Connor Iapoce is the assistant managing editor for 

joining the MJH Life Sciences team in April 2021. He graduated from The College of New Jersey with a degree in Journalism and Professional Writing. He enjoys listening to records, going to the movies, and playing with his cat, Squish. You can reach him at 

Connor Iapoce

Patient factors, including sociodemographic, healthcare, and clinical elements, were linked to the initiation of semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1 RA), in a population with 

Among more than 97,000 commercially insured adults in a recent cohort study, approximately 2.0% began semaglutide treatment within 6 months of an obesity diagnosis, with sex, insurance plan, and medication use found to be relevant factors for medication initiation.

“The association of these factors with semaglutide initiation were quantified using multivariable logistic regression, and use of common medications, insurance plan structure, employer industry type, and sex were all significantly associated with semaglutide initiation,” wrote the investigative team, led by Andrew C. Stokes, PhD, department of global health, school of public health, Boston University.

As obesity and overweight affect nearly 74% of individuals in the US, the demand for obesity medications, such as GLP-1 RAs, is growing, with approximately 6% of the US population currently taking one.

 Previously, GLP-1 RAs were exclusively approved to treat T2D, with recent clinical trials reporting their benefit for weight management and cardiovascular disease (CVD) prevention.

The US Food and Drug Administration (FDA) approved semaglutide (Wegovy) in June 2021 for weight management in individuals with overweight or obesity.

 Populations with obesity, but not diabetes, are a unique population in determining uptake of GLP-1 agonists, with limited evidence on the factors involved in medication initiation. Evidence has, however, suggested this subgroup, at risk of developing diabetes and other cardiometabolic conditions, may be undertreated due to clinician and patient perception of obesity as a risk factor, not a disease.

For this study, Stokes and colleagues explored patient access to GLP-1 agonists based on individual factors, implementing a machine-learning approach to factor identification and multivariable regression modeling to measure the link between these factors and semaglutide initiation.

Collecting data from the Merative MarketScan Commercial Claims and Encounters Database, the retrospective, observational cohort included US adults aged ≥18 years with a first diagnosis of obesity between June 2021 and July 2022 in an outpatient or inpatient setting. Patients could not have been prescribed prior anti-obesity medications, have undergone bariatric surgery, or had a diabetes claim in the 12 months before obesity diagnosis.

In the analysis, conducted from February to November 2024, Stokes and colleagues utilized a 10-fold cross-validated random forest model examining 698 potential variables associated with incident semaglutide prescription. Among 97,456 individuals who met inclusion criteria, 59.6% were female, 27.3% were aged 45–54, and 52.0% resided in the Southern US.

Approximately half (50.7%) were covered by preferred provider organization plans, but only 2.0% (n = 1963) initiated semaglutide within 6 months of the initial obesity diagnosis. Upon further analysis, the random forest model revealed an area under the receiver operative characteristic (AUROC) curve of 0.71 (95% CI, 0.69–0.74), indicating reasonable discriminative performance.

Stokes and colleagues ranked the top 20 features of the model feature importance list in a Shapley Additive Explanation plot, with the most important exposures including sex, antidepressant use, and employer industry. A multivariable logistic regression model was implemented to quantify the association of the top 20 features with semaglutide initiation. Female sex (adjusted odds ratio [aOR, 2.30; 95% CI, 2.05–2.58), antidepressant use (aOR, 1.62; 95% CI, 1.46–1.78), and insurance plan type, particularly a point-of-service plan (aOR, 1.78; 95% CI, 1.42–2.22), were noted as significant factors.

“These findings suggest that inequities persist in medication access in this understudied subgroup, and further research should investigate factors associated with GLP-1 receptor agonist use in those with public payer plans, as well as whether concurrent use of common medications impacts effectiveness,” they added.

Podolsky MI, Raquib R, Shafer PR, Hempstead K, Ellis RP, Stokes AC. Factors Associated With Semaglutide Initiation Among Adults With Obesity. JAMA Netw Open. 2025;8(1):e2455222. doi:10.1001/jamanetworkopen.2024.55222

Temple NJ. The Origins of the Obesity Epidemic in the USA-Lessons for Today. Nutrients. 2022;14(20):4253. Published 2022 Oct 12. doi:10.3390/nu14204253

Lincoff AM, Brown-Frandsen K, Colhoun HM, et al. Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes. N Engl J Med. 2023;389(24):2221-2232. doi:10.1056/NEJMoa2307563

Campbell P. Semaglutide (Wegovy) approved for chronic weight management in patients with obesity or overweight. HCP Live. April 17, 2023. Accessed January 21, 2025. https://www.hcplive.com/view/semaglutide-approved-for-chronic-weight-management-in-patients-with-obesity-or-overweight.

Articles

Patient factors such as sociodemographic, healthcare, and clinical elements influence the initiation of semaglutide, a GLP-1 receptor agonist, in obese individuals without type 2 diabetes. A cohort study of over 97,000 insured adults found that only 2% began semaglutide treatment within six months of an obesity diagnosis. Factors like sex, insurance plan, and medication use were significant. The study highlighted inequities in medication access and called for further research on GLP-1 receptor agonist use in populations with public payer plans and concurrent medication use.

Approximately 2.0% of commercially insured individuals with obesity, but not diabetes, initiated semaglutide within 6 months of diagnosis.

Patient Factors Influence Semaglutide Initiation After Obesity Diagnosis

Elevated levels of oxidized high-density lipoprotein (HDL) were associated with 

heart failure with preserved ejection fraction (HFpEF)

 in a new analysis, suggesting the presence of reduced HDL antioxidant function in this population.

This cross-sectional observational study assessed the antioxidant function of HDL in more than 350 patients with suspected heart failure, with HFpEF assessment conducted according to the current Heart Failure Society of America (HFSA) clinical guidelines.

“Our results consistently show that increased HDLox levels are associated with HFpEF in both univariate and multivariate analyses,” wrote the investigative team, led by Benjamin Sasko, department of cardiology, Medical School Theodor Fontane, University Medical Center Brandenburg an Der Have. “Therefore, our main finding is that reduced antioxidant HDL function is present in HFpEF.”

Guidelines designate HFpEF by clinical signs of HF, irrespective of a normal left ventricular ejection fraction (LVEF) of ≥50%. More than half of all HF cases are considered HFpEF, driven by an abnormal ventricular filling from impaired relaxation due to increased myocardial stiffness. Ventricular-arterial uncoupling stemming from this increased myocardial stiffness results in increased LV filling pressure.

HDL-cholesterol (HDL-C) has not previously been considered in guidelines as a contributor to HF rates, with very low and high levels of high-density HDL-C traditionally a lower indicator of cardiovascular disease (CVD). Sasko and colleagues suggested HDL function, rather than absolute HDL-C levels, could be a more accurate predictor of CVD risk, with prior research tying HDL function to an inverse association with CVD.

Across this cross-sectional study, Sasko and colleagues evaluated HDL’s antioxidant function in a population with confirmed HFpEF, hypothesizing a reduced antioxidant function linked to the presence of HFpEF. A population of 366 consecutive patients presenting with symptoms of HF, including dyspnea, orthopnea, and fatigue, at a single center in Germany underwent assessment between 2019 and 2021.

Two cohorts were built based on the assessment: patients with HFpEF determined by LVEF ≥50%, echographic evidence of cardiac functional and structural alterations, and increased NT-proBNP levels (n = 88) and patients without HF, defined by LVEF ≥50% with normal range NT-proBNP levels (n = 180). Individuals with an LVEF < 50% (n = 98) were excluded from the study.

The study used a validated cell-free biochemical assay to determine reduced HDL antioxidant function as determined by increased HDL-lipid peroxide content (HDLox), normalized by HDLC levels, and the mean value of a pooled serum control from healthy participants (nHDLox).

Patients with HF were older than patients without HF (

 <.001), with a higher proportion of females (

 = .002) and more frequently dealing with diabetes (

 <.001). Investigators identified no differences in LV function between patients with HFpEF and those without HF.

Upon analysis, those with HFpEF had 15% higher mean relative levels of nHDLox than those patients without HF. A multivariate model analysis, adjusted for age, sex, and estimated glomerular filtration rate (eGFR), found nHDLox remained a significant risk factor for HFpEF (odds ratio [OR], 2.03; 95% CI, 1.19–3.45; 

Further multivariate analysis, adjusted for diabetes, hypertension, atrial fibrillation (AF), low-density lipoprotein cholesterol (LDL-C), high-sensitivity C-reactive protein (hsCRP), and coronary artery disease (CAD), revealed nHDLox remained an independent predictor for HFpEF (

 <.05). An increase in 1-SD in nHDLox was linked to a 67% elevated risk for HFpEF, compared with patients without heart failure (OR, 1.67; 95% CI, 1.07–2.6; 

Based on these data, Sasko and colleagues called for further studies to focus on the mechanistic impact of HDLox on the cardiomyocyte and endothelial function.

“It is plausible to hypothesize that the oxidation of HDL significantly contributes to the development of HFpEF and improving HDL function is a promising target for early heart failure treatment,” Sasko and colleagues added.

 “However, further studies are needed, focusing on the mechanistic impact of HDL-lipid peroxide content on the cardiomyocyte and endothelial function.”

Sasko, B., Kelesidis, T., Kostin, S. et al. Reduced antioxidant high-density lipoprotein function in heart failure with preserved ejection fraction. Clin Res Cardiol (2025). https://doi.org/10.1007/s00392-024-02583-3

Bozkurt B, Coats AJ, Tsutsui H, et al. Universal Definition and Classification of Heart Failure: A Report of the Heart Failure Society of America, Heart Failure Association of the European Society of Cardiology, Japanese Heart Failure Society and Writing Committee of the Universal Definition of Heart Failure. J Card Fail. Published online March 1, 2021. doi:10.1016/j.cardfail.2021.01.022

Mody P, Joshi PH, Khera A, Ayers CR, Rohatgi A. Beyond Coronary Calcification, Family History, and C-Reactive Protein: Cholesterol Efflux Capacity and Cardiovascular Risk Prediction. J Am Coll Cardiol. 2016;67(21):2480-2487. doi:10.1016/j.jacc.2016.03.538

Elevated oxidized HDL levels are linked to heart failure with preserved ejection fraction (HFpEF), indicating reduced HDL antioxidant function in these patients. A study involving over 350 patients assessed HDL's antioxidant function, revealing that increased HDLox levels are associated with HFpEF. The study suggests that HDL function, rather than HDL-C levels, may better predict cardiovascular disease risk. Multivariate analyses confirmed nHDLox as an independent risk factor for HFpEF. Further research is needed to explore HDLox's mechanistic impact on cardiomyocyte and endothelial function.

Increases in oxidized HDL levels were linked to HFpEF in new analyses, suggesting reduced antioxidant HDL function is present in this patient population.

HDL Antioxidant Function Diminished in Patients with HFpEF, Study Finds 

The US Food and Drug Administration (FDA) has accepted the New Drug Application (NDA) for investigational plozasiran for the treatment of 

, assigning a Prescription Drug User Fee Act (PDUFA) target date of November 18, 2025.

Announced by Arrowhead Pharmaceuticals, Inc. on January 17, 2025, the NDA was accepted based on positive results on plozasiran reported from the Phase 3 PALISADE study. In the acceptance, the FDA indicated no plan to hold an advisory committee meeting.

“Plozasiran has achieved promising and consistent results in various patient populations representing multiple points on the spectrum of diseases caused by elevated triglycerides,” Chris Anzalone, PhD, president and chief executive officer at Arrowhead, said in a statement.

 “FCS represents the most severe and rare end of the spectrum; however, we believe that substantial unmet medical need exists in severe hypertriglyceridemia and mixed hyperlipidemia, which we are investigating in additional Phase 3 trials as part of the SUMMIT program of clinical studies.”

A severe, rare disease, FCS can lead to notably elevated triglyceride levels (≥880 mg/dL), leading to a substantially higher risk of developing acute pancreatitis and long-term complications, such as diabetes and cognitive issues. Therapeutic options are limited for patients with FCS.

Plozasiran is a first-in-class investigational RNA interference (RNAi) therapeutic designed by Arrowhead to reduce the production of apolipoprotein C-III (APOC3), a component of triglyceride-rich lipoproteins (TRLs) linked to an increase in triglyceride levels. Multiple clinical trials in the SUMMIT program have observed reductions in triglycerides and multiple atherogenic lipoproteins with plozasiran in FCS (PALISADE), severe hypertriglyceridemia, (MUIR), and mixed hyperlipidemia (CAPITAN).

The basis of the NDA submission included the positive data from PALISADE, with supplementary confirmatory evidence from the Phase 2 clinical trials in the SUMMIT program. A total of 75 participants were randomized to receive 25 mg plozasiran, 50 mg plozasiran, or matching placebo once every 3 months in the trial.

Analyses showed PALISADE met its primary endpoint of percentage change from baseline in fasting triglycerides versus placebo at Month 10. Plozasiran achieved durable reductions in triglyceride levels with an 80% median change from baseline in the 25 mg dose cohort. Key secondary endpoint analysis revealed a statistically significant 83% reduction in the risk of acute pancreatitis with plozasiran, compared with placebo, in the pooled 25 mg and 50 mg cohorts.

Plozasiran has remained well-tolerated to date across multiple clinical trials. The most frequently reported treatment-emergent adverse events (TEAEs) in PALISADE for the 25 mg dose proposed for marketing approval were abdominal pain, COVID-19, nasopharyngitis, and nausea.

The FDA previously granted Breakthrough Therapy Designation, Orphan Drug Designation, and Fast Track Designation to plozasiran for FCS.

 Arrowhead indicated plans for further submissions to additional regulatory authorities in 2025 for the approval of investigational plozasiran to treat patients with FCS.

“With the plozasiran NDA submission and FDA’s acceptance for filing complete, we are laser-focused on our ongoing work to ensure an efficient and successful commercial launch this year, pending FDA review and approval,” Anzalone added.

Arrowhead Pharmaceuticals announces acceptance of New Drug Application by U.S. FDA of Plozasiran for the treatment of familial chylomicronemia syndrome. Arrowhead Pharmaceuticals, Inc. January 17, 2025. Accessed January 20, 2025. https://arrowheadpharma.com/news-press/arrowhead-pharmaceuticals-announces-acceptance-of-new-drug-application-by-u-s-fda-of-plozasiran-for-the-treatment-of-familial-chylomicronemia-syndrome/.

Regmi M, Rehman A. Familial Hyperchylomicronemia Syndrome. [Updated 2023 Aug 8]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK551655/

Campbell P. Palisade: Plozasiran offers hope for treating familial chylomicronemia syndrome. HCP Live. September 2, 2024. Accessed January 20, 2025. https://www.hcplive.com/view/palisade-plozasiran-offers-hope-for-treating-familial-chylomicronemia-syndrome.

Iapoce C. FDA grants Breakthrough therapy designation to plozasiran for FCS. HCP Live. September 12, 2024. Accessed January 20, 2025. https://www.hcplive.com/view/fda-grants-breakthrough-therapy-designation-to-plozasiran-for-fcs.

The FDA has accepted the New Drug Application for plozasiran, an investigational RNA interference therapeutic for familial chylomicronemia syndrome (FCS), with a PDUFA target date of November 18, 2025. Plozasiran, developed by Arrowhead Pharmaceuticals, showed positive results in the Phase 3 PALISADE study, achieving significant triglyceride reductions and lowering acute pancreatitis risk. The drug targets apolipoprotein C-III to reduce triglyceride levels. Plozasiran has received multiple FDA designations and is well-tolerated, with plans for further regulatory submissions in 2025.

The FDA has assigned a Prescription Drug User Fee Act (PDUFA) target action date of November 18, 2025.

FDA Accepts Plozasiran NDA for Familial Chylomicronemia Syndrome

Complete safety and efficacy analysis of the NORSE EIGHT clinical trial revealed noninferiority of ONS-5010 (LYTENAVA), an ophthalmic formulation of bevacizumab, at 12 weeks to ranibizumab for the treatment of 

neovascular (wet) age-related macular degeneration (nAMD)

Announced by Outlook Therapeutics on January 16, 2025, the full 3-month analysis supports the company’s plan to resubmit the Biologics License Application (BLA) for ONS-5010 in the first quarter of 2025. In November 2024, preliminary topline results from the trial showed that ONS-5010 missed its pre-specific non-inferiority endpoint at Week 8.

“The 3-month data from NORSE EIGHT provides additional evidence to confirm what retina specialists expected,” Julia A. Haller, MD, ophthalmologist-in-chief at Wills Eye Hospital and Outlook Therapeutics board member, said in a statement.

 “The clinical trial continues to demonstrate that ONS-5010 injections result in immediate and sustained anatomic efficacy, with steady gains in visual acuity and reliable, consistent safety.”

NORSE EIGHT is the second of dual adequate and well-controlled clinical trials designed to evaluate ONS-5010 for wet AMD after a Special Protocol Assessment (SPA) was confirmed by the US Food and Drug Administration (FDA). Previously, in August 2023, the FDA released a Complete Response Letter (CRL) citing multiple Chemistry Manufacturing and Controls (CMC) issues and a lack of substantial evidence.

NORSE EIGHT randomized newly diagnosed patients with nAMD in a 1:1 ratio to receive 1.25 mg ONS-5010 or 0.5 mg intravitreal injections at Day 0, Week 4, and Week 8 visits, with a final visit at Week 12. Its primary endpoint was a mean change in best-corrected visual acuity (BCVA) from baseline to Week 8.

Initial analysis at Week 8 found that ONS-5010 did not meet the prespecified non-inferiority to ranibizumab endpoint decided in the SPA agreement with the FDA. However, at all time points, Outlook indicated ONS-5010 achieved increasing BCVA improvements with the presence of biologic activity.

ONS-5010 achieved mean visual acuity improvements of +5.5 letters, compared with +6.5 letters for ranibizumab, at Week 12 (95% CI, –2.865 to 0.848; 

 = .0043). Central retinal thickness (CRT) was similar across all time points, including Week 12, for both the ONS-5010 (–123.9 µm) and ranibizumab (–127.3 µm) cohorts.

Safety outcomes showed that ONS-5010 was tolerable with similar adverse event rates to ranibizumab. The full duration of NORSE EIGHT remained consistent with previously reported safety data from the NORSE ONE, NORSE TWO, and NORSE THREE clinical trials, with no cases of retinal vasculitis in either study cohort.

Outlook announced that ONS-5010 has been granted Marketing Authorization in the European Union and the United Kingdom, with plans to launch in the first half of calendar 2025. With statistically significant 12-week results for ONS-5010 in NORSE EIGHT, Outlook confirmed the complete data set and the NORSE TWO pivotal study will support the resubmission of the BLA in the US for nAMD.

“Our team continues the necessary work for the planned resubmission of our BLA in the first quarter of calendar 2025,” Lawrence Kenyon, chief financial officer and interim chief executive officer of Outlook Therapeutics, added in a statement.

 “We remain confident in the potential of ONS-5010/LYTENAVA to provide an important therapy for the treatment of wet AMD in place of off-label repackaged bevacizumab that has not received regulatory approval for use in retinal diseases here in the United States.”

Outlook therapeutics® announces complete twelve week efficacy and safety results of Norse eight clinical trial. Outlook Therapeutics, Inc. January 16, 2025. Accessed January 17, 2025. https://ir.outlooktherapeutics.com/news-releases/news-release-details/outlook-therapeuticsr-announces-complete-twelve-week-efficacy.

Iapoce C. Ons-5010 for wet AMD fails to meet noninferiority in Norse eight trial. HCP Live. November 27, 2024. Accessed January 17, 2025. https://www.hcplive.com/view/ons-5010-for-wet-amd-fails-to-meet-noninferiority-in-norse-eight-trial.

Iapoce C. Outlook therapeutics submits ONS-5010 special protocol assessment to FDA. HCP Live. January 2, 2024. Accessed January 17, 2025. https://www.hcplive.com/view/outlook-therapeutics-submits-ons-5010-special-protocol-assessment-fda.

The NORSE EIGHT clinical trial demonstrated the noninferiority of ONS-5010 (LYTENAVA), an ophthalmic bevacizumab formulation, to ranibizumab for treating neovascular age-related macular degeneration (nAMD) at 12 weeks. Despite missing the non-inferiority endpoint at Week 8, ONS-5010 showed sustained efficacy and safety, with improvements in visual acuity and similar central retinal thickness to ranibizumab. Outlook Therapeutics plans to resubmit the Biologics License Application (BLA) in early 2025, supported by the trial's results and previous studies, aiming to replace off-label bevacizumab use in the US.

With a completed 12-week analysis, Outlook Therapeutics plans to resubmit the Biologics License Application for ONS-5010 in the first quarter of 2025.