{"doi":"10.1161/jaha.121.021661","title":"Association Between Circulating GDF‐15 and Cardio‐Renal Outcomes and Effect of Canagliflozin: Results From the CANVAS Trial","abstract":"Background Studies have suggested that sodium glucose co-transporter 2 inhibitors exert anti-inflammatory effects. We examined the association of baseline growth differentiation factor-15 (GDF-15), a marker of inflammation and cellular injury, with cardiovascular events, hospitalization for heart failure (HF), and kidney outcomes in patients with type 2 diabetes in the CANVAS (Canagliflozin Cardiovascular Assessment Study) and determined the effect of the sodium glucose co-transporter 2 inhibitor canagliflozin on circulating GDF-15. Methods and Results The CANVAS trial randomized 4330 people with type 2 diabetes at high cardiovascular risk to canagliflozin or placebo. The association between baseline GDF-15 and cardiovascular (non-fatal myocardial infarction, non-fatal stroke, cardiovascular death), HF, and kidney (40% estimated glomerular filtration rate decline, end-stage kidney disease, renal death) outcomes was assessed using multivariable adjusted Cox regression models. During median follow-up of 6.1 years (N=3549 participants with available samples), 555 cardiovascular, 129 HF, and 137 kidney outcomes occurred. Each doubling in baseline GDF-15 was significantly associated with a higher risk of cardiovascular (hazard ratio [HR], 1.2; 95% CI, 1.0‒1.3), HF (HR, 1.5; 95% CI, 1.2‒2.0) and kidney (HR, 1.5; 95% CI, 1.2‒2.0) outcomes. Baseline GDF-15 did not modify canagliflozin's effect on cardiovascular, HF, and kidney outcomes. Canaglifozin treatment modestly lowered GDF-15 compared with placebo; however, GDF-15 did not mediate the protective effect of canagliflozin on cardiovascular, HF, or kidney outcomes. Conclusions In patients with type 2 diabetes at high cardiovascular risk, higher GDF-15 levels were associated with a higher risk of cardiovascular, HF, and kidney outcomes. Canagliflozin modestly lowered GDF-15, but GDF-15 reduction did not mediate the protective effect of canagliflozin.","journal":"Journal of the American Heart Association","year":2021,"id":167602,"datarank":0.5244761342199721,"base_score":3.4965075614664802,"endowment":3.4965075614664802,"self_citation_contribution":0.5244761342199721,"citation_network_contribution":0.0,"self_endowment_contribution":0.5244761342199721,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":32,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9516,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":438216,"name":"Jingwei Li","orcid":"0000-0002-2508-4859","position":1,"is_corresponding":false},{"id":300854,"name":"Brendon L. Neuen","orcid":"0000-0001-9276-8380","position":2,"is_corresponding":false},{"id":300855,"name":"Clare Arnott","orcid":"0000-0001-9370-9913","position":3,"is_corresponding":false},{"id":923,"name":"Bruce Neal","orcid":"0000-0002-0490-7465","position":4,"is_corresponding":false},{"id":75046,"name":"Vlado Perkovic","orcid":"0000-0002-4257-7620","position":5,"is_corresponding":false},{"id":75047,"name":"Kenneth W. Mahaffey","orcid":"0000-0002-3791-2148","position":6,"is_corresponding":false},{"id":75049,"name":"Wayne Shaw","orcid":null,"position":7,"is_corresponding":false},{"id":271628,"name":"William Canovatchel","orcid":"0000-0002-0093-9873","position":8,"is_corresponding":false},{"id":660509,"name":"Michael K. Hansen","orcid":"0000-0002-0062-0520","position":9,"is_corresponding":false},{"id":232682,"name":"Hiddo J.L. Heerspink","orcid":"0000-0002-3126-3730","position":10,"is_corresponding":false},{"id":666139,"name":"Taha Sen","orcid":"0000-0001-6359-2945","position":0,"is_corresponding":true}],"reference_count":31,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T23:45:58.359801Z","pmid":"34854308","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}