Pharmacology/Pharmaceutical Industry
Observational Study Emulation: Denosumab vs. Oral Bisphosphonates in Dialysis-Dependent Patients Shows Reduced Fractures but Possible Elevated Cardiovascular Risk
8 Jan, 2025 | 11:55h | UTCBackground: Patients receiving dialysis have a markedly increased risk of osteoporotic fractures, yet management options in this population remain challenging. Although oral bisphosphonates are the usual first-line treatment for osteoporosis, safety concerns exist for those with severe chronic kidney disease (CKD). Denosumab, which is not cleared via the kidney, offers a potential alternative, but limited data compare its fracture-prevention benefit and cardiovascular (CV) safety against bisphosphonates in dialysis-dependent patients.
Objective: To estimate the risk for major adverse cardiac events (MACE) and the effectiveness in preventing fractures when using denosumab compared with oral bisphosphonates among patients undergoing dialysis.
Methods: This study emulated a target trial using an observational Japanese administrative claims database (April 2014 to October 2022). Adults aged 50 years or older, receiving dialysis and newly prescribed denosumab (60 mg subcutaneously) or oral bisphosphonates (alendronate, risedronate, ibandronate, or minodronate) were included. Exclusions involved recent acute myocardial infarction, stroke, or heart failure. Inverse probability of treatment weighting (IPTW) based on propensity scores was used to balance baseline characteristics. The primary safety outcome was MACE (acute myocardial infarction, stroke, hospitalization for heart failure, or CV death), and the primary effectiveness outcome was all fractures. Three-year risks, risk differences, and risk ratios were estimated.
Results: Among 658 denosumab users and 374 oral bisphosphonate users (mean age, 74.5 years; 62.9% women) followed for up to 3 years, denosumab was associated with a higher weighted risk of MACE (3-year risk ratio, 1.36 [95% CI, 0.99 to 1.87]; risk difference, 8.2% [–0.2% to 16.7%]) compared with oral bisphosphonates. Although the point estimate suggests a notable increase, the 95% CI includes 1.0, indicating that statistical significance was not definitively achieved. Denosumab showed a significantly lower composite fracture risk (3-year risk ratio, 0.55 [0.28 to 0.93]; risk difference, –5.3% [–11.3% to –0.6%]). Individual fracture sites (e.g., hip, vertebral) had imprecise estimates but trended toward fewer nonvertebral fractures with denosumab. Mortality rates did not differ substantially between the groups.
Conclusions: In dialysis-dependent patients with osteoporosis, denosumab may reduce fracture risk while potentially elevating the likelihood of MACE. However, the higher MACE estimate did not surpass the conventional threshold for statistical significance, warranting cautious interpretation. Although these data suggest a clinically meaningful reduction in fractures, the findings regarding cardiovascular outcomes remain imprecise and require further confirmation.
Implications for Practice: Clinicians treating dialysis-dependent patients should weigh denosumab’s fracture-prevention advantage against its possible heightened CV risk. Oral bisphosphonates, though sometimes restricted in severe CKD, may confer lower risk of MACE. Careful monitoring of electrolyte levels, especially calcium, and CV status is essential when administering denosumab in end-stage kidney disease.
Study Strengths and Limitations: Strengths include a large, real-world cohort and the use of target trial emulation with robust propensity score weighting. Limitations involve potential residual confounding, reliance on claims-based definitions of outcomes, and absent lab data (e.g., serum calcium, glomerular filtration rate). Consequently, causality and generalizability should be interpreted with caution, especially outside Japan.
Future Research:
Prospective trials and additional observational studies using detailed clinical data (including renal function parameters and bone mineral density) are needed to clarify the relative net benefits of denosumab versus bisphosphonates in advanced CKD. Investigations into other safety outcomes, such as long-term renal function and hypocalcemia-related complications, would further inform clinical decision-making.
Reference: Masuda S, Fukasawa T, Matsuda S, Kawakami K. “Cardiovascular Safety and Fracture Prevention Effectiveness of Denosumab Versus Oral Bisphosphonates in Patients Receiving Dialysis: A Target Trial Emulation.” Annals of Internal Medicine. DOI:
https://doi.org/10.7326/ANNALS-24-03237
Systematic Review: GLP-1 Receptor Agonists and Co-Agonists Facilitate Significant Weight Loss in Adults Without Diabetes
8 Jan, 2025 | 11:04h | UTCBackground: Obesity is increasingly treated as a chronic disease requiring long-term management. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) were originally developed for type 2 diabetes but subsequently demonstrated substantial weight loss benefits in individuals with overweight or obesity. Although several GLP-1 RAs and related dual or triple co-agonists have been assessed in diverse populations, their overall efficacy and safety profile among adults without diabetes had not been thoroughly evaluated.
Objective: To systematically appraise the efficacy and safety of GLP-1 RAs (including single, dual, and triple agonists) for weight loss in otherwise healthy adults with overweight or obesity and without diabetes.
Methods: Investigators searched MEDLINE, Embase, and Cochrane CENTRAL through 4 October 2023 for placebo-controlled randomized controlled trials (RCTs). Eligible studies enrolled adults with body mass index (BMI) ≥27 kg/m^2 (plus one weight-related comorbidity) or ≥30 kg/m^2, in the absence of diabetes or other major diseases. Trials had to last at least 16 weeks and report changes in body weight and safety outcomes. The primary endpoint was percent or absolute change in body weight from baseline. Safety assessments included adverse events (AEs), serious AEs (SAEs), and gastrointestinal (GI) events.
Results: Twenty-six RCTs encompassing 15,491 participants (72% female; mean BMI range, 30–41 kg/m^2; mean age range, 34–57 years) evaluated 12 agents. Three drugs (liraglutide, semaglutide, tirzepatide) are commercially available for weight management; nine are premarket (e.g., retatrutide, orforglipron, mazdutide). Treatment periods ranged from 16 to 104 weeks (median, 43 weeks). Across studies, GLP-1 RAs and co-agonists consistently demonstrated significant weight reductions compared with placebo. Tirzepatide (15 mg weekly) reached up to a 17.8% (95% CI, 16.3% to 19.3%) weight reduction after 72 weeks, whereas semaglutide (2.4 mg weekly) achieved up to 13.9% (95% CI, 11.0% to 16.7%) after 68 weeks. Liraglutide produced more modest losses of up to 5.8% (95% CI, 3.6% to 8.0%) after 26 weeks. Novel agents, particularly the triple agonist retatrutide (12 mg weekly), reported greater average weight losses of up to 22.1% (95% CI, 19.3% to 24.9%) after 48 weeks. Although AEs were often very common (GLP-1 RA vs. placebo: 80%–97% vs. 63%–100%), most were GI-related (47%–84% vs. 13%–63%) and mild or moderate. Importantly, only a smaller proportion of participants (0%–26% vs. 0%–9%) discontinued treatment due to AEs, and SAEs (0%–10% vs. 0%–12%) occurred at relatively lower rates overall. While select SAEs of interest, including severe GI events, biliary disorders, pancreatitis, and psychiatric disorders, were inconsistently reported, they were generally rare (severe GI and biliary disorders, ≤3.5%; pancreatitis, <2%; psychiatric disorders, ≤15% [including less severe events, such as insomnia and mood alterations]).
Conclusions: GLP-1 RAs and co-agonists appear highly efficacious for weight reduction in adults without diabetes, with GI events as the principal safety concern. Among emerging agents, retatrutide in particular has shown even greater efficacy, though further research is needed to clarify comparative effectiveness, costs, and real-world feasibility.
Implications for Practice: Clinicians considering GLP-1 RAs or dual and triple co-agonists for obesity treatment should monitor for GI side effects and counsel patients about long-term use to sustain weight loss. As these newer treatments often come with higher price points and uncertain insurance coverage, cost-effectiveness and sponsor bias should be weighed. Careful patient selection, ongoing monitoring, and discussion of adherence requirements are critical to optimize outcomes in real-world practice.
Study Strengths and Limitations: This review incorporated RCTs with substantial sample sizes and used predefined inclusion criteria focused on healthy adults without diabetes, ensuring a clearer understanding of weight-loss outcomes in this group. However, head-to-head comparisons among agents were lacking, and heterogeneity in trial designs (varying lifestyle interventions, follow-up durations, and dose-escalation approaches) precluded meta-analysis of pooled data. Reporting of specific adverse outcomes was also inconsistent.
Future Research: Larger, longer-term head-to-head RCTs are warranted to evaluate comparative effectiveness, durability of weight loss, and cost implications. Investigations should also explore safety beyond GI events, including rare but serious outcomes such as thyroid disease, gallbladder disorders, or pancreatitis, and determine whether combination therapies (e.g., cagrilintide–semaglutide) confer added benefits.
Reference: Moiz A, Filion KB, Toutounchi H, Tsoukas MA, Yu OHY, Peters TM, Eisenberg MJ. Efficacy and Safety of Glucagon-Like Peptide-1 Receptor Agonists for Weight Loss Among Adults Without Diabetes: A Systematic Review of Randomized Controlled Trials. Annals of Internal Medicine. DOI: https://doi.org/10.7326/ANNALS-24-01590
RCT: Sequential Oral Agents Not Noninferior to Insulin for Gestational Diabetes
8 Jan, 2025 | 11:05h | UTCBackground: Gestational diabetes mellitus (GDM) affects a growing number of pregnant individuals worldwide. While insulin has long been the standard pharmacological treatment, oral glucose-lowering agents (metformin and glyburide) have gained traction.
Objective: This trial investigated whether a sequential oral glucose-lowering regimen—beginning with metformin and adding glyburide as needed—was noninferior to an insulin-based strategy in reducing the risk of infants born large for gestational age (LGA).
Methods: This open-label, randomized, noninferiority trial enrolled 820 participants with singleton pregnancies at 16 to 34 weeks of gestation across 25 Dutch centers. Participants were randomized 1:1 to either (1) metformin initiated at 500 mg once daily and increased every three days up to 1000 mg twice daily or the highest tolerated dose with glyburide at 2.5 mg 30-60 minutes before each meal (with a dose increase up to a maximum of 5 mg three times per day) added if needed, and insulin added only if both failed, discontinuing glyburide, or (2) standard insulin therapy. The primary outcome was LGA (>90th percentile for gestational age and sex).
Results: Among those allocated to oral therapy (n=409), 79% achieved glycemic control without insulin. However, 23.9% of infants in the oral-therapy group were LGA vs 19.9% in the insulin group (absolute risk difference 4.0%; 95% CI, −1.7% to 9.8%). This exceeded the predefined 8% absolute risk difference noninferiority margin (P = .09 for noninferiority). Maternal hypoglycemia occurred more often with oral agents (20.9% vs 10.9%; absolute risk difference, 10.0%; 95% CI, 3.7%-21.2%), and neonatal intravenous glucose therapy was administered more frequently to those randomized to oral agents (6.4% vs 3.2%). Exploratory analysis not powered for definitive conclusions of participants requiring only metformin (no glyburide) showed a somewhat lower LGA rate (19.7%).
Conclusions: A sequential oral pharmacotherapy strategy—beginning with metformin and adding glyburide if needed—did not meet noninferiority criteria compared to insulin for preventing LGA births in GDM. While oral agents can reduce the overall need for insulin, the higher rate of maternal hypoglycemia, the higher rate of neonatal hypoglycemia requiring intravenous glucose therapy, and the borderline higher LGA incidence underscore the continued importance of insulin-based strategies, especially considering that the results support a larger body of evidence that glyburide is a suboptimal treatment for gestational diabetes. These results reinforce that insulin remains the preferred first-line pharmacological treatment for GDM, in line with current guidelines. Although patient satisfaction can be higher with oral agents, clinicians should carefully weigh the risks. Further research is needed to clarify the role of metformin-only approaches in GDM management.
Strengths and Limitations: Strengths include a large multicenter design and a clear noninferiority framework. Limitations include the open-label design, which introduces the possibility of bias in treatment allocation and outcome assessment, the reliance on local clinical protocols for insulin adjustments, and variations in diagnostic criteria.
Future Research: Ongoing trials are examining whether metformin alone might match insulin’s efficacy for GDM. Further studies should address long-term offspring outcomes.
Reference:
Rademaker D, de Wit L, Duijnhoven RG, et al. Oral Glucose-Lowering Agents vs Insulin for Gestational Diabetes: A Randomized Clinical Trial. JAMA. Published online January 6, 2025. DOI: http://doi.org/10.1001/jama.2024.23410
Powe CE. For Gestational Diabetes Pharmacotherapy, Insulin Reigns Supreme (Editorial). JAMA. Published online January 6, 2025. DOI: http://doi.org/10.1001/jama.2024.27148
ATS Guidelines on Invasive Pulmonary Aspergillosis and Antifungal Strategies in Critically Ill Adults
7 Jan, 2025 | 12:29h | UTCIntroduction: This summary provides an overview of a recent American Thoracic Society clinical practice guideline addressing two core questions in adult pulmonary and critical care practice. First, it examines whether combination therapy with a mold-active triazole (most data concern voriconazole, though newer agents such as isavuconazole or posaconazole may also be considered) plus an echinocandin (specifically caspofungin, micafungin, or anidulafungin) offers added benefit over mold-active triazole monotherapy for patients with proven or probable invasive pulmonary aspergillosis (IPA). Second, it evaluates whether routine use of prophylactic or empiric antifungal agents against Candida species is advisable in critically ill, nonneutropenic, nontransplant patients at risk of invasive candidiasis (IC). By synthesizing available evidence using the GRADE approach, this guideline aims to support clinicians in optimizing therapeutic strategies and improving patient outcomes in these complex infections.
Key Recommendations:
Initial Combination Therapy vs. Monotherapy for IPA
- For patients with proven or probable IPA, the guideline makes a conditional recommendation, meaning the best choice isn’t entirely clear. Both initial combination therapy (mold-active triazole + echinocandin) and monotherapy (mold-active triazole alone) are considered reasonable options.
- Evidence stems primarily from studies in hematologic malignancy (HM) or hematopoietic stem cell transplant (HSCT) recipients, with mixed findings in observational cohorts and a key randomized trial favoring combination therapy, particularly in a subgroup diagnosed by positive galactomannan assays.
- When critical illness or triazole resistance is a concern, combination therapy may be considered, but there is insufficient evidence to categorically endorse one approach over the other.
Prophylactic or Empiric Antifungal Therapy for Candida in Critically Ill Patients
- In nonneutropenic, nontransplant adult ICU patients at risk for IC, the guideline makes a conditional recommendation against routinely using prophylactic or empiric antifungal therapy. This means the benefits of withholding these treatments likely outweigh the risks, but there’s still some uncertainty.
- Low-quality evidence from multiple randomized controlled trials showed no significant mortality benefit in administering antifungals prophylactically or empirically compared with placebo.
- Although IC carries substantial morbidity and mortality, its overall incidence in this population remains low, and ongoing surveillance or targeted diagnostics may be preferable to universal antifungal administration.
Conclusion: The panel emphasizes that these recommendations should be applied with clinical judgment, especially in patients with severe disease, likely high fungal burden, or concerns for antifungal resistance. Combination therapy for IPA may be particularly relevant when critical illness or limited triazole efficacy is suspected. Meanwhile, prophylactic or empiric anti-Candida therapy in the broader ICU setting does not appear to substantially reduce mortality. Continued advances in rapid diagnostics, close monitoring of local resistance patterns, and new antifungal agents may further refine best practices. Future research should focus on validating these findings in diverse patient populations, exploring novel combination regimens, and establishing more precise risk assessments for IC in the ICU.
Reference: Epelbaum O, Marinelli T, Haydour Q, Pennington KM, Evans SE, Carmona EM, Husain S, Knox KS, Jarrett BJ, Azoulay E, Hope WW, and others. “Treatment of Invasive Pulmonary Aspergillosis and Preventive and Empirical Therapy for Invasive Candidiasis in Adult Pulmonary and Critical Care Patients: An Official American Thoracic Society Clinical Practice Guideline.” American Journal of Respiratory and Critical Care Medicine (2025). https://doi.org/10.1164/rccm.202410-2045ST
RCT: Assessing Procalcitonin-Based Antibiotic Management in Critically Ill Patients With Sepsis
7 Jan, 2025 | 14:00h | UTCBackground: Optimal antibiotic duration for sepsis remains uncertain. Procalcitonin (PCT) and C-reactive protein (CRP) are thought to support shorter courses, but prior research was small-scale or at risk of bias. This multicenter, randomized trial (ADAPT-Sepsis) evaluated whether daily PCT- or CRP-guided protocols could reduce antibiotic use without increasing 28-day all-cause mortality in critically ill adults with suspected sepsis.
Objective: To determine if daily biomarker-guided (PCT or CRP) strategies decrease total antibiotic days among critically ill adults while maintaining acceptable 28-day mortality, compared with standard care.
Methods: From 2018 to 2024 (with enrollment paused March–August 2020 due to COVID-19), 2760 adults (≥18 years) on intravenous antibiotics for suspected sepsis (acute organ dysfunction and presumed infection) and likely to continue antibiotics for at least 72 hours were randomized across 41 UK NHS ICUs within 24 hours of antibiotic initiation. They were assigned in a 1:1:1 ratio to (1) daily PCT-guided advice (n=918), (2) daily CRP-guided advice (n=924), or (3) standard care (n=918). Biomarker results were concealed; clinicians received automated daily prompts recommending continuation or discontinuation. The co-primary outcomes were (1) total antibiotic duration (randomization to day 28) and (2) 28-day all-cause mortality. Secondary measures included antibiotic duration for the initial sepsis episode, 90-day mortality, readmissions, and length of stay.
Results: Among 2760 participants (mean age, 60.2 years; 60.3% men; ~50% with septic shock), over 96% provided 28-day data. Patients in the PCT-guided arm had a statistically significant mean reduction in total antibiotic duration vs standard care (9.8 vs 10.7 days; difference, 0.88 days; 95% CI, 0.19–1.58; p=0.01). The PCT strategy met the prespecified 5.4% noninferiority margin for 28-day mortality (20.9% vs 19.4%; absolute difference, 1.57; 95% CI, –2.18 to 5.32; p=0.02), implying noninferiority but not fully excluding a small risk of excess mortality. CRP-guided protocols did not shorten total antibiotic use (10.6 vs 10.7 days; p=0.79) and were inconclusive for noninferiority regarding mortality (21.1% vs 19.4%; difference, 1.69; 95% CI, –2.07 to 5.45; p=0.03). Notably, 90-day mortality also showed no significant differences. A post-trial commentary (PulmCCM) emphasized that some uncertainty remains with the 5.4% margin and warned that patient-level randomization could subtly discourage earlier antibiotic discontinuation in standard care, which received no explicit “stop” prompts.
Conclusions: In critically ill patients with suspected sepsis, a PCT-guided antibiotic discontinuation protocol shortened overall antibiotic use by nearly one day without exceeding the predefined noninferiority threshold for 28-day mortality. However, the chosen 5.4% margin allows for the possibility of clinically relevant harm. A CRP-guided protocol did not reduce total antibiotic use and showed inconclusive mortality findings.
Implications for Practice: Adopting PCT-based stewardship may modestly decrease antibiotic exposure without a clear short-term mortality penalty, potentially limiting antibiotic resistance. Clinicians should remain vigilant, recognizing the risk tolerance implied by the 5.4% margin. PCT results should complement, not replace, comprehensive clinical judgment.
Study Strengths and Limitations: Strengths include the large sample size, multi-center design, blinded biomarker allocation, and distinct emphasis on both effectiveness and safety outcomes. Limitations include the acceptance of a 5.4% potential excess mortality as the noninferiority threshold, uncertainty about rare but significant harms, and the possibility of bias introduced by patient-level randomization. Generalizability to lower-resource settings may also be limited.
Future Research: Further randomized trials with lower noninferiority margins or cluster-level allocation are needed to better define the safety and efficacy of PCT-guided strategies for reducing antibiotic duration in sepsis. Additional investigations are needed for long-term patient-centered outcomes, cost-effectiveness, and the role of alternative biomarkers or combined strategies in sepsis care.
Reference:
Dark P, Hossain A, McAuley DF, et al. Biomarker-Guided Antibiotic Duration for Hospitalized Patients With Suspected Sepsis: The ADAPT-Sepsis Randomized Clinical Trial. JAMA. 2024; published online December 9. DOI: http://doi.org/10.1001/jama.2024.26458
PulmCCM Commentary: “Is procalcitonin ‘safe’ to guide antibiotic use in patients with sepsis? ADAPT-Sepsis tests the strategy in the U.K., with global ambitions.” Jan 02, 2025. https://www.pulmccm.org/p/is-procalcitonin-safe-to-guide-antibiotic
Joint ATS/CDC/ERS/IDSA Guideline Recommends Shorter, All-Oral Regimens for Drug-Susceptible and Drug-Resistant TB
5 Jan, 2025 | 11:30h | UTCIntroduction: This summary outlines new clinical practice guidelines from the American Thoracic Society, U.S. Centers for Disease Control and Prevention, European Respiratory Society, and Infectious Diseases Society of America on updated treatment regimens for tuberculosis (TB) in low-incidence settings. These recommendations build on recent clinical trials, World Health Organization (WHO) guidance, and were developed using the GRADE and GRADE-ADOLOPMENT methodology. The guidelines aim to shorten treatment duration, reduce pill burden, and improve patient outcomes for both drug-susceptible (DS) and drug-resistant (DR) TB, and they apply to settings where mycobacterial cultures, molecular and phenotypic drug susceptibility tests, and radiographic studies are routinely available. A separate news release from CIDRAP highlights the significance of these shorter, all-oral regimens for adults and children. Directly observed therapy (DOT) remains the standard of care.
Key Recommendations:
Four-Month Regimen for DS-TB in Adults:
- For people aged 12 years or older with isoniazid- and rifampin-susceptible pulmonary TB, a new four-month regimen of isoniazid, rifapentine, moxifloxacin, and pyrazinamide (2HPZM/2HPM) is conditionally recommended. This shortened course is based on a large, randomized trial (Study 31/A5349) demonstrating noninferior efficacy compared to the standard six-month regimen (84.6% vs 85.4% cure, respectively), no increase in adverse events, and potential benefits in completion rates. Exclusions include TB meningitis and other complicated forms of extrapulmonary TB, and clinicians should obtain rapid fluoroquinolone susceptibility tests before initiating this regimen.
Four-Month Regimen for DS-TB in Children:
- For children and adolescents aged 3 months to 16 years with nonsevere, drug-susceptible pulmonary TB, a four-month regimen of isoniazid, rifampin, pyrazinamide, and ethambutol for the initial phase, followed by isoniazid and rifampin, is strongly recommended. Evidence from the SHINE trial showed high success (97.1% vs 96.9%) and similar safety with the shorter course compared to the 6-month regimen. Nonsevere TB generally excludes extensive cavitary disease, advanced extrapulmonary TB, or complicated forms. Close clinical and radiographic follow-up is important to confirm effective cure.
Six-Month BPaL Regimen for Rifampin-Resistant, Fluoroquinolone-Resistant or Intolerant TB:
- For rifampin-resistant (RR) pulmonary TB with resistance or patient intolerance to fluoroquinolones in adolescents aged 14 and older and adults, a six-month all-oral bedaquiline, pretomanid, and linezolid (BPaL) regimen is strongly recommended, replacing much longer regimens that often included injectables. Clinical trials (Nix-TB, ZeNix) demonstrated higher cure rates and lower toxicity with this regimen compared to longer regimens, though vigilance is needed for linezolid-related adverse events (e.g., neuropathy, myelosuppression). Baseline and monthly lab and ECG checks are advised.
Six-Month BPaLM Regimen for Rifampin-Resistant, Fluoroquinolone-Susceptible TB:
- For RR pulmonary TB that remains fluoroquinolone-susceptible in adolescents aged 14 and older and adults, a six-month bedaquiline, pretomanid, linezolid, and moxifloxacin (BPaLM) regimen is strongly recommended over traditional 15-month or longer regimens in patients with MDR/RR-TB. Data from the TB-PRACTECAL trial showed high success rates and fewer serious adverse events. BPaLM is the first-line recommendation for this group. Close monitoring of cardiac status (QTc prolongation) and blood counts is advised.
Both BPaL and BPaLM regimens require detailed drug susceptibility testing and cautious management of potential drug–drug interactions, particularly for patients with comorbidities or HIV infection. Of note, the certainty of evidence for the outcomes in the DR-TB trials was rated as very low, due to multiple factors including bias, small event numbers, lack of blinding, and inconsistent outcomes.
Conclusion: These new recommendations markedly shorten TB treatment courses for adults and children in low-incidence settings with access to appropriate diagnostic tools, while avoiding injectables and reducing serious toxicities. By replacing older, more complex regimens with all-oral, shorter-duration therapy, and using DOT as the standard of care, the guidelines aim to improve adherence, lessen the burden on healthcare systems, and enhance patient quality of life. Ongoing research will further refine dosing, safety for special populations (e.g., pregnant individuals), and the role of advanced drug susceptibility testing.
Reference:
Jussi J. Saukkonen, Raquel Duarte, Sonal S. Munsiff, et al. “Updates on the Treatment of Drug-Susceptible and Drug-Resistant Tuberculosis: An Official ATS/CDC/ERS/IDSA Clinical Practice Guideline.” American Journal of Respiratory and Critical Care Medicine, (2025). https://doi.org/10.1164/rccm.202410-2096ST
News release commentary: “New guidelines expand recommendations for shorter, all-oral TB treatments” (CIDRAP). https://www.cidrap.umn.edu/tuberculosis/new-guidelines-expand-recommendations-shorter-all-oral-tb-treatments
Managing Autonomic Dysfunction, Pain, and Sleep Disturbances in Parkinson’s Disease: Key Points from the German Society of Neurology Guideline
5 Jan, 2025 | 11:00h | UTCIntroduction: This text summarizes a practice-oriented 2023 guideline from the German Society of Neurology addressing non-motor manifestations of Parkinson’s disease (PD). The guideline focuses on evidence-based approaches for diagnosing and treating autonomic failure (including urogenital, cardiovascular, and gastrointestinal dysfunction), pain, and sleep disturbances—problems that often reduce quality of life and accelerate disease progression. The guideline was developed using PICO (Patient, Intervention, Comparison, Outcome) questions, comprehensive literature searches, and a consensus process among German Parkinson’s experts. By presenting stepwise recommendations, the guideline aims to help clinicians manage these non-motor aspects more effectively and improve patient outcomes.
Key Recommendations:
Autonomic Failure
- Bladder Dysfunction: Encourage behavioral modifications (e.g., timed fluid intake, bladder training) and, if necessary, consider antimuscarinics (e.g., solifenacin, trospium) or β3 agonists (e.g., mirabegron 50 mg once daily). Specifically, solifenacin 5 mg once daily, trospium 15–30 mg twice daily or darifenacin 7.5–15 mg once daily are preferred, due to their lower risk of cognitive side effects.
- In patients who have responded inadequately to oral therapy, intravesical botulinum toxin A injection (200 U or customized) may be considered for treating severe urinary urge incontinence, if the individual motor and cognitive performance enables the subsequently likely necessary intermittent catheterization.
- For nocturia, limit evening fluid intake and consider a 10°–20° head-up tilt in bed. In nocturnal polyuria, desmopressin (5–40 µg once daily nasal spray or 100–800 µg once daily per os) may be used with close monitoring of blood pressure, serum electrolytes and body weight.
- Orthostatic Hypotension (OH): Apply a four-step approach: (1) address aggravating factors (e.g., infections, dehydration); (2) review medications; (3) use non-pharmacological measures (increased fluid/salt intake if no contraindications, abdominal binders, head-up tilt sleeping); (4) add medications to raise blood pressure (e.g., midodrine 2.5–10 mg two to three times a day, fludrocortisone 0.1–0.3 µg once daily). For the diagnosis of OH, a Schellong test or tilt table examination should be performed.
- Monitor for supine hypertension, which may require evening antihypertensives (e.g., low-dose losartan 25–100 mg or transdermal nitroglycerin 0.1–0.2 mg/h) and further adjustments. PD individuals with neurogenic OH should be screened for the presence of supine and nocturnal hypertension.
- Constipation: Follow the general German guideline on “Chronic Constipation.” Emphasize adequate hydration (1.5-2 L per day), fiber intake, and exercise.
- First-line drug therapy is macrogol (polyethylene glycol, PEG, 13–26 g once daily). Consider bisacodyl (5–10 mg once daily), sodium picosulfate (5–10 mg once daily), or prucalopride (1–2 mg once daily) if needed.
- Male Erectile Dysfunction: First-line treatment involves phosphodiesterase type 5 (PDE-5) inhibitors (e.g., sildenafil 50–100 mg on demand), used cautiously in patients with orthostatic hypotension. A multidisciplinary approach with urologists is necessary.
Pain Management
- Classification: Differentiate PD-related pain (nociceptive, neuropathic, or nociplastic) from pain arising independently of PD. Use PD-specific scales, such as the King’s Parkinson’s Disease Pain Scale (KPPS) or the Parkinson’s Disease Pain Classification System (PD-PCS), to clarify pain etiology and guide therapy.
- Approach: Optimize dopaminergic therapy, especially if pain correlates with wearing-off.
- Treat nociceptive pain per the WHO 3-step analgesic ladder (which recommends starting with non-opioid analgesics like acetaminophen or NSAIDs, then moving to mild opioids like codeine if needed, and finally to strong opioids like morphine for severe pain).
- For neuropathic pain, preference is given to anticonvulsants (e.g., gabapentin 300–1800 mg, especially in case of concomitant restless legs syndrome) or antidepressants (e.g., duloxetine 60–120 mg, in case of concomitant depression).
- Opioids (e.g., prolonged-release oxycodone/naloxone 5/2.5–20/10 mg, rarely up to 40/20 mg) may be considered in severe or refractory cases.
Sleep Disturbances
- Screening & Diagnosis: Use the Parkinson’s Disease Sleep Scale-2 (PDSS-2) to identify problems such as insomnia, nocturnal akinesia, restless legs, and REM sleep behavior disorder (RBD).
- Objective tests—actigraphy, polygraphy, or video-polysomnography—are recommended for complex or treatment-refractory sleep issues.
- Treatment: Address comorbid conditions (e.g., restless legs syndrome, sleep apnea) following standard guidelines.
- If motor fluctuations disturb sleep, adjust dopaminergic therapy (e.g., use long-acting levodopa or dopamine agonists at night).
- RBD management typically includes creating a safe sleep environment and considering clonazepam (0.125–3 mg) or melatonin (2–9 mg).
- Insomnia linked to circadian disruption may benefit from good sleep hygiene, bright light therapy, structured exercise, and (if indicated) low-dose agents such as eszopiclone (1 mg), doxepin (25 mg), zolpidem (5 mg), trazodone (50 mg), melatonin (2 mg), venlafaxine (37.5 mg, in case of comorbid depression), nortriptyline (25 mg) or mirtazapine (7.5 mg).
- Excessive daytime sleepiness calls for an etiology-driven approach, with non-pharmacological strategies (e.g., scheduled naps, light therapy, exercise) and possible use of modafinil (200–400 mg) if needed. Driving should be reassessed if sleep attacks occur.
Clinical Impact: Poor sleep worsens cognitive decline, motor deficits, caregiver burden, and overall disease progression. RBD in early PD often predicts faster deterioration and earlier cognitive complications. The guideline also addresses the prognostic implications of sleep disturbances.
Conclusion: This guideline underscores the critical importance of identifying and managing non-motor symptoms in Parkinson’s disease. A structured, practice-oriented, etiology-driven stepwise approach to autonomic failure, pain, and sleep problems helps reduce the risk of dangerous complications, alleviates patient distress, and may delay the progression of both motor and cognitive domains. By integrating evidence-based recommendations into daily practice—focusing on precise assessment, tailored interventions, and regular follow-up—clinicians can improve outcomes and quality of life for individuals with PD and their caregivers.
Reference: Fanciulli A, Sixel-Döring F, Buhmann C, Krismer F, Hermann W, Winkler C, Woitalla D, Jost WH, German Parkinson’s Guideline Group, Trenkwalder C & Höglinger G (2025). Diagnosis and treatment of autonomic failure, pain and sleep disturbances in Parkinson’s disease: guideline “Parkinson’s disease” of the German Society of Neurology. Journal of Neurology (2025). DOI: https://doi.org/10.1007/s00415-024-12730-5
Phase 2b/3 QUASAR Program: Guselkumab for Induction and Maintenance Therapy in Moderate-to-Severe Ulcerative Colitis
7 Jan, 2025 | 13:00h | UTCBackground: Ulcerative colitis (UC) is a chronic inflammatory condition affecting the colon’s mucosal surface, frequently accompanied by debilitating symptoms such as bloody diarrhea, urgency, and abdominal discomfort. Despite the availability of corticosteroids, immunosuppressants, and advanced biologic or small-molecule therapies, many patients still experience suboptimal outcomes. Targeting interleukin (IL)-23, a critical cytokine in the inflammatory cascade, has gained increasing attention. Guselkumab, a human IgG1 monoclonal antibody against the IL-23p19 subunit, has shown clinical promise in psoriasis, psoriatic arthritis, and Crohn’s disease. This article reports findings from the phase 2b/3 QUASAR clinical development program evaluating guselkumab in UC.
Objective: To assess the efficacy and safety of intravenous (IV) guselkumab induction therapy (200 mg every 4 weeks) compared to placebo, followed by subcutaneous (SC) maintenance regimens (200 mg every 4 weeks or 100 mg every 8 weeks) compared to placebo (withdrawal) in adults with moderately to severely active UC who had inadequate responses or intolerance to at least one conventional or advanced therapy.
Methods: In these double-blind, randomized, placebo-controlled studies within the QUASAR program, adults with a baseline modified Mayo (mMayo) score of 5–9 (which excludes the physician’s global assessment) and evidence of active UC underwent IV induction with either guselkumab or placebo at Weeks 0, 4, and 8. The primary endpoint of the induction trial was clinical remission at Week 12 in the primary analysis population (patients with mMayo score 5-9), defined by improved stool frequency, rectal bleeding, and endoscopic findings. Responders from both the phase 2b and phase 3 induction studies then entered the maintenance study, randomized to SC guselkumab (either 200 mg Q4W or 100 mg Q8W) or placebo (withdrawal, meaning patients who had previously responded to guselkumab). The primary endpoint for the maintenance phase was clinical remission at Week 44 in the primary analysis population. Key secondary outcomes included endoscopic improvement, histological remission, corticosteroid-free remission, and patient-reported measures.
Results: A total of 701 patients with a baseline mMayo score of 5-9 (primary analysis population) were evaluated in the phase 3 induction study. By Week 12, a higher proportion of those receiving IV guselkumab (23%) achieved clinical remission compared to placebo (8%; p<0.0001). Patients also demonstrated improvement in endoscopic outcomes and had early symptomatic relief (notably a reduction in rectal bleeding as early as Week 1). In the subsequent maintenance phase, 568 guselkumab induction responders from both phase 2b and phase 3 studies (primary analysis population) were randomized. At Week 44, clinical remission was significantly more frequent in patients receiving guselkumab SC (50% on 200 mg Q4W, 45% on 100 mg Q8W) vs 19% on placebo (both p<0.0001). Endoscopic and histological indices indicated improved mucosal healing with active therapy. Most patients in remission were free of corticosteroids, highlighting a significant steroid-sparing effect.
Conclusions: Guselkumab induction (200 mg IV every 4 weeks) followed by either of the two SC maintenance regimens (200 mg Q4W or 100 mg Q8W) demonstrated substantial efficacy in adults with moderate-to-severe UC, with improved clinical, endoscopic, and histological endpoints relative to placebo. No new safety concerns were observed compared to the known safety profile of guselkumab.
Implications for Practice: Guselkumab offers a new therapeutic option for UC, particularly for individuals who have not responded to, or could not tolerate, other treatments. The study suggests that guselkumab can be considered for both biologic-naive and biologic-experienced patients. As with any novel therapy, careful patient selection and close follow-up are advisable.
Study Strengths and Limitations: Strengths include the rigorous, global, phase 2b/3 design with objective assessments of clinical, endoscopic, and histological response. The large population permitted detailed subgroup analyses (e.g., efficacy was observed in both biologic-naive and biologic-experienced populations). Limitations include the exclusion of certain therapy-refractory cases and lack of active comparator arms. The randomized-withdrawal maintenance design means only induction responders were evaluated further, potentially enhancing observed effect sizes.
Future Research: Extended follow-up will elucidate the durability of remission beyond one year and clarify long-term safety considerations. Head-to-head trials against other IL-23 antagonists or advanced therapies could further guide treatment algorithms. Real-world evidence evaluating diverse populations will be instrumental in determining broader applicability.
Reference: Rubin DT, Allegretti JR, Panés J, Shipitofsky N, Yarandi SS, Huang K-HG, Germinaro M, Wilson R, Zhang H, Johanns J, Feagan BG, Hisamatsu T, Lichtenstein GR, Bressler B, Peyrin-Biroulet L, Sands BE, Dignass A; QUASAR Study Group. Guselkumab in patients with moderately to severely active ulcerative colitis (QUASAR): phase 3 double-blind, randomised, placebo-controlled induction and maintenance studies. The Lancet. 2025;405(10472):33–49. DOI: http://doi.org/10.1016/S0140-6736(24)01927-5
RCT: Camrelizumab Increases Pathological Complete Response in Early or Locally Advanced Triple-Negative Breast Cancer
7 Jan, 2025 | 12:00h | UTCBackground: Triple-negative breast cancer (TNBC) accounts for approximately 15% of all breast malignancies and is known for its aggressive clinical course and limited therapeutic options. Neoadjuvant chemotherapy has become standard of care for many patients with stage II or III TNBC, aiming to downstage tumors and enhance surgical outcomes. Recent trials suggest that adding immune checkpoint inhibitors, such as anti–programmed death 1/ligand 1 (PD-1/PD-L1) agents, to anthracycline- and platinum-based regimens can further improve response rates. Camrelizumab, a humanized monoclonal anti–PD-1 antibody, has shown antitumor activity in various malignancies, including advanced TNBC. This study, the CamRelief trial, evaluated whether camrelizumab combined with intensive chemotherapy (nab-paclitaxel plus carboplatin followed by dose-dense anthracycline-cyclophosphamide) increases pathological complete response (pCR) in patients with early or locally advanced TNBC.
Objective: To determine if the addition of camrelizumab to a platinum-containing neoadjuvant chemotherapy regimen significantly improves pCR in operable or locally advanced TNBC compared with placebo plus the same chemotherapy backbone.
Methods: This randomized, double-blind, phase 3 trial enrolled 441 female patients aged 18 to 75 years from 40 Chinese centers. Eligible participants had stage II or III TNBC (T2N0-1M0/T3N0M0 or T2N2-3M0/T3N1-3M0) and an Eastern Cooperative Oncology Group performance-status score of 0 or 1. Patients were randomized 1:1 to receive camrelizumab (200 mg) or placebo plus chemotherapy. Chemotherapy consisted of nab-paclitaxel (100 mg/m^2) and carboplatin (area under the curve, 1.5) on days 1, 8, and 15 every 28 days for 16 weeks, then epirubicin (90 mg/m^2) and cyclophosphamide (500 mg/m^2) every two weeks for 8 weeks. Camrelizumab or placebo was administered every two weeks during the 24 weeks of chemotherapy. The primary end point was pCR (ypT0/Tis ypN0), assessed by a local pathologist masked to treatment assignment, at the time of surgery. Secondary end points included event-free survival, disease-free survival, distant disease-free survival, and safety.
Results: Of the 441 randomized patients, 89.2% in the camrelizumab-chemotherapy group and 91.3% in the placebo-chemotherapy group proceeded to surgery. Pathological complete response was observed in 56.8% (95% CI, 50.0%-63.4%) of patients receiving camrelizumab-chemotherapy vs 44.7% (95% CI, 38.0%-51.6%) of those receiving placebo-chemotherapy (rate difference, 12.2% [95% CI, 3.3%-21.2%]; 1-sided P = .004). Serious adverse events occurred more frequently with camrelizumab-chemotherapy (34.7% vs 22.8%), including decreased neutrophil count, decreased platelet count, and decreased white blood cell count, but most immune-related events (eg, reactive capillary endothelial proliferation, hypothyroidism) were low grade and manageable. Longer-term outcomes (event-free survival, disease-free survival, distant disease-free survival) remain immature at a median follow-up of 14.4 months, with hazard ratios of 0.80 (95% CI, 0.46-1.42), 0.58 (95% CI, 0.27-1.24), and 0.62 (95% CI, 0.29-1.33), respectively.
Conclusions: In patients with early or locally advanced TNBC, adding camrelizumab to a platinum-containing, dose-dense anthracycline-cyclophosphamide regimen significantly increased pCR rates compared with placebo plus the same chemotherapy backbone. Safety profiles were consistent with known effects of camrelizumab and dose-dense chemotherapy, with no unexpected toxicities detected.
Implications for Practice: These findings support the integration of camrelizumab into an intensive neoadjuvant regimen for TNBC, potentially offering higher rates of tumor eradication across various nodal stages. Clinicians should, however, anticipate and monitor immune-related adverse events, particularly in higher-risk populations. Given the toxicity profile, patient selection and vigilant supportive care are important.
Study Strengths and Limitations: Strengths include the randomized, double-blind design and the inclusion of higher-risk, node-positive cohorts (including N3). The dose-dense chemotherapy backbone further strengthens the applicability of results in more advanced operable disease. Limitations involve the short follow-up time, which precludes conclusive survival analyses, and the study’s restriction to a single geographic population.
Future Research: Longer follow-up is necessary to determine if improved pCR translates into sustained survival benefits. Biomarker-driven approaches, including further PD-L1 and immunogenomic analyses, may refine patient selection. Studies in broader populations and direct comparisons with other checkpoint inhibitors will help define the optimal immunotherapy-partner regimens in TNBC.
Reference:
Chen L, Li H, Zhang H, et al. Camrelizumab vs Placebo in Combination With Chemotherapy as Neoadjuvant Treatment in Patients With Early or Locally Advanced Triple-Negative Breast Cancer: The CamRelief Randomized Clinical Trial. JAMA. Published online December 13, 2024. DOI: http://doi.org/10.1001/jama.2024.23560
Joensuu H. Neoadjuvant Camrelizumab for Triple-Negative Breast Cancer. Editorial. JAMA. Published online December 13, 2024. DOI: http://doi.org/10.1001/jama.2024.25927
Meta-analysis: Therapeutic-Dose Heparin Improves 28-Day Mortality in COVID-19 Hospitalized Patients
6 Jan, 2025 | 12:00h | UTCBackground: High rates of thrombotic events and systemic inflammation among COVID-19 hospitalized patients led researchers to test whether intensified anticoagulation strategies could reduce morbidity and mortality. Previous trials yielded conflicting results, partly due to varying doses of anticoagulants—prophylactic, intermediate, or therapeutic—and heterogeneous patient severity. This comprehensive investigation, conducted by the WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group, aimed to clarify the benefits and risks of escalated anticoagulation dosing in patients hospitalized for COVID-19.
Objective: To estimate whether higher-dose anticoagulation (therapeutic or intermediate) improves 28-day all-cause mortality compared with lower-dose anticoagulation (prophylactic or intermediate), and to evaluate secondary outcomes, including progression to mechanical ventilation, thromboembolic events, and major bleeding.
Methods: This prospective meta-analysis included randomized trials comparing higher- versus lower-dose anticoagulation for hospitalized COVID-19 patients. Investigators collected trial-level summary data, focusing primarily on heparins. Dosing categories—therapeutic, intermediate, and prophylactic—were predefined. The main outcome was 28-day mortality; secondary outcomes included progression to invasive mechanical ventilation (IMV), venous or arterial thrombotic events, and major hemorrhage. Data were analyzed using a fixed-effects model, with odds ratios (ORs) pooled across trials.
Results: Overall, 22 trials (over 11 000 total participants) contributed data, primarily evaluating heparins. For therapeutic versus prophylactic-dose heparin, 28-day mortality was significantly reduced (OR, 0.77; 95% CI, 0.64–0.93), especially among patients requiring low-flow oxygen or no supplemental oxygen. Therapeutic dose reduced thromboembolic events (OR 0.48; 95% CI, 0.36-0.64) but increased major bleeding (OR 1.90; 95% CI, 1.19-3.05) compared to prophylactic dose. In contrast, when therapeutic was compared to intermediate-dose heparin, the summary OR for 28-day mortality was 1.21 (CI, 0.93–1.58), suggesting a potential trend toward higher mortality that did not reach statistical significance. Intermediate versus prophylactic-dose comparisons revealed no conclusive mortality difference (OR, 0.95; CI, 0.76–1.19). Across all higher-dose arms, thromboembolic events decreased, while the risk of major bleeding increased, underscoring the delicate risk–benefit balance. Subgroup analyses by respiratory support level, D-dimer, and baseline severity did not indicate strong interaction effects, although sample sizes were limited in more severe illness subgroups.
Conclusions: Therapeutic-dose heparin reduces 28-day mortality relative to prophylactic-dose in hospitalized patients with COVID-19, mainly among those not requiring invasive ventilation. Mortality was similar or potentially worse when therapeutic was compared to intermediate-dose. Clinicians must weigh the lower rate of thrombotic complications against the higher bleeding risk, particularly in critically ill patients.
Implications for Practice: Although higher anticoagulant dosing appears beneficial for certain hospitalized COVID-19 patients, especially those with mild to moderate respiratory compromise, individualized assessment remains key. Current guidelines broadly recommend prophylactic dosing for the critically ill and suggest considering higher doses only in carefully selected patients. Evolving viral variants and changes in standard of care further complicate direct application of these findings to present-day hospital settings.
Study Strengths and Limitations: Strengths include prospective planning, collaboration with multiple trials, and a large pooled sample. Limitations encompass heterogeneity in dose definitions, partial reliance on published data where individual-level parameters could not be fully harmonized, and potential temporal changes in COVID-19 clinical profiles. Moreover, bleeding severity beyond major hemorrhage was not universally reported, limiting robust safety assessments.
Future Research: Further studies should focus on individualized anticoagulant strategies that consider biomarkers (for example, D-dimer) and evolving treatment protocols. Investigations examining optimal timing, duration, and post-discharge management will help refine anticoagulation practices.
Reference:
The WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group. Anticoagulation Among Patients Hospitalized for COVID-19: A Systematic Review and Prospective Meta-analysis. Annals of Internal Medicine. DOI: https://doi.org/10.7326/ANNALS-24-00800
Shappell CN, Anesi GL. Anticoagulation for COVID-19: Seeking Clarity and Finding Yet More Gray. Annals of Internal Medicine. DOI: https://doi.org/10.7326/ANNALS-24-03244
Avian Influenza A(H5N1) Outbreak Among US Farm Exposures: Clinical Findings and Early Treatment Outcomes
2 Jan, 2025 | 17:01h | UTCBackground: Highly pathogenic avian influenza A(H5N1) has reemerged in the United States with documented infections in poultry and dairy cows since 2021. From March through October 2024, 46 human cases were identified, most of whom were workers engaged in poultry depopulation or dairy-farm activities where infected or presumably infected animals were present.
Objective: To characterize the clinical presentations, exposure settings, and outcomes of individuals with laboratory-confirmed H5N1 infection and to investigate potential routes of transmission, disease severity, and risk to public health.
Methods: Using a standardized case-report form, data were collected on exposure history, symptom onset, and use of personal protective equipment (PPE). Respiratory and conjunctival swabs from symptomatic persons underwent real-time RT-PCR for H5 subtyping at both state laboratories and the Centers for Disease Control and Prevention (CDC). Genetic sequencing was performed on available samples. Investigators also monitored close household contacts to evaluate the risk of secondary transmission. An additional hospitalized patient with no identifiable exposure source was detected through routine influenza surveillance.
Results: Of the 46 adult case patients, 20 were exposed to infected poultry, 25 to infected or presumably infected dairy cows, and 1 had unknown exposure. Among the 45 occupationally exposed patients, illness was mild, with no hospitalizations or deaths. Conjunctivitis was present in 93% of cases; 49% reported fever, and 36% had respiratory symptoms. Fifteen patients had only conjunctivitis, highlighting the utility of conjunctival specimens for detection. Early antiviral therapy with oseltamivir was common, initiated at a median of two days after symptom onset. No additional cases were found among 97 closely monitored household contacts, indicating no evidence of sustained human-to-human transmission. Genetic analyses revealed clade 2.3.4.4b viruses, with some genotypic differences between poultry-related (D1.1 genotype) and cow-related (B3.13 genotype) infections.
Conclusions: In this observational study, H5N1 infections in US adults were generally mild, self-limited, and predominantly associated with conjunctivitis. The absence of critical illness or fatalities contrasts with historical reports of more severe H5N1 disease. Although no ongoing person-to-person transmission was documented, continued vigilance is warranted, given the virus’s potential for rapid adaptation.
Implications for Practice: Occupational health measures, such as consistent PPE use (especially eye protection), timely surveillance, and prompt antiviral treatment, may reduce the impact of H5N1 infections among exposed workers. Clinicians should consider conjunctival sampling for symptomatic patients with relevant animal contact. Policy efforts should focus on improving biosecurity practices in both poultry and dairy settings.
Study Strengths and Limitations: Strengths include systematic surveillance, robust laboratory testing of both respiratory and conjunctival specimens, and early antiviral administration. Limitations involve possible underreporting of mild or asymptomatic cases, incomplete details on exposure duration, and limited data on specific routes of cow-to-human transmission.
Future Research: Further studies should explore viral evolution in cows, the significance of raw milk as a transmission vehicle, and the potential for more severe infections, as highlighted by sporadic reports of severe H5N1 illness worldwide.
Reference: Garg S, Reinhart K, Couture A, Kniss K, Davis CT, Kirby MK, Murray EL, et al. Highly Pathogenic Avian Influenza A(H5N1) Virus Infections in Humans. New England Journal of Medicine. Published December 31, 2024. Link: https://www.nejm.org/doi/full/10.1056/NEJMoa2414610
- Editorial: Ison MG, Marrazzo J. The Emerging Threat of H5N1 to Human Health. New England Journal of Medicine. Published December 31, 2024. Link: https://www.nejm.org/doi/full/10.1056/NEJMe2416323
Meta-Analysis: Glutamatergic Agents May Improve Obsessive-Compulsive and Related Disorder Symptoms
4 Jan, 2025 | 12:08h | UTCBackground: Obsessive-compulsive and related disorders (OCRDs) affect approximately 2% to 3% of the general population and encompass conditions such as OCD, skin-picking disorder, and trichotillomania, leading to substantial distress and impaired daily functioning. Glutamatergic dysfunction within cortico-striatal-thalamo-cortical circuits has emerged as a potential target, prompting investigations into whether glutamatergic agents can enhance outcomes either alone or alongside selective serotonin reuptake inhibitors (SSRIs).
Objective: To determine whether glutamatergic medications, used as monotherapy or as augmentation to SSRIs, can improve clinical symptoms across different OCRDs compared to placebo, with emphasis on changes in standardized measures such as the Yale-Brown Obsessive Compulsive Scale (Y-BOCS).
Methods: This systematic review and meta-analysis included 27 double-blind, placebo-controlled randomized clinical trials involving 1369 participants with OCRDs. Eligible studies examined agents including N-acetylcysteine (NAC), memantine, lamotrigine, riluzole, and topiramate, among others. Data extraction focused on changes in symptom severity, and pooled effect sizes were calculated using random-effects meta-analysis. Subgroup analyses evaluated potential moderators, such as disorder subtype, age group, refractoriness, and augmentation strategies, while sensitivity analyses and publication bias assessments (e.g. Egger test) were performed to ensure robustness.
Results: Overall, glutamatergic medications showed a large effect size in reducing OCRD symptoms (Cohen’s d = −0.80). Specifically for OCD (n=23 trials), a significant mean reduction in Y-BOCS scores (−4.17 points) indicated clinically meaningful improvement. Publication bias was detected in the broader OCRD meta-analysis but not in the OCD-specific analysis. Heterogeneity was high across studies, reflecting varied populations and treatment designs. Despite these findings, the certainty of evidence ranged from low to moderate, mandating cautious interpretation.
Conclusions: Glutamatergic interventions appear promising for OCRDs, particularly OCD, where moderate-certainty evidence suggests meaningful symptom improvement. Nevertheless, elevated heterogeneity and signs of publication bias highlight the need for larger, more rigorous trials to confirm optimal dosing parameters and elucidate which patient subsets may benefit most.
Implications for Practice: Clinicians might consider adding or switching to glutamatergic agents for individuals with inadequate response to SSRIs. However, these findings do not warrant unrestrained enthusiasm. Each case should be weighed individually, taking into account possible mild to moderate gastrointestinal side effects (particularly with NAC).
Study Strengths and Limitations: Strengths include the focus on double-blind RCTs, diverse glutamatergic agents, and robust statistical approaches. Limitations comprise high between-study heterogeneity, limited data for less common disorders (e.g., body dysmorphic disorder), and potential publication bias. Additionally, few trials specifically tested novel agents like ketamine.
Future Research: Studies with larger sample sizes, clearly defined outcomes, and detailed dose-response evaluations are needed. Future trials should explore underrepresented OCRDs, such as hoarding disorder, and newer glutamatergic compounds (e.g., troriluzole) to further optimize therapeutic strategies.
Reference: Coelho DRA, Yang C, Suriaga A, et al. Glutamatergic Medications for Obsessive-Compulsive and Related Disorders: A Systematic Review and Meta-Analysis. JAMA Netw Open. 2025;8(1):e2452963. DOI: http://doi.org/10.1001/jamanetworkopen.2024.52963
Meta-Analysis: Long Half-Life Phosphodiesterase Inhibitors Reduce HbA1c in Adults with Elevated Baseline Levels
6 Jan, 2025 | 08:00h | UTCBackground: Phosphodiesterase type 5 (PDE5) inhibitors are traditionally used to treat erectile dysfunction and pulmonary arterial hypertension. Recent evidence suggests that PDE5 inhibitors could also be repurposed to lower hemoglobin A1c (HbA1c) in patients with type 2 diabetes. Given the disparity in half-lives among these agents, this meta-analysis focused on whether longer half-life PDE5 inhibitors (tadalafil, PF-00489791) produce a more sustained HbA1c reduction compared to short half-life PDE5 inhibitors (sildenafil, avanafil).
Objective: To evaluate the effect of PDE5 inhibitors on HbA1c levels in individuals with baseline values above 6%, comparing agents with short and long half-lives to assess differential clinical benefits in glycemic control.
Methods: This systematic review and meta-analysis included only randomized controlled trials (RCTs) in which participants received any PDE5 inhibitor for at least four weeks, with control or placebo for comparison. Major databases (Cochrane CENTRAL, PubMed Central, ClinicalTrials.gov, and WHO ICTRP) were searched through September 2024 without language restrictions. Statistical analyses were performed using a random-effects model, reporting mean differences in HbA1c. Secondary outcomes (HOMA-IR, lipid profiles, fasting glucose, and others) were also explored.
Results: Thirteen RCTs were eligible (N=1083). Long half-life agents showed a significant mean reduction of approximately −0.40% in HbA1c (p=0.002) in the overall analysis, whereas short half-life PDE5 inhibitors exhibited no significant change. In more stringent subgroup analyses (≥8 weeks’ duration, exclusive type 2 diabetes, baseline HbA1c ≥6.5%), long half-life PDE5 inhibitors maintained a significant decrease (−0.50%), while short half-life agents paradoxically showed a slight but significant increase (+0.36%, p=0.03). In trials enrolling patients with poorly controlled diabetes (baseline HbA1c near 10%), tadalafil’s HbA1c reductions were considerably larger, aligning with the efficacy of other standard oral antidiabetic medications.
Conclusions: Long half-life PDE5 inhibitors appear to confer meaningful reductions in HbA1c, comparable to established oral antidiabetic agents, particularly in patients whose HbA1c is inadequately controlled. In contrast, short half-life PDE5 inhibitors did not show a consistent benefit and may paradoxically raise HbA1c in certain subgroups, although further large-scale studies are warranted to confirm these findings.
Implications for Practice: Long half-life PDE5 inhibitors could serve as an adjunctive therapy in type 2 diabetes management, especially in individuals with higher baseline HbA1c. Yet, caution is advised given limited data on adverse events and the short duration of most included trials. Physicians should remain prudent until more robust evidence, especially in populations with markedly elevated HbA1c, becomes available.
Study Strengths and Limitations: Strengths include a direct comparison between short and long half-life PDE5 inhibitors in a clinically relevant population, plus systematic subgroup analyses. Limitations involve heterogeneity in trial designs, relatively low baseline HbA1c in most participants, and a lack of long-term follow-up data or major clinical endpoints.
Future Research: Subsequent trials should target populations with poorly controlled diabetes (HbA1c ≥9.0%) and assess longer durations (≥3 months) to capture the full impact of PDE5 inhibitor therapy. A deeper examination of combination regimens, pharmacokinetic optimization, and clinical outcomes like cardiovascular events would further clarify the role of these agents in diabetes care.
Reference: Kim J, Zhao R, Kleinberg LR, Kim K. (2025) “Effect of long and short half-life PDE5 inhibitors on HbA1c levels: a systematic review and meta-analysis.” eClinicalMedicine, 80, 103035. Available at: DOI: http://doi.org/10.1016/j.eclinm.2024.103035
RCT: Chlorthalidone Shows No Renal Advantage Over Hydrochlorothiazide Under Equivalent Dosing in Older Adults With Hypertension
3 Jan, 2025 | 09:00h | UTCBackground: Hypertension is a critical factor in chronic kidney disease (CKD) progression and cardiovascular risk. Thiazide-type diuretics, such as chlorthalidone and hydrochlorothiazide, are first-line antihypertensive treatments. However, whether one agent confers stronger renal protection remains contested, especially at doses considered pharmacologically comparable. Prior observational studies suggested potential discrepancies in kidney outcomes and hypokalemia incidence. This secondary analysis of the Diuretic Comparison Project (DCP) further clarifies the comparative effectiveness of chlorthalidone versus hydrochlorothiazide on renal endpoints.
Objective: To evaluate whether chlorthalidone (12.5–25 mg/day) prevents CKD progression more effectively than hydrochlorothiazide (25–50 mg/day) in adults ≥65 years with hypertension and no pre-specified exclusion by renal function.
Methods: The DCP is a pragmatic, open-label randomized clinical trial embedded in Veterans Affairs (VA) facilities across the United States. Between June 1, 2016, and December 31, 2023, patients already receiving hydrochlorothiazide (25 or 50 mg/day) for hypertension were randomized either to continue that medication or switch to chlorthalidone (12.5–25 mg/day), reflecting equivalent potency.
The prespecified primary kidney outcome was a composite of doubling of serum creatinine, a terminal estimated glomerular filtration rate (eGFR) <15 mL/min, or dialysis initiation. Secondary measures included ≥40% eGFR decline, incident CKD (new eGFR <60 mL/min), eGFR slope, and relevant adverse events. Laboratory data were obtained through usual clinical care rather than protocol-driven testing.
Results: Among 13,523 randomized participants, 12,265 had analyzable renal data (mean [SD] age, 71 [4] years; 96.8% male). The mean (SD) follow-up was 3.9 (1.3) years. Chlorthalidone did not demonstrate superiority over hydrochlorothiazide for the composite kidney endpoint (6.0% vs 6.4%; hazard ratio, 0.94; 95% CI, 0.81–1.08; P=.37). Additional analyses showed no differences in CKD incidence, ≥40% eGFR decline, or eGFR slope. Hypokalemia occurred more frequently in chlorthalidone users (overall ~2% higher rate of low potassium measurements), and hospitalizations for hypokalemia also trended higher.
Conclusions: Under dosing regimens designed to achieve equivalent antihypertensive potency, chlorthalidone provided no measurable renal benefit over hydrochlorothiazide but posed a modestly elevated risk of hypokalemia. These findings reinforce the clinical interchangeability of both agents for long-term blood pressure management in older adults, provided serum potassium is monitored.
Implications for Practice: Clinicians can confidently employ either chlorthalidone or hydrochlorothiazide in older patients with hypertension, including those with mild or moderate CKD, since renal deterioration rates did not differ significantly. Importantly, the trial used half the milligram amount of chlorthalidone (12.5–25 mg/day) to match the usual doses of hydrochlorothiazide (25–50 mg/day). Recognizing this equivalence helps guide therapy transitions and dosing decisions. Vigilant monitoring of electrolytes remains essential, particularly when prescribing chlorthalidone, given the slightly higher incidence of hypokalemia.
Study Strengths and Limitations: Strengths include the randomized design, broad participant inclusion, and pragmatic structure that mirrors real-world prescribing. Limitations involve potential underestimation or overestimation of renal events due to reliance on routine (rather than scheduled) lab tests. Also, nearly all participants had prior hydrochlorothiazide exposure, which may have influenced tolerance and adherence patterns.
Future Research: Further clinical trials focusing on more advanced CKD stages, distinct comorbidities, or combination regimens (e.g., with potassium-sparing agents) would expand our understanding of how thiazide-type diuretics influence long-term kidney outcomes. Extended follow-up or additional subgroup analyses could also shed light on the interplay of dose-response effects in highly vulnerable populations.
Reference: Ishani A, Hau C, Raju S, et al. “Chlorthalidone vs Hydrochlorothiazide and Kidney Outcomes in Patients With Hypertension: A Secondary Analysis of a Randomized Clinical Trial.” JAMA Netw Open. 2024;7(12):e2449576. DOI: http://doi.org/10.1001/jamanetworkopen.2024.49576
RCT: Discontinuing First-Line DMT in Long-Term Stable Relapsing MS Leads to Recurrence of Disease Activity
3 Jan, 2025 | 08:00h | UTCBackground: Increasing numbers of patients with relapsing-onset multiple sclerosis (MS) are receiving first-line disease-modifying therapies (DMTs) to control inflammatory lesions and reduce disability progression. Yet, extended therapy raises questions regarding overtreatment, adverse effects, and costs, especially in older or clinically stable individuals.
Objective: This randomized, multicenter, rater-blinded clinical trial (DOT-MS) assessed whether discontinuing first-line DMT in adults with MS who had at least five years of clinical and radiological stability is safe in terms of recurrence of significant inflammatory disease activity.
Methods: Eighty-nine participants (median age 54 years, 67% female) were randomly assigned 1:1 to either continue or discontinue their first-line DMT. Inclusion required relapse-onset MS without new, sizeable brain MRI lesions (≤1 new T2 lesion in the previous five years or ≤3 new T2 lesions in the past ten years). Follow-up included clinical evaluations, gadolinium-enhanced brain MRI at baseline and months 3, 6, 12, 18, and 24, and optional unscheduled visits. The primary endpoint was significant inflammatory disease activity, defined as clinical relapse and/or ≥3 new T2 lesions or ≥2 contrast-enhancing lesions. The trial was prematurely terminated by the data safety monitoring board due to higher-than-expected disease activity in the discontinue arm.
Results: After a median follow-up of 15.3 months, none of the 44 participants in the continue group had significant disease activity, versus 8 of 45 (17.8%) in the discontinue group (95% CI for difference, 0.09–0.32). Nearly all events were MRI-detected new or enhancing lesions, though two participants experienced clinical relapses. Most individuals with reactivation were able to regain stability upon DMT reintroduction. Serum neurofilament light levels rose during episodes of inflammatory activity, but neither NfL nor GFAP levels reliably predicted disease recurrence at baseline. No difference in serious adverse events emerged between groups.
Conclusions: In this trial, discontinuation of first-line DMT in long-term stable MS was associated with a significant risk (about 20%) of inflammatory reactivation, particularly noted in participants under 55 years old. As a result, close clinical and MRI monitoring should be mandatory if discontinuation is attempted, with early DMT reinitiation if necessary.
Implications for Practice: Clinicians may consider stopping first-line DMT in select patients who exhibit prolonged stability, especially in older adults, but must remain vigilant. Rapid detection of any radiological or clinical sign of reactivation is crucial, as reintroducing therapy may reestablish disease control.
Study Strengths and Limitations: Strengths include its randomized design, systematic imaging schedule, and thorough biomarker sampling. Limitations involve early trial termination, restricting subgroup analyses and definitive noninferiority testing. Routine spinal cord imaging was not performed, potentially underestimating subclinical disease activity.
Future Research: Longer-term observational follow-up is ongoing to clarify how these participants fare over time and to identify biomarkers that may better predict risk of rebound activity. Evaluating cost-effectiveness and long-term clinical outcomes will guide future decisions about DMT discontinuation.
Reference: Coerver EME, et al. Discontinuation of First-Line Disease-Modifying Therapy in Patients With Stable Multiple Sclerosis: The DOT-MS Randomized Clinical Trial. JAMA Neurology. 2024. DOI: http://doi.org/10.1001/jamaneurol.2024.4164
Phase 2 RCT: CRISPR-Based Therapy Reduces Attacks in Hereditary Angioedema
2 Jan, 2025 | 10:00h | UTCBackground: Hereditary angioedema (HAE) is a rare autosomal dominant disorder characterized by unpredictable attacks of angioedema involving cutaneous tissues, the gastrointestinal tract, and, potentially, the larynx, posing a risk of asphyxiation. Current prophylactic treatments require frequent administration, often leading to suboptimal adherence and ongoing disease burden. NTLA-2002 is an in vivo CRISPR-Cas9–based therapy designed to permanently inactivate the KLKB1 gene in hepatocytes, thereby reducing plasma kallikrein levels and, hypothetically, lowering attack frequency in patients with HAE.
Objective: To evaluate whether a single intravenous infusion of NTLA-2002 (25 mg or 50 mg) would safely and effectively decrease HAE attack rates and reduce plasma kallikrein protein levels over a 16-week primary observation period, as compared with placebo.
Methods: This phase 2, randomized, double-blind, placebo-controlled trial included 27 adults with confirmed type 1 or type 2 HAE. Participants were assigned in a 2:2:1 ratio to receive a one-time dose of 25 mg or 50 mg of NTLA-2002 or placebo. The primary endpoint was the investigator-confirmed number of angioedema attacks per month from Week 1 through Week 16. Secondary endpoints included the number of moderate-to-severe attacks, use of on-demand therapy, adverse events, and changes in total plasma kallikrein protein levels (analyzed by immunoassays). Exploratory measures encompassed patient-reported outcomes using the Angioedema Quality of Life (AE-QoL) questionnaire.
Results: During the 16-week period, the mean monthly attack rate decreased by 75% in the 25 mg group and 77% in the 50 mg group relative to placebo (estimated rates of 0.70 vs. 0.65 vs. 2.82 attacks per month, respectively). Notably, 4 of 10 patients (40%) in the 25 mg group and 8 of 11 (73%) in the 50 mg group reported no attacks or further prophylaxis use after dosing. Placebo recipients showed only a 16% reduction from baseline. Adverse events were predominantly mild to moderate; headache, fatigue, and nasopharyngitis were most common. Infusion-related reactions occurred in a few patients but resolved without sequelae. A single transient grade 2 elevation in alanine aminotransferase was recorded in one participant given 25 mg of NTLA-2002. By Week 16, total plasma kallikrein levels decreased by 55% in the 25 mg group and 86% in the 50 mg group, with no meaningful changes in placebo.
Conclusions: A single intravenous infusion of NTLA-2002 significantly lowered attack frequency and reduced total plasma kallikrein levels in HAE. Most patients treated at 50 mg experienced no attacks, suggesting that long-term prophylaxis might be unnecessary for many. Longer observation supports durability, yet cost and potential long-term effects of gene editing warrant cautious interpretation.
Implications for Practice: If confirmed by larger phase 3 trials, this gene-editing approach could alter the management of HAE, reducing or eliminating the need for continuous prophylaxis. However, clinicians must weigh the high upfront cost, possible unpredictable immune responses, and the novelty of CRISPR-based therapies before integrating them into standard care.
Study Strengths and Limitations: Strengths include a placebo-controlled design, meaningful improvement in patient-reported outcomes, and robust plasma kallikrein protein reduction. Limitations are the small sample size, short primary observation period, and uncertain long-term safety in diverse populations.
Future Research: Ongoing phase 3 studies with larger cohorts and extended follow-up are essential to confirm safety, long-term efficacy, and cost-effectiveness.
Reference: Cohn DM, Gurugama P, Magerl M, et al. CRISPR-Based Therapy for Hereditary Angioedema. New England Journal of Medicine. 2024; DOI: http://doi.org/10.1056/NEJMoa2405734
- Editorial: Musunuru K. A Milestone for Gene-Editing Therapies. New England Journal of Medicine. 2024; DOI: http://doi.org/10.1056/NEJMe2412176
RCT: Pembrolizumab with Preoperative Radiotherapy Shows Potential in Stage III Soft Tissue Sarcoma
2 Jan, 2025 | 09:00h | UTCBackground: Patients with locally advanced, high-grade soft tissue sarcomas of the extremity often face a high risk of metastatic disease, despite curative-intent surgery and radiotherapy. Traditional doxorubicin-based chemotherapy provides variable benefits and can cause considerable toxicity, prompting investigations into alternative strategies. Emerging data from smaller trials hinted that immune checkpoint inhibitors might offer targeted benefit in sarcomas, but robust evidence in the neoadjuvant setting remains limited.
Objective: To assess whether adding neoadjuvant and adjuvant pembrolizumab to preoperative radiotherapy and surgical resection could enhance disease-free survival (DFS) in individuals with resectable grade 2 or 3, stage III undifferentiated pleomorphic sarcoma or liposarcoma of the extremity and limb girdle.
Methods: This open-label, randomized trial (SU2C-SARC032) enrolled 143 participants at 20 academic centers in Australia, Canada, Italy, and the USA. Eligible patients were 12 years or older, presented with primary tumors >5 cm, and did not receive chemotherapy as part of this protocol. Participants were randomized 1:1 to standard preoperative radiotherapy (50 Gy/25 fractions) plus surgery (control) or the same radiotherapy combined with pembrolizumab (200 mg every three weeks) in the neoadjuvant setting, followed by up to 14 adjuvant cycles. The primary endpoint was disease-free survival, analyzed in a modified intention-to-treat cohort of 127 evaluable patients, with a median follow-up of 43 months.
Results: The pembrolizumab group demonstrated a higher 2-year DFS rate (67%) compared with controls (52%), suggesting a favorable hazard ratio (0.61) for recurrence or death. Nonetheless, grade 3 or higher adverse events were more common in the pembrolizumab arm (56% vs 31%). Secondary endpoints, including distant disease-free survival and overall survival, also appeared to favor the pembrolizumab arm, but these comparisons were not powered for definitive conclusions.
Conclusions: Neoadjuvant and adjuvant pembrolizumab in combination with radiotherapy and surgery demonstrated a DFS advantage in stage III undifferentiated pleomorphic sarcoma or liposarcoma, reinforcing the potential role of immunotherapy in high-risk settings. However, given the increased incidence of adverse events and the relatively short follow-up for overall survival, cautious interpretation is warranted. Further evidence is required to determine long-term benefits and confirm whether these findings extend to other sarcoma subtypes.
Implications for Practice: These data suggest that incorporating pembrolizumab could be considered in selected patients, particularly those with large, high-grade tumors unresponsive to or unsuitable for traditional chemotherapy. Clinicians must balance the incremental risk of immunotherapy-induced side effects against the observed gains in disease-free survival and the ongoing need for extended follow-up.
Study Strengths and Limitations: Strengths include a multicenter randomized design, focus on a high-risk population, and a robust primary endpoint. Limitations encompass a relatively small sample size, inherent to rare cancers, underpowered subgroup analyses, and absence of long-term survival data. Confirmation of these early signals in larger cohorts and over more extended follow-up periods remains necessary.
Future Research: Additional trials should explore optimal radiotherapy fractionation, potential synergies with cytotoxic or targeted agents, and predictive biomarkers of response. Understanding immune correlates, including circulating tumor DNA and tumor microenvironmental factors, may refine treatment selection and enhance therapeutic outcomes.
Reference: Mowery YM, et al. Safety and efficacy of pembrolizumab, radiation therapy, and surgery versus radiation therapy and surgery for stage III soft tissue sarcoma of the extremity (SU2C-SARC032): an open-label, randomised clinical trial. The Lancet. 2024;404(10467). DOI: http://doi.org/10.1016/S0140-6736(24)01812-9
RCT: Daratumumab Monotherapy Prevents Progression in High-Risk Smoldering Multiple Myeloma
26 Dec, 2024 | 15:44h | UTCBackground: Smoldering multiple myeloma (SMM) is an asymptomatic plasma cell disorder that can progress to active multiple myeloma, especially when risk factors place patients in a high-risk subset. Although daratumumab has been approved for multiple myeloma, no treatments have been approved for high-risk SMM. This study (AQUILA) examined whether subcutaneous daratumumab could prevent or significantly delay progression to symptomatic myeloma.
Objective: To evaluate the effectiveness of subcutaneous daratumumab monotherapy versus active monitoring in prolonging time to disease progression (defined by SLiM–CRAB criteria) or death in patients with high-risk SMM.
Methods: In this open-label phase 3 trial, 390 patients with high-risk SMM were randomly assigned (1:1) to either daratumumab (1800 mg subcutaneously) or active monitoring. Daratumumab was administered weekly for cycles 1–2, every two weeks for cycles 3–6, and then every four weeks for up to 39 cycles (36 months) or until confirmed disease progression. Active monitoring followed the same schedule for disease evaluations without any specific therapy. The primary endpoint was progression-free survival (PFS), assessed by an independent committee. Secondary endpoints included overall survival, response rates, and time to subsequent therapy.
Results: After a median follow-up of 65.2 months, disease progression or death occurred in 34.5% of patients in the daratumumab group compared to 50.5% in the active-monitoring group (HR, 0.49; 95% CI, 0.36–0.67; p<0.001). At five years, the PFS rate was 63.1% with daratumumab and 40.8% with active monitoring. Overall survival was also higher in the daratumumab arm: 93.0% versus 86.9% at five years (HR for death, 0.52; 95% CI, 0.27–0.98). Treatment discontinuation due to adverse events was low (5.7%), and no new safety signals emerged. Grade 3 or 4 adverse events, primarily hypertension (5.7% vs. 4.6%), occurred at similar rates in both arms. Infections of grade 3 or 4 were more frequent with daratumumab (16.1% vs. 4.6%), including COVID-19 pneumonia, yet overall tolerability remained acceptable. Patient-reported outcomes, including quality-of-life measures, were largely preserved in both groups during the study.
Conclusions: Subcutaneous daratumumab monotherapy substantially delayed progression to symptomatic multiple myeloma and improved overall survival among patients with high-risk SMM. The safety profile was consistent with prior daratumumab studies, suggesting a favorable risk–benefit balance. Early intervention with daratumumab may thus alter the disease trajectory for select patients, sparing them from end-organ damage and improving long-term clinical outcomes.
Implications for Practice: While active monitoring has been the standard of care for high-risk SMM, these findings support early therapeutic intervention for patients with multiple high-risk features. Clinicians should remain cautious, however, when generalizing across different risk stratification models. Additional research on optimal treatment durations, combination strategies, and real-world outcomes will further refine patient selection and management of high-risk SMM.
Study Strengths and Limitations: This trial featured robust follow-up (median of over five years) and clear outcome definitions. However, the classification of high-risk features has evolved, and certain populations (e.g., Black patients) were underrepresented. These factors may limit the generalizability of the findings in broader clinical settings.
Future Research: Ongoing trials are investigating alternative dosing schedules, combination regimens (e.g., daratumumab-based quadruplets), and the role of minimal residual disease monitoring to optimize patient outcomes. Additional studies will clarify whether more intense or shorter treatments might maintain efficacy with fewer side effects.
Reference: Dimopoulos MA, Voorhees PM, Schjesvold F, Cohen YC, Hungria V, Sandhu I, Lindsay J, +29, for the AQUILA Investigators. Daratumumab or Active Monitoring for High-Risk Smoldering Multiple Myeloma. New England Journal of Medicine. 2024; DOI: http://doi.org/10.1056/NEJMoa2409029
Three Phase 3, Placebo-Controlled Trials Show Rapid Benefits of Oral Atogepant for Migraine Prevention
26 Dec, 2024 | 12:17h | UTCBackground: Preventive therapies for migraine often require long titration and may take weeks to achieve their full effect. This analysis integrates data from three randomized, placebo-controlled Phase 3 trials (ADVANCE, ELEVATE, PROGRESS) assessing atogepant 60 mg once daily (QD) over 12 weeks, focusing on the first four weeks. A key point is that atogepant was compared only to placebo, not to other well-established migraine preventives.
Objective: To determine whether atogepant provides early efficacy in reducing migraine frequency and improving functional outcomes within the initial weeks of therapy, for both episodic and chronic migraine.
Methods: All three studies enrolled participants aged 18–80 years with a ≥1-year history of migraine. ADVANCE and ELEVATE focused on episodic migraine (EM; 4–14 monthly migraine days), while PROGRESS studied chronic migraine (CM; ≥15 monthly headache days, ≥8 of which met migraine criteria). In ELEVATE, participants had previously failed 2–4 classes of oral migraine preventives. Throughout each trial, patients recorded daily migraine-related data and completed validated functional assessments (AIM-D and EQ-5D-5L). For this pooled analysis, only the atogepant 60 mg QD and placebo arms were examined.
Results: Atogepant recipients had a significantly lower proportion of patients with a migraine day on day 1 in all three trials, suggesting a rapid onset of benefit. Reductions in weekly migraine days (WMDs) emerged as early as week 1 and remained consistently greater than placebo over the first four weeks. Functional measures improved within this same timeframe, with patients on atogepant reporting reductions in activity impairment and enhanced self-rated health. These positive findings were observed in EM (with or without prior prophylaxis failures) and in CM populations.
Conclusions: Atogepant 60 mg QD was linked to early and significant reductions in migraine days, as well as enhancements in physical functioning and daily activities, across three placebo-controlled studies. The data suggest that atogepant may offer clinically meaningful, rapid-onset prophylactic benefits.
Implications for Practice: Clinicians may consider atogepant for patients seeking a preventive migraine therapy that demonstrates a potentially faster impact on symptom frequency and daily functioning. However, direct comparisons with established active treatments are lacking, and appropriate caution in interpreting the early onset of benefit is recommended.
Study Strengths and Limitations: Major strengths include robust, double-blind methodologies and consistent findings across diverse migraine populations. A key limitation is the exclusive use of placebo as the comparator, so the relative advantage over standard preventives remains unknown. The predominantly female and White study cohorts also restrict generalizability.
Future Research: Further investigations should evaluate atogepant in direct comparisons with existing active migraine preventives, examine long-term outcomes, and recruit more diverse populations. Such efforts could better define the therapy’s place in routine migraine care.
Reference: Lipton RB, et al. Early Improvements With Atogepant for the Preventive Treatment of Migraine: Results From 3 Randomized Phase 3 Trials. Neurology. 2025;104(2). DOI: https://doi.org/10.1212/WNL.0000000000210212
Meta-analysis: Incidence Rate Difference of Adverse Events from Canabinoids in Middle-Aged and Older Adults
25 Dec, 2024 | 12:19h | UTCBackground: Growing evidence suggests that cannabinoid-based medicines (CBMs) are increasingly prescribed to individuals aged 50 years and above for various clinical conditions. While these agents may offer therapeutic benefits, questions remain about the incidence of adverse events (AEs), particularly in older adults with multiple comorbidities. This systematic review and meta-analysis aims to quantify the incidence rate difference (IRD) of AEs and determine whether weekly doses of delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are associated with any dose-dependent increase in risk.
Objective: To evaluate whether adults aged ≥50 years exposed to CBMs, including THC-alone formulations and THC combined with CBD, experience a higher incidence of AEs than controls, and to assess how variations in weekly THC and CBD doses might affect AE rates.
Methods: Researchers searched MEDLINE, PubMed, EMBASE, CINAHL, PsychInfo, Cochrane Library, and ClinicalTrials.gov from January 1, 1990, to June 12, 2023. Randomized clinical trials involving middle-aged and older adults (mean age ≥50 years) using medicinal CBMs for all indications were included. Data on common and serious AEs, withdrawals, and deaths were extracted and pooled using a random-effects model. Further meta-regression analyses examined THC and CBD weekly doses as predictors of AEs in THC-only and THC:CBD trials.
Results: Fifty-eight randomized clinical trials (n=6611) met inclusion criteria, with 3450 participants receiving CBMs. Compared to controls, individuals on THC-alone experienced significantly higher incidence of dizziness, somnolence, impaired coordination, dissociative symptoms, and dry mouth, often in a dose-dependent manner. Similarly, THC:CBD combinations increased nausea, vomiting, fatigue, dizziness, and disorientation. The incidence of serious AEs, withdrawals, or mortality did not differ significantly between CBM and control groups, although neurological or psychiatric side effects were more pronounced with higher THC doses.
Conclusions: THC-containing CBMs can provoke dose-related gastrointestinal, neurological, and psychiatric adverse events, posing additional risks in older adults susceptible to falls and cognitive disturbances. However, the meta-analysis found no significant increases in serious AEs or deaths. Clinicians should weigh potential benefits against the likelihood of common side effects, especially when prescribing higher THC doses or combining cannabinoids with other medications frequently used by older patients.
Implications for Practice:
- Physicians should exercise caution when initiating or escalating THC-based therapies in middle-aged and older adults, monitoring for neurological or psychiatric AEs.
- Using lower THC doses, titrating gradually, and adding CBD may mitigate some side effects.
- Though severe AEs are uncommon, vigilance is warranted in individuals with complex medication regimens.
Study Strengths and Limitations:
- Strength: This review merges diverse clinical conditions and provides a comprehensive assessment of THC vs. THC:CBD. Its large pooled population allows for more precise IRD estimates.
- Limitation: Short treatment durations in many trials limit understanding of long-term toxicity, and some studies lacked rigorous reporting of randomization and outcome measures, potentially introducing bias.
Future Research:
- Longer-duration trials focused on older populations are needed to clarify chronic safety profiles.
- Studies exploring drug-drug interactions between CBMs and medications commonly prescribed to older adults will further elucidate real-world tolerability.
Reference: Velayudhan L, Pisani S, Dugonjic M, McGoohan K, Bhattacharyya S. Adverse events caused by cannabinoids in middle aged and older adults for all indications: a meta-analysis of incidence rate difference. Age and Ageing. 2024;53(11):afae261. DOI: https://doi.org/10.1093/ageing/afae261
Bayesian Network Meta-Analysis: Chlorpromazine IV/IM Emerges as a Top Choice for Acute Migraine Relief in the ED
25 Dec, 2024 | 11:18h | UTCBackground: Acute migraine is a prevalent cause of emergency department (ED) visits, necessitating prompt pain control. Although numerous drugs are available, there is debate about the most effective and safest options. Traditional pairwise meta-analyses fail to capture all treatment comparisons in a single framework, making network meta-analyses, particularly Bayesian, an appealing approach to inform clinical decision-making.
Objective: This systematic review and Bayesian network meta-analysis aimed to compare multiple pharmacologic therapies—single agents or combinations—for acute migraine relief in adults presenting to the ED. The goal was to identify those most likely to achieve adequate pain relief, reduce rescue medication use, and minimize significant adverse reactions.
Methods: The authors searched MEDLINE, Embase, and Web of Science from inception to February 9, 2024, for randomized controlled trials comparing any pharmacologic therapy to another or to placebo in ED patients with migraine. Four primary outcomes were analyzed: (1) adequate pain relief at two hours, (2) change in pain intensity at one hour, (3) need for rescue drug at two hours, and (4) significant adverse reaction (eg, sedation, akathisia, hypotension).
Results: Twenty-four to twenty-seven trials contributed to each outcome network. Chlorpromazine IV/IM was ranked highest for adequate pain relief (SUCRA=87.3%) and also significantly reduced the need for rescue medication (SUCRA=93.2%). Ibuprofen IV and valproate IV emerged among the least effective for pain relief, while dexamethasone IV was the most probable to cause fewer serious adverse reactions (SUCRA=79.5%). However, most comparisons were of low or very low certainty, limiting the strength of the findings.
Conclusions: Chlorpromazine IV/IM appears among the most effective single agents for acute migraine in the ED, although it may carry higher risks of sedation or hypotension. Certain analgesics (eg, ibuprofen IV, valproate IV, and possibly ketorolac IV/IM) demonstrated lower efficacy. Due to variability in trial size, dosing, and participant characteristics, the overall certainty of evidence remains limited.
Implications for Practice: Clinicians may consider parenteral chlorpromazine for rapid migraine relief, balancing its adverse event profile with potential efficacy. Dexamethasone’s lower probability of serious side effects could make it a complementary option. The findings highlight the need for individualized treatment, taking into account patient comorbidities and preferences.
Study Strengths and Limitations: This network meta-analysis offers a broad comparative perspective on diverse pharmacologic interventions for ED-based migraine management. Nonetheless, there is notable heterogeneity in study methodologies, small sample sizes, and sparse direct comparisons for many interventions, all of which reduce certainty in the estimates.
Future Research: Larger, more standardized trials are needed to confirm these results and directly compare drugs like chlorpromazine, prochlorperazine, and metoclopramide-NSAID combinations. Rigorous safety reporting is crucial to clarify adverse reaction risks for various agents, especially those with less available evidence.
Reference: deSouza IS, Anthony N, Thode H Jr, et al. Effectiveness and Safety of Pharmacologic Therapies for Migraine in the Emergency Department: A Systematic Review and Bayesian Network Meta-analysis. Annals of Emergency Medicine. DOI: http://doi.org/10.1016/j.annemergmed.2024.11.004
RCT: Levofloxacin for the Prevention of Multidrug-Resistant Tuberculosis in Vietnam
24 Dec, 2024 | 12:53h | UTCBackground:
Multidrug-resistant (MDR) and rifampin-resistant tuberculosis pose significant global health challenges. Preventing active disease among contacts exposed to resistant strains is critical, yet limited evidence exists on targeted chemopreventive interventions. This study investigated whether a six-month course of daily levofloxacin could reduce the incidence of bacteriologically confirmed tuberculosis among household contacts of individuals with confirmed MDR or rifampin-resistant tuberculosis in Vietnam.
Objective:
To assess if levofloxacin prophylaxis decreases the 30-month incidence of active tuberculosis among high-risk contacts. Primary endpoints included bacteriologically confirmed disease, and secondary outcomes encompassed adverse events, mortality, and development of fluoroquinolone-resistant Mycobacterium tuberculosis.
Methods:
Researchers conducted a double-blind, placebo-controlled, randomized trial. Eligible participants were household contacts of persons who had started MDR tuberculosis treatment within the previous three months, had a positive tuberculin skin test or immunosuppressive condition, and showed no clinical or radiographic signs of active disease. Enrolled individuals received weight-based oral levofloxacin (up to 750 mg/day) or an identical placebo for 180 days. Monthly visits supported adherence and monitored adverse events. Participants underwent follow-up visits every six months until 30 months for tuberculosis screening, chest radiography, and sputum testing where indicated.
Results:
Of 2041 randomized contacts, 1995 (97.7%) completed 30 months of follow-up or reached a primary endpoint. Confirmed tuberculosis was diagnosed in 6 participants (0.6%) in the levofloxacin group and 11 (1.1%) in the placebo group (incidence rate ratio, 0.55; 95% CI, 0.19–1.62), a difference that did not achieve statistical significance. Severe (grade 3 or 4) adverse events were infrequent in both groups, while mild adverse events were more common with levofloxacin (31.9% vs. 13.0%). Acquired fluoroquinolone resistance was not detected.
Conclusions:
Daily levofloxacin for six months showed a numerically lower incidence of tuberculosis than placebo, but the difference was not statistically significant due to lower-than-expected case counts. Treatment was generally well tolerated; however, higher discontinuation rates occurred among levofloxacin recipients, often due to mild musculoskeletal complaints. Further studies may clarify the role of fluoroquinolone-based regimens in preventing MDR tuberculosis across diverse epidemiologic contexts.
Implications for Practice:
These findings suggest that levofloxacin prophylaxis could benefit contacts at high risk of MDR tuberculosis, albeit with caution regarding adherence challenges and low-grade side effects. Broader implementation would require diligent screening, consideration of background fluoroquinolone resistance, and strategies to manage mild adverse events that could undermine treatment completion.
Study Strengths and Limitations:
Strengths include a rigorous double-blind, placebo-controlled design, nearly complete follow-up, and thorough exclusion of prevalent tuberculosis at baseline. Limitations involve an unexpectedly low incidence of confirmed disease, limiting statistical power, and a study population with low HIV prevalence, which may reduce generalizability.
Future Research:
Further research is necessary to confirm these findings in diverse settings, explore alternative or shorter regimens (including newer agents like delamanid), and investigate optimal approaches for patients with fluoroquinolone-resistant strains. The long-term impact on transmission dynamics and microbiome shifts also warrants additional investigation.
Guideline: Metformin to Prevent Antipsychotic-Induced Weight Gain
23 Dec, 2024 | 20:55h | UTCIntroduction:
This guideline was developed to address a pressing need for strategies to prevent antipsychotic-induced weight gain (AIWG), a frequent and troubling adverse effect of treatment in individuals with severe mental illness (SMI). Although metformin has shown consistent benefits in mitigating weight gain when initiated alongside antipsychotics, clinical uptake remains limited. The guideline follows the AGREE II framework and synthesizes both randomized and observational research, including Cochrane and meta-analytic data. The primary objective is to outline explicit indications, dosing approaches, and duration for using metformin to avert AIWG.
Key Recommendations:
- Co-initiation With High-Risk Agents: In patients requiring higher-risk antipsychotics (olanzapine, clozapine), start metformin simultaneously. Evidence suggests that concurrent treatment may lessen weight gain by 3 to 5 kg in the early months, potentially yielding greater benefits over time.
- Co-initiation With Medium-Risk Agents: For individuals prescribed quetiapine, paliperidone, or risperidone who have at least one cardiometabolic risk factor (such as diabetes, prediabetes, hypertension, or BMI above 25) or who are 10 to 25 years old, begin metformin at antipsychotic initiation to curb rapid weight changes.
- Initiation During the First Year: If, at any point in the first year of antipsychotic treatment, weight gain exceeds 3% over baseline, consider adding metformin regardless of the antipsychotic being used.
- Titration Schedule and Safety: The guideline advises starting at 500 mg once daily, then moving to 500 mg twice daily after about two weeks, with subsequent increases every two weeks up to 1 g twice daily (2 g/day) as tolerated. Metformin must be discontinued if lactic acidosis is suspected, if BMI falls below 20, or if the antipsychotic is stopped. Avoid its use in harmful alcohol consumption.
- Additional Treatment Options: In cases of obesity (BMI ≥30) or comorbid metabolic disorders, clinicians should consider adding glucagon-like peptide-1 receptor agonists (GLP-1) where available. If cost, supply, or access is limited, metformin remains a practical alternative.
Conclusion:
This is the first evidence-based guideline focused on preventing AIWG by starting metformin at the time of antipsychotic initiation or upon early weight gain signs. By reducing the magnitude of weight increase, metformin may alleviate health risks tied to obesity, as well as psychological distress and nonadherence to treatment. Implementing the guideline involves continuous weight monitoring, structured dose adjustments, and shared decision-making. Ensuring clear communication about benefits and potential side effects will be crucial for sustaining adherence and improving patient outcomes.
Reference:
Carolan A, Hynes-Ryan C, Agarwal SM, Bourke R, Cullen W, Gaughran F, Hahn MK, Krivoy A, Lally J, Leucht S, et al. Metformin for the Prevention of Antipsychotic-Induced Weight Gain: Guideline Development and Consensus Validation. Schizophrenia Bulletin. 2024; sbae205.
DOI: https://doi.org/10.1093/schbul/sbae205
Additional Commentaries:
- Psychiatric News Alert: https://alert.psychnews.org/2024/12/new-guideline-advises-metformin-to.html
- Zagorski N. Metformin May Reduce Weight Gain in Youth Taking Antipsychotics. Psychiatric News. 2024; 59(01). https://psychiatryonline.org/doi/full/10.1176/appi.pn.2024.01.1.22
Guideline: Doxycycline Postexposure Prophylaxis to Reduce Bacterial STI Incidence in High-Risk Populations
19 Dec, 2024 | 22:32h | UTCIntroduction: This summary presents key recommendations from the 2024 Centers for Disease Control and Prevention (CDC) guidelines on using doxycycline postexposure prophylaxis (doxyPEP) to prevent bacterial sexually transmitted infections (STIs), including syphilis, gonorrhea, and chlamydia. Targeting men who have sex with men (MSM) and transgender women with at least one bacterial STI in the past 12 months, these guidelines aim to reduce recurrence rates and improve sexual health outcomes through timely prophylactic intervention.
Key Recommendations:
- Offer doxyPEP counseling to MSM and transgender women with a recent bacterial STI history, addressing the benefits, harms, and uncertainties of prophylactic doxycycline use.
- Advise eligible patients to take a single 200 mg dose of doxycycline as soon as possible (ideally within 72 hours) following condomless oral, anal, or vaginal sexual exposure to reduce their subsequent STI risk.
- Reinforce periodic screening (every 3–6 months) for STI markers, including syphilis and HIV serologies, as well as nucleic acid amplification tests for gonorrhea and chlamydia at relevant anatomical sites.
- Integrate doxyPEP into comprehensive sexual health services that include risk-reduction counseling, condom use, recommended immunizations, and linkage to HIV preexposure prophylaxis (PrEP) or HIV care, thereby enhancing overall prevention strategies.
- Consider extending doxyPEP to other high-risk groups, including heterosexual individuals with recurrent STIs, guided by clinical judgment and shared decision-making.
- Monitor and address adverse events, particularly gastrointestinal symptoms, and acknowledge the potential for antimicrobial resistance. Continued vigilance is warranted given the risk of resistance in commensal flora and key STI pathogens, such as Neisseria gonorrhoeae.
- Assess social and ethical dimensions of doxyPEP implementation, ensuring equitable access and minimizing potential harms, including stigma or intimate partner violence related to prophylaxis disclosure.
Conclusion: Implementing doxyPEP for MSM and transgender women who have experienced a recent bacterial STI can substantially lower the incidence of recurrent infections. By combining prophylactic doxycycline with routine surveillance, comprehensive preventive services, and careful consideration of resistance patterns, clinicians may enhance patient care and strengthen STI control efforts. Further investigation is needed to establish efficacy in cisgender women, transgender men, nonbinary persons, and other populations at risk. Longer-term, population-based studies focused on antimicrobial resistance and community-level effects will help guide sustainable and equitable use of this prevention strategy.
Review: New and Emerging Treatments for Major Depressive Disorder
19 Dec, 2024 | 22:21h | UTCIntroduction: This is a summary of a review on new and emerging treatments for major depressive disorder (MDD), a globally prevalent condition with substantial morbidity and socioeconomic burden. While conventional monoaminergic antidepressants often provide benefit, many patients do not achieve remission, leading to treatment-resistant depression. Novel approaches, including psychedelics (psilocybin, ketamine/esketamine), anti-inflammatory agents, opioid modulators, neuropeptides, botulinum toxin injections, and various neuromodulatory techniques (newer forms of transcranial magnetic stimulation and light-based therapies), are under investigation. This summary highlights their potential efficacy, tolerability, and current limitations.
Key Recommendations:
- Ketamine and Esketamine: Consider these as adjunctive treatments for patients with refractory MDD, given their rapid antidepressant and anti-suicidal effects. Carefully monitor for blood pressure elevations and potential habituation. Long-term cost-effectiveness and sustained benefits remain uncertain.
- Psychedelics (Psilocybin, Ayahuasca): Psilocybin-assisted therapy may produce rapid symptom improvement, but scalability, required therapeutic support, and possible increases in suicidality raise concern. Ayahuasca shows early promise, yet lacks robust long-term data and standardized administration protocols.
- Neuromodulation (rTMS, TBS, Accelerated TMS, Light Therapy): Repetitive transcranial magnetic stimulation (rTMS) and its variants (theta burst stimulation, accelerated protocols) demonstrate modest efficacy with good tolerability. Bright light therapy may enhance neuromodulation outcomes. Optimal protocols and positioning in treatment pathways are not well established.
- Anti-inflammatory and Other Agents: Preliminary findings suggest potential adjunctive roles for minocycline, NSAIDs, statins, omega-3 fatty acids, and a buprenorphine-samidorphan combination. However, larger, high-quality trials are needed to confirm their efficacy and safety profiles.
- Onabotulinumtoxin A: A single glabellar injection may confer antidepressant effects, but the underlying mechanism and durability are unclear. Methodological issues, including difficulties with blinding, limit strong recommendations.
- More Invasive Interventions (DBS, MST): Deep brain stimulation (DBS) and magnetic seizure therapy (MST) are invasive approaches supported by limited evidence, restricting their use to highly refractory cases. The balance of benefit, risk, and resource intensity remains uncertain.
Conclusion: Although these emerging treatments offer potential avenues beyond traditional antidepressants, most remain investigational. Key challenges include limited comparative data, uncertain long-term outcomes, and scaling difficulties. Further rigorous research, including head-to-head trials, long-term follow-ups, and clarity regarding optimal psychotherapeutic support, is required. As evidence matures, these novel interventions may become more integrated into standard care, potentially improving outcomes for patients with difficult-to-treat MDD.