Polly Q. X. Lim1,2  iD · Merridy J. Lithgow1,2  iD  · Michelle R. Kaminski1,3,4   iD · Karl B. Landorf1,2  iD  · Hylton B. Menz1,2    iD· Shannon E. Munteanu1,2  iD

Polly Q. X. Lim

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1 Discipline of Podiatry, School of Allied Health, Human Services and Sport, La Trobe University, Melbourne, Victoria 3086, Australia

2 La Trobe Sport and Exercise Medicine Research Centre, School of Allied Health, Human Services and Sport, La Trobe University, Melbourne, Victoria 3086, Australia

3 Department of Podiatry, Monash Health, Melbourne, Victoria 3168, Australia

4 School of Primary and Allied Health Care, Monash University, Melbourne, Victoria 3199, Australia

Received: 1 March 2023 / Accepted: 31 March 2023 / Published online: 24 April 2023 © The Author(s) 2023

Abstract

      This systematic review aims to investigate the efficacy of non-surgical interventions for midfoot osteoarthritis (OA). Key databases and trial registries were searched from inception to 23 February 2023. All trials investigating non-surgical interventions for midfoot OA were included. Quality assessment was performed using the National Institutes of Health Quality Assessment Tool. Outcomes were pain, function, health-related quality of life, and adverse events. Effects (mean differences, standardised mean differences, risk ratios) were calculated where possible for the short (0 to 12 weeks), medium (>12 to 52 weeks), and long (>52 weeks) term. Six trials (231 participants) were included (one feasibility trial and five case series)— all were judged to be of poor methodological quality. Two trials reported arch contouring foot orthoses to exert no-to-large effects on pain in the short and medium term, and small-to-very-large effects on function in the short and medium term. Two trials reported shoe stiffening inserts to exert medium-to-huge effects on pain in the short term, and small effects on function in the short term. Two trials of image-guided intra-articular corticosteroid injections reported favourable effects on pain in the short term, small effects on pain and function in the medium term, and minimal long term effects. Two trials reported minor adverse events, and none reported health-related quality of life outcomes. The current evidence suggests that arch contouring foot orthoses, shoe stiffening inserts and corticosteroid injections may be effective for midfoot OA. Rigorous randomised trials are required to evaluate the efficacy of non-surgical interventions for midfoot OA.

Keywords Foot · Foot joints · Midfoot · Osteoarthritis · Midfoot osteoarthritis

Shelby Sydnor . Swarnendu Chatterjee . Philip Cooney . Simarjeet Kaur . Tom Macmillan iD . Daisy Stewart  . Isobel Munro iD . Ca ´tia Bandeiras iD . Abby Paine iD . Federico Felizzi

Received: March 24, 2023 / Accepted: April 12, 2023 / Published online: May 17, 2023

© The Author(s) 2023

S. Sydnor

Novartis Pharmaceuticals UK Ltd., London, England, UK

S. Chatterjee  S. Kaur

CONEXTS, Novartis Healthcare Pvt. Ltd., Hyderabad, India

P. Cooney  C. Bandeiras

CONEXTS, Novartis Ireland Ltd., Dublin, Ireland

T. Macmillan  D. Stewart  A. Paine

Source Health Economics, Oxford, England, UK

I. Munro

Source Health Economics, London, England, UK

F. Felizzi (&)

Novartis Pharma AG, Fabrikstrasse 2, 4056 Basel, Switzerland

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ABSTRACT

Introduction: Key clinical guidelines recommend anti-vascular endothelial growth factor (VEGF) therapy as first-line treatment for visual impairment due to diabetic macular oedema (DMO). A systematic literature review (SLR) and network meta-analysis (NMA) were conducted comparing the relative efficacy of the anti-VEGF brolucizumab with a focused network of the most relevant comparator dosing regimens approved in countries other than the USA (aflibercept, ranibizumab). The safety and tolerability of brolucizumab were also assessed.

Methods: A broad SLR was conducted to identify randomised controlled trials to ensure all relevant potential comparators were captured. Identified studies were refined to those appropriate for inclusion in the NMA. A Bayesiani NMA was conducted comparing brolucizumab 6 mg (every 12 [Q12W]/every 8 weeks [Q8W]) with relevant aflibercept 2 mg and ranibizumab 0.5 mg regimens.

Results: Fourteen studies were included in the NMA. At 1-year follow-up, the various aflibercept 2 mg and ranibizumab 0.5 mg regimens were mostly comparable with brolucizumab 6 mg Q12W/Q8W across key visual and anatomical outcomes, except brolucizumab 6 mg was favoured over ranibizumab 0.5 mg every 4 weeks (Q4W) for the change from baseline (CFB) in best-corrected visual acuity (BCVA), and BCVA loss/gain of pre-specified numbers of letters, and over ranibizumab 0.5 mg pro re nata for CFB in diabetic retinopathy severity scale, and retinal thickness. At year 2, where data were available, brolucizumab 6 mg showed similar results across efficacy outcomes versus all other anti-VEGFs. In most cases, discontinuation rates (all cause, and due to adverse events [AE]) and serious and overall rates of AEs excluding ocular inflammatory events were similar (in unpooled and pooled-treatment analyses) versus comparators.

Conclusion: Brolucizumab 6 mg Q12W/Q8W was comparable or superior to aflibercept 2 mg and ranibizumab 0.5 mg regimens for various visual and anatomical efficacy outcomes and discontinuation rates.

Keywords: Aflibercept; Anti-VEGF; Bestcorrected visual acuity; Brolucizumab; Diabetic macular oedema; Diabetic retinopathy; Network meta-analysis; Ranibizumab; Retinal thickness; Visual impairment

Key Summary Points

Diabetic macular oedema (DMO) leads to progressive retinal dysfunction and if left untreated, irreversible vision loss. The disease affects 5.47% of patients with diabetes, globally.

Across key clinical guidelines, antivascular endothelial growth factor (VEGF) therapies, administered via intravitreal (IVT) injection, are recommended as first line treatment for patients with visual impairment due to DMO. The efficacy and safety of the anti-VEGF brolucizumab for this indication has been investigated by two phase 3 randomised head-to-head studies versus aflibercept (KESTREL and KITE).

The main aim of this study was to compare the relative efficacy of brolucizumab 6 mg via network metaanalysis (NMA) based on a focused network of the most relevant available anti-VEGFs (aflibercept 2 mg, ranibizumab 0.5 mg) approved in a number of countries other than the USA, including the UK; the safety and tolerability of brolucizumab were also assessed.

      Brolucizumab 6 mg showed similar efficacy for key visual and anatomic outcomes including best-corrected visual acuity, diabetic retinopathy severity, and retinal thickness outcomes versus the relevant anti-VEGFs. Brolucizumab 6 mg showed an overall favourable benefit/risk \ profile with comparable rates of discontinuation and serious and overall adverse events to the other anti-VEGFs, except for ocular inflammatory and occlusive events.

      This is the first analysis assessing the efficacy and safety of brolucizumab 6 mg for the treatment of patients with visual impairment due to DMO using this focused network of comparators.

Jonathan V. Mui1  · Lifang Li2  · Oscar Hou In Chou1,3  ·iD. Nida Azfar1  · Athena Lee1,4 · Jeremy Hui1,3 · Sharen Lee1  · Gary Tse1,5,6,8,9 · Jiandong Zhou7

Received: 29 October 2022 / Accepted: 24 February 2023 / Published online: 31 March 2023 © The Author(s) 2023

Abstract

Introduction The risk of new onset depression associated with sodium-glucose co-transporter 2 inhibitor (SGLT2I) use in patients with type 2 diabetes mellitus (T2DM) remains unclear. This study investigated the risk of new onset depression between SGLT2I and dipeptidyl peptidase 4 inhibitor (DPP4I) users.

Methods This was a population-based cohort study of T2DM patients in Hong Kong between January 1st, 2015, and December 31st, 2019. T2DM patients over 18 with either SGLT2I or DPP4I use were included. 1:1 propensity-score matching using the nearest-neighbour method was conducted based on demographics, past comorbidities and non-DPP4I/SGLT2I medication use. Cox regression analysis models were used to identify significant predictors for new onset depression.

Results The study cohort included a total of 18,309 SGLT2I users and 37,269 DPP4I users (55.57% male, mean age: 63.5±12.9 years) with a median follow-up duration of 5.56 (IQR: 5.23–5.8) years. After propensity score matching, SGLT2I use was associated with a lower risk of new onset depression compared to DPP4I use (HR: 0.52, 95% CI: [0.35, 0.77], P=0.0011). These findings were confirmed by Cox multivariable analysis and sensitive analyses.

Conclusion SGLT2I use is associated with significantly lower risk of depression compared to DPP4 use in T2DM patients using propensity score matching and Cox regression analyses.

Keywords Type 2 diabetes · Depression · Anti-diabetic medication · SGLT2 inhibitor · DPP4 inhibitor

Jonathan V. Mui and Lifang Li are joint first authors.

“This article belongs to the topical collection “Health Education and Psycho-Social Aspects, managed by Massimo Porta and Marina Trento”.

Gary Tse

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* Jiandong Zhou

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1 Diabetes Research Unit, Cardiovascular Analytics Group, Hong Kong, China

2 Department of Biostatistics and Health Informatics, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK

3 Department of Medicine, The University of Hong Kong, Hong Kong, China

4 Department of Medicine & Therapeutics, The Chinese University of Hong Kong, Hong Kong, China

5 Department of Cardiology, Second Hospital of Tianjin Medical University, Tianjin, China

6 Kent and Medway Medical School, Canterbury, UK

7 Nufeld Department of Medicine, University of Oxford, Oxford, UK

8 School of Nursing and Health Studies, Hong Kong Metropolitan University, Hong Kong, China

9 Tianjin Institute of Cardiology, The Second Hospital of Tianjin Medical University, Tianjin 300211, China

D.Caldeira1,2,3· M. Alves3,4,5 · J. J. Ferreira3,4 · F. J. Pinto1,2

Received: 5 October 2022 / Accepted: 29 December 2022 / Published online: 18 January 2023 © The Author(s) 2023

D. Caldeira

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1 Centro Cardiovascular da Universidade de Lisboa–CCUL (CCUL@RISE), Faculdade de Medicina, CEMBE, CAML, Universidade de Lisboa, Lisbon, Portugal

2 Serviço de Cardiologia, Hospital Universitário de Santa Maria–CHULN, Lisbon, Portugal

3 Laboratory of Clinical Pharmacology and Therapeutics, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal

4 Faculdade de Medicina, Instituto de Medicina Molecular, Universidade de Lisboa, Lisbon, Portugal

5 Serviço de Medicina III, Hospital Pulido Valente, CHLN, Lisbon, Portugal

Abstract

Purpose Aspirin use among patients with diabetes in primary prevention is still a matter of debate. We aimed to evaluate the potential cardiovascular risk benefit of aspirin in primary prevention, using data from a contemporary cohort.

Methods Retrospective analysis of the VITAL cohort with>20,000 individuals at primary prevention who were followed for a median of 5.3 years. The population was evaluated according to the baseline diabetes status, and then aspirin use was evaluated among diabetic patients. Cox regression models were used to estimate the risks of mortality and cardiovascular outcomes. The estimates were reported using adjusted hazard ratio (HR) and 95% confidence intervals (95%CI).

Results Diabetic patients (n=3549; 13.7%) showed to increase the risk of all-cause mortality (HR 1.61, 95%CI 1.33–1.94), and major adverse cardiovascular events (MACE) (HR 1.36 95%CI 1.11–1.68) than non-diabetic population. Diabetic patients taking aspirin were older, more frequently man, hypertensive, current users of statins, and current smokers compared with diabetic patients who did not use aspirin at baseline. There was no difference between diabetic aspirin users and non-users regarding all-cause mortality (HR 0.80, 95%CI 0.59, 1.10), MACE (HR 0.92, 95%CI 0.64, 1.33), coronary heart disease (HR 0.98, 95%CI 0.67, 1.43), or stroke (HR 0.87, 95%CI 0.48, 1.58).

Conclusions The VITAL data confirmed diabetes as an important risk factor for cardiovascular events in a contemporary cohort but did not show cardiovascular benefits of aspirin in primary prevention among people with diabetes who were shown to be at higher risk of cardiovascular events.

Keywords Cardiovascular disease · Primary prevention · Aspirin · Diabetes