ACCORD Lipid: Expert analysis from HDL Forum

The recently reported Action to Control Cardiovascular Risk in Diabetes (ACCORD) Lipid Treatment trial did not show any significant benefit for the primary outcome or any of the secondary cardiovascular outcomes. However, these results are not unexpected given the less than optimal patient population that was recruited. Commenting on these findings, Professor Philip Barter, HDL Forum Editor from the Heart Research Institute, Sydney Australia said: I would urge those with interest in this field to conduct a prospective outcomes trial in the appropriate patient population - low levels of high-density lipoprotein cholesterol (HDL-C) and elevated triglycerides -  to address this controversy. 

 The ACCORD Study Group. Effects of combination lipid therapy in type 2 diabetes mellitus. N Eng J Med 2010. Published on-line 14 March 2010. DOI:10.1056/NEJMoa1001282.

 The original intention of the ACCORD Lipid Investigators was to include patients with sufficiently elevated triglycerides that would usually justify therapeutic intervention. At baseline, although HDL-C levels were low (mean 38 mg/dL), median triglycerides were 162 mg/dL (interquartile range 113-229 mg/dL). In other words, a substantial proportion of patients had triglycerides which would not normally be treated in routine clinical practice (Table 1).

 Adding fenofibrate to simvastatin led to an 8% reduction in the primary endpoint (cardiovascular death, nonfatal MI or nonfatal stroke) versus simvastatin monotherapy (hazard ratio 0.92, 95% CI 0.79-1.08, p=0.32). Similar non-significant reductions were observed for the secondary outcomes. 

 However, in a pre-defined subgroup analysis in patients with baseline triglycerides at least 204 mg/dL (2.3 mmol/L)  and HDL-C levels 34 mg/dL (0.88 mmol/L) or lower, representing 17% of the total study population, there was suggestion of benefit. Adding fenofibrate resulted in a further 31% reduction in major cardiovascular events versus simvastatin treatment alone (Fig. 1). These data are consistent with other subgroup analyses in patients with elevated triglycerides and/or low HDL-C from other fibrate trials.1-5 For balance, however, it should be noted that the findings from the ACCORD Lipid subgroup were not as positive as observed with other fibrates.

 Another subgroup analysis is also worrying. Investigation of the gender interaction (in all study patients) suggested possible harm for women (increase in cardiovascular risk by 38%), whereas there was benefit in men (decrease in risk by 17%) (p=0.01 for interaction). Clearly there is a need to investigate this further.

 ACCORD Lipid adds to evidence suggestive of clinical benefits with fibrates in the right type of patient (elevated triglycerides and low HDL-C). However, the results are far from conclusive. Clearly there is a need for further study.

 HDL Forum has discussed these and other issues with Dr Henry Ginsberg, principal investigator for ACCORD Lipid (see interview report).

 About ACCORD Lipid

 The ACCORD trial was a randomized multicentre study, incorporating two 2 x 2 factorial treatment arms (Lipid Treatment Arm and Blood Pressure Treatment Arm). The overall aim of the study was to test whether intensifying treatment (for glycemic or blood pressure control) or combination lipid-modifying therapy could reduce cardiovascular risk in type 2 diabetes patients. The main ACCORD study compared intensive versus conventional glycemic control in 10,251 subjects with type 2 diabetes. The intensive glycemic treatment arm was subsequently discontinued due to excess all-cause mortality and patients continued on conventional glycemic control.6

The ACCORD Lipid population comprised a cohort of 5,518 high-risk type 2 diabetic patients at goal for LDL cholesterol. The key question was whether, in the context of good glycemic control, fenofibrate plus simvastatin was more effective in reducing cardiovascular events than simvastatin monotherapy. Fenofibrate is very effective in treating elevated triglycerides, with the magnitude of response dependent on baseline levels.7 Efficacy in treating low HDL cholesterol is less than that observed with niacin.7,8 

 The primary endpoint of ACCORD Lipid was a composite of cardiovascular death, non-fatal MI and non-fatal stroke. Secondary endpoints included a composite macrovascular endpoint (primary endpoint plus revascularisation or hospitalisation for heart failure), total mortality, as well as the individual components of the composite outcomes. 

 ACCORD Lipid also evaluated the effect of combination fenofibrate-simvastatin treatment on a composite microvascular outcome (fatal or non-fatal renal failure as defined by renal transplantation or initiation of dialysis or a rise in serum creatinine >3.3 mg/dl in the absence of an acute reversible cause, or retinal photocoagulation or vitrectomy for diabetic retinopathy). The rationale for evaluating treatment effects on this outcome was based on previous studies which have implicated low HDL-C and/or elevated triglycerides in microvascular residual risk, as reviewed recently.9

 References

1. Scott R, OˇŻBrien R, Fulcher G et al. The effects of fenofibrate treatment on cardiovascular disease risk in 9795 people with type 2 diabetes and various components of the metabolic syndrome: the FIELD study. Diabetes Care 2009;32:493-8.

2. 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;85:37-45.

3. Rubins HB, Robins SJ, Collins D et al. Diabetes, plasma insulin, and cardiovascular disease. Subgroup analysis from the Department of Veterans Affairs High-density Lipoprotein Intervention Trial (VA-HIT). Arch Intern Med 2002;162:2597-2604.

4. Tenkanen L, Mantarri M, Manninen V. Some coronary risk factors related to the insulin resistance syndrome and treatment with gemfibrozil: experience from the Helsinki Heart Study. Circulation 1995; 92: 1779-85.

5. Tenenbaum A, Motro M, Fisman EZ, Tanne D, Boyko V, Behar S. Bezafibrate for the secondary prevention of myocardial infarction in patients with metabolic syndrome. Arch Intern Med 2005; 165: 1154-60.

6. Action to Control Cardiovascular Risk in Diabetes Study Group, Gerstein HC, Miller ME, Byington RP et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;358:2545-59.

7. Farnier M, Salko T, Isaacsohn JL, et al. Effects of baseline level of triglycerides on changes in lipid levels from combined fluvastatin + fibrate (bezafibrate, fenofibrate, or gemfibrozil). Am J Cardiol 2003;92:794-7.

8. Grundy SM, Vega GL, McGovern ME et al. Efficacy, safety, and tolerability of once-daily niacin for the treatment of dyslipidemia associated with type 2 diabetes. Results of the Assessment of Diabetes control and Evaluation of the Efficacy of Niaspan Trial. Arch Intern Med 2002;162:1568-76.

9. Fioretto P, Dodson PM, Ziegler D, Rosenson RS. Residual microvascular risk in diabetes: unmet needs and future directions. Nat Rev Endocrinol 2010;6:19-25.


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