GLP-1 RA medications safe and very effective for treating obesity in adults without diabetes

Embargoed for release until 5:00 p.m. ET on Monday 6 January 2025   

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Below please find summaries of new articles that will be published in the next issue of Annals of Internal Medicine. The summaries are not intended to substitute for the full articles as a source of information. This information is under strict embargo and by taking it into possession, media representatives are committing to the terms of the embargo not only on their own behalf, but also on behalf of the organization they represent.         
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1. GLP-1 RA medications safe and very effective for treating obesity in adults without diabetes

Data also shows some very promising options that are not yet FDA approved

Abstract: https://www.acpjournals.org/doi/10.7326/ANNALS-24-01590  

URL goes live when the embargo lifts          

A systematic review of randomized controlled trials (RCTs) assessed the efficacy and safety of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and co-agonists for obesity in adults without diabetes. The study found that GLP-1-based drugs are effective for weight loss in adults with obesity but without diabetes, including some promising options that are not yet FDA approved. The study is published in Annals of Internal Medicine.

Researchers from McGill University reviewed 26 RCTs comprising 15,491 participants investigating 12 GLP-1 RAs and co-agonists for treating obesity in adults without diabetes. Twelve GLP-1 RA medications were studied, 3 that are FDA-approved (liraglutide, semaglutide, and tirzepatide) and 9 that are not yet approved for weight management. Treatment periods lasted from 16 to 104 weeks. The greatest weight loss was reported in an RCT of retatrutide (12 mg once weekly), a triple agonist targeting GLP-1, GIP, and glucagon receptors that is not yet FDA-approved or commercially available. Participants using this medication lost up to 22.1% more of their starting weight after 48 weeks compared with participants taking placebo. Tirzepatide (15 mg once weekly), a dual agonist targeting GLP-1 and GIP receptors, produced weight loss of up to 17.8% after 72 weeks, and semaglutide (2.4 mg once weekly) produced weight loss of up to 13.9% after 68 weeks, both compared to placebo. Safety was similar across agents, with most side effects being mild gastrointestinal events, such as nausea and diarrhea. According to the authors, these findings support the use of GLP-1 RAs and co-agonists for the treatment of overweight or obesity among otherwise healthy patients without diabetes.

Media contacts: For an embargoed PDF, please contact Angela Collom at acollom@acponline.org. To speak with corresponding author, please contact Mark J. Eisenberg, MD, MPH at mark.eisenberg@mcgill.ca.

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2. Gabapentin is not associated with greater risk of falls in older adults with neuropathy or fibromyalgia

Abstract: https://www.acpjournals.org/doi/10.7326/ANNALS-24-00636

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A comparator study using a target trial emulation framework compared the risk for fall-related visits and hospitalizations in the 6 months after initiating gabapentin versus duloxetine among patients with evidence of common conditions for which either medication could be reasonable to use, such as neuropathy or fibromyalgia. The researchers found that compared with duloxetine, gabapentin was not associated with increased fall-related visits during the peri-initiation period. The study is published in Annals of Internal Medicine. 

Painful conditions, like neuropathy, significantly increase the risk of falls in older adults, as can the medications used to treat those painful conditions. One of the most common medications used to treat these painful conditions is gabapentin. In 2020, nearly 50 million prescriptions for gabapentin were written, but after several studies highlighted potential safety concerns, 20% fewer gabapentin prescriptions were written in 2022. However, because both gabapentin and the conditions it treats are associated with the same adverse health events, current studies are at risk of incorrectly attributing the health risks associated with the painful conditions themselves to gabapentin. This would mean overestimating the risks of harms gabapentin, which could lead to undertreatment of pain.

Researchers from the University of Michigan, Brigham and Women's Hospital, and Harvard Medical School studied data from 57,086 adults aged 65 years or older with diabetic neuropathy, postherpetic neuralgia, or fibromyalgia who were newly prescribed gabapentin or duloxetine between January 2014 and December 2021. Prior studies have suggested a potential increased risk for falls associated with gabapentin, however, these studies are at risk of bias because they compare users with nonusers. Here, the researchers chose to use a new user, active comparator study design with a target trial emulation framework to more rigorously describe the risk for fall-related injuries and other clinical outcomes in adults receiving gabapentin versus the comparator duloxetine. Participants included in the study met selective criteria to further reduce the risk of confounding. Notably, these criteria included being age 65 or older, having a diagnosis of postherpetic neuralgia, diabetic neuropathy, or fibromyalgia in the 365 days before cohort entry, and 365 days or more of continuous health plan enrollment before and inclusive of the cohort entry date. Additionally, participants were not allowed to have filled a prescription for either gabapentin or duloxetine in the 365 days before cohort entry, filled a script for both gabapentin and duloxetine at the time of cohort entry, or have active cancer, epilepsy/seizure disorders, or depression/anxiety. The primary outcome was any fall-related visit to an inpatient or outpatient facility. There were three secondary outcomes: a hip fracture–fall event that included a same-day fall-related visit, a fall-related visit to an emergency department and a fall-related hospitalization. Unlike in past work, the researchers did not observe a greater risk for falls with gabapentin use compared to duloxetine use.

According to the authors, patients with pain often report feeling undertreated. This makes accurate risk/benefit estimates for pain medications especially important. These findings should inform conversations between physicians and patients who are considering starting gabapentin.

Media contacts: For an embargoed PDF, please contact Angela Collom at acollom@acponline.org. To speak with corresponding author Alexander Chaitoff, MD, MPH, please email Kara Gavin at kegavin@med.umich.edu.

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3. Study suggests higher risk of CV events when initiating denosumab for osteoporosis in dialysis patients

Abstract: https://www.acpjournals.org/doi/10.7326/ANNALS-24-03237

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An observational study emulated a target trial to determine the risk for major adverse cardiovascular events (MACE) and fracture prevention effects with denosumab versus bisphosphonates in dialysis-dependent patients. The researchers estimated that denosumab lowers fracture risk by 45% but increases MACE risk by 36%. The researchers note that more studies are needed to confirm these findings. The study is published in Annals of Internal Medicine.

Researchers from Kyoto University studied data from 1,032 dialysis-dependent patients aged 50 and older identified by a Japanese administrative claims database as initiating either denosumab or oral bisphosphonates for osteoporosis. Since fracture morbidity in dialysis patients is high, the researchers aimed to provide evidence on optimal management strategies for osteoporosis. The researchers used observational data from the database to emulate a target trial comparing the risk for MACE and the effectiveness in fracture prevention among dialysis-dependent patients taking denosumab vs bisphosphonates. Eligible patients for the study had to be at least 50 years old, undergoing dialysis, diagnosed with osteoporosis and newly initiated either denosumab or an oral bisphosphonate for osteoporosis management between April 2015 and October 2021. Of the 1,032 eligible patients identified, 658 were denosumab users and 374 were oral bisphosphonate users. The primary safety outcome evaluated was MACE, including acute myocardial infarction, stroke, hospitalization for heart failure, or cardiovascular death, and the effectiveness outcome were all types of composite fractures. The researchers estimated that that the risk for fractures was 45% lower and the risk for MACE was 36% higher for denosumab compared with oral bisphosphonates. At a three-year follow up, the risk for MACE increased by 8.2%. The findings are consistent across patient subgroups and raise concerns about treating dialysis-dependent patients with denosumab. Although the researchers note that their estimates need to be confirmed in future studies, the findings are consistent with a recent meta-analysis that found a 46% increase in cardiovascular adverse events with denosumab compared with bisphosphonates in postmenopausal women. The researchers hope that these results will inform future studies on the comparative effectiveness and safety of these medications in dialysis-dependent patients.

Media contacts: For an embargoed PDF, please contact Angela Collom at acollom@acponline.org. To speak with corresponding author Koji Kawakami, MD, PhD, please email kawakami.koji.4e@kyoto-u.ac.jp.

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4. Prominent editors’ group issues warning to early career authors about predatory journals

Abstract: https://www.acpjournals.org/doi/10.7326/ANNALS-24-03636

URL goes live when the embargo lifts         

In a new editorial, Annals of Internal Medicine Editor-in-Chief Christine Laine, MD, MPH and colleagues from the International Committee of Medical Journal Editors (ICMJE) describe the significant rise in predatory journals and how authors, research institutions, and journal editors and publishers can protect the scientific community. Common practices of predatory journals include aggressive solicitation of submissions; the promise of quick turnaround times; and lack of transparency around article submission, processing, and withdrawal charges. These journals often mimic the name and branding of established, legitimate journals, which causes early-career authors who lack experience and mentorship to be particularly vulnerable to their deceptive targeting.

The authors say that researchers need guidance to combat the threat of predatory journals. Organizations including The World Association of Medical Editors and ThinkCheckSubmit.org offer resources and recommendations to help authors identify and vet trusted journals and publishers. Academic institutions and funders can ensure these resources are available via institutional channels, especially for early career authors. Finally, journal editors and publishers should help to alert authors of the threat of predatory journals and direct them to resources to identify such journals. Countering the threat of predatory journals requires awareness and action from all stakeholders in the scientific community.

Media contacts: For an embargoed PDF or to speak with Dr. Laine, please contact Angela Collom at acollom@acponline.org.

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