Pharmacological treatment of obesity in adults in Norway 2004-2022.

AIMS: To describe trends in the use of anti-obesity drugs in Norway during the period 2004-2022. MATERIALS AND METHODS: We assessed the annual utilization of any available drug indicated for obesity recorded in the nationwide Norwegian Prescribed Drug Register for adults (age 18-79 years) from 1 January 2004 to 31 December 2022. Prevalence was stratified by sex and age group (18-29 years and 10-year age groups thereafter). Additional analyses were performed in individuals initiating treatment with an anti-obesity drug and on the cost of the anti-obesity drugs since 2017. RESULTS: The prevalence of anti-obesity drug use decreased from 2009, when sibutramine and rimonabant were withdrawn from the market, and increased again after the approval of bupropion-naltrexone in 2017 and liraglutide in 2018. The use of the peripheral-acting anti-obesity drug orlistat decreased from 2004. In 2022, 1.04% of the adult Norwegian population (72.8% women) filled at least one prescription of bupropion-naltrexone, 0.91% used liraglutide (Saxenda; 74.2% women), and semaglutide without reimbursement was used by 0.68% (76.7% women). The prevalence increased with age, peaking in the age group 50 to 59 years, and decreased in older age groups. From 2017 to 2022, 2.8% of the adult residents initiated treatment with an anti-obesity drug. The total sale of those drugs increased from 1.1 million euros in 2017 to 91.8 million euros in 2022. CONCLUSIONS: The use of anti-obesity drugs in Norway has increased substantially in recent years, especially among women aged 40 to 59 years. Changes in availability and reimbursement have influenced the use of these drugs in recent years.

A randomized Phase I study of the safety, tolerability, pharmacokinetics and pharmacodynamics of BI 456906, a dual glucagon receptor/glucagon-like peptide-1 receptor agonist, in healthy Japanese men with overweight/obesity.

AIM: To report a Phase I study of subcutaneous glucagon receptor (GCGR)/glucagon-like peptide-1 receptor (GLP-1R) dual agonist BI 456906 versus placebo in healthy Japanese men with overweight/obesity. MATERIALS AND METHODS: We investigated multiple rising doses of BI 456906 escalated over 16 weeks (maximum doses: 1.8 mg once weekly [dose group {DG} 1], 4.8 mg once weekly [DG 2] and 2.4 mg twice weekly [DG 3]) in Japanese men with a body mass index of 23 to 40 kg/m2 . RESULTS: Thirty-six participants were treated (n = 9 per DG and placebo). Overall, 10 participants (37.0%) treated with BI 456906 withdrew from dose escalation due to adverse events (amylase increase, n = 1; decreased appetite, n = 9), and the proportion of participants was higher in DG 2 (n = 6, 66.7%) versus DGs 1 and 3 (both n = 2, 22.2%). No participants receiving placebo withdrew from dose escalation. BI 456906 exposure increased with dose and dose escalation in each DG. Treatment with BI 456906 decreased placebo-corrected bodyweight after 16 weeks (placebo +1.06%): DG 1, -5.57%; DG 2, -12.37%; DG 3, -9.62%. Paracetamol absorption decreased in Week 1 for DGs 2 and 3, indicating transient delayed gastric emptying. BI 456906 reduced plasma alanine and glucagon levels, indicating indirect target engagement at GCGRs and GLP-1Rs. Drug-related adverse events were reported for all participants receiving BI 456906 and four receiving placebo, the most frequent being decreased appetite (n = 24, 66.7%). CONCLUSIONS: BI 456906 showed no unexpected tolerability concerns and it reduced placebo-corrected bodyweight by up to 12.37% in Japanese men with overweight/obesity after 16 weeks of treatment.

Semaglutide for the treatment of overweight and obesity: A review.

Obesity is a chronic, relapsing disease associated with multiple complications and a substantial morbidity, mortality and health care burden. Pharmacological treatments for obesity provide a valuable adjunct to lifestyle intervention, which often achieves only limited weight loss that is difficult to maintain. The Semaglutide Treatment Effect in People with obesity (STEP) clinical trial programme is evaluating once-weekly subcutaneous semaglutide 2.4 mg (a glucagon-like peptide-1 analogue) in people with overweight or obesity. Across STEP 1, 3, 4 and 8, semaglutide 2.4 mg was associated with mean weight losses of 14.9%-17.4% in individuals with overweight or obesity without type 2 diabetes from baseline to week 68; 69%-79% of participants achieved ≥10% weight loss with semaglutide 2.4 mg (vs. 12%-27% with placebo) and 51%-64% achieved ≥15% weight loss (vs. 5%-13% with placebo). In STEP 5, mean weight loss was -15.2% with semaglutide 2.4 mg versus -2.6% with placebo from baseline to week 104. In STEP 2 (individuals with overweight or obesity, and type 2 diabetes), mean weight loss was -9.6% with semaglutide 2.4 mg versus -3.4% with placebo from baseline to week 68. Improvements in cardiometabolic risk factors, including high blood pressure, atherogenic lipids and benefits on physical function and quality of life were seen with semaglutide 2.4 mg. The safety profile of semaglutide 2.4 mg was consistent across trials, primarily gastrointestinal adverse events. The magnitude of weight loss reported in the STEP trials offers the potential for clinically relevant improvement for individuals with obesity-related diseases.

Perceptions, behaviours and potential barriers to effective obesity care. Results from the ACTION-DK study.

AIM: Weight bias, stigma and discrimination are pervasive in the health care system and society and may result in biased treatment of people living with obesity (PwO). We aimed to identify perceptions, attitudes and potential barriers that exist between people with obesity and health care professionals (HCPs) in Denmark. METHODS: The ACTION-DK survey was a cross-sectional, non-interventional, descriptive study conducted in Denmark. The cohort included 879 PwO (body mass index ≥30.0 kg/m2 ) based on self-reported height and body weight, and 100 HCPs from the primary and secondary sectors who frequently encountered PwO. RESULTS: Several discrepancies between PwO and HCPs were identified, including recognition of obesity as a chronic disease (PwO: 49% vs. HCPs: 84%) and whether PwO were responsible for their weight loss (PwO: 81% vs. HCPs: 17%). Among PwO, 46% were motivated to lose weight, but only 28% of HCPs shared this perception. Untimely initiation of obesity care consultations was also identified as a potential barrier to proper obesity care, as PwO waited 7 years, on average, from their initial decision to lose weight before having their first obesity care consultation. In addition, only 24% of PwO had a follow-up consultation after the initial obesity care discussion. Almost half of HCPs (46%) considered weight loss medication effective, but only 10% brought up this possibility during an obesity care discussion. CONCLUSIONS: Our findings suggest that it is pivotal to improve obesity care in Denmark by ensuring a better follow-up and alignment of the perceptions and attitudes toward obesity between PwO and HCPs.

The herbal composition GGEx18 from Laminaria japonica, Rheum palmatum, and Ephedra sinica inhibits visceral obesity and insulin resistance by upregulating visceral adipose genes involved in fatty acid oxidation.

CONTEXT: The herbal composition Gyeongshingangjeehwan 18 (GGEx18) extracted from Rheum palmatum L. (Polygonaceae), Laminaria japonica Aresch (Laminariaceae), and Ephedra sinica Stapf (Ephedraceae) is traditionally used as an anti-obesity drug by local clinics in Korea. OBJECTIVE: This study investigates the effects of GGEx18 on visceral obesity and insulin resistance and determines the molecular mechanisms involved in this process. MATERIALS AND METHODS: After C57BL/6J mice were fed a high-fat diet supplemented with GGEx18 (125, 250, and 500 mg/kg) for 8 weeks and 3T3-L1 adipocytes were treated with GGEx18 (0.1, 1, and 10 µg/ml); variables and determinants of visceral obesity and insulin resistance were measured using in vivo and in vitro approaches. RESULTS: Administration of GGEx18 to obese mice decreased visceral adipose tissue weight with an ED50 value of 232 mg/kg. 3T3-L1 adipocytes treated with GGEx18 showed a reduction in lipid accumulation with an ED50 value of 0.7 µg/ml. GGEx18 significantly increased the expression of fatty acid oxidation genes, including adiponectin, AMPKs, PPARα and its target enzymes, and CPT-1, in both mesenteric adipose tissues and 3T3-L1 cells. However, GGEx18 treatment decreased the mRNA levels of adipocyte marker genes such as PPARγ, aP2, TNFα, and leptin. GGEx18 normalized hyperglycemia and hyperinsulinemia in obese mice. Blood glucose levels of GGEx18-treated mice were significantly reduced during oral glucose tolerance tests compared with obese controls. DISCUSSION AND CONCLUSION: These results suggest that GGEx18 may treat visceral obesity and visceral obesity-related insulin resistance by upregulating the visceral adipose expression of fatty acid oxidative genes.

Semaglutide alleviates gut microbiota dysbiosis induced by a high-fat diet.

This study investigated the effects of semaglutide (Sema) on the gut microbiota of obese mice induced with high-fat diet (HFD). Male C57BL/6 J mice aged 6 weeks were enrolled and randomly distributed to four groups, which were provided with a normal control diet (NCD,NCD + Sema) and a 60% proportion of a high-fat diet (HFD,HFD + Sema), respectively. HFD was given for 10 weeks to develop an obesity model and the intervention was lasted for 18 days. The results showed semaglutide significantly reduced body weight gain, areas under the curve (AUC) of glucose tolerance test and insulin resistance test, as well as adipose tissue weight in mice. Semaglutide effectively reduced lipid deposition and lipid droplet formation in the liver of obese mice, and regulated the expression of genes related to abnormal blood glucose regulation. Additionally, semaglutide influenced the composition of gut microbiota, mitigating the microbial dysbiosis induced by a high-fat diet by impacting the diversity of the gut microbiota. After the high-fat diet intervention, certain strains such as Akkermansia, Faecalibaculum, and Allobaculum were significantly decreased, while Lachnospiraceae and Bacteroides were significantly increased. However, the application of semaglutide restored the lost flora and suppressed excessive bacterial abundance. Moreover, semaglutide increased the content of tight junction proteins and repaired the damage to intestinal barrier function caused by the high-fat diet intervention. Furthermore, correlation analysis revealed inverse relationship among Akkermansia levels and weight gain, blood glucose levels, and various obesity indicators. Correlation analysis also showed that Akkermansia level was negatively correlated with weight gain, blood glucose levels and a range of obesity indicators. This phenomenon may explain the anti-obesity effect of semaglutide, which is linked to alterations in gut microbiota, specifically an increase in the abundance of Akkermansia. In summary, our findings indicate that semaglutide has the potential to alleviate gut microbiota dysbiosis, and the gut microbiota may contribute to the obesity-related effects of this drug.

Central inhibition of HDAC6 re-sensitizes leptin signaling during obesity to induce profound weight loss.

Leptin resistance during excess weight gain significantly contributes to the recidivism of obesity to leptin-based pharmacological therapies. The mechanisms underlying the inhibition of leptin receptor (LepR) signaling during obesity are still elusive. Here, we report that histone deacetylase 6 (HDAC6) interacts with LepR, reducing the latter's activity, and that pharmacological inhibition of HDAC6 activity disrupts this interaction and augments leptin signaling. Treatment of diet-induced obese mice with blood-brain barrier (BBB)-permeable HDAC6 inhibitors profoundly reduces food intake and leads to potent weight loss without affecting the muscle mass. Genetic depletion of Hdac6 in Agouti-related protein (AgRP)-expressing neurons or administration with BBB-impermeable HDAC6 inhibitors results in a lack of such anti-obesity effect. Together, these findings represent the first report describing a mechanistically validated and pharmaceutically tractable therapeutic approach to directly increase LepR activity as well as identifying centrally but not peripherally acting HDAC6 inhibitors as potent leptin sensitizers and anti-obesity agents.

Genome-guided approaches and evaluation of the strategies to influence bioprocessing assisted morphological engineering of Streptomyces cell factories.

Streptomyces genera serve as adaptable cell factories for secondary metabolites with various and distinctive chemical structures that are relevant to the pharmaceutical industry. Streptomyces' complex life cycle necessitated a variety of tactics to enhance metabolite production. Identification of metabolic pathways, secondary metabolite clusters, and their controls have all been accomplished using genomic methods. Besides this, bioprocess parameters were also optimized for the regulation of morphology. Kinase families were identified as key checkpoints in the metabolic manipulation (DivIVA, Scy, FilP, matAB, and AfsK) and morphology engineering of Streptomyces. This review illustrates the role of different physiological variables during fermentation in the bioeconomy coupled with genome-based molecular characterization of biomolecules responsible for secondary metabolite production at different developmental stages of the Streptomyces life cycle.

Lorcaserin and phentermine exert anti-obesity effects with modulation of the gut microbiota.

Although drugs have been reported to modulate the gut microbiota, the effects of anti-obesity drugs on the gut microbiota remain unclear. Lorcaserin (LS) and phentermine (PT) are commonly used anti-obesity drugs. However, to our best knowledge, no studies have simultaneously assessed the effects of LS and PT on obesity and gut microbiota. This study aimed to explore the relationship between the anti-obesity effects of LS and PT and re-modulation of host gut microbiota. To test hypothesis, we fed C57BL/6J mice with a high-fat diet supplemented with LS and PT via oral gavage for 8 weeks. After sacrifice, body weight, fat accumulation, and serum biomarkers were measured, and the gut microbial composition was analyzed using 16 s rRNA amplicon sequencing. LS and PT were observed to modulate the gut microbial composition and restore gut microbial dysbiosis, as indicated by an increased Firmicutes/Bacteroidetes ratio. Significantly modulated genera by LS and PT treatment were strongly correlated with obesity-related markers. Additionally, LS and PT increased the mRNA level of G protein-coupled receptor 120 (GPR120) in the colon tissue. ASV3566, which corresponds to Eubacterium coprostanoligenes, was correlated with GPR120 and obesity-related markers such as glutamic pyruvic transaminase (GPT) and serum triglyceride (TG). In conclusion, LS and PT can modulate the gut microbiota dysbiosis and the gut microbiota plays a role in mediating the anti-obesity effect of drugs.

Impact of the herbal medicine, Ephedra sinica stapf, on gut microbiota and body weight in a diet-induced obesity model.

Obesity is a chronic metabolic disease caused by excessive body fat and has become a global public health problem. Evidence suggests that obesity and obesity-induced metabolic disorders are closely related to gut microbiota. Bupropion (BP), an antidepressant medicine, and Ephedra sinica Stapf [Ephedraceae; Ephedrae Herba], a herbal medicine, are sympathetic stimulants and have weight loss effects. However, to our best knowledge, no studies have simultaneously assessed the effects of drugs and herbal medicines on obesity and gut microbiota. This study aimed to determine the effects of BP and ES on weight loss and re-modulation of host gut microbiota. To test this hypothesis, we fed C57BL/6J mice with a high-fat diet supplemented with bupropion (BP; 30 mg/kg/day) and Ephedra sinica Stapf extract (ES; 150 mg/kg/day) via oral gavage for eight weeks. Further, we evaluated the effects of BP and ES on body weight and fat accumulation. In addition, we evaluated the effects of BP and ES on gut microbiota using 16S rRNA amplicon sequencing. Our results showed that weight loss was confirmed in both BP and ES; however, it was more pronounced in ES. ES changed the overall composition of the gut microbiota by restoring the relative abundance of Oscillospiraceae, Lachnospiraceae, and the Firmicutes/Bacteroidetes ratio, an indicator of gut microbiota dysbiosis. Nine amplicon sequence variants (ASVs) of the gut microbiome were significantly recovered by BP and ES treatment, of which eight ASVs correlated with body weight and fat accumulation. Additionally, three ASVs were significantly recovered by ES treatment alone. In conclusion, the anti-obesity effects of BP and ES, especially fat accumulation, are related to the regulation of gut microbiota. Moreover, ES had a greater influence on the gut microbiota than BP.

Regulation of feeding and therapeutic application of bioactive peptides.

Obesity and obesity-related diseases, such as diabetes mellitus and dyslipidemia, are worldwide pandemics; therefore, studies have been conducted energetically to elucidate the mechanism of obesity and develop anti-obesity drugs. Robust progress in the peptide chemistry and molecular biology has identified many peptides that regulate appetite and energy metabolism over the past dozen years. Several drugs, such as analogs or receptor agonists of anorectic peptides, have been developed. Overall, peptide-related drugs have powerful anti-obesity effects with fewer adverse effects than previous anti-obesity drugs. Liraglutide, a glucagon-like peptide-1 receptor agonist, was first used as an antidiabetic drug, and then high-dose liraglutide was used as an anti-obesity drug. Several candidates have been developed to explore their anti-obesity effects. Additionally, hybrid peptides consisting of two or more peptide sequences with strong anorectic effects have been designed. Here, we review peptides that are important for feeding regulation in terms of their mechanisms of action, interactions, and clinical application as anti-obesity drugs.

The Effect of Orlistat on Sterol Metabolism in Obese Patients.

Background: Orlistat, a reversible inhibitor of pancreatic and gastric lipase, is known to have anti-obesity and antioxidant properties. Cholesterol intermediates and metabolites have diverse and important functions in cardiovascular disease. Therefore, we aimed to evaluate the effect of orlistat on sterol metabolism in overweight and obese adults after weight loss during the intervention or weight loss at 12 weeks. Methods: A total of 51 (27 in the control group and 24 in the experimental group), patients with a BMI of 27 or greater were randomly assigned in a 1:1 ratio to receive either orlistat (120 mg) three times a day plus phentermine hydrochloride (37.5 mg) once daily or a placebo three times a day plus phentermine hydrochloride (37.5 mg) once daily. The primary study outcome was sterol metabolism. Results: The experimental group exhibited significantly decreased metabolic signatures of serum sterols, free cholesterol, sitosterol, 7α-hydroxycholesterol (7α-OHC), and 7ß-OHC at 12 weeks. The experimental group also exhibited significantly decreased metabolic ratios of sitosterol and 7α-OHC to cholesterol at 12 weeks. Regarding changes in sterol signatures from baseline to 6-month follow-up, free cholesterol, plant sterols, and cholesterol precursors tended to decrease with weight loss during the intervention and increase again as the weight was regained in both groups. Conclusion: Orlistat treatment improves oxysterol metabolism in overweight and obese adults. Our findings support that orlistat plays a crucial role in the process of endothelial dysfunction and atherosclerosis via oxysterol modulation.

Development and validation of UPLC and LC-MS/MS methods for the simultaneous determination of anti-obesity drugs in foods and dietary supplements.

Recently, the number of the cases in which weight loss products have been sold with illegal adulterants has increased, as awareness of the problems of obesity grows. In this study, we developed simultaneous analysis methods to rapidly and accurately identify ingredients illegally mixed with foods and dietary supplements. Twenty-three anti-obesity drugs in foods and dietary supplements were determined by developed and validated UPLC and LC-MS/MS methods. The UPLC method were validated for the LOD and LOQ in the ranges 0.05-3.0 and 0.2-10.0 µg/mL, respectively. The determination coefficient was over 0.999, precision was <6.2 %, and the accuracy was 80.8-103.9 %. The mean recoveries ranged from 80.3 to 109.3 % and RSD of stability was less than 2.1 %. The determination of the 23 anti-obesity drugs was accomplished by electrospray ionization LC-MS/MS using multiple reaction monitoring (MRM). The LODs and LOQs were in the ranges 0.03-7.5 and 0.09-30.0 ng/mL, respectively. The LC-MS/MS method was validated for linearity (r(2) > 0.99), precision (RSD < 10.7 %), accuracy (94.1-109.1 %), recovery (80.5-113.5 %), and the RSD of stability was <7.8 %. Using the newly developed and validated method, 193 samples were tested, and 55 were found to be adulterated.

Detection of thermogenesis in rodents in response to anti-obesity drugs and genetic modification.

Many compounds and genetic manipulations are claimed to confer resistance to obesity in rodents by raising energy expenditure. Examples taken from recent and older literature, demonstrate that such claims are often based on measurements of energy expenditure after body composition has changed, and depend on comparisons of energy expenditure divided by body weight. This is misleading because white adipose tissue has less influence than lean tissue on energy expenditure. Application of this approach to human data would suggest that human obesity is usually due to a low metabolic rate, which is not an accepted view. Increased energy expenditure per animal is a surer way of demonstrating thermogenesis, but even then it is important to know whether this is due to altered body composition (repartitioning), or increased locomotor activity rather than thermogenesis per se. Regression analysis offers other approaches. The thermogenic response to some compounds has a rapid onset and so cannot be due to altered body composition. These compounds usually mimic or activate the sympathetic nervous system. Thermogenesis occurs in, but may not be confined to, brown adipose tissue. It should not be assumed that weight loss in response to these treatments is due to thermogenesis unless there is a sustained increase in 24-h energy expenditure. Thyroid hormones and fibroblast growth factor 21 also raise energy expenditure before they affect body composition. Some treatments and genetic modifications alter the diurnal rhythm of energy expenditure. It is important to establish whether this is due to altered locomotor activity or efficiency of locomotion. There are no good examples of compounds that do not affect short-term energy expenditure but have a delayed effect. How and under what conditions a genetic modification or compound increases energy expenditure influences the decision on whether to seek drugs for the target or take a candidate drug into clinical studies.

The use of lorcaserin in the management of obesity: a critical appraisal.

Obesity is a chronic disease with a high prevalence in both developed and developing countries. Effective management of this worldwide epidemic will have a significant impact on the health care system globally. Lifestyle interventions, such as restricting calorie consumption and increasing physical activity, remain a major component of weight-reduction programs. The development of pharmacotherapy for the management of obesity is still at the infancy stage. Side effects have been the key issue for anti-obesity drugs previously withdrawn from the market. The focus of this review, lorcaserin, is a selective serotonin receptor agonist that is currently undergoing Phase III evaluations. The efficacy of this drug in reducing body weight and improving metabolic parameters of obese patients has been demonstrated in two recent clinical trials. The available evidence indicates that this drug does not show unwanted effects on heart valves or pulmonary artery pressure, and the treatment improves the risk factors for type 2 diabetes and cardiovascular diseases. Despite these promising results, additional experimental and clinical studies are critical for the approval of lorcaserin as a new anti-obesity monodrug therapy by the US Food and Drug Administration.