Internal Medicine

Meta-Analysis: Beta-Blockers Show No Mortality Reduction in Myocardial Infarction with Preserved Ejection Fraction

15 Jan, 2025 | 13:06h | UTC

Background: Beta-blockers have been a cornerstone of care following myocardial infarction (MI), primarily benefiting patients with reduced left ventricular ejection fraction (LVEF). However, the evidence supporting their routine use in patients with a preserved LVEF remains inconsistent, especially in the context of current revascularization strategies and guideline-directed medical therapy.

Objective: This systematic review and meta-analysis aimed to determine whether beta-blockers confer mortality or cardiovascular event benefits among patients with MI and a preserved LVEF in the contemporary reperfusion era.

Methods: Researchers conducted a PRISMA-compliant search of PubMed and EMBASE, identifying randomized controlled trials (RCTs) that compared long-term beta-blocker therapy versus no beta-blocker therapy in patients with MI and LVEF ≥40%. Three RCTs (total n = 9512) were included. The primary outcome was a composite of all-cause mortality and recurrent MI. Secondary outcomes included all-cause mortality, cardiovascular mortality, MI, and stroke. Risk ratios (RRs) with 95% confidence intervals (CIs) were pooled using a random-effects model. Heterogeneity was assessed via I² statistics. Risk of bias was evaluated with the Cochrane RoB 2.0 tool, and the quality of evidence was reviewed according to GRADE recommendations.

Results: Across the three RCTs, beta-blockers did not significantly reduce the composite of all-cause mortality and MI (RR 0.97, 95% CI: 0.84–1.12; p = 0.671; I² = 0%). Secondary endpoints also showed no significant effect: all-cause mortality (RR 0.96, 95% CI: 0.79–1.17), cardiovascular mortality (RR 1.22, 95% CI: 0.87–1.72), recurrent MI (RR 0.97, 95% CI: 0.78–1.19), and stroke (RR 0.96, 95% CI: 0.66–1.38). Sensitivity analyses, including leave-one-out approaches, yielded consistent findings. There was minimal heterogeneity overall, suggesting stable results. Although one trial strictly excluded patients with LVEF <50%, others allowed mildly reduced LVEF (40–50%), highlighting variability in definitions of “preserved” function.

Conclusions: In contemporary patients with MI and preserved LVEF, beta-blockers did not lower overall mortality, recurrent MI, or stroke. These data suggest that, under current revascularization practices and adjunctive therapies, beta-blockers may not offer the same advantage observed in earlier trials among individuals without significant systolic dysfunction.

Implications for Practice: Clinicians managing MI in patients with preserved LVEF should carefully weigh potential side effects and the absence of clear mortality benefit when deciding on beta-blocker therapy. While widely prescribed, beta-blockers may not improve outcomes for this subgroup in modern practice. Guidelines that currently reflect broad beta-blocker use may need refinement to account for these latest findings.

Study Strengths and Limitations: Major strengths include a focus on contemporary, randomized evidence and rigorous risk-of-bias assessment. The analysis is limited by the small number of RCTs, variable definitions of “preserved” ejection fraction, and a predominantly male study population. Underrepresentation of women and patients with borderline LVEF reduces generalizability to broader clinical cohorts.

Future Research: Ongoing RCTs (such as REBOOT-CNIC, BETAMI, and DANBLOCK) will provide further insight into the impact of beta-blockers in patients with normal or mildly reduced LVEF, particularly regarding safety profiles (e.g., bradyarrhythmias, hypotension, respiratory exacerbations) and subgroup analyses by sex. These data may inform more nuanced guideline recommendations.

Reference: Sabina M, Shah S, Grimm M, Daher JC, Campillo P, Boozo MB, Al-Abdouh A, Abusnina W, D’Ascenzo F, Bizanti A. Beta-Blockers in Patients with Myocardial Infarction and Preserved Left Ventricular Ejection: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Journal of Clinical Medicine. 2025;14(1):150. DOI: https://doi.org/10.3390/jcm14010150

 

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RCT: Empagliflozin Lowers Urinary Supersaturation in Nondiabetic Adults With Calcium and Uric Acid Kidney Stones

15 Jan, 2025 | 12:03h | UTC

Background: Kidney stones represent a major health challenge worldwide, with calcium-based (calcium oxalate or phosphate) and uric acid (UA) stones accounting for most cases. Despite multiple preventive measures—including hydration, dietary modification, and, in certain cases, pharmacotherapy—recurrence rates remain high. Recent retrospective analyses suggest sodium-glucose cotransporter 2 (SGLT2) inhibitors may reduce stone episodes in patients with type 2 diabetes. These agents could theoretically lower stone risk by promoting urinary citrate excretion, altering urine pH, and enhancing UA clearance. However, prospective data are lacking in nondiabetic individuals. This phase 2, single-center, double-blind, placebo-controlled, crossover study (SWEETSTONE) explored whether empagliflozin (25 mg daily) modifies urinary relative supersaturation ratios (RSRs)—a validated surrogate of stone risk—in adults without diabetes who have a history of either calcium or UA stones.

Objective: To determine if empagliflozin significantly reduces RSRs for calcium oxalate (CaOx), calcium phosphate (CaP), and UA in nondiabetic adults with recurrent kidney stones and to assess short-term safety.

Methods: A total of 53 participants (28 calcium stone formers, 25 UA stone formers) were randomized to empagliflozin 25 mg once daily or placebo for two weeks, followed by a 2–6-week washout, then crossed over to the alternative treatment. Primary outcomes were changes in RSR CaOx, RSR CaP, and RSR UA. Secondary measures included 24-hour urine pH, citrate, calcium, and UA, as well as key blood parameters. Analyses were performed separately for calcium and UA stone groups using a generalized linear mixed effects model. The per protocol set was used for the main analysis, with additional intention-to-treat assessments for confirmation.

Results: In calcium stone formers, empagliflozin lowered RSR CaP by 36% (95% CI −48% to −21%; p<0.001) compared with placebo but did not significantly change RSR CaOx. Uric acid supersaturation rose modestly, yet nonsignificantly. Among UA stone formers, empagliflozin reduced RSR UA by 30% (95% CI −44% to −12%; p=0.002), with no significant effect on RSR CaOx or RSR CaP. Both groups showed substantial increases in 24-hour urine citrate (60% for calcium stones, 40% for UA stones) and marked reductions in plasma UA levels. Urine calcium rose in some calcium stone formers, but no severe adverse events were reported during the study.

Conclusions: Short-term treatment with empagliflozin produced meaningful decreases in key urinary supersaturation indices among nondiabetic adults with calcium or UA stones, while exhibiting an acceptable safety profile. These favorable laboratory changes offer mechanistic promise but do not establish definitive evidence that long-term stone recurrence is reduced.

Implications for Practice: Although the pronounced improvement in urinary lithogenic profiles is encouraging, it remains unclear whether these shifts will translate into sustained reductions in actual stone formation. Consequently, clinicians should be cautious about recommending off-label SGLT2 inhibition for stone prevention solely on the basis of these short-term biochemical improvements. Larger, longer-duration trials with clinical endpoints (i.e., stone recurrence) are warranted before SGLT2 inhibitors can be broadly endorsed for this indication. In addition, practical considerations—such as cost, insurance coverage, and potential off-target effects—must be weighed in individualized clinical decisions.

Study Strengths and Limitations: Strengths include the randomized crossover design and distinct analyses for calcium and UA stone phenotypes. Nevertheless, the sample size was modest, and the treatment duration too brief to capture definitive impacts on stone recurrence. The predominance of white male participants also limits generalizability to more diverse populations.

Future Research: Extended follow-up is crucial to determine the long-term clinical effectiveness of empagliflozin in preventing stone events. Future work should also explore potential mechanisms in larger cohorts, assess cost-effectiveness in real-world settings, and evaluate whether other SGLT2 inhibitors elicit comparable effects.

Reference: Anderegg MA, Schietzel S, Bargagli M, et al. Empagliflozin in nondiabetic individuals with calcium and uric acid kidney stones: a randomized phase 2 trial. Nature Medicine (2025). DOI: https://doi.org/10.1038/s41591-024-03330-x

 

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Diagnosis and Management of Eosinophilic Esophagitis: Updated ACG Clinical Guideline Summary

14 Jan, 2025 | 13:46h | UTC

Introduction: This summary highlights the updated American College of Gastroenterology (ACG) Clinical Guideline on eosinophilic esophagitis (EoE), a chronic, immune-mediated disease of the esophagus characterized by esophageal eosinophilia and clinical symptoms of esophageal dysfunction. Over the last decade, the incidence and prevalence of EoE have increased significantly. This guideline incorporates new diagnostic strategies, therapeutic advances, and monitoring practices, aiming to improve patient outcomes and minimize disease complications such as strictures, food impactions, and impaired quality of life. The document underscores the importance of assessing both the inflammatory and fibrostenotic components of EoE through endoscopy, histopathology, and symptom evaluation.

Key Recommendations:

• Diagnosis:
  • Diagnose EoE when patients present with symptoms of esophageal dysfunction and at least 15 eosinophils per high-power field (eos/hpf) on esophageal biopsies, after exclusion of other causes of esophageal eosinophilia.
  • Use a systematic scoring tool such as the EoE Endoscopic Reference Score (EREFS) to assess edema, rings, exudates, furrows, and strictures at every endoscopy.
  • Obtain at least six esophageal biopsies from two or more levels (e.g., distal and proximal) to minimize diagnostic miss rates; quantify peak eosinophil counts in each specimen.
• Pharmacologic Therapy:
  1. Proton Pump Inhibitors (PPIs):
     • Consider high-dose PPIs (e.g., twice daily) as a first-line treatment option. Although originally used for acid suppression, PPIs also reduce eotaxin-3 expression and improve esophageal barrier function in EoE.
     • Maintain therapy long term in patients who respond, as discontinuation frequently leads to disease recurrence.
  2. Topical Corticosteroids (Swallowed Steroids):
     • Budesonide or fluticasone can be delivered via specially formulated suspensions/tablets or by swallowing inhaler medication.
     • Expect histologic remission rates of around 60%–70%.
     • Oral/esophageal candidiasis is the most common adverse event. Routine adrenal suppression testing is generally not necessary for short-term use.
  3. Dietary Elimination:
     • Empiric elimination diets (e.g., 2-food or 6-food elimination) help identify specific food triggers. Histologic remission rates can exceed 70%, particularly with the 6-food approach.
     • Less-restrictive diets (e.g., milk-only elimination) may be tried first (the “step-up” approach).
     • Do not rely on currently available skin prick or Ig-based tests to guide elimination diets, as these have poor predictive value for EoE triggers.
  4. Biologic Therapy:
     • Dupilumab (anti–IL-4 receptor alpha) is recommended in adolescents and adults (≥12 years, ≥40 kg) and is now approved for children as young as 1 year (≥15 kg) with moderate to severe, PPI-refractory EoE. Expect significant histologic, endoscopic, and symptom improvements in most patients, along with an overall favorable safety profile.
     • Other biologics (e.g., cendakimab, benralizumab, mepolizumab) remain under investigation; current data are insufficient for routine clinical use.
  5. Esophageal Dilation:
     • Perform endoscopic dilation to treat symptomatic strictures or narrow-caliber esophagi. Dilation reduces dysphagia promptly but does not alter the underlying inflammation.
     • Combine dilation with anti-inflammatory therapy to address the disease’s inflammatory component and help prevent recurrent stricture formation.
• Maintenance and Monitoring:
  • Because EoE is chronic, continue effective therapy over the long term. Abrupt cessation of treatment often leads to relapses in symptoms and inflammation.
  • Evaluate treatment response by assessing symptoms, endoscopic findings (e.g., EREFS), and histopathology (peak eosinophil counts).
  • A target of <15 eos/hpf and near-normal endoscopic appearance (EREFS ≤2) is commonly used to define remission, although some patients aim for histologic normalization.
  • In children, ensure regular assessment of growth, development, and feeding behaviors. Referral to a nutritionist or feeding therapist is recommended if feeding difficulties or failure to thrive are present.

Conclusion: These updated ACG guidelines underscore the importance of a comprehensive, individualized approach to EoE that encompasses diagnosis, treatment of the inflammatory state, dilation of fibrotic strictures, and ongoing monitoring to maintain long-term remission. The introduction of biologics (particularly dupilumab) expands treatment options for patients nonresponsive to PPIs or topical steroids. Clinicians should adopt a structured assessment strategy—integrating clinical history, endoscopic scoring, and histological evaluation—to guide therapy selection, document treatment response, and prevent complications. With improved understanding of disease pathogenesis and evolving therapeutic tools, outcomes for patients with EoE are expected to continue to improve.

Reference: Dellon ES, Muir AB, Katzka DA, Shah SC, Sauer BG, Aceves SS, Furuta GT, Gonsalves N, Hirano I. ACG Clinical Guideline: Diagnosis and Management of Eosinophilic Esophagitis. The American Journal of Gastroenterology. 2025;120(1):31–59. DOI: https://doi.org/10.14309/ajg.0000000000003194

 

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AGA Clinical Practice Update on Potassium-Competitive Acid Blockers for Foregut Disorders

14 Jan, 2025 | 11:20h | UTC

Introduction: This summary presents the key points of a recently published American Gastroenterological Association (AGA) Clinical Practice Update that reviews the role of potassium-competitive acid blockers (P-CABs) in managing acid-related foregut disorders. P-CABs offer a unique mechanism of action compared with proton pump inhibitors (PPIs) and histamine_2-receptor antagonists, potentially delivering more rapid and prolonged acid suppression. The aim of this review is to provide clinicians with evidence-based guidance on P-CAB use in gastroesophageal reflux disease (GERD), Helicobacter pylori (HP) infection, and peptic ulcer disease (PUD), clarifying their benefits, limitations, and potential place in therapy.

Key Recommendations:

1. Overall Use of P-CABs: Clinicians should generally avoid using P-CABs as first-line therapy for acid-related conditions unless there is proven clinical superiority over PPIs. Factors such as higher costs, more limited availability, and less comprehensive long-term safety data often outweigh the advantages of P-CABs, particularly for milder disease.
2. Cost-Effectiveness: Current U.S. costs for P-CABs may not justify routine first-line use, even if modest clinical benefits exist compared with double-dose PPIs. Long-term data on cost-effectiveness and safety remain limited.
3. Nonerosive GERD: P-CABs are not recommended as initial treatment for heartburn without endoscopic findings (uninvestigated GERD) or nonerosive reflux disease. Clinicians may consider P-CABs for patients who have confirmed acid-related reflux and show inadequate response to twice-daily PPI therapy.
4. On-Demand Therapy: Rapid onset of P-CABs suggests potential utility in on-demand regimens for patients previously responsive to acid suppression. While limited data show efficacy compared to placebo, further trials against PPIs and histamine_2-receptor antagonists are needed before making firm recommendations.
5. Mild Erosive Esophagitis (LA Grade A/B): For Los Angeles classification (LA) grade A/B erosive esophagitis (EE), standard PPIs remain first-line treatment. P-CABs may be an option for patients whose esophagitis persists despite optimal PPI therapy, but initial evidence does not support routine, front-line use.
6. Severe Erosive Esophagitis (LA Grade C/D): In more advanced EE, P-CABs can be considered for healing and maintenance, as some data suggest superior efficacy compared with standard-dose PPI. However, the lack of comparative trials with high-dose PPIs and the higher cost of P-CABs complicate their routine use as first-line therapy in severe disease.
7. HP Eradication: P-CAB–based regimens for H pylori treatment often show higher or noninferior cure rates compared with PPI-based therapies, particularly in the presence of clarithromycin resistance. The more potent and prolonged acid suppression may enhance antibiotic efficacy, supporting the use of P-CABs in most patients with HP infection.
8. Peptic Ulcer Disease Treatment and Prophylaxis: Current evidence indicates that P-CABs are noninferior to PPIs for ulcer healing and prevention of recurrent ulcers in patients requiring aspirin or nonsteroidal anti-inflammatory drugs. However, in light of their higher cost and similar clinical outcomes, P-CABs should not replace PPIs as first-line therapy unless patients fail PPI regimens.
9. Ulcer Bleeding: Although data are preliminary, P-CABs may be useful following endoscopic hemostasis in high-risk ulcer bleeding. Their rapid and potent acid suppression suggests they could match or exceed high-dose PPI efficacy, but more robust comparative trials are needed.

Conclusion: Potassium-competitive acid blockers represent a valuable therapeutic option in selected patients who do not respond adequately to traditional PPIs or who have complex acid-related conditions (such as severe erosive esophagitis or antibiotic-resistant H pylori). While their more rapid onset of action and prolonged effect can be advantageous, the limited availability of long-term safety data, cost considerations, and lack of substantial clinical superiority over standard or double-dose PPIs in many indications currently limit widespread adoption. Further investigations are needed to establish cost-effectiveness, clarify safety profiles, and identify specific patient populations most likely to benefit from P-CABs.

Reference: Patel A, Laine L, Moayyedi P, Wu J. AGA Clinical Practice Update on Integrating Potassium-Competitive Acid Blockers Into Clinical Practice: Expert Review. Gastroenterology. 2024;167(6):1228–1238. https://doi.org/10.1053/j.gastro.2024.06.038

 

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Comprehensive Glycemic Goals and Hypoglycemia Management in Diabetes: 2025 ADA Standards

13 Jan, 2025 | 12:39h | UTC

Introduction: This summary provides key points from the American Diabetes Association’s (ADA) 2025 guidance on glycemic targets, monitoring, and hypoglycemia management in type 1 and type 2 diabetes. It emphasizes individualized A1C goals, the clinical use of continuous glucose monitoring (CGM)—a system that measures interstitial glucose levels throughout the day—and the prevention and treatment of hypoglycemia. The main objective is to help clinicians optimize glucose control, reduce acute and chronic complications, and improve patient outcomes.

Key Recommendations:

1. Individualized Glycemic Targets
   • An A1C goal of <7% (<53 mmol/mol) is generally appropriate for many nonpregnant adults without frequent or severe hypoglycemia.
   • Lower or higher A1C goals may be appropriate in specific situations. For example:
     • Comorbidities: Individuals with significant cardiovascular disease, kidney dysfunction, or other conditions may benefit from a more conservative A1C target (e.g., <8%), balancing the risks of intensive treatment (such as hypoglycemia) against the benefits of tighter control.
     • Hypoglycemia Risk: Those with a history of severe or frequent hypoglycemia might need to relax A1C targets to avoid life-threatening low glucose episodes. In contrast, highly motivated patients with robust hypoglycemia awareness and access to advanced monitoring tools could safely aim for A1C closer to 6%.
     • Life Expectancy: Younger, healthier individuals with fewer complications can pursue tighter A1C targets because they have time to benefit from reduced microvascular and macrovascular risks. Older adults or those with serious illnesses and limited life expectancy may adopt higher A1C goals to reduce treatment burden and prevent hypoglycemic events.
2. Monitoring Glycemic Status
   • A1C Testing: Measure at least twice a year when glucose levels are stable and quarterly (or more often) when adjusting therapy or when targets are not met. If A1C is unreliable (e.g., hemoglobin variants), fructosamine or glycated albumin may be used.
   • Continuous Glucose Monitoring (CGM): CGM devices automatically measure glucose day and night, providing valuable data for clinical decision-making. Key CGM metrics include:
     • Time in Range (TIR): The percentage of readings between 70 and 180 mg/dL, with >70% as a common target in most nonpregnant adults.
     • Time Below Range: Ideal is <4% of readings under 70 mg/dL and <1% for older adults.
     • Time Above Range: Common goals are <25% for mild hyperglycemia and <5% for severe hyperglycemia, though this may vary with age and comorbidities.
   • When refining diabetes therapies, review CGM reports (e.g., ambulatory glucose profiles) to identify patterns of high or low glucose. This helps personalize adjustments to medications, diet, and exercise. For instance, consistent nocturnal hypoglycemia might prompt a reduction or timing change of basal insulin, while excessive morning hyperglycemia may require earlier medication dosing or lifestyle interventions.
3. Hypoglycemia Prevention and Management
   • Classification: Level 1 (<70 mg/dL), Level 2 (<54 mg/dL), and Level 3 (severe, requiring assistance).
   • Assessment: At each visit, review hypoglycemia history, symptom awareness, and potential triggers (e.g., exercise, medication errors, missed meals).
   • Treatment: In conscious patients, use 15 g of fast-acting carbohydrates (glucose tablets or similar). Recheck glucose in 15 minutes and repeat if still low.
   • Glucagon Prescription: Recommended for anyone on insulin or otherwise high-risk. Ready-to-inject or nasal glucagon formulations are preferred for ease of use.
   • Therapeutic Adjustment: Deintensify or modify medications (insulin, sulfonylureas) if patients experience recurrent moderate or any severe hypoglycemia.
4. Hyperglycemic Crises
   • DKA and HHS: Promptly recognize and treat diabetic ketoacidosis (DKA) and hyperglycemic hyperosmolar state (HHS), especially in patients presenting with nausea, vomiting, dehydration, or altered mental status.
   • Prevention: Provide “sick day” advice on ketone checks, hydration, and insulin adjustments during illness. Recurrent crises often reflect limited access to medications or inadequate education; address these barriers to reduce re-hospitalizations.
5. Long-Term Impact on Complications
   • Early intensive glycemic control significantly lowers the risk of microvascular complications (retinopathy, nephropathy, neuropathy) in both type 1 and type 2 diabetes.
   • Long-term studies in type 1 diabetes show that sustained glucose management can reduce cardiovascular events. In type 2 diabetes, the addition of newer agents (e.g., GLP-1 receptor agonists or SGLT2 inhibitors) can further decrease cardiovascular and kidney risks, independent of current A1C levels.

Conclusion: The 2025 ADA Standards reinforce the need for customized glycemic targets, informed by comorbidities, hypoglycemia risk, life expectancy, and patient preferences. Using a combination of A1C and CGM data provides a more complete picture of glucose patterns and helps clinicians fine-tune therapies. Preventing hypoglycemia through medication adjustments, structured self-management education, and tailored CGM strategies is paramount. Overall, consistent and individualized glucose control offers better long-term outcomes, fewer complications, and improved quality of life for individuals with diabetes.

Reference: American Diabetes Association Professional Practice Committee. 6. Glycemic Goals and Hypoglycemia: Standards of Care in Diabetes—2025. Diabetes Care 2025;48(Supplement_1):S128–S145.
https://doi.org/10.2337/dc25-S006

 

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2024 Focused Guideline Update on Corticosteroid Use in Sepsis, ARDS, and Community-Acquired Pneumonia

13 Jan, 2025 | 11:04h | UTC

Introduction: This summary presents the key points from a 2024 focused update of the guidelines on corticosteroid use for hospitalized adult patients with sepsis, acute respiratory distress syndrome (ARDS), and community-acquired pneumonia (CAP). Developed by a panel of international experts in critical care, endocrinology, and methodology, the update aims to incorporate new evidence into recommendations regarding dosage, duration, and timing of corticosteroid therapy. Pediatric-specific recommendations could not be made due to limited data.

Key Recommendations:

1. Sepsis and Septic Shock
   • Conditional Recommendation: In adult patients with septic shock requiring vasopressor support, the panel suggests administering corticosteroids (typically hydrocortisone 200–300 mg/day IV for about 5–7 days, with or without fludrocortisone).
   • Strong Recommendation Against High Dose/Short Duration: High-dose corticosteroids (> 400 mg/day hydrocortisone equivalent given for fewer than 3 days) are not recommended, as they confer increased risk of adverse effects without demonstrating benefit.
2. Acute Respiratory Distress Syndrome (ARDS)
   • Conditional Recommendation: In adult patients hospitalized with ARDS (including those with COVID-19 ARDS), the panel suggests using corticosteroids (e.g., methylprednisolone, dexamethasone, or hydrocortisone) to lower short-term mortality and potentially reduce duration of mechanical ventilation. No specific agent or dosing regimen is mandated; choices should be guided by clinical judgment and patient context.
3. Community-Acquired Pneumonia (CAP)
   • Strong Recommendation (Severe CAP): In adults hospitalized with severe bacterial CAP, the panel recommends corticosteroids (commonly moderate-dose IV hydrocortisone or methylprednisolone for 5–7 days). Recent data indicate a clear mortality benefit in these high-risk patients.
   • No Recommendation (Less Severe CAP): For adults with less severe bacterial CAP, current evidence is inconclusive regarding mortality benefit. Although some findings suggest improvements in certain outcomes, the panel reached no consensus on whether corticosteroids should be routinely administered.

Conclusion: These updated guidelines emphasize the overall safety and potential survival benefits of corticosteroids in specific populations with critical illness, particularly those with septic shock, ARDS, or severe CAP. For each condition, the recommendations balance desirable effects—such as reduced mortality, organ dysfunction, and length of hospital stay—against possible harms, including hyperglycemia and neuromuscular weakness. Evidence remains insufficient to support pediatric guidance or clarify whether less severe CAP consistently merits treatment. Future research should address optimal dosing strategies, pediatric outcomes, long-term adverse effects, and potential cost-effectiveness across diverse healthcare settings.

Reference:
Chaudhuri, Dipayan MD, MSc, FRCPC, et al. 2024 Focused Update: Guidelines on Use of Corticosteroids in Sepsis, Acute Respiratory Distress Syndrome, and Community-Acquired Pneumonia. Critical Care Medicine 52(5): e219–e233, May 2024. DOI: http://dx.doi.org/10.1097/CCM.0000000000006172

 

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Review: Heart Failure with Preserved Ejection Fraction

9 Jan, 2025 | 11:42h | UTC

Introduction: This summary reviews the 2025 New England Journal of Medicine article by Antonio Cannata, M.D., and Theresa A. McDonagh, M.D., which addresses the clinical syndrome of heart failure with preserved ejection fraction (HFpEF). The document describes its heterogeneous nature, diagnostic challenges, and emerging therapeutic approaches. Key objectives include emphasizing the importance of ruling out mimickers (e.g., respiratory disease or amyloidosis) and reviewing the evidence for guideline-directed therapies that reduce hospitalizations and improve quality of life.

Key Recommendations:

• Diagnostic Steps:
  • Confirm an ejection fraction ≥50% and evidence of diastolic dysfunction or raised filling pressures.
  • Exclude confounding conditions (e.g., COPD, hypertrophic cardiomyopathy, cardiac amyloidosis) through imaging (echocardiography, cardiac MRI) and relevant laboratory tests (natriuretic peptides).
  • Consider invasive hemodynamic assessment if the diagnosis remains unclear.
• Initial Management:
  1. Diuretics: Use loop diuretics or thiazides to relieve congestion and peripheral edema. Titrate to the lowest effective dose once euvolemia is achieved.
  2. Blood Pressure and Comorbidity Control: Optimize antihypertensive therapy with agents such as renin–angiotensin–system (RAS) inhibitors or mineralocorticoid receptor antagonists (MRAs) to address underlying hypertension and other cardiovascular risk factors.
• Specific Pharmacotherapies:
  • SGLT2 Inhibitors: Empagliflozin and dapagliflozin reduce the composite risk of cardiovascular death or heart-failure hospitalization, primarily by lowering hospitalization rates.
  • RAS Blockade (ACE Inhibitors/ARBs/ARNIs): Although large trials did not show a clear mortality benefit, some studies indicated fewer hospitalizations.
  • MRAs (e.g., Spironolactone, Finerenone): Evidence for HFpEF is mixed, though a recent trial (FINEARTS-HF) supports the potential role of finerenone in reducing hospitalization in patients with left ventricular ejection fraction ≥40%.
  • GLP-1 Receptor Agonists: Agents like semaglutide (and the dual GIP/GLP-1 agonist tirzepatide) showed improvements in weight reduction, exercise tolerance, and quality of life in patients with HFpEF and obesity, suggesting an emerging cardiometabolic strategy.
  • Beta-Blockers: Widespread use in HFpEF often relates to other comorbidities, but trials have not demonstrated significant outcome benefits specifically for preserved ejection fraction.
• Adjunct Therapies and Devices:
  • Pulmonary Artery Pressure Monitoring (CardioMEMS): Can help guide diuretic adjustments and has shown reductions in hospitalizations for heart failure across ejection-fraction ranges.
  • Interatrial Shunt Devices: Trials so far have not shown conclusive benefits and may pose increased risk in patients with higher ejection fractions.
• Lifestyle and Comorbidity Management:
  • Address obesity, type 2 diabetes, and physical inactivity through dietary and exercise interventions.
  • Evaluate for sleep-disordered breathing, as optimizing respiratory status can improve symptoms and reduce hospitalizations.

Conclusion: HFpEF is a complex syndrome often associated with obesity, hypertension, and other coexisting conditions that contribute to clinical variability. While no single agent has definitively reduced mortality, trials have shown meaningful reductions in hospitalizations and improvements in quality of life, especially with SGLT2 inhibitors and, in obese patients, GLP-1 receptor agonists. Ongoing research into pathophysiology-driven therapies may enhance future outcomes. For now, clinicians should employ a multimodal approach targeting volume status, cardiometabolic health, and comorbidity control to optimize management.

Reference:
Cannata A, McDonagh TA. Heart Failure with Preserved Ejection Fraction. New England Journal of Medicine. 2025;392:173–184.
DOI: https://doi.org/10.1056/NEJMcp2305181

 

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Observational Study Emulation: Denosumab vs. Oral Bisphosphonates in Dialysis-Dependent Patients Shows Reduced Fractures but Possible Elevated Cardiovascular Risk

8 Jan, 2025 | 11:55h | UTC

Background: 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

 

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Systematic Review: GLP-1 Receptor Agonists and Co-Agonists Facilitate Significant Weight Loss in Adults Without Diabetes

8 Jan, 2025 | 11:04h | UTC

Background: 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

 

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RCT: Sequential Oral Agents Not Noninferior to Insulin for Gestational Diabetes

8 Jan, 2025 | 11:05h | UTC

Background: 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

 

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ATS Guidelines on Invasive Pulmonary Aspergillosis and Antifungal Strategies in Critically Ill Adults

7 Jan, 2025 | 12:29h | UTC

Introduction: 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

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RCT: Assessing Procalcitonin-Based Antibiotic Management in Critically Ill Patients With Sepsis

7 Jan, 2025 | 14:00h | UTC

Background: 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

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Joint ATS/CDC/ERS/IDSA Guideline Recommends Shorter, All-Oral Regimens for Drug-Susceptible and Drug-Resistant TB

5 Jan, 2025 | 11:30h | UTC

Introduction: 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

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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 | UTC

Introduction: 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

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Meta-Analysis: Tailored Hydration Strategies Decrease CI-AKI and MACE in Coronary Angiography

6 Jan, 2025 | 13:00h | UTC

Background: Contrast-induced acute kidney injury (CI-AKI) poses a considerable burden on patients undergoing coronary angiography or percutaneous coronary intervention (PCI). Beyond the direct tubular toxicity of iodine contrast, several risk factors, including chronic kidney disease (CKD) and hemodynamic instability, further increase the likelihood of renal damage. Although guideline-based prevention strategies recommend peri-procedural intravenous hydration, the optimal volume and method remain unclear.

Objective: This meta-analysis aimed to determine whether patient-tailored intravenous fluid administration (using parameters other than body weight alone) can reduce the incidence of CI-AKI, as well as major adverse cardiovascular events (MACE), compared with conventional non-tailored hydration protocols in patients undergoing coronary angiography and/or PCI.

Methods: A systematic review of randomized controlled trials (RCTs) was performed, including 13 studies and 4,458 participants. Tailored hydration strategies encompassed left ventricular end-diastolic pressure (LVEDP)-guided infusion, diuresis-driven matched replacement (RenalGuard®), bioimpedance vector analysis, central venous pressure, or inferior vena cava ultrasound measurements. These were compared against standard non-tailored fluid protocols. The primary outcome was CI-AKI (variously defined but measured within 7 days), and secondary outcomes included MACE, all-cause mortality, and renal replacement therapy (RRT).

Results: Across 12 RCTs (n=3,669), tailored hydration significantly reduced CI-AKI rates (risk ratio 0.56, 95% CI [0.46–0.69], p<0.00001; I²=26%). Ten studies (n=3,377) revealed lower MACE incidence in the tailored hydration arm (RR=0.57, 95% CI [0.42–0.78], p=0.0005; I²=12%). A significant reduction in all-cause mortality (RR=0.57, 95% CI [0.35–0.94], p=0.03) and RRT requirement (RR=0.51, 95% CI [0.29–0.89], p=0.02) was also observed, with no significant increase in pulmonary edema. Subgroup analyses (e.g., CKD) supported the overall benefit of individualizing fluid regimens.

Conclusions: Tailored hydration strategies appear superior to standard approaches in lowering the risk of CI-AKI, MACE, mortality, and RRT after coronary angiography or PCI. Although LVEDP-guided protocols are simple to implement and effective, the RenalGuard® system may offer additional benefits in selected populations, albeit at higher cost and complexity.

Implications for Practice: Clinicians should consider personalized hydration based on physiological or hemodynamic parameters to optimize fluid volume, reduce renal injury, and potentially improve clinical outcomes. Nevertheless, practical challenges include access to specialized equipment and the need for close monitoring in some techniques.

Study Strengths and Limitations: This systematic review highlights consistent treatment effects across diverse RCTs and methods. However, potential biases due to lack of blinding, varying CI-AKI definitions, and limited head-to-head comparisons among tailored approaches constrain definitive conclusions. The small sample size of certain studies and underpowered subgroup analyses also limit the generalizability of findings.

Future Research: Further large-scale trials are warranted to compare various tailored protocols directly, focusing on cost-effectiveness, ease of implementation, and patient-centered endpoints. Ongoing investigations, such as the NEPTUNE trial, aim to clarify whether combining multiple parameters (like LVEDP and contrast volume/eGFR ratio) yields optimal renal protection.

Reference: Cossette F, Trifan A, Prévost-Marcotte G, et al. Tailored Hydration for the Prevention of Contrast-Induced Acute Kidney Injury After Coronary Angiogram or PCI: A Systematic Review and Meta-Analysis. American Heart Journal. Published online January 4, 2025. DOI: http://doi.org/10.1016/j.ahj.2025.01.002

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Meta-analysis: Therapeutic-Dose Heparin Improves 28-Day Mortality in COVID-19 Hospitalized Patients

6 Jan, 2025 | 12:00h | UTC

Background: 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

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Review: Nutritional Support in Critically Ill Patients

6 Jan, 2025 | 11:00h | UTC

Introduction: This summary is derived from a state-of-the-art review on nutritional support in the intensive care unit (ICU) published in The BMJ. Critically ill patients experience metabolic disturbances, inflammation, and profound muscle wasting. Nutritional therapy aims to mitigate these effects, though recent randomized controlled trials (RCTs) challenge the dogma of early, aggressive provision of high-calorie and high-protein diets for all ICU patients. Instead, emerging evidence indicates that moderate energy and protein restriction, particularly during the first week, may enhance recovery and reduce complications such as hospital-acquired infections, muscle weakness, and ICU-acquired morbidity. Nonetheless, identifying ideal feeding strategies remains complex, given the dynamic nature of critical illness and the interplay with other interventions such as sedation and physical rehabilitation.

Key Recommendations:

1. Individualized Timing and Dose: Limit caloric and protein loads during the acute phase (roughly the first seven days), especially in patients with hemodynamic instability or shock. Later, as patients transition to recovery, gradually increase macronutrient delivery to meet evolving metabolic needs.
2. Preferred Feeding Route: Enteral nutrition is generally recommended when the gastrointestinal tract is functional, particularly after shock resolution. Parenteral nutrition can be reserved for prolonged gut dysfunction or inability to meet needs enterally. Studies comparing enteral versus parenteral feeding have shown no clear outcome differences, but early enteral feeding is often favored for physiological and cost reasons.
3. Avoid Overfeeding and Overzealous Protein Provision: Several large RCTs (including EFFORT-Protein, EDEN, and NUTRIREA-3) observed no mortality benefit—and in some instances, worse outcomes—when patients received full or high doses of energy and protein in the first week. Metabolic “resistance” and inhibition of protective processes such as autophagy might explain why restricted early feeding sometimes confers advantages.
4. Monitoring and Assessment: Traditional tools (NUTRIC, NRS-2002) and biomarkers (albumin, prealbumin) do not reliably predict who benefits from higher or lower feeding levels. Ultrasound or computed tomography to assess muscle mass may hold promise, but no validated approach exists to guide individualized macronutrient targets.
5. Micronutrients and Specialized Formulations: Broad-spectrum pharmaconutrients (glutamine, antioxidants, etc.) have not improved outcomes in well-powered trials. Instead, standard vitamin and trace element supplementation consistent with recommended daily allowances appears sufficient in most cases.
6. Long-term Rehabilitation: Combined nutritional support and physical exercise are critical for mitigating long-term impacts of ICU-acquired weakness and functional decline. Evidence increasingly highlights the need for prolonged, structured rehabilitation to optimize muscle recovery and quality of life.

Conclusion: Although nutritional support remains central to critical care, it is most effective when carefully adapted to disease phase, patient comorbidities, and evolving organ dysfunction. Key evidence suggests a more conservative approach to energy and protein during the acute phase, followed by gradual escalation and integration with rehabilitation. Ongoing research seeks to identify physiological markers that distinguish when to intensify nutritional therapy and how best to align macronutrient delivery with other therapies to promote muscle function and reduce complications.

Reference: Reignier J, Rice TW, Arabi YM, Casaer M. Nutritional Support in the ICU. BMJ. 2025;388:e077979. DOI: https://doi.org/10.1136/bmj-2023-077979

 

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Avian Influenza A(H5N1) Outbreak Among US Farm Exposures: Clinical Findings and Early Treatment Outcomes

2 Jan, 2025 | 17:01h | UTC

Background: 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

 

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Meta-Analysis: Glutamatergic Agents May Improve Obsessive-Compulsive and Related Disorder Symptoms

4 Jan, 2025 | 12:08h | UTC

Background: 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

 

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Meta-Analysis: Long Half-Life Phosphodiesterase Inhibitors Reduce HbA1c in Adults with Elevated Baseline Levels

6 Jan, 2025 | 08:00h | UTC

Background: 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

 

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AGA Clinical Practice Update on Managing Portal Vein Thrombosis in Cirrhotic Patients: Expert Review

3 Jan, 2025 | 10:00h | UTC

Introduction: This summary highlights key recommendations from an AGA expert review on portal vein thrombosis (PVT) in cirrhotic patients. PVT is common in cirrhosis, with an estimated five-year incidence of around 11%, and may worsen portal hypertension and elevate mortality. Management is challenging because of limited evidence, the potential complications of both PVT and anticoagulation, and significant heterogeneity regarding clot characteristics, host factors, and cirrhosis severity. This review presents the latest guidance on identifying clinically relevant PVT, selecting anticoagulation, and considering endovascular interventions, including TIPS (transjugular intrahepatic portosystemic shunt).

Key Recommendations:

1. No Routine Screening: Asymptomatic patients with compensated cirrhosis do not require regular screening for PVT in the absence of suggestive clinical changes.
2. Imaging Confirmation: When Doppler ultrasound reveals suspected PVT, contrast-enhanced CT or MRI is recommended to confirm the diagnosis, exclude malignancy, and characterize clot extent and occlusion.
3. Hypercoagulability Testing: Extensive thrombophilia workup is not indicated unless there is family or personal history of thrombotic events, or associated laboratory abnormalities.
4. Intestinal Ischemia Management: Patients who develop PVT with evidence of intestinal ischemia should receive prompt anticoagulation and, ideally, multidisciplinary team care involving gastroenterology, hepatology, interventional radiology, hematology, and surgery.
5. Observation of Minor or Recent Thrombi: In cirrhotic patients without ischemia, with recent (<6 months) thrombi that are <50% occlusive, close imaging follow-up every three months is a reasonable option to track potential spontaneous clot regression.
6. Anticoagulation for Significant PVT: Consider anticoagulation for more extensive or obstructive (>50%) recent PVT, especially if the main portal vein or mesenteric vessels are involved. Candidates for liver transplantation and those with inherited thrombophilia may derive additional benefit.
7. Chronic Cavernous PVT: Anticoagulation is generally not advised in patients with long-standing (>6 months) complete occlusion and well-formed collateral channels.
8. Variceal Screening: Perform endoscopic screening or ensure prophylaxis for varices. Avoid delays in initiating anticoagulation, as timeliness is essential for better recanalization outcomes.
9. Choice of Anticoagulant: Vitamin K antagonists, low-molecular-weight heparin, and direct oral anticoagulants (DOACs) are all viable options in cirrhosis. DOACs may be appropriate in well-compensated (Child-Turcotte-Pugh class A or certain class B) cirrhosis but should be avoided in class C. Treatment selection should consider patient preferences, monitoring feasibility, and risk of bleeding.
10. Duration of Therapy: Reassess clot status with cross-sectional imaging every three months. Continue anticoagulation for transplant-eligible individuals who show partial or complete recanalization, and consider discontinuation in nonresponders after six months if futility is evident.
11. TIPS Revascularization: Portal vein revascularization using TIPS may be pursued in patients who have other TIPS indications (like refractory ascites or variceal bleeding) or to improve transplant feasibility by recanalizing portal flow.

Conclusion: PVT in cirrhosis remains a complex clinical issue requiring careful evaluation of clot extent, timing, and the potential need for transplantation. The recommendations presented here underscore prompt imaging, timely anticoagulation for high-risk thrombi, and individualized therapy based on Child-Turcotte-Pugh classification and bleeding risk. When necessary, multidisciplinary collaboration is key to achieving optimal patient outcomes. Prospective randomized trials and standardized classifications of PVT will be instrumental in refining future guidelines.

Reference:
Davis JPE, Lim JK, Francis FF, Ahn J. AGA Clinical Practice Update on Management of Portal Vein Thrombosis in Patients With Cirrhosis: Expert Review. Gastroenterology. 2024. DOI: http://doi.org/10.1053/j.gastro.2024.10.038

 

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Cohort study: Higher Telehealth Use Linked to Lower Rates of Select Low-Value Services in Medicare

3 Jan, 2025 | 09:30h | UTC

Background: Telehealth has rapidly expanded in recent years, potentially transforming how primary care is delivered. However, questions remain regarding its impact on low-value services—tests or procedures that confer minimal benefit and might be wasteful. Previous research raised concerns that virtual encounters could either reduce or increase unnecessary care, but rigorous data on this matter have been limited.

Objective: To assess whether a primary care practice’s adoption of telehealth is associated with changes in the rate of eight established low-value services, comprising office-based procedures, laboratory tests, imaging studies, and mixed-modality interventions.

Methods: This retrospective cohort study used Medicare fee-for-service claims from 2019 through 2022 for 577,928 beneficiaries attributed to 2,552 primary care practices in Michigan. Practices were grouped into low, medium, or high tertiles of telehealth volume in 2022. A difference-in-differences approach was performed, comparing annualized low-value service rate changes between the prepandemic (2019) and postpandemic (2022) periods.

Results: Overall, high-telehealth practices demonstrated reduced rates of certain office-based low-value services, specifically cervical cancer screening (−2.9 services per 1000 beneficiaries, 95% CI −5.3 to −0.4) among older women. Additionally, high-telehealth practices showed lower rates of select low-value thyroid tests (−40 per 1000 beneficiaries, 95% CI −70 to −9). For five other measures—including imaging for low back pain, imaging for uncomplicated headache, and PSA tests in older men—no significant association was observed between greater telehealth use and low-value service rates. Notably, telehealth volume increased markedly from 2019 to 2022, while in-person visits generally decreased.

Conclusions: These findings suggest that widespread telehealth adoption in Michigan primary care was not associated with elevated low-value service use. In fact, certain office-based low-value tests appeared to decline, possibly owing to fewer face-to-face opportunities to perform unnecessary interventions. Nonetheless, caution is warranted in generalizing these findings, as telehealth’s effects may vary across different clinical contexts.

Implications for Practice: Health care systems should consider structured telehealth protocols that encourage judicious testing and minimize overuse. While telehealth can broaden access, clinicians must remain vigilant to avoid missing necessary care. Clear guidelines, effective triage, and patient education might help balance convenience with quality.

Study Strengths and Limitations: Strengths include a large Medicare population and established low-value service metrics, enhancing the study’s validity. Limitations include a single-state focus (Michigan) and reliance on claims data without detailed clinical information, restricting the scope of outcomes assessed.

Future Research: Further investigation is needed to verify whether these trends extend to other states, different insurance models, and additional low-value services (including medications). Evaluations of telehealth’s role in both low-value and high-value care could offer deeper insights into its broader effects on cost and quality.

Reference: Liu T, Zhu Z, Thompson MP, et al. Primary Care Practice Telehealth Use and Low-Value Care Services. JAMA Network Open. 2024;7(11):e2445436. DOI: http://doi.org/10.1001/jamanetworkopen.2024.45436

 

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RCT: Chlorthalidone Shows No Renal Advantage Over Hydrochlorothiazide Under Equivalent Dosing in Older Adults With Hypertension

3 Jan, 2025 | 09:00h | UTC

Background: 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

 

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Cohort Study: One in Four Patients Demonstrates Covert Cognition Despite Behavioral Unresponsiveness

3 Jan, 2025 | 08:30h | UTC

Background: Cognitive motor dissociation (CMD) refers to the presence of specific neuroimaging or electrophysiological responses to commands in patients otherwise incapable of voluntary behavioral output. Detecting CMD is clinically relevant because its underdiagnosis may lead to premature decisions regarding goals of care, life-sustaining treatment, and rehabilitation efforts. Although several single-center studies have suggested that CMD may exist in 10–20% of patients with disorders of consciousness, larger multinational data were lacking, particularly using both functional magnetic resonance imaging (fMRI) and electroencephalography (EEG).

Objective: To determine how often CMD occurs in a large, multinational cohort of adults with impaired consciousness and to evaluate the clinical variables potentially associated with this phenomenon.

Methods: This prospective cohort study included 353 adults with disorders of consciousness recruited from six international centers between 2006 and 2023. Enrolled participants had at least one behavioral assessment using the Coma Recovery Scale–Revised (CRS-R) and underwent task-based fMRI, EEG, or both. Sites utilized validated analytic pipelines and automated data processing to minimize false positives. Participants were divided into two groups: those without observable responses to verbal commands (coma, vegetative state, or minimally conscious state–minus) and those with observable responses (minimally conscious state–plus or emerged). CMD was defined as the absence of any observable behavioral response to commands, combined with a positive command-following signal on fMRI or EEG.

Results: Among 241 participants with no overt command-following, 25% showed CMD through either fMRI alone, EEG alone, or both. CMD was more common in younger patients, those assessed later after injury, and those with traumatic brain injury. Interestingly, in 112 participants who did exhibit command-following on bedside exams, only 38% demonstrated confirmatory responses on fMRI or EEG. These findings support the notion that the tasks used for neuroimaging and electrophysiological assessments may require more sustained cognitive engagement than typical bedside evaluations.

Conclusions: CMD was identified in about one in four patients who lacked behavioral command-following. Combining fMRI with EEG likely increases detection rates compared to either modality alone. The results highlight the need for increased awareness of covert cognitive activity in this population, given potential ramifications for prognosis, family counseling, and clinical care.

Implications for Practice: Clinicians should consider the possibility of CMD in patients who appear unresponsive at the bedside. When feasible, employing both fMRI and EEG might reveal hidden cognitive capacities that can guide patient-centered decisions, encourage targeted therapies, and allow healthcare teams to respect potential consciousness and autonomy. However, such technologies remain limited to specialized centers.

Study Strengths and Limitations: Strengths include a diverse sample from multiple international sites and the integration of two complementary neurodiagnostic techniques. Limitations involve heterogeneous recruitment practices, variations in local data acquisition methods, and potential selection biases toward patients who survived until advanced testing was available. Additionally, the absence of standardized paradigms across sites reduced consistency of results.

Future Research: Further large-scale investigations should standardize fMRI and EEG protocols and determine whether earlier and more consistent identification of CMD affects functional outcomes. Efforts to refine and validate automated analytic pipelines could facilitate widespread adoption of these techniques in routine clinical settings.

Reference: Bodien YG, Allanson J, Cardone P, et al. Cognitive Motor Dissociation in Disorders of Consciousness. New England Journal of Medicine. 2024;391:598-608. DOI: http://doi.org/10.1056/NEJMoa2400645

 

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Dose-Response Meta-Analysis: At Least 150 Weekly Minutes of Aerobic Exercise Needed for Significant Waist and Fat Reduction

2 Jan, 2025 | 09:30h | UTC

Background: Elevated body weight and adiposity remain major public health concerns worldwide, with overweight and obesity affecting nearly half of the adult population. Although various guidelines advocate for aerobic exercise as a core strategy in weight management, robust meta-analyses exploring dose-response relationships are scarce.

Objective: To clarify how different doses and intensities of supervised aerobic exercise affect body weight, waist circumference, and body fat in adults with overweight or obesity.

Methods: This systematic review and meta-analysis encompassed 116 randomized clinical trials (RCTs) including a total of 6880 participants (mean [SD] age, 46 [13] years). All studies involved supervised continuous aerobic interventions (e.g., walking or running) for at least 8 weeks. Comparisons were made against sedentary or usual-activity controls. Frequency, duration (minutes per week), and intensity (moderate, vigorous, or combined) of aerobic sessions were extracted.

Results: Across all trials, each additional 30 minutes per week of aerobic exercise was linked to a mean reduction of 0.52 kg in body weight (95% CI, −0.61 to −0.44), 0.56 cm in waist circumference, and 0.37 percentage points in body fat. Body weight and waist circumference showed largely linear decreases with increasing weekly exercise, whereas body fat percentage displayed a pattern suggesting that at least 150 minutes per week may be required to achieve clinically meaningful reductions (>2% reduction in body fat). Aerobic training was generally well tolerated, although a modest increase in mild musculoskeletal complaints was noted (risk difference, 2 more events per 100 participants).

Conclusions: Engaging in up to 300 minutes per week of aerobic exercise was associated with progressively greater benefits for weight control, waist circumference, and body fat. While even small doses yielded modest improvements, these findings suggest that an intensity of at least moderate level and a duration of at least 150 minutes per week may be necessary to achieve clinically important reductions in central obesity and fat percentage.

Implications for Practice: Clinicians managing patients with overweight or obesity can recommend a minimum of 150 minutes per week of moderate-to-vigorous aerobic training to achieve significant anthropometric changes. Gradual progression is essential to balance effectiveness and safety, especially in individuals with musculoskeletal constraints.

Study Strengths and Limitations: Strengths include the large number of RCTs, robust dose-response analyses, and consistent directions of effects. However, high heterogeneity, publication bias for certain fat measures, and limited data on medication use and health-related quality of life in longer trials were noted.

Future Research: Further trials should explore additional subgroup analyses (e.g., older adults, individuals with chronic comorbidities), longer durations of follow-up, and the integration of resistance training to optimize cardiometabolic outcomes.

Reference: Jayedi A, Soltani S, Emadi A, et al. Aerobic Exercise and Weight Loss in Adults: A Systematic Review and Dose-Response Meta-Analysis. JAMA Network Open. 2024;7(12):e2452185. DOI: http://doi.org/10.1001/jamanetworkopen.2024.52185

 

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