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.

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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.

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/m 2 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.

Background: The efficacy of anti-obesity medications in combination with lifestyle modification is robustly supported by randomized controlled trials, but there is a paucity of data on their effectiveness for weight loss maintenance in clinical practice. Objectives: To investigate real-world effectiveness of anti-obesity medications (AOM) to maintain weight loss over 2 years. Methods: A retrospective chart review of patients who established care at an academic weight management center between 4/2014-4/2016 was performed by three independent reviewers. Patients who had both 1-year and 2-year follow-up appointments were identified. Demographics, medications, and weight changes after pharmacotherapy initiation were recorded during 2-year follow-up. Results: Of 1775 new patients, 883 met eligibility criteria, and 423 patients had weight data recorded at 1-year and 2-year time points. Patients were 74.2% female with an average age of 50.9 + 13.8 years, and 17.0% had type 2 diabetes (T2DM). The mean baseline weight and BMI were 98.6 + 22.5 kg and 35.3 + 6.87 kg/m2, respectively. The mean weight loss at year-1 and year-2 was similar (-9.9 + 7.7% vs. -10.3 + 8.8%, p=0.31). There was no statistically significant difference in weight loss between the T2DM and non-DM cohorts at 2 years (-8.69% vs. -10.48%, p=0.12). The average BMI change at 2 years was -10.7 + 9.4% (p<0.001). Seventy-five percent of patients achieved ≥ 5% weight loss at 1 year, and of these, 87.4% maintained that loss at 2 years. Forty-six percent of patients achieved ≥10% weight loss at 1 year, of which 76.9% maintained that loss at 2 years. At 2 years, 96.2% of patients remained on > 1 weight loss medication with an average of 2.4 + 1.2 drugs. The most commonly prescribed weight-loss pharmacotherapies were metformin (71.5%), phentermine (23.3%) and topiramate (19.9%). Conclusions: Clinically significant weight loss maintenance over 2 years is achievable with the use of multi-drug weight-loss pharmacotherapy in a specialty care center. Disclosure B.G. Tchang: None. M. Aras: None. L. Mandel: None. L.I. Igel: None. R. Kumar: Speaker's Bureau; Self; Janssen Pharmaceuticals, Inc., Novo Nordisk Inc. Stock/Shareholder; Self; VIVUS, Inc., Zafgen, Inc. K.H. Saunders: None. J. Waitman: None. L. Aronne: Advisory Panel; Self; Eisai Inc., Gelesis, Jamieson Wellness Inc., Janssen Pharmaceuticals, Inc., Novo Nordisk Inc., Pfizer Inc., Real Appeal, Inc., UnitedHealth Group Inc. Board Member; Self; BMIQ Professionals Program, Jamieson Wellness Inc., MYOS Corp. Consultant; Self; Eisai Inc., Gelesis, Jamieson Wellness Inc., Janssen Pharmaceuticals, Inc., Novo Nordisk Inc., Real Appeal, Inc., UnitedHealth Group Inc. Research Support; Self; Allurion, Aspire Bariatrics, AstraZeneca, Eisai Inc., Janssen Pharmaceuticals, Inc., Novo Nordisk Inc. Stock/Shareholder; Self; BMIQ Professionals Program, ERX Pharmaceuticals, Inc., Gelesis, Jamieson Wellness Inc., MYOS Corp, Zafgen, Inc. A. Shukla: None.