Gordon Guyatt

Pharmacotherapy for adults with overweight and obesity: a systematic review and network meta-analysis of randomised controlled trials

BACKGROUND Pharmacotherapy provides an option for adults with overweight and obesity to reduce their bodyweight if lifestyle modifications fail. We summarised the latest evidence for the benefits and harms of weight-lowering drugs. METHODS This systematic review and network meta-analysis included searches of PubMed, Embase, and Cochrane Library (CENTRAL) from inception to March 23, 2021, for randomised controlled trials of weight-lowering drugs in adults with overweight and obesity. We performed frequentist random-effect network meta-analyses to summarise the evidence and applied the Grading of Recommendations Assessment, Development, and Evaluation frameworks to rate the certainty of evidence, calculate the absolute effects, categorise interventions, and present the findings. The study was registered with PROSPERO, CRD 42021245678. FINDINGS 14 605 citations were identified by our search, of which 132 eligible trials enrolled 48 209 participants. All drugs lowered bodyweight compared with lifestyle modification alone; all subsequent numbers refer to comparisons with lifestyle modification. High to moderate certainty evidence established phentermine-topiramate as the most effective in lowering weight (odds ratio [OR] of ≥5% weight reduction 8·02, 95% CI 5·24 to 12·27; mean difference [MD] of percentage bodyweight change -7·98, 95% CI -9·27 to -6·69) followed by GLP-1 receptor agonists (OR 6·33, 95% CI 5·00 to 8·00; MD -5·79, 95% CI -6·34 to -5·25). Naltrexone-bupropion (OR 2·69, 95% CI 2·10 to 3·44), phentermine-topiramate (2·40, 1·68 to 3·44), GLP-1 receptor agonists (2·22, 1·74 to 2·84), and orlistat (1·71, 1·42 to 2·05) were associated with increased adverse events leading to drug discontinuation. In a post-hoc analysis, semaglutide, a GLP-1 receptor agonist, showed substantially larger benefits than other drugs with a similar risk of adverse events as other drugs for both likelihood of weight loss of 5% or more (OR 9·82, 95% CI 7·09 to 13·61) and percentage bodyweight change (MD -11·40, 95% CI -12·51 to -10·29). INTERPRETATION In adults with overweight and obesity, phentermine-topiramate and GLP-1 receptor agonists proved the best drugs in reducing weight; of the GLP-1 agonists, semaglutide might be the most effective. FUNDING 1.3.5 Project for Disciplines of Excellence, West China Hospital, Sichuan University.

Multicentre, 2×2 factorial, randomised, open-label trial of neuromodulators and cough control therapy for refractory or unexplained chronic cough: the FORTITUDE trial protocol

INTRODUCTION: While clinicians commonly prescribe neuromodulators for the treatment of refractory or unexplained chronic cough, no trials have directly compared these treatments. Furthermore, although guidelines recommend non-pharmacological management involving physiotherapy and speech-language therapy, few trials have evaluated its effectiveness. METHODS AND ANALYSIS: rapy) is a 6-week, 2×2 factorial, randomised, open-label trial with an observational extension up to 1 year. The trial will include Canadian hospital sites enrolling 124 patients. Patients ≥18 years old with either refractory or unexplained chronic cough will undergo independent 1:1 randomisation to pharmacotherapy-either low-dose morphine (up to 5 mg two times per day) or pregabalin (up to 150 mg two times per day)-and concurrent cough control therapy (CCT) or no CCT. The CCT will consist of five virtual sessions delivered over 6 weeks by a trained physiotherapist or speech-language pathologist. Change from baseline in 24-hour cough frequency at 6 weeks represents the primary outcome. Secondary outcomes include change from baseline in awake, sleep and cough bout frequencies; cough severity on the McMaster Cough Severity Questionnaire and the 100-mm Visual Analogue Scale; and cough quality of life on the Leicester Cough Questionnaire at 6 weeks. We will analyse safety and tolerability at 6 weeks and explore potential interactions between neuromodulators and CCT. Follow-up in an observational extension of up to 12 months post-randomisation will assess long-term treatment patterns, adherence and safety in a real-world setting. ETHICS AND DISSEMINATION: Health Canada's Pharmaceutical Drugs Directorate has provided approval to conduct this study. We have approval from the Hamilton Integrated Research Ethics Board of the Main Coordinating Site, with ethics pending at other participating sites. Results of the main trial and the observational extension will be published as manuscripts in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT07288528.

Personalised decision-making in hepatocellular carcinoma: conceptual evolution over two decades

BACKGROUND: Evidence-based medicine (EBM) was conceived to support decisions for individual patients by integrating the best available evidence, clinical expertise, and patient values. However, the application of EBM in many fields has become associated with rigid algorithms and guideline pathways, sometimes interpreted as prescriptive rather than as aids to decision-making. Hepatocellular carcinoma (HCC) offers an informative case study of this dichotomy. This paper traces the evolution of personalized decision-making in HCC over two decades and its implications for the future of EBM. METHODS: This is a narrative, conceptual review. Rather than a systematic synthesis, it draws selectively on landmark staging frameworks, guidelines, and methodological literature to construct a schematic account of how clinical reasoning in HCC has evolved. RESULTS: HCC decision-making has evolved through a sequence of schematic frames: from stage-centred algorithms (the Ptolemaic frame), to recognition of differential treatment effects (the Copernican shift), to multiparametric expert deliberation (the Newtonian perspective), and finally to dynamic, time-dependent, bidirectional strategies (the Einsteinian perspective). The expansion of systemic immunotherapy options has reinforced this bidirectional logic while complicating stage reassessment. This trajectory culminates in a Heisenberg moment, in which uncertainty is acknowledged as intrinsic to individual decisions. The multiparametric therapeutic hierarchy, developed within multidisciplinary HCC practice, reflects this maturation towards a personalized, transparent, context-sensitive approach. CONCLUSION: HCC is a paradigmatic example of personalized decision-making in complex, multidisciplinary care. The future of EBM lies not in choosing between algorithms and personalization, but rather in transparent approaches that apply evidence rigorously while acknowledging uncertainty and respecting patient values and local context.

Clinicians’ decisions about antibiotic treatment in advanced dementia: an international survey

Values, preferences, and informational needs of individuals living with ANCA-associated vasculitis: a systematic review

Integrating users’ perspectives during the development of the Chronic Pain Recommendation Map: protocol for a qualitative descriptive study

Perioperative AF after non-cardiac surgery is linked to higher 1-year risk of stroke, MI, and death.

Global complications among patients with mpox: a systematic review and meta-analysis

Background: Despite increasing global attention, significant knowledge gaps remain regarding the incidence of adverse outcomes associated with mpox. To support the development of World Health Organization (WHO) mpox guidelines, this systematic review and meta-analysis evaluated the incidence of complications among patients with mpox. Methods: We searched Medline, Embase, CENTRAL, CINAHL, Global Health, medRxiv, bioRxiv, and SSRN from database inception to December 20, 2025, for studies reporting complications in patients with laboratory-confirmed mpox of all ages. Paired reviewers independently screened studies, extracted data, and assessed risk of bias. We conducted proportional meta-analyses using the inverse variance method fixed-effect model with the Freeman-Tukey double arcsine transformation and evaluated the certainty of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework. We classified mpox as severe or non-severe based on the need for hospitalization or the study's criteria. We registered the protocol with PROSPERO (CRD42024595685). Findings: Of 4566 records, 170 studies with 127,564 patients (mean age 6.9-43.0 years) proved eligible. Among patients with non-severe mpox, serious complications were rare. Mortality, intensive care unit admission, sepsis, pneumonia, encephalitis, epiglottitis, myocarditis, gastrointestinal bleeding, and pleural effusion all occurred in ≤0.5% of patients (moderate to high certainty evidence). Urinary retention, mechanical ventilation, urethritis, gastroenteritis, and keratitis occurred in 0.7%-1.8% (moderate to high certainty evidence). Severe pain, abscess, tonsillitis, conjunctivitis, and cellulitis occurred in 2.2%-3.7% of patients (moderate certainty evidence) and hospitalization occurred in 4.4% (low certainty evidence). Patients who were vaccinated had a lower hospitalization rate than those who were unvaccinated. Patients in low- and middle-income countries (LMICs) had a higher rate of pneumonia (2.21% versus 0.02%) than those in high-income countries (HICs). In patients with severe mpox, complication rates were substantially higher. All-cause mortality, abscess, sepsis, tonsillitis, keratitis, and mechanical ventilation occurred in 2.5%-5.5% of patients (moderate certainty evidence). Acute kidney injury, pleural effusion, respiratory failure, and conjunctivitis occurred in 1.4%-2.0% (moderate to high certainty evidence). Patients with severe mpox in LMICs had a higher mortality (3.18% versus <0.01%) than those in HICs. Interpretation: Non-severe mpox is associated with low complication rates and very low mortality, while severe disease carries substantial risks of life-threatening complications and death. These findings provide baseline risk estimates for both patients with severe and non-severe mpox, emphasize the importance of early risk stratification in clinical management, and highlight the need for tailored approaches based on disease severity. The data also reveal health inequities in mpox care between HICs and LMICs, underscoring the urgent need for increased resources in LMICs.

Replacing saturated with polyunsaturated fat reduces mortality and MACE in high-risk but not low-risk patients.

Reporting guidelines for studies involving generative artificial intelligence applications: what do I use, and when?

The rise in publications addressing the use of general artificial intelligence (GAI), namely large language models (LLMs), for health purposes has generated the need to guide authors on transparent reporting practices 1 , 2 . Although LLMs currently dominate, other GAI applications such as diffusion models and large multimodal models are gaining popularity 3 . One key distinction between GAI and conventional AI is the ability of GAI to create new information based on its training data. Varying methodology and incomplete reporting among studies applying GAI for health purposes compromise the ability of readers to accurately interpret the study findings 3 , which is a particularly relevant issue when evaluating the effectiveness of complex GAI platforms in a healthcare context.

Understanding the Determinants That Influence the Development and Implementation of Evidence‐Based Practice Guidelines During Health Emergencies: An Exploratory Sequential Mixed‐Methods Study Protocol

Introduction The COVID‐19 pandemic highlighted the crucial role of evidence‐based practice guidelines (EBPGs) in healthcare systems. Reliable and timely guidelines are essential in health emergencies. This study aims to identify and comprehensively understand the determinants that influence the development and implementation of EBPGs during health emergencies from the perspective of guideline developers and implementers. In this article, we describe the study protocol. Methodology We will conduct an exploratory sequential mixed‐methods study composed of four phases: (I) a qualitative descriptive study to document the experiences of guideline developers and implementers and use this data to generate a list of determinants that influence the development and implementation of EBPG; (II) exploratory integration for survey development and validation using the data of phase I; (III) cross‐sectional study to administer the survey to a large sample and estimate the frequency and perceived impact of those determinants; (IV) interpretation of the results: a combination of qualitative and quantitative findings through the narrative description and joint displays to generate a comprehensive understanding of those determinants. We will explore if results vary across subgroups of interest (participants' roles, gender, and type of organization). We will include people worldwide from five groups participating in an EBPG development and implementation process during the pandemic. Discussion This study will provide insights into the determinants that influence the development and implementation of EBPGs during health emergencies. Its potential impact includes improving future health emergency preparedness, addressing equity gaps, and enhancing guideline development and implementation.

Integrating Seattle Heart Failure Model predictions with physician judgment improved prognostic accuracy for 1-year mortality, achieving a C-statistic of 0.82 compared to 0.75 for cardiologists alone.

Patient Values and Preferences in Chronic Urticaria Treatment

Pharmacotherapy for adults with metabolic dysfunction associated steatotic liver disease (MASLD) and metabolic dysfunction associated steatohepatitis (MASH): a systematic review and network meta analysis.

Reporting Guideline for Chatbot Health Advice Studies

Including conference abstracts rarely changed systematic review conclusions: A Case Study from a Living Network Meta-Analysis of COVID-19 Treatments

A Qualitative Protocol for Evaluating Online Social Work Interventions for Cancer Survivors Using an AI-Enhanced WeChat Mini-Application

European Association of Endoscopic Surgery Clinical Practice Guideline Protocol: Evidence‐Informed Recommendations on the Management of Cholecystitis With ESAIC and ESR Participation

Cardiovascular, kidney related, and weight loss effects of therapeutics for type 2 diabetes: a living clinical practice guideline.

Reply to “Notable Concerns in Methodology and Conclusions of the Wang et al. Meta-Analysis in BMJ by the American Academy of Pain Medicine” by Schuster et al