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The ACCORD (Action to Control Cardiovascular Risk in Diabetes) Lipid Trial

What we learn from subgroup analyses
HENRY N. GINSBERG,
MD

therosclerotic cardiovascular disease is increased severalfold in most patients with type 2 diabetes, particularly patients who are older and have other risk factors (1,2). These associated risk factors include hypertension, obesity, and dyslipidemia. Diabetic dyslipidemia, which has also been called atherogenic dyslipidemia (a term that describes the lipid abnormalities in people with insulin resistance, metabolic syndrome, and type 2 diabetes), is characterized by elevated plasma triglyceride (TG) levels, low levels of HDL cholesterol, and smaller cholesterol esterdepleted LDL (3). Despite the fact that statins, which mainly lower blood levels of LDL cholesterol, have the same relative effectiveness in type 2 diabetic patients as in nondiabetic subjects, absolute rates of atherosclerotic cardiovascular disease events remained higher in patients with diabetes who participated in all of the statin trials (4,5). These ndings have raised interest in the use of combination therapy, particularly the combination of a statin plus a drug that would lower plasma TG levels and raise plasma HDL cholesterol levels. ACCORD (Action to Control Cardiovascular Risk in Diabetes) was specically designed to determine the effects of intensive treatment of blood glucose, and either blood pressure (ACCORD Blood Pressure) or plasma lipids (ACCORD

Lipid), on atherosclerotic cardiovascular disease outcomes in patients with type 2 diabetes who were at high risk of such an outcome (6). The ACCORD Lipid trial tested the hypothesis that treatment of patients with type 2 diabetes with fenobrate to increase plasma HDL cholesterol levels and reduce plasma TG concentrations, on the background of simvastatin therapy, would result in additional cardiovascular benet compared with simvastatin therapy alone (7). The ACCORD Lipid trial used fenobrate because 1) data from the Fenobrate Intervention and Event Lowering in Diabetes (FIELD) trial indicated that the risk of myositis when fenobrate was combined with a statin was negligible; 2) fenobrate was expected to lower TG levels by ~25% and increase HDL cholesterol levels by ~510% while having minimal effects on LDL cholesterol concentrations; 3) niacin, an alternative that would have probably had much greater effects on HDL cholesterol, would have caused problems for the glycemic component of ACCORD; and 4) niacin would have also reduced LDL cholesterol signi cantly, making it difcult to attribute any benet to changes in TG and HDL cholesterol levels. There were concerns, however, regarding the use of fenobrate. Thus, although gemibrozil treatment had been benecial in both a primary prevention nondiabetic population in the Helsinki

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From the Department of Medicine and the Irving Institute for Clinical and Translational Research, Columbia University College of Physicians and Surgeons, New York, New York. Corresponding author: Henry N. Ginsberg, hng1@columbia.edu. This publication is based on the presentations at the 3rd World Congress on Controversies to Consensus in Diabetes, Obesity and Hypertension (CODHy). The Congress and the publication of this supplement were made possible in part by unrestricted educational grants from AstraZeneca, Boehringer Ingelheim, BristolMyers Squibb, Daiichi Sankyo, Eli Lilly, Ethicon Endo-Surgery, Generex Biotechnology, F. Hoffmann-La Roche, Janssen-Cilag, Johnson & Johnson, Novo Nordisk, Medtronic, and Pzer. DOI: 10.2337/dc11-s203 2011 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for prot, and the work is not altered. See http://creativecommons.org/ licenses/by-nc-nd/3.0/ for details.

Heart Study (8) and in a secondary prevention diabetic subgroup in the Veterans Affairs High-Density Lipoprotein Intervention Trial (VA-HIT) (9,10), fenobrate did not signicantly reduce coronary heart disease death or nonfatal myocardial infarction in the FIELD study, which was a mixed primary/secondary prevention trial (11). A total of 5,518 men and women with type 2 diabetes were enrolled in the ACCORD Lipid trial. All participants received simvastatin (2040 mg/day) and were also randomly assigned to masked fenobrate (160 or 54 mg/day, depending on renal function) or placebo. The primary outcome was the rst postrandomization occurrence of a nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. The mean followup was 4.7 years. The primary outcome occurred at a rate of 2.4%/year in the placebo group and 2.2%/year in the fenobrate group. This result gave a hazard ratio of 0.92 (95% CI 0.791.08), which was not signicant (P = 0.32). Thus, the ACCORD Lipid trial did not conrm its primary hypothesis. There were a number of secondary outcomes, including each component of the primary composite outcome tested individually, an expanded cardiovascular outcome, major coronary events, and total mortality. None of these outcomes showed differences that were statistically signicant. In some prior brate trials, cardiovascular and/or total mortality tended to be increased in brate-treated groups. In the ACCORD Lipid trial, annual cardiovascular mortality was 0.77% in the fenobrate group and 0.83% in the placebo group; total mortality was 1.47% in the fenobrate group and 1.61% in the placebo group. There was no evidence of increased mortality with fenobrate. The ACCORD Lipid trial had 11 prespecied subgroup analyses. The rst six were dened by demographic characteristics or allocation to intensive versus standardized glucose control. Of those six subgroups, there was a signicant interaction (P = 0.011) for treatment effect by
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The ACCORD trial sex; men had an ~16% lower primary event rate on fenobrate, whereas women had an ~38% greater primary event rate on feno brate. Neither of these sexspecic effects of fenobrate versus placebo was signicant. The second ve subgroups were dened by baseline lipids (tertiles for LDL cholesterol, HDL cholesterol, and TG), a subgroup dened by the presence of both a TG level in the upper third and an HDL cholesterol level in the lower third at baseline (dyslipidemic group) versus all others, and groups dened by HbA1c levels above or below 8.0% at baseline. There was a trend for an interaction (P = 0.057) for treatment by lipid levels only for the group with both high TG and low HDL cholesterol compared with all others. The dyslipidemic group had an ~30% lower outcome on fenobrate compared with placebo (in the absence of a signicant interaction P value, statistical analysis was not conducted on the outcome in the dyslipidemic group). There was no difference at all in event rates between the feno brate and the placebo groups who were not dyslipidemic. The dyslipidemic group made up ~15% of the overall cohort in the ACCORD Lipid trial. We do not have an explanation at this time for the difference in outcomes based on sex. There was no sex difference in the primary outcome in the FIELD study (11); additional analyses are underway. Of note, in the subgroup dened by both high TG and low HDL, women, who made up ~20% of that group, had a similar benet from fenobrate as the men. The results from the dyslipidemic subgroup in the ACCORD Lipid trial, which was a prespecied analysis, are similar to post hoc analyses performed in prior brate studies, including the Helsinki Heart Study (12), the Bezabrate Infarction Prevention (BIP) trial (13), and FIELD (14). In each of those trials, analysis of a dyslipidemic subgroup revealed either signicantly greater benet than in the overall trial cohort (11) or the only actual positive outcome in the study (13,14). Overall, the ACCORD Lipid trial was negative. There is no evidence from this trial to indicate that fenobrate should be routinely added to a statin for the treatment of lipids in patients with type 2 diabetes. Indeed, routine addition of fenobrate might be harmful for women with type 2 diabetes. However, the ACCORD data, together with post hoc analyses of three other brate trials, suggest that, when TG is . 200 mg/dL and HDL is ,35 mg/dL after statin therapy has significantly reduced LDL cholesterol levels, brate treatment can be considered, at least in men.
Acknowledgments No potential conicts of interest relevant to this article were reported. Targets (TNT) study. Diabetes Care 2006; 29:12201226 Buse JB, Bigger JT, Byington RP, et al. Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial: design and methods. Am J Cardiol 2007;99:21i33i Ginsberg HN, Elam MB, Lovato LC, et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med 2010;362:15631574 Frick MH, Elo O, Haapa K, et al. Helsinki Heart Study: primary-prevention trial with gembrozil in middle-aged men with dyslipidemia: safety of treatment, changes in risk factors, and incidence of coronary heart disease. N Engl J Med 1987;317:1237 1245 Rubins HB, Robins SJ, Collins D, et al. Gembrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. N Engl J Med 1999;341:410418 Rubins HB, Robins SJ, Collins D, et al. Diabetes, plasma insulin, and cardiovascular disease: subgroup analysis from the Department of Veterans Affairs HighDensity Lipoprotein Intervention Trial (VA-HIT). Arch Intern Med 2002;162: 25972604 Keech A, Simes RJ, Barter P, et al. Effects of long-term fenobrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet 2005; 366:18491861 Manninen V, Tenkanen L, Koskinen P, et al. Joint effects of serum triglyceride and LDL cholesterol and HDL cholesterol concentrations on coronary heart disease risk in the Helsinki Heart Study: implications for treatment. Circulation 1992;85:3745 Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary artery disease: the Bezabrate Infarction Prevention (BIP) study. Circulation 2000;102:2127 Scott R, OBrien R, Fulcher G, et al. Effects of fenobrate treatment on cardiovascular disease risk in 9,795 individuals with type 2 diabetes and various components of the metabolic syndrome: the Fenobrate Intervention and Event Lowering in Diabetes (FIELD) study. Diabetes Care 2009;32:493498

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