. as an add-on to glucose-lowering therapy. A total of 752 patients with a mean age of 60.2 years, a mean HbA1c level of 8.5%, a mean body weight of 101.6 kg, and a mean T2DM duration of 10 years were included. At 12 months, compared with baseline, there was a mean difference of -2.1% in HbA1c levels (p < 0.001) and a mean difference of 9.2 kg in body weight (p < 0.001). Moreover, there were statistically significant differences (p < 0.001) between baseline and month 12 in both HbA1c and body weight in the four subgroups receiving semaglutide OW s.c. as an add-on to glucose-lowering therapy. Semaglutide OW s.c. was well tolerated, with gastrointestinal disorders being the most commonly reported side effects. In this RW study, 12 months of treatment with semaglutide OW s.c. in patients with T2DM was associated with significant and clinically relevant improvements in glycemic control and weight loss, regardless of the glucose-lowering therapy received, and the overall safety profile was positive.

The efficacy and safety of GLP-1 agonists in PCOS women living with obesity in promoting weight loss and hormonal regulation: A meta-analysis of randomized controlled trials.

BACKGROUND: The efficacy of GLP1 receptor agonists (GLP1-RAs) in treating polycystic ovarian syndrome (PCOS) remains unclear. While GLP1-RAs are known to promote weight loss in patients with diabetes and living with obesity, their impact on weight reduction and hormonal regulation in women with PCOS is understudied. Therefore, we aimed to assess the efficacy of GLP1-RAs in PCOS women living with obesity through a meta-analysis, comparing their effects to placebo. HYPOTHESIS: The use of GLP1-RAs in PCOS women living with obesity can reduce body mass index and waist circumference as well as improve hyperinsulinism, and hyperandrogenism as well as normalize total testosterone, total cholesterol and HOMA-IR markers in PCOS women living with obesity. METHODS: We systematically searched the PubMed, Cochrane Central, Scopus and Embase databases to identify randomized controlled trials (RCT) comparing GLP1-RAs versus placebo among women diagnosed with PCOS based on the Rotterdam Criteria. Our primary outcomes of interest included body mass index (BMI), triglycerides, waist circumference, total testosterone, total cholesterol, and HOMA-IR. We performed data extraction and quality assessment for studies that met the inclusion criteria. We pooled mean difference (MD) and 95 % confidence intervals (CI) with a random-effect model for continuous endpoints. RESULTS: We included 176 participants from four RCTs. Semaglutide and Liraglutide were used in 23 (13 %) and 103 (58 %) participants, respectively. GLP1-RAs use was associated with a significant reduction in waist circumference (MD: -5.16 cm; 95 % CI: -6.11 to -4.21; p ˂ 0.00001), body mass index (BMI) (MD: -2.42; 95 % CI: -3.10 to -1.74; p ˂ 0.00001), serum triglycerides (MD: -0.20; 95 % CI: -0.30 to -0.11; p ˂ 0.00001) and total testosterone levels (MD: -1.33; 95 % CI: -2.55 to -0.12; p = 0.03) when compared to placebo. There was no significant difference in total cholesterol (MD: -0.04; 95 % CI: -0.10 to 0.01; p = 0.15) and HOMA-IR (MD: -0.30; 95 % CI: -0.92 to 0.32; p = 0.35) levels. Adverse events information was available for 112 patients, where 49 had light side effects such as nausea and abdominal pain. CONCLUSION: The use of GLP1-RAs demonstrates efficacy in reducing BMI, triglycerides, waist circumference and total testosterone. There was no significant difference in total cholesterol and HOMA-IR levels. These results signify its viability as a favourable treatment option for managing PCOS symptoms in women living with obesity.

AT-7687, a novel GIPR peptide antagonist, combined with a GLP-1 agonist, leads to enhanced weight loss and metabolic improvements in cynomolgus monkeys.

OBJECTIVES: Obesity represents a global health crisis with significant patient burdens and healthcare costs. Despite the advances with glucagon-like peptide-1 (GLP-1) receptor agonists in treating obesity, unmet needs remain. This study characterizes a novel glucose-dependent insulinotropic polypeptide receptor (GIPR) peptide antagonist, AT-7687, evaluating its potential to enhance obesity treatment. METHODS: We assessed the in vitro potency and pharmacokinetics of AT-7687, alongside its therapeutic effects when administered subcutaneously (SC) alone and in combination with liraglutide to high-fat-diet-fed obese non-human primates (NHP). The study spanned a 42-day treatment period and a 15-day washout period. RESULTS: AT-7687 demonstrated a subnanomolar cAMP antagonistic potency (pKB of 9.5) in HEK-293 cells and a 27.4 h half-life in NHPs. It effectively maintained weight stability in obese monkeys, whereas placebo recipients had an 8.6% weight increase by day 42 (P = 0.01). Monotherapy with liraglutide resulted in a 12.4% weight reduction compared to placebo (P = 0.03) and combining AT-7687 with liraglutide led to a 16.3% weight reduction (P = 0.0002). The combination therapy significantly improved metabolic markers, reducing insulin levels by 52% (P = 0.008), glucose by 30% (P = 0.02), triglycerides by 39% (P = 0.05), total cholesterol by 29% (P = 0.03), and LDL cholesterol by 48% (P = 0.003) compared to placebo. AT-7687 treatment was well tolerated and not associated with any side effects. CONCLUSIONS: This study underscores the potential of AT-7687 as a promising addition to current obesity treatments.

ADO09, a co-formulation of pramlintide and insulin A21G, lowers body weight versus insulin lispro in type 1 diabetes.

AIM: To study safety, efficacy and weight loss with ADO09, a co-formulation of insulin A21G and pramlintide, in type 1 diabetes. MATERIALS AND METHODS: A randomized, two-arm ambulatory 16-week study compared ADO09 with insulin lispro in 80 participants with type 1 diabetes. We compared changes of weight, glycated haemoglobin, glycaemic patterns during continuous glucose monitoring, and insulin doses at baseline and at the end of treatment. RESULTS: A significant and continuing weight loss, the primary endpoint, was observed with ADO09 compared with lispro as prandial insulin. In the whole group, the weight loss with ADO09 relative to lispro was 2.1 kg. Glycaemic control was relatively good (7.7% mean glycated haemoglobin) in both groups and did not change during treatment. Prandial insulin doses were reduced by 21% in the ADO09 group, whereas basal insulin dosage was not modified. Gastrointestinal symptoms were more frequent with ADO09, but no clear difference in hypoglycaemia was observed. CONCLUSIONS: These results extend previous observations on the efficacy and safety of this insulin/pramlintide co-formulation. They show a beneficial effect on weight, using less mealtime insulin and without increased hypoglycaemia.

The Pathology of US Health Care-The Example of Weight Loss Medications.

This JAMA Forum discusses the cost of newly approved weight loss medications in the US compared with other countries and provides arguments for why these medications should be more available for individuals in the US and covered by more insurers.

An efficient approach to expand equitable access to antiobesity medications: deprescribing after weight loss plateau.

The authors advocate for a consideration of 2 distinct phases of obesity management (ie, active weight loss and maintenance of weight loss) to allow substantially more people access to antiobesity medications.