New insights into the treatment of obesity.

Obesity is a chronic, progressive and relapsing disease with a rising global prevalence associated with increased morbidity and mortality and reduced quality of life. Treatment of obesity requires a comprehensive medical approach that includes behavioural interventions, pharmacotherapy and bariatric surgery. The degree of weight loss with all approaches is highly heterogeneous, and long-term weight maintenance remains challenging. For years, antiobesity medications have been limited in number, often delivering meagre efficacy and raising numerous safety concerns. Therefore, there is a need for the development of highly efficacious and safe new agents. Recent insights into the complex pathophysiology of obesity have increased our understanding of intervenable targets for pharmacotherapies to treat obesity and improve weight-related cardiometabolic complications, namely, type 2 diabetes, hyperlipidaemia and hypertension. As a result, novel potent therapies have emerged, such as semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA) recently approved for the treatment of obesity. Semaglutide 2.4 mg once weekly significantly reduces body weight by approximately 15%, with simultaneous improvement in cardiometabolic risk factors and physical functioning in people with obesity. Tirzepatide, the first dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1RA, has recently demonstrated that body weight reduction exceeding 20% in people with obesity and coupled with improved cardiometabolic measures is feasible. Thus, these novel agents promise to narrow the gap between the weight-loss effects of behaviour interventions, previous pharmacotherapies, and bariatric surgery. In this narrative review, we highlight established and emerging therapeutic treatments for long-term obesity management and position them in a framework according to their weight loss effects.

Long-term weight loss maintenance with obesity pharmacotherapy: A retrospective cohort study.

Objective: To determine the association of anti-obesity medications (AOMs) with weight loss maintenance over 2 years. Methods: This is a retrospective observational cohort study of adults treated for obesity between 1 April 2014 and 1 April 2016 at a tertiary academic weight management center and who completed 2 years of follow-up. Main outcome measures were mean percent weight loss, percent of individuals who achieved clinically significant long-term weight loss (≥5% weight loss over 2 years), and long-term weight loss maintenance (achievement of ≥5% weight loss at 1 year and maintenance of the ≥5% reduction for the second year). Results: Of the 1566 new patients, 421 completed 1- and 2-year follow-up appointments. Patients were mostly female and on average 51 years old; they weighed 100.1 kg and had a BMI of 35.8 kg/m2 at initial visit. Mean weight losses at 1 and 2 years were 10.1% and 10.2%, respectively. The proportion of patients who experienced ≥5% weight loss was 75.5% at 1 year and 72.9% at 2 years. Long-term weight loss maintenance was achieved by 65.3% of patients. Almost all (96.2%) were on ≥1 AOM at 2 years, with metformin, phentermine, and topiramate among the most prescribed. AOM usage and older age demonstrated trends toward predicting weight loss maintenance over 2 years. Conclusions: Long-term weight loss maintenance was observed among adults with medically managed obesity who completed 2 years of follow-up.

Obesity and Diabetes.

Obesity is the most significant risk factor for the development of diabetes. Both obesity and diabetes rates have continued to increase in tandem and pose increased mortality for patients and increased health care costs for the community. Weight loss of 5% or more of total body weight renders improvements in glycemic control, decreases in the need for diabetes medications, and improved quality of life. Cotreatment of obesity and diabetes requires a comprehensive medical approach that encompasses intensive lifestyle modification including behavioral changes, nutrition, and physical activity, as well as pharmacotherapy and possible surgical management.

An update on pharmacotherapeutic strategies for obesity.

INTRODUCTION: The field of obesity medicine has evolved over the past several years. With greater understanding of its pathophysiology, obesity is regarded more as a chronic disease than a lifestyle choice. However, it is difficult to treat with lifestyle modifications alone due to the complexity of energy dysregulation. The availability of anti-obesity medications (AOMs) provides practitioners with more effective and sustainable ways to treat obesity. AREAS COVERED: This review briefly summarizes the weight loss efficacy of AOMs currently approved for long-term use and expands on their therapeutic potential beyond weight loss with particular focus on obesity-related comorbidities. Possible future AOMs with promising phase II or III data are also covered. EXPERT OPINION: The future of obesity medicine is in recognizing obesity as a disease and approaching treatment similarly to other chronic diseases. Lifestyle interventions alone are rarely sufficient in the treatment of chronic diseases, and pharmacotherapy often plays a necessary role in changing the course of disease. Current AOMs have proven efficacy in weight management and emerging therapeutic uses in obesity-related comorbidities, such as non-alcoholic fatty liver disease, obstructive sleep apnea, and polycystic ovarian syndrome. The development of new AOMs will further empower providers to deliver effective obesity management.

Modulation of protein aggregation by polyethylene glycol conjugation: GCSF as a case study.

Polyethylene glycol (PEG) conjugation to proteins has emerged as an important technology to produce drug molecules with sustained duration in the body. However, the implications of PEG conjugation to protein aggregation have not been well understood. In this study, conducted under physiological pH and temperature, N-terminal attachment of a 20 kDa PEG moiety to GCSF had the ability to (1) prevent protein precipitation by rendering the aggregates soluble, and (2) slow the rate of aggregation relative to GCSF. Our data suggest that PEG-GCSF solubility was mediated by favorable solvation of water molecules around the PEG group. PEG-GCSF appeared to aggregate on the same pathway as that of GCSF, as evidenced by (a) almost identical secondary structural transitions accompanying aggregation, (b) almost identical covalent character in the aggregates, and (c) the ability of PEG-GCSF to rescue GCSF precipitation. To understand the role of PEG length, the aggregation properties of free GCSF were compared to 5kPEG-GCSF and 20kPEG-GCSF. It was observed that even 5kPEG-GCSF avoided precipitation by forming soluble aggregates, and the stability toward aggregation was vastly improved compared to GCSF, but only marginally less stable than the 20kPEG-GCSF. Biological activity measurements demonstrated that both 5kPEG-GCSF and 20kPEG-GCSF retained greater activity after incubation at physiological conditions than free GCSF, consistent with the stability measurements. The data is most compatible with a model where PEG conjugation preserves the mechanism underlying protein aggregation in GCSF, steric hindrance by PEG influences aggregation rate, while aqueous solubility is mediated by polar PEG groups on the aggregate surface.