Family Medicine

Non-inferiority RCT: Reduced-Dose vs Full-Dose Direct Oral Anticoagulants for Extended VTE Treatment

8 Mar, 2025 | 17:46h | UTC

Background: Venous thromboembolism (VTE) carries a high risk of recurrence once anticoagulation is stopped, particularly in those with unprovoked events or persistent risk factors. Extended anticoagulation is therefore recommended for patients at high risk, but optimal dosing remains uncertain. Reduced-dose direct oral anticoagulants (DOACs) may lower bleeding risk compared with full-dose regimens. However, prior trials that tested reduced-dose anticoagulation enrolled patients with less definitive indications for continuation and were not powered for head-to-head efficacy comparisons.

Objective: The RENOVE trial aimed to determine whether reduced-dose DOACs (apixaban 2.5 mg twice daily or rivaroxaban 10 mg once daily) are non-inferior to full-dose DOACs (apixaban 5 mg twice daily or rivaroxaban 20 mg once daily) in preventing VTE recurrence during extended treatment, while potentially reducing bleeding risk.

Methods: RENOVE was a non-inferiority, multicenter, randomized, open-label, blinded-endpoint trial conducted in 47 French hospitals. It included adult patients (n=2768) who had completed 6–24 months of uninterrupted full-dose anticoagulation for symptomatic pulmonary embolism or proximal deep vein thrombosis and were deemed at high risk for recurrence. Participants were randomly assigned 1:1 to a reduced-dose or a full-dose DOAC regimen. The primary outcome was symptomatic recurrent VTE (non-fatal or fatal). The main secondary outcomes included major bleeding or clinically relevant non-major bleeding, and a net clinical benefit composite of recurrent VTE plus major or clinically relevant non-major bleeding.

Results: After a median follow-up of 37.1 months, the primary outcome occurred in 19/1383 patients (5-year cumulative incidence 2.2%) in the reduced-dose arm and 15/1385 (1.8%) in the full-dose arm (adjusted HR 1.32; 95% CI 0.67–2.60; p=0.23 for non-inferiority). Major or clinically relevant non-major bleeding was significantly lower in the reduced-dose group (9.9% vs 15.2% at 5 years; HR 0.61; 95% CI 0.48–0.79). Major bleeding was 2.1% vs 4.0%, respectively. Net clinical benefit (recurrent VTE or clinically relevant bleeding) was 11.8% in the reduced-dose group versus 16.5% in the full-dose group (HR 0.67; 95% CI 0.53–0.86). Mortality and arterial events were similar between groups.

Conclusions: Reduced-dose DOACs did not meet the formal non-inferiority criterion for preventing VTE recurrence in patients requiring extended anticoagulation. Nonetheless, absolute recurrence rates were low in both arms. The reduced-dose strategy substantially lowered the risk of clinically relevant bleeding without increasing all-cause mortality. Although full-dose anticoagulation remains an option, these findings suggest that reduced-dose regimens may be clinically reasonable for many patients who need ongoing therapy.

Implications for Practice: Clinicians could consider a reduced-dose DOAC regimen for extended VTE treatment, especially in individuals at high bleeding risk, given the observed safety benefits. Treatment decisions should still account for patient-specific factors (e.g., obesity, history of severe VTE) where full-dose regimens might remain preferable.

Study Strengths and Limitations: Major strengths include the large sample size, well-defined endpoints adjudicated by a blinded committee, and extended follow-up. Limitations include the open-label design and the low rate of recurrence, which led to a sample size increase mid-study. Subgroup analyses may be underpowered to detect meaningful differences in specific populations.

Future Research: Further trials or pooled analyses are needed to clarify whether certain high-risk subgroups (e.g., those with severe obesity or active malignancy) might benefit more from continuing a full-dose regimen. Additional prospective studies could refine criteria for safe dose reductions.

Reference:

1. Couturaud F, Schmidt J, Sanchez O, et al. Extended treatment of venous thromboembolism with reduced-dose versus full-dose direct oral anticoagulants in patients at high risk of recurrence: a non-inferiority, multicentre, randomised, open-label, blinded endpoint trial. The Lancet. 2025;405(10480). DOI: https://doi.org/10.1016/S0140-6736(24)02842-3
2. Middeldorp S, Leentjens J. Anticoagulation for extended venous thromboembolism treatment: less is really more. The Lancet. 2025;405(10480). DOI: https://doi.org/10.1016/S0140-6736(25)00099-6

 

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Systematic Review: Shorter Antibiotic Courses Often Prove Non-Inferior for Common Bacterial Infections

3 Feb, 2025 | 10:00h | UTC

Background: The overuse of antibiotics contributes significantly to the global rise in antimicrobial resistance (AMR). Shorter antibiotic treatment courses have gained traction as an important antimicrobial stewardship intervention. They can potentially reduce drug-related side effects, healthcare costs, and selection pressure favoring resistant pathogens. This review synthesizes findings from randomized controlled trials (RCTs) on antibiotic duration across various common bacterial infections—including respiratory tract, genitourinary, skin and soft tissue, bone/joint, and intra-abdominal infections—to inform practical, day-to-day clinical decision-making.

Objective:

1. To assess the comparative efficacy of short- versus long-course antibiotic therapy for frequent bacterial infections.
2. To highlight key evidence gaps, particularly for severe infections, critically ill populations, and low- to middle-income settings.
3. To propose practical treatment durations in light of current guidelines and study outcomes.

Methods:

• Comprehensive search of MEDLINE and Embase through July 2024 (PROSPERO 2021, CRD42021276209).
• Inclusion: RCTs that compared differing antibiotic durations for bacterial infections or perioperative prophylaxis, reporting clinical cure, relapse, or mortality.
• Exclusion: Non-bacterial infections (viral/fungal), pilot studies, non-randomized designs.
• Data extraction: Patient demographics, infection type, interventions, outcomes, adherence, and risk-of-bias assessment per the RoB 2 tool.
• Guideline review: Major international guidelines (e.g., IDSA, NICE, WHO) were examined to contextualize trial findings.

Results:

• A total of 315 RCTs were included; 85% concluded no difference, non-inferiority, or equivalence of shorter compared with longer antibiotic courses.
• Shorter therapy (often 5–7 days) is well-supported for uncomplicated bacterial sinusitis, community-acquired pneumonia (CAP), simple urinary tract infections (UTIs), cellulitis, and intra-abdominal infections with adequate surgical source control.
• Evidence for reducing duration in severe infections (e.g., bloodstream infections, ventilator-associated pneumonia caused by non-fermenting Gram-negative bacilli) or in critically ill populations remains limited.
• Only 7% of RCTs involved intensive care unit (ICU) patients, and 14% were conducted in low- or middle-income countries.
• Methodologically, 15% of trials posed a low risk of bias; however, non-adherence to assigned durations was common (median 11% per study). Very few trials tracked emergence of resistant organisms through follow-up cultures.

Key findings:

1. Acute GAS Pharyngotonsillitis:
   10 days of penicillin V or amoxicillin remains the conventional standard to ensure microbiological eradication and minimize rheumatic fever risk. While 5 days of azithromycin may be used in macrolide-responsive settings, it is not preferred as first-line therapy due to broader-spectrum activity and limited evidence for preventing complications, particularly in high-risk populations.
2. Community-Acquired Pneumonia (CAP):
   • Outpatient adults with mild to moderate CAP typically improve with 5 days of appropriate therapy (e.g., amoxicillin, doxycycline, or a macrolide), provided patients show clinical stability.
   • Severe CAP or complicated presentations (e.g., MRSA, Pseudomonas, multi-lobar involvement) may need 7–10 days or until clinical stability is achieved.
3. Acute Bacterial Sinusitis (Adults):
   • 5–7 days of amoxicillin/clavulanate or other first-line agents usually suffice if the diagnosis is certain.
4. Genitourinary Infections:
   • Uncomplicated Cystitis (Non-Pregnant Women):
     • 3–5 days of nitrofurantoin or trimethoprim/sulfamethoxazole is often adequate, reflecting strong RCT support.
   • Pyelonephritis or Complicated UTIs (e.g., in men, catheter-associated):
     • While some RCTs show 7 days can be as effective as 14 days in afebrile males with mild UTI, a trial in febrile males demonstrated inferior outcomes with shorter courses. Clinicians should exercise caution in febrile or higher-risk cases.
5. Skin and Soft Tissue Infections (e.g., Cellulitis):
   • 5–6 days of effective oral therapy is sufficient for uncomplicated cellulitis if there is marked clinical improvement by Day 5.
   • For recurrent abscesses or complicated scenarios, duration may need to be extended or individualized.
6. Bone and Joint Infections:
   • 6 weeks is often sufficient for vertebral osteomyelitis in stable patients.
   • For prosthetic joint infections with retained hardware, 6 weeks of therapy was inferior to 12 weeks in a key trial, necessitating individualized duration based on surgical management.
7. Intra-Abdominal Infections:
   • With adequate source control, 4–5 days of antibiotics commonly yields outcomes on par with extended courses.
   • Longer therapy (≥7 days) may be needed when abscesses are not fully drained or in immunocompromised patients.
8. Perioperative Prophylaxis:
   • A single preoperative dose (possibly repeated if surgery is prolonged or blood loss is excessive) is sufficient in most procedures.
   • Continuing prophylaxis beyond 24 hours rarely provides additional benefit and may increase adverse events.

Conclusions: Numerous well-conducted RCTs support shorter antibiotic courses for many common bacterial infections. Nonetheless, high-quality data are sparse for severe or complex infections, pediatric populations with significant comorbidities, and low-resource settings. Clinicians should tailor antibiotic duration to the infection type, disease severity, patient factors, and local resistance patterns—while remaining cognizant that shorter courses can safely balance efficacy, safety, and stewardship aims in many cases.

Study Strengths and Limitations:

• Strengths: Large volume of RCTs, broad infection scope, and inclusion of diverse study designs. Substantial evidence supports shortening antibiotic regimens for multiple common infections.
• Limitations: Underrepresentation of severe, ICU-level infections, children with serious comorbidities, and low-resource settings. High variation in diagnostic criteria, antibiotic choices, and adherence monitoring. Many trials reported low event rates, posing potential non-inferiority bias.

Future Research:

• Well-powered RCTs focusing on severe infections (e.g., MDR Gram-negative bloodstream infections, staphylococcal bacteremia, ventilator-associated pneumonia with resistant pathogens).
• Trials in low- and middle-income countries with robust microbiological and economic assessments.
• Studies using adaptive designs and validated biomarkers to refine duration–response relationships and detect shifts in AMR at the population level.

Reference: Mo Y, Tan WC, Cooper BS. Antibiotic duration for common bacterial infections—a systematic review. JAC-Antimicrobial Resistance. 2025;7(1):dlae215. DOI: https://doi.org/10.1093/jacamr/dlae215

 

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Introducing Our Free WhatsApp Channels for Daily Internal Medicine Articles!

28 Jan, 2025 | 00:54h | UTC

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Cohort Study: GLP-1 Receptor Agonists Demonstrate Wide-Ranging Benefits but Elevate Gastrointestinal, Renal, and Musculoskeletal Risks

31 Jan, 2025 | 10:30h | UTC

Background: GLP-1 receptor agonists (GLP-1RAs) are widely prescribed for type 2 diabetes and obesity due to their robust effects on glycemic control and weight reduction. Recent evidence indicates that these agents may exert broader cardiometabolic and neurocognitive benefits. However, uncertainties remain regarding their overall safety profile, prompting a need for large-scale, systematic investigation across multiple organ systems.

Objective: This study aimed to systematically map the associations of GLP-1RA use with 175 clinical outcomes, including cardiovascular, renal, gastrointestinal, musculoskeletal, and neuropsychiatric endpoints, compared to several active antihyperglycemic therapies and to usual care.

Methods: A retrospective cohort analysis was conducted using US Department of Veterans Affairs databases (2017–2023). Adults with type 2 diabetes (n=215,970) who initiated GLP-1RA therapy were compared to individuals starting sulfonylureas, DPP4 inhibitors, SGLT2 inhibitors, a combined active-control cohort, and a usual care group (total >1.9 million controls). Those with key contraindications were excluded. The primary analysis employed inverse probability weighting to adjust for demographics, comorbidities, and medication use. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using weighted Cox models, with Benjamini–Hochberg correction for multiple comparisons.

Results: Compared with usual care, GLP-1RA use was associated with reduced risks of cardiac arrest, myocardial infarction, heart failure, stroke, acute kidney injury, and chronic kidney disease, as well as decreased rates of neuropsychiatric disorders (including substance use disorders, psychotic disorders, suicidal ideation, and dementia). Notably, the risk of Alzheimer’s disease was also lower (HR 0.88). At the same time, GLP-1RAs increased risks for several gastrointestinal events (nausea, vomiting, gastroesophageal reflux disease), hypotension, syncope, and renal conditions such as nephrolithiasis and interstitial nephritis. A key finding was drug-induced acute pancreatitis (HR 2.46). Additionally, musculoskeletal complications emerged, including arthritis and arthralgia, both with HR 1.11.

Conclusions: While significant benefits—spanning cardiovascular, metabolic, and neuropsychiatric domains—were observed, clinicians should remain vigilant regarding gastrointestinal, renal, and musculoskeletal adverse events. In particular, drug-induced pancreatitis and arthritic disorders may pose important safety considerations.

Implications for Practice: GLP-1RAs appear beneficial for patients with type 2 diabetes or obesity who require improved cardiometabolic control and may gain additional neuropsychiatric advantages. However, these drugs can be costly and demand careful monitoring, especially for pancreatitis, renal complications, and arthritis. Tailored patient selection, combined with other lifestyle or pharmacologic measures, will likely optimize clinical outcomes.

Study Strengths and Limitations: Strengths include a large, diverse cohort and robust comparative analyses with multiple active controls. Limitations involve residual confounding typical of observational designs and a predominantly male, veteran population that may affect generalizability. Absolute event rates for certain outcomes require further clarification to gauge clinical relevance.

Future Research: Randomized trials and post-approval pharmacovigilance are warranted to further delineate mechanistic pathways, within-class variations, and cost-effectiveness. Studies focusing on subpopulations (e.g., women, younger adults, and different racial groups) and head-to-head comparisons of specific GLP-1RAs are also needed.

Reference: Xie, Y., Choi, T. & Al-Aly, Z. Mapping the effectiveness and risks of GLP-1 receptor agonists. Nature Medicine (2025). DOI: https://doi.org/10.1038/s41591-024-03412-w

 

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RCT: Dapagliflozin Plus Calorie Restriction Achieves Higher Remission Rate of Type 2 Diabetes

30 Jan, 2025 | 10:10h | UTC

Background: Type 2 diabetes (T2DM) is often regarded as a chronic, progressive disease. Nonetheless, trials such as DiRECT have challenged this view by demonstrating that remission may be achieved through substantial weight loss. SGLT2 inhibitors—among them dapagliflozin—induce urinary glucose excretion and moderate weight reduction, yet their ability to promote sustained remission of early T2DM is not fully understood. Recent editorials highlight the promise of combining pharmacological therapies with dietary interventions while stressing the need to address cost, sustainability, and patient selection for best outcomes.

Objective: This study aimed to determine whether adding dapagliflozin (10 mg/day) to a moderate calorie restriction diet (energy deficit of 500–750 kcal/day) could increase T2DM remission rates in overweight or obese adults with a notably short median diabetes duration of 0.2–0.3 years, relative to calorie restriction alone.

Methods: Researchers conducted a multicenter, double-blind, placebo-controlled, randomized trial at 16 centers in China, recruiting 328 adults (20–70 years old, body mass index >25) with early T2DM (duration <6 years). Patients who were currently using any antidiabetic medications other than metformin were excluded. Participants were allocated to receive dapagliflozin 10 mg/day or placebo for 12 months. Both groups received dietary counseling and were instructed to maintain a calorie deficit of 500–750 kcal/day. When individuals achieved normoglycemia (fasting plasma glucose <110 mg/dL and HbA1c <6.5%) for two consecutive months, all antidiabetic medications—including dapagliflozin—were discontinued. The primary outcome was diabetes remission (HbA1c <6.5% and fasting plasma glucose <126 mg/dL for ≥2 months off medications). Secondary endpoints included changes in weight, body composition, blood pressure, insulin resistance (HOMA-IR), and lipid profiles.

Results: Over 12 months, 44% of participants in the dapagliflozin-plus-diet arm achieved remission, compared with 28% in the diet-alone arm (risk ratio 1.56, 95% CI 1.17 to 2.09; P=0.002). Mean weight loss was −5.0 kg in the dapagliflozin group versus −3.2 kg in placebo, with additional improvements in body fat, systolic blood pressure, HDL cholesterol, and triglycerides. Mild and moderate adverse events occurred at similar rates in both groups, and two patients in the dapagliflozin arm experienced serious urinary tract infections requiring hospitalization. No deaths occurred during the trial.

Conclusions: Dapagliflozin combined with moderate calorie restriction resulted in a significantly higher remission rate of early T2DM (median duration 0.2–0.3 years) compared with calorie restriction alone. This combined intervention also led to greater reductions in body weight and improvements in cardiometabolic risk factors, with an acceptable safety profile over 12 months.

Implications for Practice: For clinicians managing adults with relatively short-duration T2DM, the addition of dapagliflozin to a structured dietary program may offer a promising route toward remission. Nevertheless, cost considerations—particularly for long-term SGLT2 inhibitor therapy—require thoughtful assessment in routine practice. While the required weight loss was more modest than in some very-low-calorie interventions, maintaining remission may still depend on ongoing lifestyle modification. Providers should also evaluate patient eligibility carefully, noting that the greatest benefits may be realized in those with early-stage disease and minimal comorbidity.

Study Strengths and Limitations: Strengths include a randomized, placebo-controlled design across multiple centers, a feasible dietary regimen, and robust participant adherence. Limitations include a relatively short follow-up after drug discontinuation, potentially overestimating durable remission, and use of a two-month remission definition that may not reflect sustained outcomes. Furthermore, the study population had very early-stage diabetes (median duration 0.2–0.3 years), limiting applicability to patients with longer-standing disease or different ethnic backgrounds.

Future Research: Longer-term trials are needed to assess whether extending the period of drug or lifestyle support can sustain remission and to identify subgroups most likely to benefit. Additional research should also evaluate how discontinuing SGLT2 inhibitors might impact cardiovascular and renal outcomes over time. Comparisons with newer agents that produce greater weight loss (e.g., GLP-1 receptor agonists) could further clarify optimal approaches.

Reference:

1. Liu Y, Chen Y, Ma J, et al. Dapagliflozin plus calorie restriction for remission of type 2 diabetes: multicentre, double blind, randomised, placebo controlled trial. The BMJ 2025; 388:e081820. DOI: https://doi.org/10.1136/bmj-2024-081820
2. Hope D, Valabhji J. SGLT2 inhibitors and dietary calorie restriction for type 2 diabetes remission (Editorial). The BMJ 2025; 388:r40. DOI: https://doi.org/10.1136/bmj.r40

 

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RCT: Sodium Zirconium Cyclosilicate Improves Spironolactone Uptitration in HFrEF but Raises Concern for Increased HF Events

28 Jan, 2025 | 10:00h | UTC

Background: Hyperkalemia remains a major barrier to optimal use of mineralocorticoid receptor antagonists (MRAs) in patients with heart failure and reduced ejection fraction (HFrEF). While MRAs significantly reduce morbidity and mortality, real-world data show that fears surrounding hyperkalemia often lead to MRA down-titration or discontinuation. Sodium zirconium cyclosilicate (SZC), a newer oral potassium binder, has shown promise in managing hyperkalemia. However, its impact on MRA optimization and clinical outcomes in HFrEF has not been fully established.

Objective: To determine whether SZC can enable optimal dosing of spironolactone (≥25 mg/day) by preventing hyperkalemia in patients with symptomatic HFrEF, and to assess potential effects on heart failure outcomes.

Methods: This prospective, double-blind, randomized-withdrawal trial (REALIZE-K) enrolled adult patients with left ventricular ejection fraction ≤40% (NYHA class II-IV), on guideline-directed medical therapy but not on a full-dose MRA due to either prevalent hyperkalemia (serum potassium [K⁺] 5.1-5.9 mEq/L) or high hyperkalemia risk. During an open-label run-in, spironolactone was up-titrated (target 50 mg/day), and participants with hyperkalemia received SZC. Only those who achieved normokalemia (3.5-5.0 mEq/L) on spironolactone ≥25 mg/day continued into a 6-month randomized-withdrawal phase (SZC vs placebo). The primary endpoint was maintenance of normokalemia while on ≥25 mg/day spironolactone without rescue therapy for hyperkalemia. Key secondary outcomes included the time to first hyperkalemia event, time to spironolactone dose reduction/discontinuation due to hyperkalemia, and changes in health-related quality of life (Kansas City Cardiomyopathy Questionnaire–Clinical Summary Score).

Results: A total of 203 participants were randomized (SZC: n=102; placebo: n=101). SZC significantly increased the proportion of participants who maintained normokalemia on ≥25 mg/day spironolactone (71% vs 36%; OR: 4.45; 95% CI: 2.89-6.86; p<0.001). Rates of hyperkalemia were also lower with SZC (HR: 0.51; 95% CI: 0.37-0.71; p<0.001), and fewer patients required spironolactone down-titration or discontinuation (HR: 0.37; 95% CI: 0.17-0.73; p=0.006). There was no difference in KCCQ-Clinical Summary Score between groups (p=0.72). Notably, more participants in the SZC arm had adjudicated heart failure events (10 vs 2 in placebo) over the 6-month period, although the trial was not powered to detect differences in clinical outcomes.

Conclusions: In patients with symptomatic HFrEF and prevalent or incident hyperkalemia, sodium zirconium cyclosilicate (SZC) successfully enabled higher spironolactone doses by maintaining potassium levels in the normal range. However, the increased rate of heart failure (HF) events in the SZC group raises concern, particularly given the study’s limited power for clinical outcomes and baseline imbalances favoring higher HF risk in the SZC group (older age, lower eGFR, higher NT-proBNP). Although these findings do not establish a definitive causal relationship, they underscore a possible risk of fluid retention and the importance of cautious use in higher-risk populations. Larger, event-driven trials are crucial to confirm whether SZC-related sodium exchange may exacerbate HF decompensation despite the benefits of more effective MRA therapy.

Implications for Practice: SZC offers clinicians a means to sustain or escalate spironolactone dosing in hyperkalemia-prone HFrEF patients who would otherwise face MRA discontinuation. Still, the unexpected signal of increased HF events highlights the need for vigilant patient selection, fluid status monitoring, and regular follow-up. Clinicians should balance the advantages of maintaining guideline-recommended MRA doses against potential costs, the patient’s baseline HF severity, and possible sodium retention. Individualized care, particularly in older patients or those with high NT-proBNP levels, remains critical until more robust outcome data are available.

Study Strengths and Limitations: Strengths include strict definitions of hyperkalemia, a rigorous protocol for titrating spironolactone and SZC, and high rates of concurrent guideline-directed therapies. Limitations encompass the modest sample size, short follow-up period, and imbalance in baseline risk factors favoring the placebo group. Also, the study was not powered for major clinical events, limiting interpretability of the heart failure outcome signals.

Future Research: Further large-scale, long-term investigations are needed to clarify whether the higher incidence of HF events seen with SZC reflects underlying population differences or a genuine treatment-related risk. Such studies should prioritize hard clinical endpoints (eg, HF hospitalization, cardiovascular mortality), capture real-world tolerability data, and incorporate cost-effectiveness analyses. Research into the mechanisms of sodium exchange in compromised HF patients may also help identify subgroups that stand to gain the most from potassium-binding strategies or, conversely, experience undue risk.

Reference: Kosiborod MN, Cherney DZI, Desai AS, et al. “Sodium Zirconium Cyclosilicate for Management of Hyperkalemia During Spironolactone Optimization in Patients With Heart Failure.” Journal of the American College of Cardiology. 2025; DOI: https://doi.org/10.1016/j.jacc.2024.11.014

 

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2024 VA/DOD Clinical Practice Guideline for Stroke Rehabilitation

26 Jan, 2025 | 17:07h | UTC

Introduction:
This document summarizes the updated 2024 clinical practice guideline (CPG) jointly developed by the U.S. Department of Veterans Affairs (VA) and the U.S. Department of Defense (DOD). It addresses stroke rehabilitation across inpatient, outpatient, and community settings, emphasizing an interdisciplinary approach. The main objective is to provide evidence-based recommendations to guide clinical decision-making and improve functional outcomes and quality of life for adult stroke survivors.

Key Recommendations:

1. Transition to Community
   • Case Management: Suggest using case management services at discharge to enhance activities of daily living (ADLs) and functional independence (“weak for”).
   • Behavioral/Psychosocial Interventions: Recommend psychosocial supports, such as stress management and motivational interviewing, to improve patient and caregiver depression, family function, and overall quality of life (“weak for”).
   • Psychoeducation: Encourage structured education on stroke care and self-management for patients and their caregivers to boost functional independence and social support.
2. Motor Therapy
   • Task-Specific Practice: Strongly recommend repetitive or task-oriented practice to improve motor function, gait, posture, and ADLs (“strong for”).
   • Mirror Therapy: Suggest mirror therapy to improve motor outcomes, ADLs, and unilateral spatial neglect (“weak for”).
   • Rhythmic Auditory Stimulation: Suggest adding external auditory cues (e.g., music or metronome) to assist in gait training (“weak for”).
   • Neuromuscular Electrical Stimulation: Suggest neuromuscular electrical stimulation for enhancing upper- or lower-extremity motor recovery (“weak for”).
   • Botulinum Toxin for Spasticity: Suggest botulinum toxin for focal spasticity, considering patient-specific characteristics and preferences, though evidence shows comparable efficacy to oral baclofen except in ankle spasticity (“weak for”).
3. Dysphagia, Aphasia, and Cognition
   • Dysphagia Rehabilitation:
     • Chin tuck against resistance for swallowing impairment (“weak for”).
     • Respiratory muscle strength training (for those without tracheostomy) to reduce aspiration risk (“weak for”).
   • Aphasia Rehabilitation:
     • No specific intensity level of language therapy is proven superior; tailor therapy duration and frequency to individual needs (“neither for nor against”).
   • Cognitive Outcomes:
     • Current evidence does not support or refute SSRIs for cognitive recovery; consider other individualized cognitive rehabilitation strategies (“neither for nor against”).
   • Unilateral Spatial Neglect:
     • Mirror therapy may help address neglect and improve ADLs (“weak for”).
4. Mental Health
   • Depression Treatment:
     • Suggest SSRIs or SNRIs for patients with established poststroke depression (“weak for”).
     • Recommend psychotherapy (e.g., cognitive behavioral therapy) and consider mindfulness-based therapies for depression following stroke (“weak for”).
   • Prevention of Depression:
     • Suggest against prophylactic antidepressants for preventing poststroke depression due to risk of adverse effects, such as fractures (“weak against”).
5. Telehealth
   • Consider telerehabilitation as an alternative or adjunct to in-person therapy if it aligns with patient preferences and clinical feasibility (“weak for”).
   • Evidence is inconclusive regarding telerehabilitation for dysphagia, aphasia, or caregiver support; use individualized judgment (“neither for nor against”).
6. Noninvasive Brain Stimulation
   • Insufficient evidence to recommend for or against repetitive transcranial magnetic stimulation (rTMS), transcranial direct current stimulation (tDCS), or continuous theta burst stimulation to enhance motor recovery (“neither for nor against”).

Conclusion:
These updated 2024 VA/DOD stroke rehabilitation guidelines underscore the importance of an interdisciplinary and patient-centered approach that integrates medical, psychological, and rehabilitative strategies. Adopting these recommendations—particularly around early case management, targeted motor therapies (task-specific practice, mirror therapy, neuromuscular electrical stimulation), dysphagia interventions, and tailored mental health treatments—can improve functional outcomes, optimize quality of life, and reduce poststroke morbidity.

Reference:

• Eapen BC, Tran J, Ballard-Hernandez J, et al. Stroke Rehabilitation: Synopsis of the 2024 U.S. Department of Veterans Affairs and U.S. Department of Defense Clinical Practice Guidelines. Annals of Internal Medicine. 2025. DOI: https://doi.org/10.7326/ANNALS-24-02205
• Cramer SC. Moving Stroke Rehabilitation Forward and Into the Future. Annals of Internal Medicine. 2025. DOI: https://doi.org/10.7326/ANNALS-24-03568

 

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RCT: Albendazole–Ivermectin Co-Formulation Achieves Higher Cure Rates for T. trichiura and Hookworms

22 Jan, 2025 | 12:41h | UTC

Background: Soil-transmitted helminthiases (STH) affect an estimated 1.5 billion people worldwide, with Trichuris trichiura and hookworms remaining particularly challenging to treat. Although single-dose albendazole or mebendazole is standard in mass deworming programs, these agents show limited efficacy against T. trichiura and often leave Strongyloides stercoralis under-treated. Ivermectin has demonstrated broad activity against multiple parasites, suggesting that a combined albendazole–ivermectin regimen might enhance treatment outcomes, simplify protocols, and potentially curb emerging drug resistance.

Objective: This trial aimed to evaluate the safety, efficacy, and acceptability of a novel fixed-dose co-formulation (FDC) tablet containing albendazole (400 mg) plus a higher-than-standard, fixed dose of ivermectin (9 mg or 18 mg), administered once daily (FDC×1) or for three consecutive days (FDC×3). Investigators compared these regimens against single-dose albendazole alone for the treatment of T. trichiura, hookworms, and S. stercoralis in children and adolescents.

Methods: In this adaptive, randomized, parallel-group, phase 2/3 trial, 1001 participants aged 5–18 years were recruited from schools in Ethiopia, Kenya, and Mozambique. All were infected with at least one of T. trichiura, hookworms, or S. stercoralis. Eligible participants were allocated (by computer-generated block randomization) to either a single dose of albendazole 400 mg (control), a single-dose FDC of albendazole–ivermectin (FDC×1), or a three-day FDC regimen (FDC×3). Primary endpoints included safety (phase 2) and efficacy (phase 3), determined by cure rates at day 21 using the Kato–Katz and Baermann methods. Laboratory staff were blinded to treatment assignment.

Results: No serious adverse events were reported; mild-to-moderate gastrointestinal symptoms were the most frequent treatment-related events, resolving spontaneously within 48 hours. Cure rates for T. trichiura were 35.9% (95% CI 27.7–44.1) in the albendazole group, 82.9% (78.2–87.5) in FDC×1, and 97.2% (95.2–99.3) in FDC×3. For hookworms, cure rates were 65.1% (56.0–74.2) with albendazole, 79.8% (72.8–86.9) with FDC×1, and 95.0% (91.1–98.9) with FDC×3. Egg reduction rates in FDC arms consistently surpassed those of albendazole alone, especially for multi-day dosing. The sample size for S. stercoralis was insufficient to power a definitive efficacy conclusion, though ivermectin-containing arms trended toward favorable results. Palatability questionnaires indicated the orodispersible FDC was well accepted in taste, texture, and overall ease of administration.

Conclusions: A new co-formulation of albendazole plus ivermectin delivered at higher, fixed doses demonstrated an excellent safety profile and superior efficacy against T. trichiura and hookworms compared with albendazole monotherapy. This approach may streamline programmatic control of multiple STH species, including S. stercoralis, while contributing to reduced transmission in endemic communities.

Implications for Practice: For mass deworming initiatives, a single-dose FDC offers improved cure rates over albendazole alone while preserving simplicity. Where higher efficacy is critical—such as programs targeting near-elimination goals or in clinical settings—the three-day regimen may be preferable. Nonetheless, implementation feasibility, cost considerations, and further confirmation of efficacy against S. stercoralis and other co-endemic parasites remain important next steps.

Study Strengths and Limitations: Strengths include a multicenter design across three countries and a rigorous adaptive protocol that assessed both safety and efficacy. Limitations include the lack of blinding for participants and care providers (though outcome assessors were blinded), the underpowered sample size for S. stercoralis, and reliance on single-stool diagnostics, which may underestimate residual infections.

Future Research: Additional large-scale studies should confirm these findings in varied geographic regions and evaluate the cost-effectiveness of both single-dose and multi-day FDC strategies. Integrating albendazole–ivermectin with treatment programs for other neglected tropical diseases (e.g., onchocerciasis) could further amplify public health benefits. Genomic and pharmacokinetic analyses will clarify resistance patterns and optimize dosing regimens for broader implementation.

Reference: Krolewiecki A, Kepha S, Fleitas PE, van Lieshout L, Gelaye W, Messa A Jr, et al. “Albendazole–ivermectin co-formulation for the treatment of Trichuris trichiura and other soil-transmitted helminths: a randomised phase 2/3 trial.” The Lancet Infectious Diseases. Published January 10, 2025. DOI: https://doi.org/10.1016/S1473-3099(24)00669-8

 

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2024 ACC/AHA Guideline for the Management of Lower Extremity Peripheral Artery Disease

21 Jan, 2025 | 12:44h | UTC

Introduction:
This summary highlights key points from the 2024 ACC/AHA guideline on managing patients with lower extremity peripheral artery disease (PAD). It addresses diagnosis, risk stratification, and treatment strategies to reduce major adverse cardiovascular events (MACE) and major adverse limb events (MALE), focusing on four clinical subsets of PAD—asymptomatic PAD, chronic symptomatic PAD, chronic limb-threatening ischemia (CLTI), and acute limb ischemia (ALI). Its overarching goal is to optimize cardiovascular risk reduction, preserve limb function, and improve quality of life (QOL).

Key Recommendations:

1. Clinical Assessment and Diagnosis
   • Perform a thorough history and physical examination in patients at risk of PAD (e.g., older adults, those with diabetes, hypertension, dyslipidemia, smokers, or known atherosclerosis).
   • Measure the ankle-brachial index (ABI) to establish the diagnosis of PAD; use toe-brachial index (TBI) for patients with noncompressible arteries.
   • Obtain imaging (e.g., duplex ultrasound, CT angiography, MR angiography) when planning revascularization or in cases with inconclusive ABI.
2. Risk Factor Management (Guideline-Directed Medical Therapy)
   • Antiplatelet and Antithrombotic Therapy:
     • Recommend single antiplatelet therapy (e.g., aspirin or clopidogrel) for symptomatic PAD to reduce MACE.
     • Consider low-dose rivaroxaban (2.5 mg twice daily) plus low-dose aspirin in patients at low bleeding risk to reduce MALE.
   • Lipid-Lowering Therapy:
     • Initiate high-intensity statin therapy in all patients with PAD to reduce cardiovascular and limb events.
     • Add ezetimibe or a PCSK9 inhibitor if LDL-C levels remain above target (≥70 mg/dL).
   • Blood Pressure Control:
     • Target a systolic blood pressure <130 mm Hg in patients with PAD; ACE inhibitors or angiotensin-receptor blockers can further reduce cardiovascular risk.
   • Diabetes Management:
     • Optimize glycemic control, especially in CLTI; newer agents (e.g., SGLT2 inhibitors, GLP-1 receptor agonists) can reduce cardiovascular risk in PAD with type 2 diabetes.
   • Smoking Cessation:
     • Strongly advise cessation of all forms of tobacco and nicotine; offer pharmacotherapy (e.g., varenicline, bupropion, nicotine replacement) and behavioral counseling.
3. Exercise Therapy
   • Supervised Exercise Therapy (SET):
     • A cornerstone of care for patients with claudication to improve walking performance and quality of life.
     • Generally performed 3 times per week for at least 12 weeks in a supervised setting (e.g., cardiac rehab facility).
   • Structured Community-Based (Home-Based) Programs:
     • Include regularly prescribed walking regimens, with periodic clinical follow-up and coaching to promote adherence.
4. Revascularization for Chronic Symptomatic PAD
   • Initial Approach:
     • Offer revascularization (endovascular, surgical, or hybrid) if patients have functionally limiting claudication that fails to improve with medical therapy and structured exercise.
   • Endovascular vs. Surgical:
     • Select a strategy based on lesion characteristics, availability of adequate vein conduit, and patient comorbidities.
     • Combining revascularization with supervised exercise generally yields better functional outcomes.
   • Common Femoral Disease:
     • Surgical endarterectomy remains a highly durable option.
     • Endovascular approaches can be considered for select cases, particularly where surgical risk is high or anatomy is favorable.
5. Management of Chronic Limb-Threatening Ischemia (CLTI)
   • Team-Based Care:
     • Collaborate with vascular specialists, podiatrists, wound-care experts, and other clinicians for optimal outcomes.
   • Revascularization Goals:
     • Prevent amputation, heal wounds, and reduce rest pain.
     • Both endovascular and surgical methods can be effective; selection depends on anatomy, available vein conduit, and patient risk profile (e.g., the BEST-CLI and BASIL-2 trials guide decisions).
   • Adjunctive Wound Care:
     • Use local wound management (e.g., debridement, negative pressure therapy, offloading) to facilitate healing.
     • Treat infection aggressively; urgent revascularization plus antibiotics is essential.
   • Pressure Offloading:
     • Custom footwear and casts/shoes reduce plantar pressure and help prevent or heal foot ulcers.
6. Acute Limb Ischemia (ALI)
   • Immediate Recognition:
     • Suspect ALI in patients with sudden onset of pain, pallor, pulselessness, paresthesia, and paralysis.
     • Determine limb viability (categories I–III) rapidly.
   • Treatment:
     • Begin anticoagulation (e.g., IV unfractionated heparin) unless contraindicated.
     • Urgent revascularization (surgical embolectomy, catheter-directed thrombolysis, or mechanical thrombectomy) for salvageable limbs.
     • Monitor for compartment syndrome and consider fasciotomy if needed.
7. Preventive Foot Care
   • Educate patients on self-inspection, daily hygiene, and protective footwear.
   • Screen regularly for high-risk conditions (neuropathy, calluses, deformities, infection).
   • Promptly address any foot lesions to avoid progression to ulceration, infection, or gangrene.
8. Longitudinal Follow-Up
   • Schedule regular visits to monitor:
     • Cardiovascular risk factor control (lipids, blood pressure, glycemic targets, smoking).
     • Lower extremity symptoms, functional status, and foot health.
     • Need for repeat ABI, duplex ultrasound, or imaging after revascularization to detect restenosis.
   • Reinforce adherence to structured exercise, medication regimens, and foot care strategies.

Conclusion:
These recommendations underscore the importance of personalized, multidisciplinary care that addresses both cardiovascular and limb-related outcomes in patients with lower extremity PAD. A combination of comprehensive risk-factor modification, supervised or structured exercise programs, and strategic use of revascularization can significantly reduce the risk of major limb loss, improve symptoms, and enhance QOL. Ongoing follow-up is critical to detect disease progression, optimize therapy, and maintain patient engagement in preventative care.

Reference:
2024 ACC/AHA/AACVPR/APMA/ABC/SCAI/SVM/SVN/SVS/SIR/VESS Guideline for the Management of Lower Extremity Peripheral Artery Disease: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2024; DOI: https://doi.org/10.1161/CIR.0000000000001251

 

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Pseudo-Endocrine Disorders: Clinical Realities and Responsible Management

20 Jan, 2025 | 11:42h | UTC

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Network Meta-analysis: Oseltamivir Fails to Improve Key Outcomes in Nonsevere Influenza

20 Jan, 2025 | 11:17h | UTC

Background: Influenza causes significant respiratory morbidity and can lead to severe complications, especially in high-risk individuals. Current guidelines endorse antiviral therapy, yet the evidence for reducing mortality, hospital admission, and symptom duration in nonsevere cases remains controversial. Recent recommendations have often focused on neuraminidase inhibitors (e.g., oseltamivir), despite uncertainties regarding clinical impact and adverse effects. An editorial accompanying this study underscores the need to reexamine routine antiviral use, especially oseltamivir, given minimal benefit observed in outpatient populations.

Objective: To assess and compare the efficacy and safety of direct-acting antiviral medications (baloxavir, oseltamivir, laninamivir, zanamivir, peramivir, umifenovir, favipiravir, and amantadine) in treating patients with nonsevere influenza.

Methods: This systematic review and network meta-analysis included 73 randomized clinical trials (N=34,332) that evaluated antivirals vs placebo, standard care, or another antiviral. Eligible studies enrolled nonhospitalized patients with confirmed or suspected influenza. Outcomes included mortality, hospital admission, time to symptom alleviation, adverse events, and emergence of antiviral resistance. Risk of bias was assessed with a modified Cochrane tool, and the certainty of evidence was rated using the GRADE approach. Pooled estimates were generated with a frequentist random-effects model, focusing on both absolute risk differences and relative measures.

Results:

• Mortality: Across all antiviral agents, there was high-certainty evidence of little or no effect on mortality in both low-risk and high-risk patients compared with standard care or placebo.
• Hospital Admission: In low-risk patients, none of the antivirals significantly altered admission rates (high certainty). In high-risk patients, oseltamivir had little or no effect on hospitalization (high certainty), whereas baloxavir may reduce admissions (low certainty).
• Time to Alleviation of Symptoms: Baloxavir shortened symptom duration by approximately one day (moderate certainty) without increasing adverse events. Oseltamivir and zanamivir likely produced smaller decreases (<1 day; moderate certainty). Umifenovir may also shorten symptoms (low certainty).
• Adverse Events: Baloxavir did not increase treatment-related adverse events (high certainty) but may lead to viral resistance in around 10% of cases (low certainty). Oseltamivir probably increases adverse events such as nausea and vomiting (moderate certainty).
• Serious Outcomes (ICU Admission, Duration of Hospitalization): Data were limited, with uncertainty regarding meaningful reductions in these measures.

Conclusions: Baloxavir may reduce hospital admissions for high-risk patients and significantly shorten symptom duration without notable treatment-related adverse events. Oseltamivir shows little effect on mortality or hospitalization for nonsevere influenza, with only modest (likely not clinically important) reductions in symptom duration and a higher rate of adverse events. Other antivirals either demonstrate uncertain clinical benefits or likely provide no major advantages in this patient population.

Implications for Practice: These findings suggest that routine use of oseltamivir for outpatients with nonsevere influenza should be reconsidered, especially in low-risk groups. Baloxavir appears favorable for high-risk patients, though clinicians should monitor potential drug resistance. Given the minimal impact on major outcomes and the cost considerations, prescribers should weigh the benefits and harms of these antivirals, aligning treatment decisions with patient risk profiles and clinical judgment.

Study Strengths and Limitations: Strengths include a comprehensive search, large pooled population, and rigorous GRADE-based analysis of certainty. Limitations involve low event rates for hospital admissions and mortality, limiting power for certain outcomes, and sparse data on some antivirals (e.g., amantadine). Additionally, few trials reported ICU admissions or mechanical ventilation needs, restricting conclusions about severe complications.

Future Research: Further high-quality studies should evaluate patient-important outcomes such as mechanical ventilation and severe complications in diverse populations. Investigations into combination strategies, alternative dosing, and resistance patterns would help clarify the long-term viability of baloxavir and other antivirals, particularly in high-risk cohorts.

Reference:

1. Gao Y, Zhao Y, Liu M, et al. Antiviral Medications for Treatment of Nonsevere Influenza: A Systematic Review and Network Meta-Analysis. JAMA Internal Medicine. Published online January 13, 2025. DOI: http://doi.org/10.1001/jamainternmed.2024.7193
2. Baghdadi JD, Grady D, Morgan DJ. The Limited Role for Antiviral Therapy in Influenza. JAMA Internal Medicine. Published online January 13, 2025. DOI: http://doi.org/10.1001/jamainternmed.2024.7258

 

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Network Meta-Analysis: Distinct Benefit–Risk Profiles of GLP-1 Receptor Agonists, DPP-4 Inhibitors, and SGLT2 Inhibitors

19 Jan, 2025 | 12:27h | UTC

Background: Type 2 diabetes (T2D) is a global health challenge due to its high prevalence and associated risks for cardiovascular (CV) and renal complications. Newer glucose-lowering drug (GLD) classes—dipeptidyl peptidase 4 inhibitors (DPP4i), glucagon-like peptide-1 receptor agonists (GLP-1RAs), and sodium-glucose cotransporter 2 inhibitors (SGLT2i)—offer unique benefits and safety profiles. Although many large randomized outcome trials have demonstrated their efficacy, the benefit–risk balance among these agents remains incompletely understood, especially regarding non-traditional outcomes such as psychiatric disorders and neurodegenerative diseases. Given their generally higher costs and frequent industry sponsorship of the trials, it is critical to evaluate these classes in a systematic and impartial manner.

Objective: To systematically compare the benefits and risks of DPP4i, GLP-1RAs, and SGLT2i in adults with T2D, heart failure, or chronic kidney disease, focusing on 21 outcomes spanning macrovascular and microvascular events, infections, psychiatric outcomes, and cancer risk.

Methods: Researchers searched PubMed, Embase, and CENTRAL through November 2023 for randomized placebo-controlled cardiovascular and kidney outcome trials of DPP4i, GLP-1RAs, or SGLT2i in adults with T2D, heart failure, or chronic kidney disease. Twenty-six trials (N=198,177 participants) met inclusion criteria. A novel PAtient-centered treatment ranking via Large-scale Multivariate network meta-analysis (PALM) approach was used to synthesize population-averaged odds ratios (ORs) with 95% confidence intervals (CIs). This approach allowed for the simultaneous evaluation of multiple outcomes and the generation of weighted origami plots to visualize treatment rankings across different disease categories. Heterogeneity (I²) and publication bias (Egger’s test) were also assessed.

Results:

• Macrovascular: GLP-1RAs reduced major adverse cardiovascular events (MACE) versus placebo (OR 0.85, 95% CI 0.79–0.92) and DPP4i. GLP-1RAs also lowered stroke risk (OR range 0.82–0.85 vs comparators). SGLT2i yielded the largest reduction in hospitalization for heart failure (OR 0.68, 95% CI 0.64–0.73 vs placebo). DPP4i had a lower amputation risk relative to SGLT2i (OR 0.85, 95% CI 0.75–0.95).
• Microvascular: SGLT2i most effectively reduced renal composite outcomes versus DPP4i and placebo (OR ~0.67). However, DPP4i was linked to higher neuropathy risk (OR 1.10, 95% CI 1.02–1.18 vs placebo).
• Psychiatric and Neurodegenerative: DPP4i was associated with a reduced risk of depression, suicide, and alcohol use disorder compared to placebo. A lower Parkinson’s disease risk (OR 0.54, 95% CI 0.32–0.92) was also noted. GLP-1RAs showed a possible increased risk of suicidal ideation vs DPP4i, though evidence remains inconclusive.
• Infections/Inflammation: SGLT2i substantially increased genital infections (OR 3.11, 95% CI 2.15–4.50 vs placebo). DPP4i had higher pancreatitis risk vs all comparators.
• Cancer: GLP-1RAs were linked to increased thyroid cancer risk (OR range 1.58–2.70), though overall cancer risk and pancreatic cancer did not differ significantly across treatments.

Conclusions: Each newer GLD class offers specific advantages along with distinct safety considerations. GLP-1RAs appear particularly effective for macrovascular endpoints but carry a signal for thyroid malignancy. SGLT2i provide notable cardioprotective and renoprotective effects, offset by risk of genital infections and an increased risk of amputation compared to DPP4i. DPP4i tend to have neutral CV/renal outcomes yet may protect against certain psychiatric issues and neurodegenerative conditions, balanced by increased pancreatitis risk. Personalized treatment strategies, with attention to comorbidities and adverse event profiles, remain essential—particularly given the generally elevated costs of these newer agents. It is important to note that these findings are largely based on indirect comparisons in the absence of head-to-head trials, which is a limitation.

Implications for Practice: Clinicians should weigh cardiovascular risk, kidney function, mental health status, and potential malignancy when prescribing GLDs. SGLT2i may be favored in patients with heart failure or chronic kidney disease, while GLP-1RAs may be ideal for those with high atherosclerotic CV risk. DPP4i could be considered in patients with psychiatric or neurologic comorbidities but require caution regarding pancreatitis. Cost considerations and access may also influence real-world use.

Study Strengths and Limitations: Strengths include a large number of participants, broad outcome coverage, and a multivariate network meta-analysis that accommodates indirect comparisons. Limitations arise from underreported outcomes (e.g., psychiatric, neurodegenerative), heterogeneous trial populations, potential publication bias for some outcomes, and possible off-target influences not fully captured. Furthermore, sponsor involvement in all included trials warrants cautious interpretation of benefit–risk claims.

Future Research: Head-to-head trials comparing newer GLDs for psychiatric and neurologic endpoints, along with detailed reporting of rare adverse events (e.g., pancreatitis, cancer subtypes), are needed. Studies on real-world cost-effectiveness and access issues could clarify how to optimize therapy in routine practice. Additional investigations into long-term safety signals (including suicidality and thyroid malignancies) would further guide clinical decision-making.

Reference: Tang H, Zhang B, Lu Y, Donahoo WT, Singh Ospina N, Kotecha P, Lu Y, Tong J, Smith SM, et al. “Assessing the benefit–risk profile of newer glucose-lowering drugs: A systematic review and network meta-analysis of randomized outcome trials.” Diabetes, Obesity and Metabolism. First published: 26 December 2024. DOI: http://doi.org/10.1111/dom.16147

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Review: Identification and Treatment of Alcohol Use Disorder

19 Jan, 2025 | 11:41h | UTC

Introduction: This summary provides key insights from a comprehensive review published in the New England Journal of Medicine about the clinical identification and management of alcohol use disorder (AUD). The document highlights AUD’s chronic, relapsing course, its underdiagnosis in general practice, and its wide-ranging health and social impacts. Emphasis is placed on early recognition, the importance of nonjudgmental communication, and the potential for effective treatment across various medical settings.

Key Recommendations:

• Routine Screening and Assessment: Clinicians should routinely ask about alcohol use, employing validated tools (e.g., AUDIT, AUDIT-C, or CAGE) to gauge risk. When self-reporting is unreliable, biologic markers (e.g., γ-glutamyl transpeptidase or phosphatidylethanol) can help detect recent or chronic use.
• Nonjudgmental, Patient-Centered Approach: Engagement improves when patients feel supported rather than stigmatized. Collaboration in care planning can enhance adherence, especially for individuals who are ambivalent about changing their alcohol consumption patterns.
• Brief Interventions: Time-limited counseling, guided by motivational interviewing principles, is effective in reducing alcohol use. These interventions can be delivered by primary care professionals and may motivate further treatment or pharmacotherapy.
• Psychosocial Therapies: Multiple methods—including cognitive behavioral therapy, motivational enhancement, acceptance and commitment therapy, and peer-supported programs (e.g., Alcoholics Anonymous, SMART Recovery)—offer benefit. Clinicians are encouraged to adapt and integrate these treatments based on availability, patient preference, and severity of dependence.
• Pharmacologic Treatment: Medications such as naltrexone (once daily), acamprosate (three times daily), and supervised disulfiram are approved and effective for AUD. Naltrexone helps reduce craving and heavy drinking; acamprosate supports abstinence; and disulfiram, though aversive if alcohol is consumed, can reinforce abstinence in motivated patients. Other agents (e.g., topiramate, gabapentin) show promise but are not universally approved.
• Management of Withdrawal: Outpatient or inpatient treatment of withdrawal depends on clinical stability and coexisting conditions. Benzodiazepines remain first-line for symptom control, with close monitoring to prevent complications like seizures and delirium tremens. Nutritional support, particularly thiamine replacement, is essential to avert Wernicke–Korsakoff syndrome.
• Addressing Coexisting Conditions: AUD commonly co-occurs with mental health disorders (e.g., depression, anxiety) and other substance use (especially tobacco). Screening for suicidality and referring for specialized care can improve overall outcomes. Medical complications (e.g., alcoholic liver disease, hypertension) may also improve with sustained alcohol reduction or abstinence.
• Ongoing Support and Follow-up: AUD has a relapsing course, so long-term care, repeated assessments, and revisiting treatment goals are crucial. Follow-up visits can reinforce progress, manage relapses, and promote sustained recovery efforts.

Conclusion: Recognizing and treating alcohol use disorder significantly improves patient outcomes in both physical and mental domains. Generalist clinicians play a pivotal role in screening, initiating brief interventions, and coordinating care. Timely, evidence-based interventions and a supportive, empathetic stance can reduce the immense burden of AUD, enhance treatment retention, and improve quality of life for affected individuals.

Reference: Haber PS. Identification and Treatment of Alcohol Use Disorder. New England Journal of Medicine. 2025;392:258-266. DOI: http://doi.org/10.1056/NEJMra2306511

 

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RCT: Infrequent Zoledronate Infusions Reduce Vertebral Fractures in Early Postmenopausal Women Without Osteoporosis

18 Jan, 2025 | 16:48h | UTC

Background: Osteoporosis prevention typically targets older, higher-risk populations with significantly reduced bone mineral density (BMD). However, many fragility fractures occur in women who do not meet the traditional diagnostic threshold for osteoporosis (T score ≤ –2.5). This study investigated whether infrequent administration of zoledronate could prevent vertebral fractures in early postmenopausal women (50 to 60 years of age) who have BMD values between normal and osteoporotic ranges.

Objective: To determine if administering intravenous zoledronate once at baseline—and again 5 years later—could reduce the incidence of morphometric vertebral fractures and other fracture types over a 10-year period in early postmenopausal women without osteoporosis.

Methods:

• Design: A 10-year, prospective, double-blind, randomized, placebo-controlled trial.
• Population: 1054 women (mean age 56.0) within 10 years post-menopause, with lumbar spine or hip T scores <0 but >–2.5, recruited from the electoral roll in Auckland, New Zealand.
• Interventions: Participants were randomly assigned (1:1:1) to receive:
  1. Zoledronate 5 mg at baseline and again at Year 5 (zoledronate–zoledronate)
  2. Zoledronate 5 mg at baseline and placebo at Year 5 (zoledronate–placebo)
  3. Placebo infusions at baseline and Year 5 (placebo–placebo)
• Follow-up: 10 years, with repeated BMD and spine X-ray assessments at baseline, Year 5, and Year 10.
• Primary Endpoint: Incidence of new morphometric vertebral fractures, defined by semiquantitative radiographic methods.
• Secondary Endpoints: Fragility fracture, any fracture, major osteoporotic fracture, changes in BMD, and bone-turnover markers.

Results:

• Vertebral Fractures: Over 10 years, 6.3% of participants in the zoledronate–zoledronate group and 6.6% in the zoledronate–placebo group experienced a new morphometric vertebral fracture, versus 11.1% in placebo–placebo. After imputation, the relative risks versus placebo–placebo were 0.56 (95% CI, 0.34–0.92; p=0.04) and 0.59 (95% CI, 0.36–0.97; p=0.08), respectively.
• Other Fractures: The zoledronate–zoledronate group had a 30% reduced risk of any fracture (RR, 0.70; 95% CI, 0.56–0.88), and zoledronate–placebo showed a 23% reduction (RR, 0.77; 95% CI, 0.62–0.97), both compared with placebo–placebo.
• Bone Mineral Density: At Year 10, the zoledronate–zoledronate group had sustained BMD gains (~7–9 percentage points above placebo), whereas the zoledronate–placebo group retained a moderate advantage (~5–6 percentage points above placebo).
• Bone-Turnover Markers: Markers remained suppressed in the zoledronate–zoledronate group through Year 10, while in the zoledronate–placebo group, they gradually rose after Year 5 but stayed below baseline levels.
• Safety: Few adverse events were reported. Uveitis or episcleritis after the first infusion occurred in 1.1% of zoledronate recipients. No cases of osteonecrosis of the jaw or atypical femoral fractures were observed.

Conclusions: A single 5-mg dose of zoledronate, with an optional additional dose at five years, reduced the incidence of morphometric vertebral fractures and helped preserve BMD in younger postmenopausal women without osteoporosis. Both zoledronate regimens showed notable fracture-risk reductions and sustained effects on bone turnover.

Implications for Practice: These findings extend the potential role of zoledronate in fracture prevention to younger, early postmenopausal women without osteoporosis. Infrequent infusions are attractive because of their prolonged pharmacologic action and generally favorable safety profile. However, caution is warranted before broadly implementing this strategy for all postmenopausal women, as the data come from a relatively homogenous population and do not address other risk factors or comorbidities. Real-world adherence, healthcare resource allocation, and patient preferences must all be considered. Moreover, further evaluation of cost-effectiveness is essential, especially if expanding use to large populations. Longer follow-up in broader and more diverse groups may reveal less common adverse events that were not detected in this trial. Clinicians should therefore weigh individual risk–benefit profiles and await additional data before making universal recommendations.

Study Strengths and Limitations:

• Strengths: The trial’s 10-year duration, double-blind design, and high retention rate enhance its internal validity. Using radiographic assessments for vertebral fractures adds objectivity and robustness.
• Limitations: The trial predominantly involved healthy, early postmenopausal women of European descent, limiting the applicability of the findings to other ethnicities, older populations, or those with complex comorbidities. Only two zoledronate infusions at a five-year interval were evaluated, leaving the optimal dosing frequency unresolved. Further, while adverse events appeared uncommon here, the sample size and population profile may not adequately capture rare or long-latency adverse outcomes.

Future Research: Larger trials in more diverse demographic and clinical settings are necessary to determine whether infrequent zoledronate can safely and effectively reduce fracture risk across broader patient groups. Studies comparing different dosing schedules, as well as investigations into cost-effectiveness and logistics of administration, would be highly valuable. Longer-term surveillance in real-world cohorts should help clarify the incidence of uncommon adverse events. Ultimately, such additional evidence will guide whether infrequent zoledronate infusions might be integrated into routine practice for fracture prevention in postmenopausal women without osteoporosis.

Reference:

1. Bolland MJ, Nisa Z, Mellar A, et al. Fracture Prevention with Infrequent Zoledronate in Women 50 to 60 Years of Age. New England Journal of Medicine. 2025;392:239-248. DOI: http://doi.org/10.1056/NEJMoa2407031
2. Chapurlat R. Infrequent Zoledronate — Small Individual Gain, Larger Population Gain. New England Journal of Medicine. 2025;392:281-283. DOI: http://doi.org/10.1056/NEJMe2415376

 

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Screening for Osteoporosis to Prevent Fractures: Updated USPSTF Guidelines

18 Jan, 2025 | 15:19h | UTC

Introduction: This document summarizes the 2025 US Preventive Services Task Force (USPSTF) guideline on screening for osteoporosis to prevent fragility fractures. Osteoporosis, characterized by low bone mass and decreased bone quality, can lead to fractures that impair independence, increase morbidity, and raise mortality. The revised guidance builds on evidence that screening in select populations reduces fracture risk. Although the Task Force finds moderate net benefit for screening certain groups, it concludes that evidence remains insufficient to assess benefits and harms in other segments.

Key Recommendations:

1. Population and Rationale:
   • Women 65 years or older: The USPSTF concludes with moderate certainty that screening for osteoporosis in this age group leads to moderate net benefit for preventing osteoporotic fractures.
   • Postmenopausal women younger than 65 years at increased risk: Screening is recommended if a formal risk assessment or clinical risk factors indicate elevated risk, as moderate certainty suggests moderate benefit.
   • Men: The current evidence is insufficient to establish the balance of benefits and harms of screening men without known osteoporosis or prior fragility fractures.
2. Screening Methods:
   • The USPSTF identifies central dual-energy x-ray absorptiometry (DXA) of the hip or lumbar spine as the key screening test.
   • In younger postmenopausal women, a two-step approach is suggested: (1) assess risk factors (e.g., low body weight, smoking, parental history of hip fracture); (2) apply a validated tool (e.g., Osteoporosis Risk Assessment Instrument [ORAI] or Osteoporosis Self-assessment Tool [OST]) to determine who should proceed to DXA.
   • Tools such as FRAX may be used with or without BMD input to estimate 10-year fracture probability, but clinicians should be aware that tool accuracy and calibration vary by age, race/ethnicity, and underlying data sources.
3. Screening Intervals:
   • Current data do not clearly define an optimal interval for repeated screening.
   • Some evidence suggests little added value in repeating BMD tests within four to eight years if initial results are normal or only mildly low.
4. Management Following a Positive Screening Result:
   • After osteoporosis is confirmed, patients should be counseled on modifiable risk factors (e.g., smoking cessation, fall prevention) and assessed for pharmacotherapy.
   • Approved treatments (e.g., bisphosphonates, denosumab) have demonstrated benefit in reducing vertebral, hip, and other major fractures.
5. Harms of Screening and Treatment:
   • Screening anxiety and overdiagnosis are minimal concerns, though data are limited.
   • Bisphosphonate use has not been associated with significant excess serious adverse events in short- to medium-term trials, but rare events (e.g., atypical femur fractures, osteonecrosis of the jaw) remain possible with long-term use.
   • Denosumab reduces multiple fracture outcomes, though discontinuation can lead to rebound bone loss and increased risk of vertebral fractures without follow-up management.
   • The USPSTF underscores that treatment decisions should be individualized, especially in diverse populations and those with complex comorbidities.

Conclusion: These updated recommendations highlight the importance of osteoporosis screening in women 65 years or older and in younger postmenopausal women at higher fracture risk. Early detection with central DXA, informed by clinical risk tools, can reduce fracture incidence and related burdens. Further research is needed to clarify optimal screening intervals, the role of screening in men, and long-term treatment strategies. In the meantime, clinicians should collaborate with patients to personalize screening and treatment plans, considering both clinical risks and patient preferences.

Reference:

• US Preventive Services Task Force. Screening for Osteoporosis to Prevent Fractures: US Preventive Services Task Force Recommendation Statement. JAMA. Published online January 14, 2025. DOI: http://doi.org/10.1001/jama.2024.27154
• Editorials:
  • Ensrud KE, Crandall CJ. Fracture Risk Assessment as a Component of Osteoporosis Screening—Easier Said Than Done. JAMA. Published online January 14, 2025. DOI: http://doi.org/10.1001/jama.2024.27416
  • Ott SM. Research That Could Broaden the Scope of Bone Density Screening. JAMA Netw Open. 2025;8(1):e2460746. DOI: http://doi.org/10.1001/jamanetworkopen.2024.60746
• Evidence Report:
  • Kahwati LC, Kistler CE, Booth G, et al. Screening for Osteoporosis to Prevent Fractures: A Systematic Evidence Review for the US Preventive Services Task Force. JAMA. Published online January 14, 2025. DOI: http://doi.org/10.1001/jama.2024.21653

 

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SR: Lower BP Targets Reduce Stroke Risk and Cardiovascular Events in Older Adults

16 Jan, 2025 | 12:42h | UTC

Background: Hypertension is a prevalent condition in older adults and a major risk factor for cardiovascular morbidity and mortality. Despite widely accepted benefits of treating blood pressure (BP) above 160 mmHg in this population, the optimal BP target remains uncertain. Many guidelines recommend a systolic BP (SBP) goal of < 140 mmHg in all adults, including those aged ≥ 65 years. However, evidence suggests older, possibly frail individuals might experience different benefit–risk ratios with more relaxed BP targets. This Cochrane review updates the previous 2017 analysis to determine whether aiming for higher BP targets in older adults (e.g., < 150–160 mmHg systolic) confers comparable or better outcomes than standard or more aggressive targets (< 140 mmHg).

Objective: To assess the effects of a higher BP target (SBP < 150–160 mmHg or diastolic BP < 95–105 mmHg) versus a lower (conventional or more aggressive) BP target (< 140/90 mmHg or lower) on mortality, stroke, and serious cardiovascular events in hypertensive adults aged ≥ 65 years.

Methods:

• Design and Searches: This is an updated Cochrane systematic review of randomized controlled trials (RCTs) comparing higher vs lower BP targets in older adults with hypertension. Databases searched through June 2024 included MEDLINE, Embase, CENTRAL, the Cochrane Hypertension Specialised Register, and ClinicalTrials.gov.
• Inclusion Criteria: RCTs of ≥ 1 year’s duration enrolling participants aged ≥ 65 years with baseline systolic BP ≥ 140 mmHg or diastolic BP ≥ 90 mmHg. Trials had to compare a higher BP target range (SBP < 150–160/DBP < 95–105 mmHg) to a lower BP target (< 140/90 mmHg).
• Outcomes: Primary outcomes were all-cause mortality, stroke, institutionalization, and serious cardiovascular adverse events (including myocardial infarction, heart failure, and renal failure). Secondary outcomes included cardiovascular mortality, non-cardiovascular mortality, total serious adverse events, and withdrawals due to adverse effects.

Results:

• Included Studies: Four open-label RCTs (N = 16,732) from Japan and China, with mean ages around 70 years (range 65–77). Mean follow-up ranged from 2 to 4 years.
• Mortality: Lower BP targets may result in little to no difference in all-cause mortality (RR 1.14, 95% CI 0.95–1.37; low-certainty).
• Stroke Prevention: A lower BP target clearly reduced the risk of stroke (RR 1.33, 95% CI 1.06–1.67; high-certainty), with an absolute reduction of approximately 6 stroke events per 1000 individuals treated over ~3 years.
• Serious Cardiovascular Events: A lower BP target likely reduced total serious cardiovascular adverse events (RR 1.25, 95% CI 1.09–1.45; moderate-certainty), equating to roughly 10 fewer cardiovascular events per 1000 people treated.
• Adverse Effects: Lower BP targets likely did not increase withdrawals due to adverse effects (RR 0.99, 95% CI 0.74–1.33; moderate-certainty). Data on other adverse events (e.g., hypotension) were limited but showed small absolute differences.

Conclusions: Treating older adults’ systolic BP to < 140 mmHg (vs < 150–160 mmHg) reduces stroke and likely reduces overall serious cardiovascular events without clearly affecting all-cause mortality or increasing dropouts due to adverse effects. While these findings support standard BP targets (< 140 mmHg) for many older patients, the absolute reduction in events is modest. Caution may be warranted in individuals aged ≥ 80 years or those who are frail, as the included studies had fewer such participants.

Implications for Practice: For most older adults, targeting SBP < 140 mmHg can prevent a modest but meaningful number of cardiovascular events, particularly stroke. Clinicians should balance these benefits against patient-specific concerns, such as frailty, multiple comorbidities, and polypharmacy. Monitoring for hypotension, renal function changes, and other adverse effects remains important.

Study Strengths and Limitations:

• Strengths: Inclusion of four RCTs with low attrition rates; assessment of major vascular endpoints relevant to older adults.
• Limitations: All trials were open-label, increasing risk of bias in subjective outcomes. Adverse event reporting was incomplete, and very elderly or frail individuals were often underrepresented. Most data originated from Asian populations, limiting generalizability to other regions.

Future Research: Further RCTs in populations aged ≥ 80 years, those with significant frailty, or living in nursing homes are essential to clarify optimal BP targets. Studies should capture quality-of-life measures and long-term safety outcomes, especially regarding adverse drug–drug interactions in complex older patients.

Reference: Falk JM, Froentjes L, Kirkwood JE, Heran BS, Kolber MR, Allan GM, Korownyk CS, Garrison SR. Higher blood pressure targets for hypertension in older adults. Cochrane Database of Systematic Reviews. 2024; Issue 12. DOI: http://doi.org/10.1002/14651858.CD011575.pub3

 

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SR: Efficacy and Safety of Non-Pharmacological, Pharmacological, and Surgical Treatments for Hand Osteoarthritis

16 Jan, 2025 | 10:54h | UTC

Background: Hand osteoarthritis (OA) affects a substantial proportion of older adults, contributing to pain, reduced grip strength, and functional limitations. While several clinical guidelines recommend patient education, exercise, and topical or oral non-steroidal anti-inflammatory drugs (NSAIDs), the level of evidence remains varied. In 2018, a systematic review identified efficacy data from 126 studies. This updated review includes 65 new randomized controlled trials (RCTs) published through December 2023, aiming to provide the most current evidence on hand OA treatments.

Objective: To summarize and evaluate the efficacy and safety of non-pharmacological, pharmacological, and surgical interventions for hand OA, highlighting both short-term (<3 months) and long-term (≥3 months) outcomes for pain, function, and grip strength.

Methods: The authors searched PubMed/MEDLINE, Embase, and Cochrane CENTRAL for RCTs published from June 2017 to December 2023. Risk of bias was assessed using the RoB2 tool, and certainty of evidence was evaluated with GRADE criteria. Interventions included hand exercises, orthoses, assistive devices, thermal modalities, pharmacologic therapies (e.g., oral/topical NSAIDs, glucocorticoids, disease-modifying anti-rheumatic drugs), and various surgical techniques. Meta-analyses were conducted when appropriate, and outcomes were expressed as standardized mean differences or relative risks with 95% confidence intervals.

Results:

• Non-Pharmacological Interventions: Low- to moderate-certainty evidence supports hand exercises, thumb orthoses, and assistive devices for improving pain and function. Hand exercises showed a small long-term effect on pain, while thumb orthoses offered a moderate long-term effect on pain. Assistive devices demonstrated a moderate long-term benefit for function. Few mild adverse events were reported in these categories.
• Pharmacological Interventions: There is high-certainty evidence for a very small short-term functional improvement with topical NSAIDs and low-certainty evidence of moderate short-term pain relief with oral NSAIDs. Oral glucocorticoids likely yield a small, short-term functional benefit. Methotrexate showed a possible small long-term effect on pain but no clear impact on function. No new data support intra-articular steroid injections, hydroxychloroquine, or biologic DMARDs for meaningful improvements; in these trials, sponsor bias and cost considerations underscore the need for critical appraisal, given the typically higher expense of advanced agents like biologics.
• Surgical Interventions: Ten new studies compared various surgical techniques but did not include robust controls versus nonsurgical management or sham surgery. Heterogeneity precluded pooling of results, and no definitive superiority emerged for any particular procedure.

Conclusions: This systematic review reaffirms the central role of non-pharmacological interventions, especially exercise, orthoses, and assistive devices, for improving pain and function in hand OA with minimal adverse events. Pharmacological treatments offer modest short-term benefits, particularly oral NSAIDs, although cost, side-effect profiles, and real-world adherence should be considered. Surgical approaches lack high-quality comparative data, highlighting the need for well-designed trials.

Implications for Practice: Clinicians should prioritize patient education, exercises, and readily accessible interventions (e.g., orthoses, assistive devices) given their demonstrated safety and moderate efficacy. Oral or topical NSAIDs remain suitable options for acute pain management, with the understanding that longer-term use warrants caution due to possible adverse effects. In contexts where advanced pharmacologic agents (such as biologics) are evaluated, practitioners must scrutinize costs, potential sponsor influence, and marginal benefits relative to standard care.

Study Strengths and Limitations: Strengths of this review include a comprehensive literature search, systematic appraisal of risk of bias, and application of GRADE to gauge certainty. However, most RCTs were small in size or had high or unclear risk of bias, and considerable heterogeneity in study designs reduced comparability. Additional limitations include the scarcity of direct comparisons for surgical versus non-surgical approaches and inconsistent reporting of adverse events.

Future Research: High-quality, larger-scale RCTs are needed to clarify subtypes of hand OA and tailor treatments accordingly. Trials should evaluate long-term outcomes, systematically measure adverse events, and compare surgery directly with non-surgical options. Studies employing mobile health (mHealth) tools and addressing ways to enhance grip strength may further advance evidence-based hand OA management.

Reference:
Kjeken I, Bordvik DH, Osteras N, Haugen IK, Fjeldstad KAA, Skaalvik I, Kloppenburg M, Kroon FPB, Tveter AT, Smedslund G. Efficacy and safety of non-pharmacological, pharmacological and surgical treatments for hand osteoarthritis in 2024: a systematic review. RMD Open. 2024; e004963. DOI: https://doi.org/10.1136/rmdopen-2024-004963

 

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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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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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