THE ACUTE, REVERSIBLE eGFR RESPONSE ASSOCIATED WITH FENOFIBRATE IS NOT HARMFUL: A POST HOC ANALYSIS FROM THE FIELD TRIAL
Dr Alexandra Gallagher1,2, MS RACHEL L. O’CONNELL2, A/Prof GEORGE MANGOS1,3, Dr BRENDAN SMYTH1,2, TIMOTHY M.E DAVIS4, ALICIA J. JENKINS2,5, RUSSELL S. SCOTT6, DAVID SULLIVAN7, MARJA-RIITTA TASKINEN8, ANTHONY KEECH2,9, MEG J. JARDINE2,10
1Department of Renal Medicine, St George Hospital, Kogarah, Australia, 2NHMRC Clinical Trials Centre, University of Sydney, Camperdown, Australia, 3School of Clinical Medicine, UNSW Medicine & Health St George & Sutherland Clinical Campus, Sydney, Australia, 4University of Western Australia, Medical School, Fremantle Hospital, Fremantle, Australia, 5Baker Heart and Diabetes Institute, Melbourne, Australia, 6New Zealand Clinical Research Ltd, Christchurch, New Zealand, 7Department of Chemical Pathology, Royal Prince Alfred Hospital, Sydney, Australia, 8Research Program for Clinical and Molecular Medicine Unit, Diabetes and Obesity, University of Helsinki, 00029 Helsinki, Finland, 9Department of Cardiology, Royal Prince Alfred Hospital, Sydney, Australia, 10Department of Renal Medicine, Concord Repatriation General Hospital, Sydney, Australia
Background: Several agents protective against chronic kidney disease are associated with an initial estimated Glomerular Filtration Rate (eGFR) decline. Sodium-glucose cotransporter-2 inhibitor studies have found these eGFR dips are not associated with harm although analyses were post-randomisation. Fenofibrate leads to an acute, reversible eGFR decline by non-glomerular mechanisms. In a trial where the acute eGFR response to fenofibrate was assessed pre-randomisation, we aimed to test whether the acute eGFR decline predicts benefit.
Methods: The FIELD trial randomised adults to fenofibrate or placebo. All participants were exposed to an active run-in. The Acute Fenofibrate Response (AFR) was measured and categorised as nil, mild, moderate, or large (increase/no change, 0-10%, 10-20%, >20% eGFR decline). Subgroup analyses were conducted for several cardiovascular outcomes, mortality, a clinical kidney endpoint (doubling serum creatinine, eGFR <15ml/min/1.73m2, renal related death, or kidney replacement therapy), and total (baseline to study close) and chronic (4 months post-randomisation to study close) eGFR slopes, with heterogeneity assessed using a test of trend.
Results: In 9777 participants, fenofibrate therapy did not reduce coronary events with no evidence of treatment modification by acute eGFR decline category (overall HR 0.89 [95% CI 0.75 to 1.05]); nil, mild, moderate, and large acute decline: 1.08, 0.77, 1.02 and 0.82 respectively, p-trend 0.997). AFR category did not predict harm for clinical kidney, total cardiovascular events, total microvascular events, or all-cause mortality (p-trend 0.97, 0.20, 0.46 and 0.95, respectively). Subgroups of greater AFR experienced more improvement on chronic eGFR slope, and the reverse trend for total slope (p-trend <0.0001 and 0.01, respectively).
Conclusion: There was no evidence that greater acute eGFR decline leads to fenofibrate-associated harm for a range of clinically meaningful endpoints.
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Biography:
Dr Gallagher completed an undergraduate degree in medicine through the University of Newcastle in 2012. She undertook her general physician training through a network of metropolitan, regional and rural centres before completing her specialty training in Nephrology at Royal Prince Alfred, Concord, St George, and Wollongong Hospitals. She has a Masters of Clincial Medicine; leadership and management through the University of Newcastle. She is a current PhD candidate with the Clinical Trials Centre and St George hospital, the latter of which is where she also works clinically. Her interests include blood pressure measurement, green nephrology, and cardioprotective strategies in high risk patients, including those with advanced chronic kidney disease.