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PPARA Polymorphism Influences the Cardiovascular Benefit Of Diabetes Volume 69, April 2020 771 PPARA Polymorphism Influences the Cardiovascular Benefit of Fenofibrate in Type 2 Diabetes: Findings From ACCORD-Lipid Mario Luca Morieri,1,2,3 Hetal S. Shah,1,2 Jennifer Sjaarda,4 Petra A. Lenzini,5 Hannah Campbell,5,6 Alison A. Motsinger-Reif,7 He Gao,1,2 Laura Lovato,8 Sabrina Prudente,9 Assunta Pandolfi,10 Marcus G. Pezzolesi,11 Ronald J. Sigal,12 Guillaume Paré,4 Santica M. Marcovina,13 Daniel M. Rotroff,14 Elisabetta Patorno,15 Luana Mercuri,9 Vincenzo Trischitta,9,16 Emily Y. Chew,17 Peter Kraft,18 John B. Buse,19 Michael J. Wagner,20 Sharon Cresci,5,6 Hertzel C. Gerstein,4 Henry N. Ginsberg,21 Josyf C. Mychaleckyj,22 and Alessandro Doria1,2 GENETICS/GENOMES/PROTEOMICS/METABOLOMICS Diabetes 2020;69:771–783 | https://doi.org/10.2337/db19-0973 The cardiovascular benefits of fibrates have been shown to rs6008845 T/T homozygotes experienced a cardiovascular be heterogeneous and to depend on the presence of benefitfromfibrate even in the absence of atherogenic atherogenic dyslipidemia. We investigated whether genetic dyslipidemia. Among these individuals, but not among variability in the PPARA gene, coding for the pharmacolog- carriers of other genotypes, fenofibrate treatment was ical target of fibrates (PPAR-a),couldbeusedtoimprove associated with lower circulating levels of CCL11—aproin- the selection of patients with type 2 diabetes who may flammatory and atherogenic chemokine also known as derive cardiovascular benefit from addition of this treat- eotaxin (P for rs6008845-by-fenofibrate interaction 5 ment to statins. We identified a common variant at the 0.003). The GTEx data set revealed regulatory functions PPARA locus (rs6008845, C/T) displaying a study-wide of rs6008845 on PPARA expression in many tissues. In significant influence on the effect of fenofibrate on major summary,wehavefoundacommonPPARA regulatory cardiovascular events (MACE) among 3,065 self-reported variantthatinfluences the cardiovascular effects of fenofi- white subjects treated with simvastatin and randomized to brate and that could be used to identify patients with type 2 fenofibrate or placebo in the ACCORD-Lipid trial. T/T diabetes who would derive benefitfromfenofibrate treat- homozygotes (36% of participants) experienced a 51% ment, in addition to those with atherogenic dyslipidemia. MACE reduction in response to fenofibrate (hazard ratio 0.49; 95% CI 0.34–0.72), whereas no benefitwasobserved 24 for other genotypes (Pinteraction 5 3.7 3 10 ). The Cardiovascular events due to accelerated atherogenesis are rs6008845-by-fenofibrate interaction on MACE was repli- major determinants of morbidity and mortality in patients cated in African Americans from ACCORD (N 5 585, P 5 with type 2 diabetes (1). The causes of increased athero- 0.02) and in external cohorts (ACCORD-BP, ORIGIN, and genesis in type 2 diabetes are complex and include, TRIUMPH, total N 5 3059, P 5 0.005). Remarkably, in addition to exposure to hyperglycemia, the presence 1Research Division, Joslin Diabetes Center, Boston, MA 10Department of Medical, Oral and Biotechnological Sciences, University 2Department of Medicine, Harvard Medical School, Boston, MA “G. d’Annunzio,” Chieti, Italy 3Department of Medicine, University of Padova, Padova, Italy 11Division of Nephrology and Hypertension and Diabetes and Metabolism 4McMaster University and Population Health Research Institute, Hamilton, Ontario, Center, University of Utah, Salt Lake City, UT Canada 12Departments of Medicine, Cardiac Sciences, and Community Health Sciences, 5Department of Genetics, Washington University School of Medicine, St. Louis, Cumming School of Medicine, Faculties of Medicine and Kinesiology, University MO of Calgary, Calgary, Alberta, Canada 6Department of Medicine, Washington University School of Medicine, St. Louis, 13Department of Medicine, University of Washington, and Northwest Lipid MO Metabolism and Diabetes Research Laboratories, Seattle, WA 7Biostatistics and Computational Biology Branch, National Institute of Environ- 14Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, OH mental Health Sciences, Durham, NC 15Division of Pharmacoepidemiology and Pharmacoeconomics, Department of 8Wake Forest School of Medicine, Winston Salem, NC Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, 9Research Unit of Metabolic and Cardiovascular Diseases, Fondazione IRCCS MA Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy 772 Genetics of Cardiovascular Response to Fibrates Diabetes Volume 69, April 2020 of other cardiovascular risk factors that frequently RESEARCH DESIGN AND METHODS accompany type 2 diabetes such as dyslipidemia and hy- Study Populations pertension (2). The current recommendations to prevent Accord-Lipid Trial major adverse cardiovascular events (MACE) in patients ACCORD-Lipid was part of ACCORD, a clinical trial that fi with type 2 diabetes include lifestyle modi cations, im- tested the effectiveness of intensive versus standard gly- provement of glycemic control, treatment of hypertension, cemic control in preventing MACE (a composite of and use of cholesterol-lowering therapies (1). nonfatal myocardial infarction, nonfatal stroke, and car- fi Treatment with brates as an additional intervention to diovascular death) among 10,251 subjects with type 2 di- further improve cardiovascular outcomes in type 2 diabetes abetes at high risk of atherosclerotic cardiovascular disease – has been studied several times in the last decades (3 7). (19). The trial had a double, 2 3 2 factorial design, with – Fibrates are agonists of peroxisome proliferator activated 4,733 patients additionally randomized to a blood pres- a a — receptor- (PPAR- ) a transcription factor that func- sure trial (ACCORD-BP) (20) and 5,518 to a lipid trial tions as a master regulator of lipid homeostasis, cardiac (ACCORD-Lipid) (4). Subjects were specifically enrolled fl energy metabolism, vascular in ammation, and cell dif- in ACCORD-Lipid if they had HDL-c ,55 mg/dL for a ferentiation. PPAR- activation reduces serum triglycer- women and blacks or ,50 mg/dL for all other groups, ides, raises plasma HDL cholesterol (HDL-c) levels, and LDL cholesterol level between 60 and 180 mg/dL, and fl reducessystemicin ammation (8,9). However, despite fasting triglycerides ,750 mg/dL without triglyceride- fi fi such bene cial effects, clinical trials of brates have shown lowering treatment or ,400 mg/dL if they were receiving fi inconsistent bene t of this treatment in preventing MACE triglyceride-lowering treatment. ACCORD-Lipid investigated (4,5,10), including among subjects with type 2 diabetes whether fenofibrate, given in addition to statins, was more (4,5). At the same time, analyses of these trials have effective than statins alone in preventing MACE. This trial fi fi consistently shown that brates might have a bene cial showed a modest, nonsignificant trend toward a benefitof effect among subjects with atherogenic dyslipidemia (de- fenofibrate (hazard ratio [HR] 0.92; 95% CI 0.79–1.08) (4). fi – ned by low HDL-c and high triglycerides levels) (11 14). Genetic data were available for 4,414 ACCORD-Lipid fi For these reasons, brates are not currently recommended participants (80% of the total), who had provided consent as a standard treatment to prevent MACE in type 2 diabetes for genetic studies. For avoidance of race/ethnicity con- but may be considered as second- or third-line treatments founding, genetic analyses were initially restricted to self- in patients with atherogenic dyslipidemia (1,15,16). reported non-Hispanic whites (n 5 3,065) and then fl fi The lipid and in ammatory responses to brates vary in extended to self-reported African Americans (n 5 585). the population, in part due to genetic factors (17,18). Other racial/ethnic groups were too sparse to be consid- Thus, one can hypothesize that the inconclusive results ered individually. from clinical trials may be partly due to an underlying genetic heterogeneity in the cardiovascular response to ACCORD-BP, ORIGIN, and TRIUMPH Cohorts fibrates. A corollary of this hypothesis is that it may be ACCORD-BP (blood pressure) (20) investigated whether possible to develop genetic tests that can help distinguish reducing systolic blood pressure to ,120 mmHg was more individuals who would benefit from fibrates from those effective than standard treatment (target ,140 mmHg) in who would not. We have tested these postulates in the preventing MACE among 4,733 subjects with type 2 di- Action to Control Cardiovascular Risk in Diabetes lipid abetes at high cardiovascular risk. After a median follow-up study (ACCORD-Lipid) (4), the largest randomized clinical time of 4.7 years, the study reported lack of significant trial to date on fibrate treatment as add-on to statin cardiovascular effect of this treatment. therapy in type 2 diabetes. We specifically directed our The Outcome Reduction With Initial Glargine Interven- attention to PPARA—the gene that codes for the molecule tion (ORIGIN Trial) (21) investigated, in a 2 3 2 factorial (PPAR-a) through which fibrates are believed to exert their design, the effect of titrated basal insulin versus standard pharmacological effects. care and of n-3 fatty acid supplements versus placebo on 16Department of Experimental Medicine, “Sapienza” University, Rome, Italy Corresponding author: Alessandro Doria, [email protected] 17 Division of Epidemiology and Clinical Applications, National Eye Institute, Received 29 September 2019 and accepted 21 January 2020 National Institutes of Health, Bethesda, MD This
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