{"doi":"10.1016/j.ekir.2022.01.1049","title":"Moderating Effects in Randomized Trials—Interpreting the P Value, Confidence Intervals, and Hazard Ratios","abstract":"See Clinical Research on Page xxx See Clinical Research on Page xxx The discovery of blood pressure lowering in the 1980s and the use of angiotensin-receptor blockers in the early 2000s were significant advances in protecting the kidney and the cardiovascular system from the ravages of type 2 diabetes. For nearly 2 decades, multiple interventions failed, including the use of combination renin-angiotensin system–blocking drugs. The clinical observation in phase 2 clinical trials that the sodium-glucose co-transporter 2 (SGLT2) inhibitors lowered albuminuria among patients with type 2 diabetes prompted a phase 3 randomized clinical trial that culminated in the discovery of canagliflozin improving cardiorenal outcomes in this population.1Perkovic V. Jardine M.J. Neal B. et al.Canagliflozin and renal outcomes in type 2 diabetes and nephropathy.N Engl J Med. 2019; 380: 2295-2306https://doi.org/10.1056/NEJMoa1811744Crossref PubMed Scopus (1841) Google Scholar Soon thereafter, these observations were extended to patients with chronic kidney disease (CKD) without type 2 diabetes and slightly lower levels of albuminuria.2Heerspink H.J.L. Stefansson B.V. Correa-Rotter R. et al.Dapagliflozin in patients with chronic kidney disease.N Engl J Med. 2020; 383: 1436-1446https://doi.org/10.1056/NEJMoa2024816Crossref PubMed Scopus (671) Google Scholar Specifically, in the DAPA-CKD trial, it was noted that patients with albuminuria ranging between 200 and 5000 mg/g creatinine and estimated glomerular filtration rate between 25 and 75 ml/min per 1.73 m2 with and without type 2 diabetes had reduced cardiorenal outcomes owing to dapagliflozin.2Heerspink H.J.L. Stefansson B.V. Correa-Rotter R. et al.Dapagliflozin in patients with chronic kidney disease.N Engl J Med. 2020; 383: 1436-1446https://doi.org/10.1056/NEJMoa2024816Crossref PubMed Scopus (671) Google Scholar In 2020, with the nonsteroidal mineralocorticoid receptor antagonist (MRA), finerenone, in the FIDELIO-DKD trial in patients with CKD associated with type 2 diabetes, the kidney-specific adverse clinical outcomes were abrogated by 18% and clinical cardiovascular adverse outcomes were abrogated by 14%.3Bakris G.L. Agarwal R. Anker S.D. et al.Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes.N Engl J Med. 2020; 383: 2219-2229https://doi.org/10.1056/NEJMoa2025845Crossref PubMed Scopus (247) Google Scholar In this trial, CKD was defined as albuminuria (30–5000 mg/g creatinine) with estimated glomerular filtration rate between 25 and 75 ml/min per 1.73 m2. Thus, a broader range of patients including all patients with A2 albuminuria were now included. In all the above-mentioned trials, blood pressure was controlled to <140/90 mm Hg and renin-angiotensin system–blocking drugs were prescribed in all patients. Effective cardioprotective therapies, such as statins and platelet-aggregation inhibitors, were used in most patients. After a hiatus of 2 decades, we had 2 drugs in consecutive years which were approved by the US Food and Drug Administration for cardiorenal protection in patients with CKD associated with type 2 diabetes. The obvious question that emerged was whether the combination of the 2 drugs—finerenone and the SGLT2 inhibitors—will produce greater benefits than either drug alone. Several considerations are noteworthy. Neither of these 2 trials had stratified randomization by the use of the competing cardiorenal protective drug because at the time the trials were designed, it was unclear whether either therapy was effective. Nevertheless, in the DAPA-CKD trial, including in the finerenone trials, there were a small number of patients who were on combination of the 2 drugs. For example, the DAPA-CKD study used steroidal MRA (spironolactone and eplerenone) in combination with dapagliflozin and FIDELIO-DKD and FIGARO-DKD studies used the SGLT2 inhibitors in combination with finerenone. Therefore, one could ask the question whether patients who received the combinati","journal":"Kidney International Reports","year":2022,"id":284545,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":5,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.952,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":962312,"name":"Brian S. Rifkin","orcid":"0000-0001-8395-3744","position":1,"is_corresponding":false},{"id":271623,"name":"Rajiv Agarwal","orcid":"0000-0002-3146-7231","position":0,"is_corresponding":true}],"reference_count":11,"raw_metadata":null,"created_at":"2026-07-19T00:29:36.828109Z","pmid":"35257050","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":[]}