SGLT-2 inhibitor; oral glucosuric agent; flozin

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Indications

* flozins lowest in cardiovascular mortality < GLP-1 agonists < DPP-4 inhibitors (no mention of metformin)[6][19]

* cardiovascular risk reduction[10][11]

* may lower risks for heart failure, all-cause death, major cardiovascular events, & cardiovascular death[14] independent of diabetes status[18] or renal function[43]

* benefit for heart failure & cardiovascular death across cardiometabolic spectrum[44]

* no significant effect on myocardial infarction in the general population[43]

* no effect on stroke[43]

* may improve maximal exercise capacity & quality of life in patients with heart failure HFrEF or HFpEF[38]

* use as 1st line rather than metformin may reduce risk of hospitalization for heart failure, but not myocardial infarction, stroke, or all-cause mortality[25]

* dapagliflozin 10 mg QD reduces hospitalization (all cause) & death in patients with chronic kidney disease with & without type 2 diabetes (RR ~0.8)[27]

* only canagliflozin & empagliflozin may lower cardiovascular risk; dapagliflozin & ertugliflozin may not[25]

* flozins appear safe in elderly >= 75 years of age[29]

* cardiovascular benefits persist across full spectrum of glycemic control HbA1c <7.5% to > 9%[30]

* in patients with diabetes mellitus type-2, benefits for cardiovascular risk & chronic kidney disease remain regardless of GLP-1 receptor agonist use[48]

* efficacy, safety & tolerability same in elderly > 70 years vs younger patients[37]

Contraindications

* flozins on list of drugs to avoid[5]

* flozins are associated with a lower risk for dialysis, cardiovascular events, diabetic ketoacidosis, & acute kidney injury in patients with type 2 diabetes & stage 5 chronic kidney disease[39]

Dosage

  • stop flozin 3 days prior to surgery

Adverse effects

* FDA decides no action necessary[4]

Drug interactions

Mechanism of action

Notes

More general terms

More specific terms

Additional terms

References

  1. ↑ 1.0 1.1 FDA MedWatch. May 15, 2015 SGLT2 inhibitors: Drug Safety Communication - FDA Warns Medicines May Result in a Serious Condition of Too Much Acid in the Blood. https://mail.google.com/mail/u/0/?tab=wm#inbox/14d587f1089e0791
  2. ↑ 2.0 2.1 FDA Safety Alert. Dec 4, 2015 SGLT2 Inhibitors: Drug Safety Communication - Labels to Include Warnings About Too Much Acid in the Blood and Serious Urinary Tract Infections. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm475553.htm
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 Medical Knowledge Self Assessment Program (MKSAP) 17, 19 American College of Physicians, Philadelphia 2015, 2022
    Medical Knowledge Self Assessment Program (MKSAP) 19 Board Basics. An Enhancement to MKSAP19. American College of Physicians, Philadelphia 2022
  4. ↑ 4.0 4.1 4.2 Lowes R New FDA Watch List Flags More Drugs Medscape Internal Medicine. July 3, 2017 http://www.medscape.com/viewarticle/882425
  5. ↑ 5.0 5.1 Therapeutics Letter #108. Therapeutics Initiative Drugs to Avoid. http://www.ti.ubc.ca/2018/01/04/108-drugs-avoid/
  6. ↑ 6.0 6.1 Zheng SL, Roddick AJ, Aghar-Jaffar R, et al Association Between Use of Sodium-Glucose Cotransporter 2 Inhibitors, Glucagon-like Peptide 1 Agonists, and Dipeptidyl Peptidase 4 Inhibitors With All-Cause Mortality in Patients With Type 2 Diabetes. A Systematic Review and Meta-analysis. JAMA. 2018;319(15):1580-1591. PMID: https://www.ncbi.nlm.nih.gov/pubmed/29677303 https://jamanetwork.com/journals/jama/fullarticle/2678616
  7. ↑ 7.0 7.1 Chang HY, Singh S, Mansour O, Baksh S, Alexander GC Association between sodium-glucose cotransporter 2 inhibitors and lower extremity amputation among patients with type 2 diabetes. JAMA Intern Med 2018 Aug 13; PMID: https://www.ncbi.nlm.nih.gov/pubmed/30105373
    Fralick M, Patorno E, Fischer MA Sodium-glucose cotransporter 2 inhibitors and the risk of amputation: Results and challenges from the real world. JAMA Intern Med 2018 Aug 13; PMID: https://www.ncbi.nlm.nih.gov/pubmed/30105365
  8. ↑ 8.0 8.1 FDA Safety Alert. Ag 29, 2018 SGLT2(sodium-glucose cotransporter-2) Inhibitors for Diabetes: Drug Safety Communication - Regarding Rare Occurrences of a Serious Infection of the Genital Area. https://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm618908.htm
  9. ↑ 9.0 9.1 9.2 Ueda P, Svanstrom H, Melbye M et al Sodium glucose cotransporter 2 inhibitors and risk of serious adverse events: nationwide register based cohort study. BMJ 2018;363:k4365 PMID: https://www.ncbi.nlm.nih.gov/pubmed/30429124 https://www.bmj.com/content/363/bmj.k4365
  10. ↑ 10.0 10.1 10.2 10.3 Zelniker TA, Wiviott SD, Raz I et al. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: A systematic review and meta-analysis of cardiovascular outcome trials. Lancet 2018 Nov 10; [e-pub]. (https://doi.org/10.1016/S0140-6736(18)32590-X) PMID: https://www.ncbi.nlm.nih.gov/pubmed/30424892
    Verma S, Juni P, Mazer CD. Pump, pipes, and filter: Do SGLT2 inhibitors cover it all? Lancet 2018 Nov 10; PMID: https://www.ncbi.nlm.nih.gov/pubmed/30424891
  11. ↑ 11.0 11.1 Writing Committee, Das SR, Everett BM, Birtcher KK et al 2018 ACC Expert Consensus Decision Pathway on Novel Therapies for Cardiovascular Risk Reduction in Patients With Type 2 Diabetes and Atherosclerotic Cardiovascular Disease. A Report of the American College of Cardiology Task Force on Expert Consensus Decision Pathways. J Am Coll Cardiol. Nov 2018 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/30497881 <Internet> http://www.onlinejacc.org/content/early/2018/11/23/j.jacc.2018.09.020
  12. ↑ 12.0 12.1 12.2 12.3 Bersoff-Matcha SJ, Chamberlain C, Cao C et al Fournier Gangrene Associated With Sodium-Glucose Cotransporter-2 Inhibitors: A Review of Spontaneous Postmarketing Cases. Ann Intern Med. 2019. May 7 PMID: https://www.ncbi.nlm.nih.gov/pubmed/31060053 https://annals.org/aim/article-abstract/2732837/fournier-gangrene-associated-sodium-glucose-cotransporter-2-inhibitors-review-spontaneous
  13. ↑ 13.0 13.1 Dave CV, Schneeweiss S, Kim D et al Sodium-Glucose Cotransporter-2 Inhibitors and the Risk for Severe Urinary Tract Infections: A Population-Based Cohort Study. Ann Intern Med. 2019. July 30 PMID: https://www.ncbi.nlm.nih.gov/pubmed/31357213 https://annals.org/aim/article-abstract/2739786/sodium-glucose-cotransporter-2-inhibitors-risk-severe-urinary-tract-infections
    Filion KB, Yu OH Sodium-Glucose Cotransporter-2 Inhibitors and Severe Urinary Tract Infections: Reassuring Real-World Evidence. Ann Intern Med. 2019. July 30 PMID: https://www.ncbi.nlm.nih.gov/pubmed/31357211 https://annals.org/aim/article-abstract/2739787/sodium-glucose-cotransporter-2-inhibitors-severe-urinary-tract-infections-reassuring
  14. ↑ 14.0 14.1 Pasternak B, Ueda P, Eliasson B et al. Use of sodium glucose cotransporter 2 inhibitors and risk of major cardiovascular events and heart failure: Scandinavian register based cohort study. BMJ 2019 Aug 29; 366:l4772. PMID: https://www.ncbi.nlm.nih.gov/pubmed/31467044 Free PMC Article https://www.bmj.com/content/366/bmj.l4772
  15. ↑ 15.0 15.1 Fralick M, Chen SK, Patorno E, Kim SC. Assessing the Risk for Gout With Sodium-Glucose Cotransporter-2 Inhibitors in Patients With Type 2 Diabetes: A Population-Based Cohort Study. Ann Intern Med. 2020. Jan 14. PMID: https://www.ncbi.nlm.nih.gov/pubmed/31931526 https://annals.org/aim/article-abstract/2758844/assessing-risk-gout-sodium-glucose-cotransporter-2-inhibitors-patients-type
    McCormick N, Yokose C, Wei J et al Comparative Effectiveness of Sodium-Glucose Cotransporter-2 Inhibitors for Recurrent Gout Flares and Gout-Primary Emergency Department Visits and Hospitalizations. A General Population Cohort Study. Ann Intern Med. 2023 Jul 25 PMID: https://www.ncbi.nlm.nih.gov/pubmed/37487215 https://www.acpjournals.org/doi/full/10.7326/M23-0724
    Wei J, Choi HK, Dalbeth M et al Gout Flares and Mortality After Sodium-Glucose Cotransporter-2 Inhibitor Treatment for Gout and Type 2 Diabetes. JAMA Netw Open. 2023;6(8):e2330885 PMID: https://www.ncbi.nlm.nih.gov/pubmed/37624597 https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2808753
  16. ↑ 16.0 16.1 16.2 Pasternak B et al Use of sodium-glucose co-transporter 2 inhibitors and risk of serious renal events: Scandinavian cohort study. BMJ 2020;369:m1186 PMID: https://www.ncbi.nlm.nih.gov/pubmed/32349963 https://www.bmj.com/content/369/bmj.m1186
    Smith SM SGLT2 inhibitors and kidney outcomes in the real world. BMJ 2020;369:m1584 PMID: https://www.ncbi.nlm.nih.gov/pubmed/32349997 https://www.bmj.com/content/369/bmj.m1584
  17. ↑ 17.0 17.1 17.2 Douros A et al. Sodium-glucose cotransporter-2 inhibitors and the risk for diabetic ketoacidosis: A multicenter cohort study. Ann Intern Med 2020 Jul 28; PMID: https://www.ncbi.nlm.nih.gov/pubmed/32716707 https://www.acpjournals.org/doi/10.7326/M20-0289
  18. ↑ 18.0 18.1 Zannad F et al. SGLT2 inhibitors in patients with heart failure with reduced ejection fraction: A meta-analysis of the EMPEROR-Reduced and DAPA-HF trials. Lancet 2020 Aug 30; [e-pub]. PMID: https://www.ncbi.nlm.nih.gov/pubmed/32877652 https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31824-9/fulltext
  19. ↑ 19.0 19.1 Filion KB et al Sodium glucose cotransporter 2 inhibitors and risk of major adverse cardiovascular events: multi-database retrospective cohort study. BMJ 2020;370:m3342 PMID: https://www.ncbi.nlm.nih.gov/pubmed/32967856 Free article https://www.bmj.com/content/370/bmj.m3342
  20. ↑ 20.0 20.1 Shi FH, Li H, Yue J et al Clinical Adverse Events of High-Dose vs Low-Dose Sodium-Glucose Cotransporter 2 Inhibitors in Type 2 Diabetes. A Meta-Analysis of 51 Randomized Clinical Trials. J Clin Endocrinol Metab. 2020;105(11) PMID: https://www.ncbi.nlm.nih.gov/pubmed/32841351 https://www.medscape.com/viewarticle/938944
  21. ↑ Goldberg LR. The pleiotropic effects of SGLT2 inhibitors: Remodeling the treatment of heart failure. J Am Coll Cardiol 2021 Jan 26; 77:256. PMID: https://www.ncbi.nlm.nih.gov/pubmed/33478648 https://www.sciencedirect.com/science/article/abs/pii/S0735109720378931
  22. ↑ 22.0 22.1 Monaco K SGLT-2 Inhibitors Cleared of Bone Fracture Qualms in Older T2D Patients. New Medicare users of three classes of antidiabetic agents were compared. MedPage Today October 27, 2021 https://www.medpagetoday.com/endocrinology/diabetes/95290
    Zhuo M, Hawley CE, Paik JM et al Association of Sodium-Glucose Cotransporter-2 Inhibitors With Fracture Risk in Older Adults With Type 2 Diabetes. JAMA Netw Open. 2021;4(10):e2130762 PMID: https://www.ncbi.nlm.nih.gov/pubmed/34705014 https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2785536
  23. ↑ 23.0 23.1 Geriatric Review Syllabus, 11th edition (GRS11) Harper GM, Lyons WL, Potter JF (eds) American Geriatrics Society, 2022
  24. ↑ 24.0 24.1 Zou X et al. Sodium-glucose cotransporter-2 inhibitors in patients with heart failure: A systematic review and meta-analysis. Ann Intern Med 2022 Apr 12; [e-pub]. PMID: https://www.ncbi.nlm.nih.gov/pubmed/35404670 https://www.acpjournals.org/doi/10.7326/M21-4284
  25. ↑ 25.0 25.1 25.2 Tucker ME SGLT-2 inhibitors as First-Line Therapy in Type 2 Diabetes? Medscape. May 23, 2022 https://www.medscape.com/viewarticle/974463
    Shin H et al Cardiovascular Outcomes in Patients Initiating First-Line Treatment of Type 2 Diabetes With Sodium-Glucose Cotransporter-2 Inhibitors Versus Metformin. A Cohort Study. Ann Intern Med 2022. May 24 PMID: https://www.ncbi.nlm.nih.gov/pubmed/35605236 https://www.acpjournals.org/doi/10.7326/M21-4012
  26. ↑ 26.0 26.1 Vaduganathan M et al. SGLT-2 inhibitors in patients with heart failure: A comprehensive meta-analysis of five randomised controlled trials. Lancet 2022 Sep 3; 400:757. PMID: https://www.ncbi.nlm.nih.gov/pubmed/36041474 https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(22)01429-5/fulltext
  27. ↑ 27.0 27.1 Schechter M et al. Effects of dapagliflozin on hospitalizations in patients with chronic kidney disease: A post hoc analysis of DAPA-CKD. Ann Intern Med 2022 Dec 6 PMID: https://www.ncbi.nlm.nih.gov/pubmed/36469914 https://www.acpjournals.org/doi/10.7326/M22-2115
  28. ↑ 28.0 28.1 Schwartz B Fast Five Quiz: Penis Conditions and Disorders Medscape. Nov 29, 2022 https://reference.medscape.com/viewarticle/984322
  29. ↑ 29.0 29.1 Goldman A, Fishman B, Twig G et al The real-world safety profile of sodium-glucose co-transporter-2 inhibitors among older adults (>= 75 years): a retrospective, pharmacovigilance study. Cardiovascular Diabetology. 2023 22(1):16 Jan 24 PMID: https://www.ncbi.nlm.nih.gov/pubmed/36694178 PMCID: PMC9875397 Free PMC article https://cardiab.biomedcentral.com/articles/10.1186/s12933-023-01743-5
  30. ↑ 30.0 30.1 30.2 D'Andrea E et al. Comparing effectiveness and safety of SGLT2 inhibitors vs DPP-4 inhibitors in patients with type 2 diabetes and varying baseline HbA1c levels. JAMA Intern Med 2023 Feb 6; [e-pub]. PMID: https://www.ncbi.nlm.nih.gov/pubmed/36745425 https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2800884
  31. ↑ 31.0 31.1 31.2 Cohen LP, Isaza N, Hernandez I et al Cost-effectiveness of Sodium-Glucose Cotransporter-2 Inhibitors for the Treatment of Heart Failure With Preserved Ejection Fraction. JAMA Cardiol. 2023;8(5):419-428. PMID: https://www.ncbi.nlm.nih.gov/pubmed/36870047 PMCID: PMC9985815 (available on 2024-03-04) https://jamanetwork.com/journals/jamacardiology/fullarticle/2802215
    Sandhu AT, Cohen DJ Cost-effectiveness of Sodium-Glucose Cotransporter-2 Inhibitors for Patients With Heart Failure and Preserved Ejection Fraction - Living on the Edge. JAMA Cardiol. 2023;8(5):415-416 PMID: https://www.ncbi.nlm.nih.gov/pubmed/36870043 https://jamanetwork.com/journals/jamacardiology/fullarticle/2802216
  32. ↑ 32.0 32.1 Saito T et al Impact of sodium-glucose cotransporter-2 inhibitors on the risk of hip fracture in older patients in Japan using a nationwide administrative claims database: A matched case-control study. Geriatr Gerontol Int. 2023. May 4 PMID: https://www.ncbi.nlm.nih.gov/pubmed/37139826 https://onlinelibrary.wiley.com/doi/abs/10.1111/ggi.14591
  33. ↑ 33.0 33.1 Baker WL, Smyth LR, Riche DM, Bourret EM, Chamberlin KW, White WB. Effects of sodium-glucose co-transporter 2 inhibitors on blood pressure: a systematic review and meta-analysis. J Am Soc Hypertens. 2014 Apr;8(4):262-75.e9. PMID: https://www.ncbi.nlm.nih.gov/pubmed/24602971 Review.
  34. ↑ 34.0 34.1 Dubrofsky L, Srivastava A, Cherney DZ Sodium-Glucose Cotransporter-2 Inhibitors in Nephrology Practice: A Narrative Review. Can J Kidney Health Dis. 2020 Jun 24;7:2054358120935701. PMID: https://www.ncbi.nlm.nih.gov/pubmed/32637144 PMCID: PMC7315675 Free PMC article. Review.
  35. ↑ 35.0 35.1 35.2 NEJM Knowledge+ Endocrinology
  36. ↑ 36.0 36.1 Pierce JB, Vaduganathan M, Fonarow GC et al Contemporary Use of Sodium-Glucose Cotransporter-2 Inhibitor Therapy Among Patients Hospitalized for Heart Failure With Reduced Ejection Fraction in the US. The Get With The Guidelines - Heart Failure Registry. JAMA Cardiol. 2023;8(7):652-661 PMID: https://www.ncbi.nlm.nih.gov/pubmed/37212192 PMCID: PMC10203967 (available on 2024-05-22) https://jamanetwork.com/journals/jamacardiology/fullarticle/2805332
  37. ↑ 37.0 37.1 37.2 Rigato M, Fadini GP, Avogaro A. Safety of sodium-glucose cotransporter 2 inhibitors in elderly patients with type 2 diabetes: A meta-analysis of randomized controlled trials. Diabetes Obes Metab. 2023. Jul 4 PMID: https://www.ncbi.nlm.nih.gov/pubmed/37402697
    Tumminia A, Graziano M, Vinciguerra F, Lomonaco A, Frittita L. Efficacy, renal safety and tolerability of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in elderly patients with type 2 diabetes: A real-world experience. Prim Care Diabetes. 2021. Apr;15(2):283-288 PMID: https://www.ncbi.nlm.nih.gov/pubmed/33129749
    Wang Y, Shao X, Liu Z. Efficacy and safety of sodium-glucose co-transporter 2 inhibitors in the elderly versus non-elderly patients with type 2 diabetes mellitus: a meta-analysis. Endocr J. 2022 Jun 28;69(6):669-679. PMID: https://www.ncbi.nlm.nih.gov/pubmed/35314533 Free article.
  38. ↑ 38.0 38.1 38.2 Gao M, Bhatia K, Kapoor A et al SGLT2 Inhibitors, Functional Capacity, and Quality of Life in Patients With Heart Failure: A Systematic Review and Meta-Analysis. JAMA Netw Open. 2024 Apr 1;7(4):e245135. PMID: https://www.ncbi.nlm.nih.gov/pubmed/38573633 Free article. https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2817144
  39. ↑ 39.0 39.1 39.2 Yen FS, Hwi CM, Liu JS et al Sodium-Glucose Cotransporter-2 Inhibitors and the Risk for Dialysis and Cardiovascular Disease in Patients With Stage 5 Chronic Kidney Disease. Ann Intern Med, 2024. April 30. PMID: https://www.ncbi.nlm.nih.gov/pubmed/38684099 https://www.acpjournals.org/doi/10.7326/M23-1874
  40. ↑ 40.0 40.1 Modzelewski KL, Pipilas A, Bosch NA Comparative Outcomes of Empagliflozin to Dapagliflozin in Patients With Heart Failure. JAMA Netw Open. 2024;7(5):e249305 PMID: https://www.ncbi.nlm.nih.gov/pubmed/38696170 PMCID: PMC11066699 Free PMC article. https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2818219
  41. ↑ 41.0 41.1 Nishimura A et al Older Adults with Type 2 Diabetes: A Cross-Sectional Study. Drugs Aging. 2024. May 24 Not indexed in PubMed https://link.springer.com/article/10.1007/s40266-024-01119-8
  42. ↑ 42.0 42.1 Bidulka P, Lugo-Palacios DG, Carroll O, et al. Comparative effectiveness of second line oral antidiabetic treatments among people with type 2 diabetes mellitus: Emulation of a target trial using routinely collected health data. BMJ 2024 May 8; 385:e077097. PMID: https://www.ncbi.nlm.nih.gov/pubmed/38719492 PMCID: PMC11077536 Free PMC article.
  43. ↑ 43.0 43.1 43.2 43.3 Patel SM, Kang YM, Im K et al. Sodium-Glucose Cotransporter-2 Inhibitors and Major Adverse Cardiovascular Outcomes: A SMART-C Collaborative Meta-Analysis. Circulation. 2024 Jun 4;149(23):1789-1801 PMID: https://www.ncbi.nlm.nih.gov/pubmed/38583093 PMCID: PMC11149938 Free PMC article.
  44. ↑ 44.0 44.1 Usman MS, Bhatt DL, Hameed I et al Effect of SGLT2 inhibitors on heart failure outcomes and cardiovascular death across the cardiometabolic disease spectrum: a systematic review and meta-analysis. Lancet Diabetes Endocrinol. 2024 Jul;12(7):447-461. PMID: https://www.ncbi.nlm.nih.gov/pubmed/38768620
  45. ↑ 45.0 45.1 Writing Committee; Hollenberg SM, Stevenson LW, Ahmad T et al 2024 ACC Expert Consensus Decision Pathway on Clinical Assessment, Management, and Trajectory of Patients Hospitalized With Heart Failure Focused Update: A Report of the American College of Cardiology Solution Set Oversight Committee J Am Coll Cardiol. 2024 Aug 2:S0735-1097(24)07449-7. PMID: https://www.ncbi.nlm.nih.gov/pubmed/39127954 https://www.jacc.org/doi/10.1016/j.jacc.2024.06.002
  46. ↑ 46.0 46.1 Chen TY, Lee HF, Chan YH, Chuang C, Li PR, Yeh YH, Su HC, See LC. Comparing clinical outcomes in patients with type 2 diabetes mellitus after ischaemic stroke: Sodium-glucose cotransporter 2 inhibitors users versus non-users. A propensity score matching National Cohort Study. Diabetes Obes Metab. 2024 Aug 12. PMID: https://www.ncbi.nlm.nih.gov/pubmed/39134462
  47. ↑ 47.0 47.1 Usman MS, Bhatt DL, Hameed I, et al. Effect of SGLT2 inhibitors on heart failure outcomes and cardiovascular death across the cardiometabolic disease spectrum: a systematic review and meta-analysis. Lancet Diabetes Endocrinol. 2024 Jul;12(7):447-461 PMID: https://www.ncbi.nlm.nih.gov/pubmed/38768620
  48. ↑ 48.0 48.1 Neuen BL, Fletcher RA, et al. Efficacy and safety of SGLT2 inhibitors with and without glucagon-like peptide 1 receptor agonists: a SMART-C collaborative meta-analysis of randomised controlled trials. Lancet Diabetes Endocrinol. 2024 Aug;12(8):545-557 PMID: https://www.ncbi.nlm.nih.gov/pubmed/38991584
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