Early Add-On Combination of GLP-1 Receptor Agonist and SGLT2 Inhibitor in People With Cardiovascular-Kidney-Metabolic Stage 2-3

NCT07465926 | Completed Results

• 5 other identifiers: CS1-25149NSTC 113-2314-B-040-026-MY2NSTC 114-2622-B-040-001CSH-2025-C-012CSH-2025-C-023
• Study Type: observational
• Target: 451,036
• Locations: 0 countries
• Sites: N/A

Brief Summary

This retrospective observational target-trial emulation uses electronic health record data from the TriNetX US Collaborative Network to compare early treatment intensification strategies in adults with obesity, type 2 diabetes, and cardiovascular-kidney-metabolic stage 2-3 who initiate a GLP-1 receptor agonist or an SGLT2 inhibitor. The study compares patients who, within 90 days of starting background therapy, add the alternate agent, add a DPP-4 inhibitor or sulfonylurea, or do not receive early add-on therapy. The primary outcome is all-cause mortality over 36 months, with secondary cardiorenal outcomes also evaluated. Propensity-score methods are used to reduce bias from nonrandom treatment selection.

Conditions

Cardiovascular-kidney-metabolic Syndrome; Cardiovascular Disease Risk Factor; Kidney Disease; Type 2 Diabetes; Obesity & Overweight

Keywords

GLP-1 RA; SGLT2i; Target trial emulation; TriNetX; Cardiovascular-Kidney-Metabolic Syndrome; Obesity; T2D

Outcome Measures

Primary Outcomes (4)

• All-cause Mortality (Comparison 1)

  All-cause mortality within 36 months in the propensity score-matched cohort for Comparison 1, comparing GLP-1 RA with SGLT2i add-on versus GLP-1 RA with DPP-4 inhibitor or sulfonylurea add-on in adults with obesity, type 2 diabetes, and cardiovascular-kidney-metabolic stage 2-3.

  From index through 36 months

• All-cause Mortality (Comparison 2)

  All-cause mortality within 36 months in the propensity score-matched cohort for Comparison 2, comparing GLP-1 RA with SGLT2i add-on versus GLP-1 RA without early add-on treatment in adults with obesity, type 2 diabetes, and cardiovascular-kidney-metabolic stage 2-3.

  From index through 36 months

• All-cause Mortality (Comparison 3)

  All-cause mortality within 36 months in the propensity score-matched cohort for Comparison 3, comparing SGLT2i with GLP-1 RA add-on versus SGLT2i with DPP-4 inhibitor or sulfonylurea add-on in adults with obesity, type 2 diabetes, and cardiovascular-kidney-metabolic stage 2-3.

  From index through 36 months

• All-cause Mortality (Comparison 4)

  All-cause mortality within 36 months in the propensity score-matched cohort for Comparison 4, comparing SGLT2i with GLP-1 RA add-on versus SGLT2i without early add-on treatment in adults with obesity, type 2 diabetes, and cardiovascular-kidney-metabolic stage 2-3.

  From index through 36 months

Secondary Outcomes (8)

• Major Adverse Cardiovascular Events (MACE) (Comparison 1)

  From index through 36 months

• Major Adverse Cardiovascular Events (MACE) (Comparison 2)

  From index through 36 months

• Major Adverse Cardiovascular Events (MACE) (Comparison 3)

  From index through 36 months

• Major Adverse Cardiovascular Events (MACE) (Comparison 4)

  From index through 36 months

• Major Adverse Kidney Events (MAKE) (Comparison 1)

  From index through 36 months

Study Arms (2)

GLP-1 RA Base Therapy

Adults with obesity, type 2 diabetes, and cardiovascular-kidney-metabolic stage 2-3 who initiated a GLP-1 receptor agonist as base therapy after a 6-month washout from GLP-1 RA, SGLT2i, DPP-4i, and sulfonylureas. Within this cohort, participants were classified by the first add-on treatment within 90 days into three mutually exclusive strategies: SGLT2i add-on, DPP-4i or sulfonylurea add-on, or no early add-on.

Drug: GLP-1 receptor agonist; Drug: SGLT2 inhibitor

SGLT2i Base Therapy

Adults with obesity, type 2 diabetes, and cardiovascular-kidney-metabolic stage 2-3 who initiated an SGLT2 inhibitor as base therapy after a 6-month washout from GLP-1 RA, SGLT2i, DPP-4i, and sulfonylureas. Within this cohort, participants were classified by the first add-on treatment within 90 days into three mutually exclusive strategies: GLP-1 RA add-on, DPP-4i or sulfonylurea add-on, or no early add-on.

Drug: GLP-1 receptor agonist; Drug: SGLT2 inhibitor

Interventions

GLP-1 receptor agonist DRUG

Use of a glucagon-like peptide-1 receptor agonist as background therapy or add-on therapy in adults with obesity, type 2 diabetes, and cardiovascular-kidney-metabolic stage 2-3.

GLP-1 RA Base Therapy; SGLT2i Base Therapy

SGLT2 inhibitor DRUG

Use of a sodium-glucose cotransporter-2 inhibitor as background therapy or add-on therapy in adults with obesity, type 2 diabetes, and cardiovascular-kidney-metabolic stage 2-3.

GLP-1 RA Base Therapy; SGLT2i Base Therapy

Eligibility Criteria

• Age: 20 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

Adults (≥20 years) with obesity, type 2 diabetes, and cardiovascular-kidney-metabolic stage 2-3 identified from routinely collected electronic health record data in the TriNetX US Collaborative Network. Participants initiated a GLP-1 receptor agonist or an SGLT2 inhibitor and were classified according to early add-on treatment strategies.

You may qualify if:

• Adults aged 20 years or older.
• Obesity, defined by body mass index (BMI) 27 kg/m2 or greater.
• Type 2 diabetes mellitus, defined using electronic health record data, including diagnosis codes and/or hemoglobin A1c 6.5% or greater.
• Met cardiovascular-kidney-metabolic (CKM) stage 2-3 criteria at baseline.
• Initiated a GLP-1 receptor agonist or an SGLT2 inhibitor as background therapy.
• Had treatment strategy classification based on early add-on initiation within 90 days after background therapy initiation, or no early add-on with index at the 90-day landmark.

You may not qualify if:

• Prior use of GLP-1 receptor agonists, SGLT2 inhibitors, DPP-4 inhibitors, or sulfonylureas within 6 months before cohort entry.
• Major cardiovascular disease or revascularization within 12 months before cohort entry.
• Advanced kidney disease within 12 months before cohort entry, including end-stage kidney disease, dialysis, or estimated glomerular filtration rate less than 15 mL/min/1.73 m2.
• Major cardiovascular or renal events within 6 months before index.
• Any history of non-type 2 diabetes, HIV infection, bariatric surgery, or solid-organ transplantation.
• Missing critical baseline covariates.

Sponsors & Collaborators

• Chung Shan Medical University: lead
• National Science and Technology Council, Taiwan: collaborator

Related Publications (50)

• American Diabetes Association Professional Practice Committee. 10. Cardiovascular Disease and Risk Management: Standards of Care in Diabetes-2025. Diabetes Care. 2025 Jan 1;48(1 Suppl 1):S207-S238. doi: 10.2337/dc25-S010.

  PMID: 39651970 BACKGROUND

• Baker-Smith CM, Gauen AM, Petito LC, Khan SS, Allen NB. Prevalence of Cardiovascular-Kidney-Metabolic Stages in US Adolescents and Relationship to Social Determinants of Health. J Am Heart Assoc. 2025 May 20;14(10):e040269. doi: 10.1161/JAHA.124.040269. Epub 2025 May 15.

  PMID: 40371589 BACKGROUND

• American Diabetes Association Professional Practice Committee. 11. Chronic Kidney Disease and Risk Management: Standards of Care in Diabetes-2025. Diabetes Care. 2025 Jan 1;48(1 Suppl 1):S239-S251. doi: 10.2337/dc25-S011.

  PMID: 39651975 BACKGROUND

• Aggarwal R, Ostrominski JW, Vaduganathan M. Prevalence of Cardiovascular-Kidney-Metabolic Syndrome Stages in US Adults, 2011-2020. JAMA. 2024 Jun 4;331(21):1858-1860. doi: 10.1001/jama.2024.6892.

  PMID: 38717747 BACKGROUND

• Tsai MK, Kao JT, Wong CS, Liao CT, Lo WC, Chien KL, Wen CP, Wu MS, Wu MY. Cardiovascular-kidney-metabolic syndrome and all-cause and cardiovascular mortality: A retrospective cohort study. PLoS Med. 2025 Jun 26;22(6):e1004629. doi: 10.1371/journal.pmed.1004629. eCollection 2025 Jun.

  PMID: 40570007 BACKGROUND

• Hirohama D, Fadista J, Ha E, Liu H, Abedini A, Levinsohn J, Vassalotti A, Zeng L, Li C, Mohandes S, Vitale S, Shungin D, Nguyen T, Niewczas MA, Olsson N, McAllister FE, Karihaloo A, Susztak K. The proteogenomic landscape of the human kidney and implications for cardio-kidney-metabolic health. Nat Med. 2025 Nov;31(11):3917-3929. doi: 10.1038/s41591-025-03872-8. Epub 2025 Aug 12.

  PMID: 40796935 BACKGROUND

• Hernan MA, Sauer BC, Hernandez-Diaz S, Platt R, Shrier I. Specifying a target trial prevents immortal time bias and other self-inflicted injuries in observational analyses. J Clin Epidemiol. 2016 Nov;79:70-75. doi: 10.1016/j.jclinepi.2016.04.014. Epub 2016 May 27.

  PMID: 27237061 BACKGROUND

• Wong CK, Drucker DJ. Antiinflammatory actions of glucagon-like peptide-1-based therapies beyond metabolic benefits. J Clin Invest. 2025 Nov 3;135(21):e194751. doi: 10.1172/JCI194751. eCollection 2025 Nov 3.

  PMID: 41178710 BACKGROUND

• The EMPA-KIDNEY Collaborative Group; Herrington WG, Staplin N, Wanner C, Green JB, Hauske SJ, Emberson JR, Preiss D, Judge P, Mayne KJ, Ng SYA, Sammons E, Zhu D, Hill M, Stevens W, Wallendszus K, Brenner S, Cheung AK, Liu ZH, Li J, Hooi LS, Liu W, Kadowaki T, Nangaku M, Levin A, Cherney D, Maggioni AP, Pontremoli R, Deo R, Goto S, Rossello X, Tuttle KR, Steubl D, Petrini M, Massey D, Eilbracht J, Brueckmann M, Landray MJ, Baigent C, Haynes R. Empagliflozin in Patients with Chronic Kidney Disease. N Engl J Med. 2023 Jan 12;388(2):117-127. doi: 10.1056/NEJMoa2204233. Epub 2022 Nov 4.

  PMID: 36331190 BACKGROUND

• Verma S, Bhatta M, Davies M, Deanfield JE, Garvey WT, Jensen C, Kandler K, Kushner RF, Rubino DM, Kosiborod MN. Effects of once-weekly semaglutide 2.4 mg on C-reactive protein in adults with overweight or obesity (STEP 1, 2, and 3): Exploratory analyses of three randomised, double-blind, placebo-controlled, phase 3 trials. EClinicalMedicine. 2022 Nov 29;55:101737. doi: 10.1016/j.eclinm.2022.101737. eCollection 2023 Jan.

  PMID: 36467859 BACKGROUND

• Massy ZA, Drueke TB. Combination of Cardiovascular, Kidney, and Metabolic Diseases in a Syndrome Named Cardiovascular-Kidney-Metabolic, With New Risk Prediction Equations. Kidney Int Rep. 2024 Jun 6;9(9):2608-2618. doi: 10.1016/j.ekir.2024.05.033. eCollection 2024 Sep.

  PMID: 39291205 BACKGROUND

• Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JF, Nauck MA, Nissen SE, Pocock S, Poulter NR, Ravn LS, Steinberg WM, Stockner M, Zinman B, Bergenstal RM, Buse JB; LEADER Steering Committee; LEADER Trial Investigators. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2016 Jul 28;375(4):311-22. doi: 10.1056/NEJMoa1603827. Epub 2016 Jun 13.

  PMID: 27295427 BACKGROUND

• Verma S, Sharma A, Zinman B, Ofstad AP, Fitchett D, Brueckmann M, Wanner C, Zwiener I, George JT, Inzucchi SE, Butler J, Mazer CD. Empagliflozin reduces the risk of mortality and hospitalization for heart failure across Thrombolysis In Myocardial Infarction Risk Score for Heart Failure in Diabetes categories: Post hoc analysis of the EMPA-REG OUTCOME trial. Diabetes Obes Metab. 2020 Jul;22(7):1141-1150. doi: 10.1111/dom.14015. Epub 2020 Mar 29.

  PMID: 32227432 BACKGROUND

• Zheng Z, Zong Y, Ma Y, Tian Y, Pang Y, Zhang C, Gao J. Glucagon-like peptide-1 receptor: mechanisms and advances in therapy. Signal Transduct Target Ther. 2024 Sep 18;9(1):234. doi: 10.1038/s41392-024-01931-z.

  PMID: 39289339 BACKGROUND

• Upadhyay A. SGLT2 Inhibitors and Kidney Protection: Mechanisms Beyond Tubuloglomerular Feedback. Kidney360. 2024 May 1;5(5):771-782. doi: 10.34067/KID.0000000000000425. Epub 2024 Mar 25.

  PMID: 38523127 BACKGROUND

• Bae JH. SGLT2 Inhibitors and GLP-1 Receptor Agonists in Diabetic Kidney Disease: Evolving Evidence and Clinical Application. Diabetes Metab J. 2025 May;49(3):386-402. doi: 10.4093/dmj.2025.0220. Epub 2025 May 1.

  PMID: 40367988 BACKGROUND

• Hernan MA, Dahabreh IJ, Dickerman BA, Swanson SA. The Target Trial Framework for Causal Inference From Observational Data: Why and When Is It Helpful? Ann Intern Med. 2025 Mar;178(3):402-407. doi: 10.7326/ANNALS-24-01871. Epub 2025 Feb 18.

  PMID: 39961105 BACKGROUND

• Zhu R, Wang R, He J, Wang L, Chen H, Niu X, Sun Y, Guan Y, Gong Y, Zhang L, An P, Li K, Ren F, Xu W, Guo J. Prevalence of Cardiovascular-Kidney-Metabolic Syndrome Stages by Social Determinants of Health. JAMA Netw Open. 2024 Nov 4;7(11):e2445309. doi: 10.1001/jamanetworkopen.2024.45309.

  PMID: 39556396 BACKGROUND

• Yadav K, Lewis RJ. Immortal Time Bias in Observational Studies. JAMA. 2021 Feb 16;325(7):686-687. doi: 10.1001/jama.2020.9151. No abstract available.

  PMID: 33591334 BACKGROUND

• Dib BN, Swanson SA. Emulating a Target Trial Using Observational Data. JAMA Intern Med. 2025 Apr 1;185(4):459-460. doi: 10.1001/jamainternmed.2024.8129.

  PMID: 39992643 BACKGROUND

• Savignano FA, Crajoinas RO, Pacheco BPM, Campos LCG, Shimizu MHM, Seguro AC, Girardi ACC. Attenuated diuresis and natriuresis in response to glucagon-like peptide-1 in hypertensive rats are associated with lower expression of the glucagon-like peptide-1 receptor in the renal vasculature. Eur J Pharmacol. 2017 Sep 15;811:38-47. doi: 10.1016/j.ejphar.2017.05.054. Epub 2017 May 30.

  PMID: 28576404 BACKGROUND

• Lovshin J, Cherney D. GLP-1R Agonists and Endothelial Dysfunction: More Than Just Glucose Lowering? Diabetes. 2015 Jul;64(7):2319-21. doi: 10.2337/db15-0366. No abstract available.

  PMID: 26106189 BACKGROUND

• Carraro-Lacroix LR, Malnic G, Girardi AC. Regulation of Na+/H+ exchanger NHE3 by glucagon-like peptide 1 receptor agonist exendin-4 in renal proximal tubule cells. Am J Physiol Renal Physiol. 2009 Dec;297(6):F1647-55. doi: 10.1152/ajprenal.00082.2009. Epub 2009 Sep 23.

  PMID: 19776173 BACKGROUND

• Asmar A, Cramon PK, Asmar M, Simonsen L, Sorensen CM, Madsbad S, Hartmann B, Holst JJ, Hovind P, Jensen BL, Bulow J. The Renal Extraction and the Natriuretic Action of GLP-1 in Humans Depend on Interaction With the GLP-1 Receptor. J Clin Endocrinol Metab. 2021 Jan 1;106(1):e11-e19. doi: 10.1210/clinem/dgaa643.

  PMID: 32927478 BACKGROUND

• Asmar A, Cramon PK, Simonsen L, Asmar M, Sorensen CM, Madsbad S, Moro C, Hartmann B, Jensen BL, Holst JJ, Bulow J. Extracellular Fluid Volume Expansion Uncovers a Natriuretic Action of GLP-1: A Functional GLP-1-Renal Axis in Man. J Clin Endocrinol Metab. 2019 Jul 1;104(7):2509-2519. doi: 10.1210/jc.2019-00004.

  PMID: 30835273 BACKGROUND

• Muller TD, Finan B, Bloom SR, D'Alessio D, Drucker DJ, Flatt PR, Fritsche A, Gribble F, Grill HJ, Habener JF, Holst JJ, Langhans W, Meier JJ, Nauck MA, Perez-Tilve D, Pocai A, Reimann F, Sandoval DA, Schwartz TW, Seeley RJ, Stemmer K, Tang-Christensen M, Woods SC, DiMarchi RD, Tschop MH. Glucagon-like peptide 1 (GLP-1). Mol Metab. 2019 Dec;30:72-130. doi: 10.1016/j.molmet.2019.09.010. Epub 2019 Sep 30.

  PMID: 31767182 BACKGROUND

• Yau K, Cherney DZI, van Raalte DH, Wever BE. Kidney protective mechanisms of SGLT2 inhibitors: evidence for a hemodynamic effect. Kidney Int. 2024 Jun;105(6):1168-1172. doi: 10.1016/j.kint.2024.03.019. No abstract available.

  PMID: 38777402 BACKGROUND

• Inzucchi SE, Zinman B, Fitchett D, Wanner C, Ferrannini E, Schumacher M, Schmoor C, Ohneberg K, Johansen OE, George JT, Hantel S, Bluhmki E, Lachin JM. How Does Empagliflozin Reduce Cardiovascular Mortality? Insights From a Mediation Analysis of the EMPA-REG OUTCOME Trial. Diabetes Care. 2018 Feb;41(2):356-363. doi: 10.2337/dc17-1096. Epub 2017 Dec 4.

  PMID: 29203583 BACKGROUND

• Verma S, McMurray JJV. SGLT2 inhibitors and mechanisms of cardiovascular benefit: a state-of-the-art review. Diabetologia. 2018 Oct;61(10):2108-2117. doi: 10.1007/s00125-018-4670-7. Epub 2018 Aug 22.

  PMID: 30132036 BACKGROUND

• Fioretto P, Zambon A, Rossato M, Busetto L, Vettor R. SGLT2 Inhibitors and the Diabetic Kidney. Diabetes Care. 2016 Aug;39 Suppl 2:S165-71. doi: 10.2337/dcS15-3006.

  PMID: 27440829 BACKGROUND

• Wilcox CS. Antihypertensive and Renal Mechanisms of SGLT2 (Sodium-Glucose Linked Transporter 2) Inhibitors. Hypertension. 2020 Apr;75(4):894-901. doi: 10.1161/HYPERTENSIONAHA.119.11684. Epub 2020 Mar 2.

  PMID: 32114848 BACKGROUND

• Usman MS, Bhatt DL, Hameed I, Anker SD, Cheng AYY, Hernandez AF, Jones WS, Khan MS, Petrie MC, Udell JA, Friede T, Butler J. 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. doi: 10.1016/S2213-8587(24)00102-5. Epub 2024 May 17.

  PMID: 38768620 BACKGROUND

• Kristensen SL, Rorth R, Jhund PS, Docherty KF, Sattar N, Preiss D, Kober L, Petrie MC, McMurray JJV. Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet Diabetes Endocrinol. 2019 Oct;7(10):776-785. doi: 10.1016/S2213-8587(19)30249-9. Epub 2019 Aug 14.

  PMID: 31422062 BACKGROUND

• Scheen AJ. GLP-1 Receptor Agonists and SGLT2 Inhibitors in Type 2 Diabetes: Pleiotropic Cardiometabolic Effects and Add-on Value of a Combined Therapy. Drugs. 2024 Nov;84(11):1347-1364. doi: 10.1007/s40265-024-02090-9. Epub 2024 Sep 28.

  PMID: 39342059 BACKGROUND

• Wiviott SD, Raz I, Bonaca MP, Mosenzon O, Kato ET, Cahn A, Silverman MG, Zelniker TA, Kuder JF, Murphy SA, Bhatt DL, Leiter LA, McGuire DK, Wilding JPH, Ruff CT, Gause-Nilsson IAM, Fredriksson M, Johansson PA, Langkilde AM, Sabatine MS; DECLARE-TIMI 58 Investigators. Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2019 Jan 24;380(4):347-357. doi: 10.1056/NEJMoa1812389. Epub 2018 Nov 10.

  PMID: 30415602 BACKGROUND

• Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, Broedl UC, Inzucchi SE; EMPA-REG OUTCOME Investigators. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2015 Nov 26;373(22):2117-28. doi: 10.1056/NEJMoa1504720. Epub 2015 Sep 17.

  PMID: 26378978 BACKGROUND

• Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2024 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney Int. 2024 Apr;105(4S):S117-S314. doi: 10.1016/j.kint.2023.10.018. No abstract available.

  PMID: 38490803 BACKGROUND

• Perkovic V, Tuttle KR, Rossing P, Mahaffey KW, Mann JFE, Bakris G, Baeres FMM, Idorn T, Bosch-Traberg H, Lausvig NL, Pratley R; FLOW Trial Committees and Investigators. Effects of Semaglutide on Chronic Kidney Disease in Patients with Type 2 Diabetes. N Engl J Med. 2024 Jul 11;391(2):109-121. doi: 10.1056/NEJMoa2403347. Epub 2024 May 24.

  PMID: 38785209 BACKGROUND

• Heerspink HJL, Stefansson BV, Correa-Rotter R, Chertow GM, Greene T, Hou FF, Mann JFE, McMurray JJV, Lindberg M, Rossing P, Sjostrom CD, Toto RD, Langkilde AM, Wheeler DC; DAPA-CKD Trial Committees and Investigators. Dapagliflozin in Patients with Chronic Kidney Disease. N Engl J Med. 2020 Oct 8;383(15):1436-1446. doi: 10.1056/NEJMoa2024816. Epub 2020 Sep 24.

  PMID: 32970396 BACKGROUND

• Simms-Williams N, Treves N, Yin H, Lu S, Yu O, Pradhan R, Renoux C, Suissa S, Azoulay L. Effect of combination treatment with glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 inhibitors on incidence of cardiovascular and serious renal events: population based cohort study. BMJ. 2024 Apr 25;385:e078242. doi: 10.1136/bmj-2023-078242.

  PMID: 38663919 BACKGROUND

• Cashin AG, Hansford HJ, Hernan MA, Swanson SA, Lee H, Jones MD, Dahabreh IJ, Dickerman BA, Egger M, Garcia-Albeniz X, Golub RM, Islam N, Lodi S, Moreno-Betancur M, Pearson SA, Schneeweiss S, Sharp MK, Sterne JAC, Stuart EA, McAuley JH. Transparent Reporting of Observational Studies Emulating a Target Trial-The TARGET Statement. JAMA. 2025 Sep 23;334(12):1084-1093. doi: 10.1001/jama.2025.13350.

  PMID: 40899949 BACKGROUND

• Hubbard RA, Gatsonis CA, Hogan JW, Hunter DJ, Normand ST, Troxel AB. "Target Trial Emulation" for Observational Studies - Potential and Pitfalls. N Engl J Med. 2024 Nov 28;391(21):1975-1977. doi: 10.1056/NEJMp2407586. Epub 2024 Nov 23. No abstract available.

  PMID: 39588897 BACKGROUND

• Drucker DJ. GLP-1-based therapies for diabetes, obesity and beyond. Nat Rev Drug Discov. 2025 Aug;24(8):631-650. doi: 10.1038/s41573-025-01183-8. Epub 2025 Apr 25.

  PMID: 40281304 BACKGROUND

• Huang YN, Liao WL, Huang JY, Lin YJ, Yang SF, Huang CC, Wang CH, Su PH. Long-term safety and efficacy of glucagon-like peptide-1 receptor agonists in individuals with obesity and without type 2 diabetes: A global retrospective cohort study. Diabetes Obes Metab. 2024 Nov;26(11):5222-5232. doi: 10.1111/dom.15869. Epub 2024 Aug 22.

  PMID: 39171569 BACKGROUND

• Pohlman N, Patel PN, Essien UR, Tang JJ, Joseph JJ. Novel Cardiometabolic Medications in the Cardiovascular-Kidney-Metabolic Syndrome Era. J Clin Endocrinol Metab. 2025 Jul 15;110(8):2105-2122. doi: 10.1210/clinem/dgaf295.

  PMID: 40388382 BACKGROUND

• Rao SV, O'Donoghue ML, Ruel M, Rab T, Tamis-Holland JE, Alexander JH, Baber U, Baker H, Cohen MG, Cruz-Ruiz M, Davis LL, de Lemos JA, DeWald TA, Elgendy IY, Feldman DN, Goyal A, Isiadinso I, Menon V, Morrow DA, Mukherjee D, Platz E, Promes SB, Sandner S, Sandoval Y, Schunder R, Shah B, Stopyra JP, Talbot AW, Taub PR, Williams MS. 2025 ACC/AHA/ACEP/NAEMSP/SCAI Guideline for the Management of Patients With Acute Coronary Syndromes: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2025 Apr;151(13):e771-e862. doi: 10.1161/CIR.0000000000001309. Epub 2025 Feb 27.

  PMID: 40014670 BACKGROUND

• Marx N, Federici M, Schutt K, Muller-Wieland D, Ajjan RA, Antunes MJ, Christodorescu RM, Crawford C, Di Angelantonio E, Eliasson B, Espinola-Klein C, Fauchier L, Halle M, Herrington WG, Kautzky-Willer A, Lambrinou E, Lesiak M, Lettino M, McGuire DK, Mullens W, Rocca B, Sattar N; ESC Scientific Document Group. 2023 ESC Guidelines for the management of cardiovascular disease in patients with diabetes. Eur Heart J. 2023 Oct 14;44(39):4043-4140. doi: 10.1093/eurheartj/ehad192. No abstract available.

  PMID: 37622663 BACKGROUND

• Ndumele CE, Neeland IJ, Tuttle KR, Chow SL, Mathew RO, Khan SS, Coresh J, Baker-Smith CM, Carnethon MR, Despres JP, Ho JE, Joseph JJ, Kernan WN, Khera A, Kosiborod MN, Lekavich CL, Lewis EF, Lo KB, Ozkan B, Palaniappan LP, Patel SS, Pencina MJ, Powell-Wiley TM, Sperling LS, Virani SS, Wright JT, Rajgopal Singh R, Elkind MSV, Rangaswami J; American Heart Association. A Synopsis of the Evidence for the Science and Clinical Management of Cardiovascular-Kidney-Metabolic (CKM) Syndrome: A Scientific Statement From the American Heart Association. Circulation. 2023 Nov 14;148(20):1636-1664. doi: 10.1161/CIR.0000000000001186. Epub 2023 Oct 9.

  PMID: 37807920 BACKGROUND

• Sebastian SA, Padda I, Johal G. Cardiovascular-Kidney-Metabolic (CKM) syndrome: A state-of-the-art review. Curr Probl Cardiol. 2024 Feb;49(2):102344. doi: 10.1016/j.cpcardiol.2023.102344. Epub 2023 Dec 14.

  PMID: 38103820 BACKGROUND

• Ndumele CE, Rangaswami J, Chow SL, Neeland IJ, Tuttle KR, Khan SS, Coresh J, Mathew RO, Baker-Smith CM, Carnethon MR, Despres JP, Ho JE, Joseph JJ, Kernan WN, Khera A, Kosiborod MN, Lekavich CL, Lewis EF, Lo KB, Ozkan B, Palaniappan LP, Patel SS, Pencina MJ, Powell-Wiley TM, Sperling LS, Virani SS, Wright JT, Rajgopal Singh R, Elkind MSV; American Heart Association. Cardiovascular-Kidney-Metabolic Health: A Presidential Advisory From the American Heart Association. Circulation. 2023 Nov 14;148(20):1606-1635. doi: 10.1161/CIR.0000000000001184. Epub 2023 Oct 9.

  PMID: 37807924 BACKGROUND

MeSH Terms

Conditions

Kidney Diseases; Diabetes Mellitus, Type 2; Obesity; Overweight

Interventions

Sodium-Glucose Transporter 2 Inhibitors

Condition Hierarchy (Ancestors)

Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Overnutrition; Nutrition Disorders; Body Weight; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Molecular Mechanisms of Pharmacological Action; Pharmacologic Actions; Chemical Actions and Uses; Hypoglycemic Agents; Physiological Effects of Drugs

Limitations and Caveats

This retrospective observational target-trial emulation is subject to residual confounding, misclassification, and missing or incomplete electronic health record data. Treatment strategies were not randomly assigned, and matching was performed separately for each pairwise comparison.

Results Point of Contact

• Title: Yu-Nan Huang, Ph.D.
• Organization: Chung Shan Medical University Hospital

yunanhuang83@gmail.com

886-4-24739595

Publication Agreements

• PI is Sponsor Employee: Yes
• Restrictive Agreement: No

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: RETROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor/Research Fellow

Study Record Dates

• First Submitted: March 8, 2026
• First Posted: March 12, 2026
• Study Start: January 1, 2017
• Primary Completion: January 31, 2026
• Study Completion: January 31, 2026
• Last Updated: June 22, 2026
• Results First Posted: June 22, 2026

Record last verified: 2026-05

Data Sharing

• IPD Sharing: Will not share