Priority Updates from the Research Literature from the Family Physicians Inquiries Network Jody Lounsbery, PharmD, BCPS; Shailendra Prasad, MD, Add a fi brate to a statin? MBBS, MPH; Kate Rowland, MD North Memorial For most patients with diabetes and dyslipidemia, adding Family Medicine Residency, University of Minnesota, a fi brate does not improve cardiovascular outcomes. Minneapolis (Drs. Lounsbery and Prasad); Department of Family Medicine, University of Chicago (Dr. Rowland) PRACTICE CHANGER with type 2 diabetes reduces major cardiovas- 3,4 PURLs EDITOR Do not routinely add a fi brate to a statin for cular events. We also know that adding a fi - John Hickner, MD, MSc patients with type 2 diabetes who are at high brate to statin therapy can help patients reach Cleveland Clinic risk for cardiovascular events.1 their HDL and triglyceride targets. However, the survival benefi t of the fi brate-statin combi- STRENGTH OF RECOMMENDATION nation over that of a statin alone has not been B: Based on a good-quality randomized proven. In addition, there have been concerns controlled trial. about the increased risk of adverse eff ects with Th e ACCORD Study Group. Eff ects of combination lipid therapy in type the combination. In fact, the overall benefi ts 2 diabetes mellitus. N Engl J Med. 2010;362:1563-1574. (and risks) of combining fi brates and statins for patients with diabetes and dyslipidemia ILLUSTRATIVE CASE were not addressed in a large randomized trial A 60-year-old man with cardiovascular disease until the study we report on here. and diabetes comes to your clinic for a routine check of his dyslipidemia, for which he is on statin therapy. His fasting lipid panel shows STUDY SUMMARY a low-density lipoprotein (LDL) of 70 mg/dL, Statin + fi brate = minimal benefi t triglycerides of 200 mg/dL, and a high-density for most patients lipoprotein (HDL) of 30 mg/dL. Should you rec- Th e Action to Control Cardiovascular Risk in ommend adding fenofi brate? Diabetes (ACCORD) study is among the larg- est trials conducted in adults with type 2 dia- atients with type 2 diabetes are at betes at high risk of cardiovascular events.5 increased risk for cardiovascular Th e study examined 3 approaches to lower- P events. National Cholesterol Educa- ing the risk of major cardiovascular events: tion Program Adult Treatment Panel (NCEP intensive lowering of blood sugar levels com- ATP) III guidelines recommend treatment pared with standard blood sugar treatment; of dyslipidemia for all patients with high risk intensive lowering of blood pressure (BP) of cardiovascular events to an LDL goal of compared with standard BP treatment; and <100 mg/dL (optional <70 mg/dL), HDL goal treatment of lipids with 2 drugs—a fi brate of >40 mg/dL, and triglyceride goal of plus a statin—compared with a statin alone. <150 mg/dL. Th ese recommendations include Th is summary focuses on the lipid arm of the the use of combination therapy with a statin ACCORD study.1 and fenofi brate for patients who have elevated All patients in the study had type 2 triglycerides and low HDL cholesterol despite diabetes and a hemoglobin A1c ≥7.5%. Th e being on statin therapy alone.2 study included patients ages 40 to 79 years with clinical evidence of cardiovascular disease and Survival benefi t of combo therapy patients ages 55 to 79 years with either subclin- remains unproven ical cardiovascular disease or ≥2 cardiovascu- We know that fi brate therapy alone in patients lar risk factors in addition to diabetes. 582 THE JOURNAL OF FAMILY PRACTICE | OCTOBER 2010 | VOL 59, NO 10 Th e lipid arm enrolled patients who had was no signifi cant diff erence in the incidence an LDL cholesterol of 60 to 180 mg/dL, an of hemodialysis and end-stage renal disease HDL cholesterol <55 mg/dL for women and (75 patients in the fenofi brate-statin group vs blacks and <50 mg/dL for all other groups, 77 patients in the statin group). and a triglyceride level <750 mg/dL for those not receiving lipid therapy and <400 mg/dL for those on lipid therapy. Enrollees (N=5518) WHAT’S NEW were started on open-label simvastatin 20 mg, We have evidence that combo therapy titrated up as needed to reach the LDL goal, doesn’t further reduce risk then randomized to receive either fenofi brate Th is study examined a previously unad- or placebo 1 month later. Th e mean duration dressed question, the role of combination of follow-up was 4.7 years. fi brate-statin therapy in high-risk patients ❚ The primary outcome was the fi rst oc- with type 2 diabetes. Th e fi ndings do not sup- currence of a major cardiovascular event— port the routine use of combination therapy nonfatal myocardial infarction (MI), nonfatal compared with a statin alone for most patients stroke, or death from a cardiovascular cause. with diabetes. Overall, combination therapy Th e annual rate of the primary outcome was with simvastatin and fenofi brate did not lower 2.2% (n=291) in the fenofi brate-statin group the risk of MI, stroke, or death from cardiovas- and 2.4% (n=310) in the placebo group, a non- cular disease more than simvastatin alone. signifi cant diff erence (P=.32). Th is trial showed that women with diabe- Th e results were reported by sex. Th e pri- tes and hyperlipidemia should not be treated mary outcome rate for men during the 4.7-year with both a statin and a fi brate. Men appeared follow-up was 11.2% in the fenofi brate-statin to have a very small benefi t from combina- group vs 13.3% in the placebo group; for wom- tion therapy (NNT=50). Patients with a base- en, the outcome rates were 9.1% in the treat- line HDL ≤34 mg/dL and baseline triglyceride ment group and 6.6% in the placebo group ≥204 mg/dL appeared to benefi t from the (P =.01). Th ese rates suggest a small benefi t for combination, but this group constituted only men, and harm for women. 16% of the patients in this trial and the diff er- INSTANT ❚ Subgroup analysis showed additional ence had borderline statistical signifi cance. benefi t from fenofi brate in patients with a Nonetheless, it may be reasonable to treat POLL combination of a high baseline triglyceride such patients with combination therapy until QUESTION level (≥204 mg/dL) and very low baseline HDL a defi nitive study is done. cholesterol (≤34 mg/dL), representing about Do you prescribe 16% of the study participants. Th e primary fi brates for patients outcome rate for patients in this subgroup CAVEATS with type 2 diabetes who fail to reach was 12.4% in the fenofi brate-statin group and Statin dose did not match lipid goals on statin standard practice 17.3% in the placebo group (P=.057); num- therapy alone? ber needed to treat (NNT)=20 patients for 4.7 Th is study used a low dose of statin. Th e aver- years to prevent 1 major cardiovascular event. age daily simvastatin dose was 22.3 mg in the ■ Yes, I routinely pre- ❚ Harm was similar in both groups. A fenofi brate-statin group and 22.4 mg in the pla- scribe combination small number of patients had elevations of al- cebo group. Th is constitutes low-dose therapy therapy anine aminotransferase of >3 times the upper compared with doses routinely used in practice ■ Occasionally; it limit of normal (1.9% in the fenofi brate-statin (ie, 40 or 80 mg). A higher dose of simvastatin depends on the group and 1.5% in the statin group). Th e study may have negated any outcome diff erences. patient drug was discontinued in 66 patients (2.4%) in ■ Rarely or never the fenofi brate-statin group (and the placebo was discontinued in 30 patients [1.1%] in the CHALLENGES TO IMPLEMENTATION ■ Other _____________ statin group). Th e fenofi brate or statin dose This “practice changer” was reduced in 440 patients (15.9%) in the confl icts with NCEP guidelines fenofi brate-statin group and in 194 patients Th e current NCEP ATP III guidelines recom- Go to jfponline.com (7%) in the statin group due to a decrease in mend combination fi brate-statin therapy for and take our instant poll estimated glomerular fi ltration rate. Th ere all patients when statin therapy alone is not JFPONLINE.COM VOL 59, NO 10 | OCTOBER 2010 | THE JOURNAL OF FAMILY PRACTICE 583 adequate to achieve lipid goals. Th is is a ma- fi brate-statin combinations in all patients with jor challenge to our recommendation against diabetes who do not achieve lipid goals on a using this combination for most patients with statin, and family physicians may hesitate to diabetes. Some physicians may choose to fol- contradict their recommendations. JFP low the ATP III guidelines rather than the new evidence because they feel more confi dent ACKNOWLEDGEMENT adhering to national guidelines. The PURLs Surveillance System is supported in part by Grant Clinical inertia is another challenge, as Number UL1RR024999 from the National Center for Research Resources; the grant is a Clinical Translational Science Award clinicians may be hesitant to stop therapy in to the University of Chicago. The content is solely the respon- patients already on a fi brate-statin combina- sibility of the authors and does not necessarily represent the offi cial views of the National Center for Research Resources tion. Finally, specialists may continue to use or the National Institutes of Health.