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Rationale & Objective: Despite a lack of supporting evidence, current guidance recommends against the use of metformin in people with advanced kidney impairment. This observational study compared the outcomes of patients with type 2 diabetes who continued versus stopped metformin after developing stage 4 chronic kidney disease (CKD) (estimated glomerular filtration rate [eGFR]<30mL/min/1.73m 2 )., Study Design: Nationwide observational cohort study., Setting & Participants: All adults with type 2 diabetes and incident stage 4 CKD in Scotland who were treated with metformin between January 2010 and April 2019., Exposure: Stopping versus continuing metformin within 6 months following incident stage 4 CKD., Outcome: Primary outcome was all-cause mortality. Secondary outcomes included major adverse cardiovascular events (MACE)., Analytical Approach: Target trial emulation with clone-censor-weight design and marginal structural models fit for sensitivity analyses., Results: In a population of 371,742 Scottish residents with a diagnosis of type 2 diabetes before April 30, 2019, 4,278 were identified as prevalent metformin users with incident CKD stage 4. Within 6 months of developing CKD stage IV, 1,713 (40.1%) individuals discontinued metformin. Compared with continuing metformin, stopping metformin was associated with a lower 3-year survival (63.7% [95% CI, 60.9-66.6] vs 70.5% [95% CI, 68.0-73.0]; HR, 1.26 [95% CI, 1.10-1.44]), and the incidence of MACE was similar between both strategies (HR, 1.05 [95% CI, 0.88-1.26]). Marginal structural models confirmed the higher risk of all-cause mortality and similar risk of MACE in patients who stopped versus continued metformin (all-cause mortality: HR, 1.34 [95% CI, 1.08-1.67]; MACE: HR, 1.04 [95% CI, 0.81-1.33])., Limitations: Residual confounding., Conclusions: The continued use of metformin may be appropriate when eGFR falls below 30mL/min/1.73m 2 . Randomized controlled trials are needed to confirm these findings., Plain-Language Summary: Current guidance recommends against the use of metformin in people with advanced kidney impairment despite a lack of evidence. It is therefore currently unclear how the decision to stop versus continue metformin in patients who reach stage 4 CKD impacts their risk of mortality and cardiovascular events. This study showed that stopping metformin after reaching stage 4 CKD was associated with reduced survival that did not appear to be mediated by an increase in adverse cardiovascular outcomes. These findings may support the continued use of metformin in patients with advanced kidney impairment, but further research is needed to confirm these observations., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Low-density lipoprotein cholesterol (LDL-C) and lipoprotein(a) (Lp[a]) levels are independently associated with atherosclerotic cardiovascular disease (ASCVD). However, the relationship between Lp(a) level, LDL-C level, and ASCVD risk at different thresholds is not well defined., Methods: A participant-level meta-analysis of 27 658 participants enrolled in 6 placebo-controlled statin trials was performed to assess the association of LDL-C and Lp(a) levels with risk of fatal or nonfatal coronary heart disease events, stroke, or any coronary or carotid revascularization (ASCVD). The multivariable-adjusted association between baseline Lp(a) level and ASCVD risk was modeled continuously using generalized additive models, and the association between baseline LDL-C level and ASCVD risk by baseline Lp(a) level by Cox proportional hazards models with random effects. The joint association between Lp(a) level and statin-achieved LDL-C level with ASCVD risk was evaluated using Cox proportional hazards models., Results: Compared with an Lp(a) level of 5 mg/dL, increasing levels of Lp(a) were log-linearly associated with ASCVD risk in statin- and placebo-treated patients. Among statin-treated individuals, those with Lp(a) level >50 mg/dL (≈125 nmol/L) had increased risk across all quartiles of achieved LDL-C level and absolute change in LDL-C level. Even among those with the lowest quartile of achieved LDL-C level (3.1-77.0 mg/dL), those with Lp(a) level >50 mg/dL had greater ASCVD risk (hazard ratio, 1.38 [95% CI, 1.06-1.79]) than those with Lp(a) level ≤50 mg/dL. The greatest risk was observed with both Lp(a) level >50 mg/dL and LDL-C level in the fourth quartile (hazard ratio, 1.90 [95% CI, 1.46-2.48])., Conclusions: These findings demonstrate the independent and additive nature of Lp(a) and LDL-C levels for ASCVD risk, and that LDL-C lowering does not fully offset Lp(a)-mediated risk., Competing Interests: Dr Bhatia received consulting fees from Abbott, Arrowhead, Kaneka Medical, and Novartis Pharmaceuticals. Dr Tsimikas is a coinventor and receives royalties from patents owned by University of California, San Diego and is a cofounder and has an equity interest in Kleanthi Diagnostics, LLC, and has a dual appointment at University of California, San Diego and Ionis Pharmaceuticals. The terms of this arrangement have been reviewed and approved by the University of California, San Diego in accordance with its conflict of interest policies. Drs Lesogor and Wandel, and K. Bailey are employees of Novartis. Dr Wandel holds stocks of Novartis, Alcon, and Sandoz. A. Tonkin has received consulting fees from Novartis and is on the DMC of the ORION-4 study. Dr Ridker has received institutional research grant support from Kowa, Novartis, Amarin, Pfizer, Esperion, Novo Nordisk, and the National Heart, Lung, and Blood Institute; has served as a consultant to Novartis, Flame, Agepha, Ardelyx, AstraZeneca, Janssen, Civi Biopharm, GSK, SOCAR, Novo Nordisk, Health Outlook, Montai Health, Eli Lilly, New Amsterdam, Boehringer-Ingelheim, RTI, Zomagen, Cytokinetics, Horizon Therapeutics, and Cardio Therapeutics; has minority shareholder equity positions in Uppton, Bitteroot Bio, and Angiowave; and receives compensation for service on the Peter Munk advisory board (University of Toronto), the Leducq Foundation, Paris FR, and the Baim Institute. Dr Willeit reports consulting fees from Novartis Pharmaceuticals. Dr Colhoun reports grants from IQVIA, JDRF, Chief Scientist Office, Diabetes UK, MRC (UKRI), and EU Commission; speaker bureau fees from Novo Nordisk; advisory roles with Novo Nordisk and Bayer AG; and is a shareholder in Roche Pharmaceuticals and Bayer AG. The other coauthors have nothing to disclose.

Background: Patients with overweight and obesity are at increased risk of death from multiple causes, including cardiovascular (CV) death, with few therapies proven to reduce the risk., Objectives: This study sought to assess the effect of semaglutide 2.4 mg on all-cause death, CV death, and non-CV death, including subcategories of death and death from coronavirus disease-2019 (COVID-19)., Methods: The SELECT (Semaglutide Effects on Cardiovascular Outcomes in Patients With Overweight or Obesity) trial randomized 17,604 participants ≥45 years of age with a body mass index ≥27 kg/m 2 with established CV disease but without diabetes to once-weekly subcutaneous semaglutide 2.4 mg or placebo; the mean trial duration was 3.3 years. Adjudicated causes of all deaths, COVID-19 cases, and associated deaths were captured prospectively., Results: Of 833 deaths, 485 (58%) were CV deaths, and 348 (42%) were non-CV deaths. Participants assigned to semaglutide vs placebo had lower rates of all-cause death (HR: 0.81; 95% CI: 0.71-0.93), CV death (HR: 0.85; 95% CI: 0.71-1.01), and non-CV death (HR: 0.77; 95% CI: 0.62-0.95). The most common causes of CV death with semaglutide vs placebo were sudden cardiac death (98 vs 109; HR: 0.89; 95% CI: 0.68-1.17) and undetermined death (77 vs 90; HR: 0.85; 95% CI: 0.63-1.15). Infection was the most common cause of non-CV death and occurred at a lower rate in the semaglutide vs the placebo group (62 vs 87; HR: 0.71; 95% CI: 0.51-0.98). Semaglutide did not reduce incident COVID-19; however, among participants who developed COVID-19, fewer participants treated with semaglutide had COVID-19-related serious adverse events (232 vs 277; P = 0.04) or died of COVID-19 (43 vs 65; HR: 0.66; 95% CI: 0.44-0.96). High rates of infectious deaths occurred during the COVID-19 pandemic, with less infectious death in the semaglutide arm, and resulted in fewer participants in the placebo group being at risk for CV death., Conclusions: Compared to placebo, patients treated with semaglutide 2.4 mg had lower rates of all-cause death, driven similarly by CV and non-CV death. The lower rate of non-CV death with semaglutide was predominantly because of fewer infectious deaths. These findings highlight the effect of semaglutide on mortality across a broad population of patients with CV disease and obesity. (Semaglutide Effects on Cardiovascular Outcomes in Patients With Overweight or Obesity [SELECT]; NCT03574597)., Competing Interests: Funding Support and Author Disclosures Dr Scirica has received institutional research grants to Brigham and Women’s Hospital from Better Therapeutics, Merck, Novo Nordisk, and Pfizer; has received consulting fees from Allergan, Amgen, Boehringer Ingelheim, Better Therapeutics, Elsevier Practice Update Cardiology, Esperion, Hanmi, Lexicon, and Novo Nordisk; and holds equity in Health [at] Scale and Doximity. Dr Lincoff has received research grants from AbbVie Inc, AstraZeneca, CSL Behring, Eli Lilly and Company, Esperion Therapeutics, Inc, and Novartis paid to his institution; and has served as a consultant for Akebia Therapeutics Inc, Alnylam Pharmaceuticals Inc, Ardelyx, Eli Lilly and Company, FibroGen, GlaxoSmithKline, Intarcia, Medtronic Vascular Inc, Novartis Pharmaceuticals Corporation, Novo Nordisk, Provention Bio, Entity, and ReCor Medical. Dr Lingvay has received research grants from Boehringer Ingelheim, Merck, Mylan Pharmaceuticals Inc, Novo Nordisk, Pfizer, and Sanofi US Services Inc; has served as a consultant for AstraZeneca, Bayer Healthcare Pharmaceuticals Inc, Biomea, Boehringer Ingelheim, Carmot, Eli Lilly and Company, Intarcia, Intercept Pharmaceuticals, Inc, Janssen Global Services, LLC, Johnson & Johnson Medical Devices & Diagnostics Group-Latin America, LLC, MannKind Corporation, Merck, Novo Nordisk, Pfizer Inc, Sanofi US Services Inc, Shionogi Inc, Structure Therapeutics, Target Pharma, Valeritas, Inc, and Zealand Pharma; and has received travel expenses from Boehringer Ingelheim, Eli Lilly and Company, Johnson & Johnson Medical Devices & Diagnostics Group-Latin America, LLC, Novo Nordisk, Sanofi US Services Inc, and Zealand Pharma A/S. Dr Buscemi has received advisory/consulting honoraria from Novo Nordisk, Eli Lilly, Pfizer, Boehringer Ingelheim, and Dompè. Dr Colhoun has served on advisory panels for Novo Nordisk and Bayer; has received research funding from Sanofi, Roche, and IQVIA; has received grants from Chief Scientist Office, Diabetes UK, European Commission, Juvenile Diabetes Research Foundation, and Medical Research Council; has served on the Speakers Bureau for Novo Nordisk; and holds equity in Roche Pharmaceuticals and Bayer. Dr Craciun has received advisory/consulting fees and/or other support from Novo Nordisk, Eli Lilly, Sanofi, Boehringer Ingelheim, Servier, Berlin Chemie, and Viatris. Dr Hardt-Lindberg is an employee of and stakeholder in Novo Nordisk. Dr Jeppesen is an employee of and stakeholder in Novo Nordisk. Dr Matos is an employee of and stakeholder in Novo Nordisk. Dr Node has received honoraria from AstraZeneca, Bayer Yakuhin, Boehringer Ingelheim Japan, Daiichi-Sankyo, Eli Lilly Japan, Mitsubishi Tanabe Pharma, Merck Sharp & Dohme, Novartis Pharma, and Otsuka; has received research grants from Astellas, Bayer Yakuhin, Boehringer Ingelheim Japan, Fujiyakuhin, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, and Novartis Pharma; and has received scholarships from Abbott, Boehringer Ingelheim Japan, Daiichi-Sankyo, Mitsubishi Tanabe Pharma, and Teijin Pharma. Dr Toplak has received institutional research grants from Amgen, Daiichi-Sankyo, Novo Nordisk, and Novartis; and has received consulting/speaker honoraria from Amgen, Daiichi-Sankyo, Novartis, and Novo Nordisk. Dr van Beek has been contracted via the University of Groningen (no personal payment) to undertake consultancy for Novo Nordisk, Eli Lilly, and Boehringer Ingelheim. Dr Weeke is an employee of and stakeholder in Novo Nordisk. Dr Wiviott has received research grants from Amgen, AstraZeneca, Janssen, Merck, and Pfizer; has received consulting fees from Icon, Novo Nordisk, and Verian; has received speaking honoraria from Harvard Medical School; is a member of the TIMI Study Group, which has received institutional research grant support through Brigham and Women’s Hospital from Abbott, Amgen, Anthos Therapeutics, ARCA Biopharma, Inc, AstraZeneca, Bayer HealthCare Pharmaceuticals, Inc, Daiichi-Sankyo, Eisai, Intarcia, Ionis Pharmaceuticals, Inc, Janssen Research and Development, LLC, MedImmune, Merck, Novartis, Pfizer, Quark Pharmaceuticals, Regeneron Pharmaceuticals, Inc, Roche, Siemens Healthcare Diagnostics, Inc, Softcell Medical Limited, The Medicines Company, and Zora Biosciences; and his spouse, Dr Caroline Fox, is a former employee of Merck, Flagship Labs, and current employee of Vertex. Dr Deanfield has received consulting honoraria from Amgen, Boehringer Ingelheim, Merck, Pfizer, Aegerion, Novartis, Sanofi, Takeda, Novo Nordisk, and Bayer; and has received research grants from British Heart Foundation, MRC(UK), National Institute for Health and Care Research, PHE, Merck Sharp & Dohme, Pfizer, Aegerion, Colgate, and Roche. Dr Ryan has received consulting honoraria from Altimmune, Amgen, Biohaven, Boehringer Ingelheim, Calibrate, Carmot Therapeutics, CinRx, Eli Lilly, Epitomee, Gila Therapeutics, Ifa Celtic, Novo Nordisk, Pfizer, Rhythm, Scientific Intake, Wondr Health, and Zealand; and has received stock options from Calibrate, Epitomee, Scientific Intake, and Xeno Bioscience. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Topic: To review clinical evidence on systemic factors that might be relevant to update diabetic retinal disease (DRD) staging systems, including prediction of DRD onset, progression, and response to treatment., Clinical Relevance: Systemic factors may improve new staging systems for DRD to better assess risk of disease worsening and predict response to therapy., Methods: The Systemic Health Working Group of the Mary Tyler Moore Vision Initiative reviewed systemic factors individually and in multivariate models for prediction of DRD onset or progression (i.e., prognosis) or response to treatments (prediction)., Results: There was consistent evidence for associations of longer diabetes duration, higher glycosylated hemoglobin (HbA1c), and male sex with DRD onset and progression. There is strong trial evidence for the effect of reducing HbA1c and reducing DRD progression. There is strong evidence that higher blood pressure (BP) is a risk factor for DRD incidence and for progression. Pregnancy has been consistently reported to be associated with worsening of DRD but recent studies reflecting modern care standards are lacking. In studies examining multivariate prognostic models of DRD onset, HbA1c and diabetes duration were consistently retained as significant predictors of DRD onset. There was evidence of associations of BP and sex with DRD onset. In multivariate prognostic models examining DRD progression, retinal measures were consistently found to be a significant predictor of DRD with little evidence of any useful marginal increment in prognostic information with the inclusion of systemic risk factor data apart from retinal image data in multivariate models. For predicting the impact of treatment, although there are small studies that quantify prognostic information based on imaging data alone or systemic factors alone, there are currently no large studies that quantify marginal prognostic information within a multivariate model, including both imaging and systemic factors., Conclusion: With standard imaging techniques and ways of processing images rapidly evolving, an international network of centers is needed to routinely capture systemic health factors simultaneously to retinal images so that gains in prediction increment may be precisely quantified to determine the usefulness of various health factors in the prognosis of DRD and prediction of response to treatment., Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article., (© 2024 by the American Academy of Ophthalmology.)

Objective: To investigate the association of severe coronavirus disease 2019 (COVID-19) in patients with inflammatory rheumatic diseases (IRDs) treated with immunosuppressive drugs., Method: A list of 4633 patients on targeted - biological or targeted synthetic - DMARDs in March 2020 was linked to a case-control study that includes all cases of COVID-19 in Scotland., Results: By 22 November 2021, 433 of the 4633 patients treated with targeted DMARDS had been diagnosed with COVID-19, of whom 58 had been hospitalized. With all those in the population not on DMARDs as the reference category, the rate ratio for hospitalized COVID-19 associated with DMARD treatment was 2.14 [95% confidence interval (CI) 2.02-2.26] in those on conventional synthetic (cs) DMARDs, 2.01 (95% CI 1.38-2.91) in those on tumour necrosis factor (TNF) inhibitors as the only targeted agent, and 3.83 (95% CI 2.65-5.56) in those on other targeted DMARDs. Among those on csDMARDs, rate ratios for hospitalized COVID-19 were lowest at 1.66 (95% CI 1.51-1.82) in those on methotrexate and highest at 5.4 (95% CI 4.4-6.7) in those on glucocorticoids at an average dose > 10 mg/day prednisolone equivalent., Conclusion: The risk of hospitalized COVID-19 is elevated in IRD patients treated with immunosuppressive drugs compared with the general population. Of these drugs, methotrexate, hydroxychloroquine, and TNF inhibitors carry the lowest risk. The highest risk is associated with prednisolone. A larger study is needed to estimate reliably the risks associated with each class of targeted DMARD.

Objective: To assess the real-world cardiovascular (CV) safety for sulfonylureas (SU), in comparison with dipeptidyl peptidase 4 inhibitors (DPP4i) and thiazolidinediones (TZD), through development of robust methodology for causal inference in a whole nation study., Research Design and Methods: A cohort study was performed including people with type 2 diabetes diagnosed in Scotland before 31 December 2017, who failed to reach HbA1c 48 mmol/mol despite metformin monotherapy and initiated second-line pharmacotherapy (SU/DPP4i/TZD) on or after 1 January 2010. The primary outcome was composite major adverse cardiovascular events (MACE), including hospitalization for myocardial infarction, ischemic stroke, heart failure, and CV death. Secondary outcomes were each individual end point and all-cause death. Multivariable Cox proportional hazards regression and an instrumental variable (IV) approach were used to control confounding in a similar way to the randomization process in a randomized control trial., Results: Comparing SU to non-SU (DPP4i/TZD), the hazard ratio (HR) for MACE was 1.00 (95% CI: 0.91-1.09) from the multivariable Cox regression and 1.02 (0.91-1.13) and 1.03 (0.91-1.16) using two different IVs. For all-cause death, the HR from Cox regression and the two IV analyses was 1.03 (0.94-1.13), 1.04 (0.93-1.17), and 1.03 (0.90-1.17)., Conclusions: Our findings contribute to the understanding that second-line SU for glucose lowering are unlikely to increase CV risk or all-cause mortality. Given their potent efficacy, microvascular benefits, cost effectiveness, and widespread use, this study supports that SU should remain a part of the global diabetes treatment portfolio., (© 2023 by the American Diabetes Association.)