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Macrovascular Residual Risk Studies

14 March 2010
The Action to Control Cardiovascular Risk in Diabetes (ACCORD) Lipid Trial: Targeting atherogenic dyslipidemia with fenofibrate reduces residual cardiovascular risk in simvastatin-treated type 2 diabetes patients at LDL-C goal
Effects of combination lipid therapy in type 2 diabetes mellitus. N Eng J Med 2010. DOI:10.1056/NEJMoa1001282. Published on-line 14 March 2010
The ACCORD Study Group
Objective: To evaluate whether, within the context of good glycemic control, adding fenofibrate to simvastatin can reduce the residual risk of cardiovascular (CV) events in type 2 diabetes patients at high CV risk..
Inclusion criteria:

Type 2 diabetes (HbA1c ≥7.5%) patients with pre-existing CV or atherosclerotic disease or at high risk of CV disease. Lipid eligibility criteria included:

  • Low-density lipoprotein cholesterol (LDL-C) 60-180 mg/dL (1.55‑4.65 mmol/L)
  • High-density lipoprotein cholesterol (HDL-C) <55 mg/dl (1.42 mmol/l) in women or blacks, <50 mg/dL (1.29 mmol/L) in others
  • Triglycerides (TG) <750 mg/dL (8.5 mmol/L) if not receiving lipid-lowering therapy; <400 mg/dL (4.5 mmol/L) on lipid-lowering therapy.
Exclusion criteria: ACCORD Lipid exclusion criteria included the use of medications known to interact with statins or fibrates; history of pancreatitis, myositis/myopathy, or gallbladder disease; or patient refusal to discontinue any current lipid-altering treatment
Intervention: Patients were randomized to treatment with fenofibrate (160 mg/day, adjusted according to glomerular filtration rate) + simvastatin versus simvastatin monotherapy + placebo. The average daily dose of simvastatin was 22.3 mg in the fenofibrate group versus 22.4 mg in the placebo group.
Study population:

5,518 type 2 diabetes patients (mean age 62.3 years, BMI 32.3 kg/m2, 31% women, 36.5% with previous CV disease) recruited by centers in the US and Canada.

Primary outcome:

First major CV event (non-fatal MI, non-fatal stroke or CV death)

Secondary outcomes:

Expanded macrovascular outcome: primary composite outcome plus revascularization or hospitalization for congestive heart failure;
Major coronary disease events: (fatal coronary event, non-fatal MI, unstable angina);
all stroke; all-cause death; CV death; hospitalization or death due to heart failure.

Study design:

The ACCORD trial was a randomized multicentre study, incorporating two 2 x 2 factorial treatment arms; one arm investigated lipid management and one arm investigated blood pressure control. The ACCORD Lipid arm was the only blinded comparison in the ACCORD trial.


Time to event methods, ITT analysis. Two-sided p-values were reported using likelihood ratio tests from Cox proportional-hazards regression analyses. There were 10 pre-specified subgroup analyses, including tertile analysis of TG (≤128 mg/dL, 129-203 mg/dL, ≥204 mg/dL); HDL-C (≤34 mg/dL, 35-40 mg/dL, ≥41 mg/dL) and analysis of patients with elevated TG ≥204 mg/dL and HDL-C ≤34 mg/dL (i.e. atherogenic dyslipidemia) versus others.

The mean follow-up was 4.7 years for the primary outcome and 5 years for all deaths.
Main results:

None of the primary or secondary outcomes was statistically significant. However, patients with atherogenic dyslipidemia had a 31% additional reduction in the primary endpoint (p=0.057 for interaction) with fenofibrate versus simvastatin alone. The absolute reduction in events was 4.9% (from 17.3% to 12.4%), yielding a number needed to treat (NNT) of 20.

There was also a significant interaction for gender (p=0.01); fenofibrate reduced the primary outcome in men (from 13.3% with simvastatin alone to 11.2%) but increased it in women (from 6.6% to 9.1%).

Combination fenofibrate-simvastatin treatment was well tolerated with no excess myopathy, venous thromboembolism or pancreatitis. Fenofibrate also reduced incident micro- and macroalbuminuria (p=0.001), two well-established markers of diabetic renal disease and progression.
Author's conclusion: Combination therapy with fenofibrate and simvastatin (≤40 mg/day) did not reduce the rate of major CV events compared with simvastatin alone. These results do not support the routine use of combination therapy with fenofibrate and simvastatin to reduce cardiovascular risk in the majority of high-risk patients with type 2 diabetes.


Patients with type 2 diabetes are at high risk of CV disease. This is due in part to the high prevalence of associated cardiometabolic risk factors, such as hypertension and atherogenic dyslipidemia, characterized by elevated TG and/or low HDL-C. Even with statin therapy, a high residual CV risk remains. Therefore the ACCORD trial evaluated whether intensification of drug treatment of type 2 diabetes provides further benefit. ACCORD Lipid Treatment Trial was consistent with this aim by evaluating whether adding fenofibrate (targeting elevated TG and/or low HDL-C) reduces this residual CV risk.
Fenofibrate treatment did not significantly reduce any of the primary or secondary outcomes in the total study population. This is not surprising given their baseline lipid characteristics, since the study population was composed mostly (about fourth-fifth) of patients without atherogenic dyslipidemia at baseline. Although HDL-C levels were low (mean 38.1 mg/dL), median TG were only 162 mg/dL (interquartile range 113 -229 mg/dL). Thus, there was a substantial proportion of patients in ACCORD Lipid who had TGs below levels routinely recommended for considering treatment with a fibrate by current clinical guidelines.1,2

Atherogenic dyslipidemia increases residual CV risk

However, examination of the details of this study provides valuable insights into the management of lipid-related residual CV risk in type 2 diabetes. In ACCORD Lipid, 17% of patients (n=941) had atherogenic dyslipidemia (≥204 mg/dL and HDL-C levels ≤34 mg/dL).These patients were at very high residual CV risk despite achieving LDL-C levels ~80 mg/dL with simvastatin monotherapy.
This is underlined by CV event rates that were 70% higher than in patients without this lipid profile (17.3% vs. 10.1%). Residual risk associated with atherogenic dyslipidemia and already receiving a statin was comparable to that of patients with pre-existing CV disease (17.3% versus 18.1%).

Targeting atherogenic dyslipidemia reduces residual CV risk

In this subgroup with atherogenic dyslipidemia, there was a further 31% reduction in CV risk by adding fenofibrate to simvastatin treatment. Primary outcome event rates were reduced from 17.3% (simvastatin alone) to 12.4% (simvastatin + fenofibrate), an absolute risk reduction of 4.9%. The findings are consistent with evidence from previous fibrate trials of greater clinical benefit in patients with elevated TG and/or low HDL-C.3-5 Clinically, only 20 patients would need to be treated with fenofibrate to prevent one major CV event. In contrast, the NNT with intensive blood pressure lowering in the ACCORD Blood Pressure trial was 167, over eight-fold greater.6
These data confirm that atherogenic dyslipidemia is a key driver of residual CV risk, even when LDL-C is already lowered by statin therapy, as proposed by the R3i.7,8 This component of residual risk related to lipids is modifiable by combined lipid-lowering therapy targeting all components of dyslipidemia. Further, ACCORD Lipid shows that targeting atherogenic dyslipidemia by the addition of fenofibrate to simvastatin substantially reduces residual CV risk. The proposed R3i-funded meta-analysis of patient subgroups with atherogenic dyslipidemia (high TG and low levels of HDL-C) from previous fibrate studies will confirm the magnitude of CV risk reduction in this target group.

ACCORD Lipid confirms safety of combination lipid-lowering therapy

It is reassuring that there was no excess of myopathy, venous thromboembolic events or pancreatitis with fenofibrate combination therapy versus compared with simvastatin alone. There were also fewer deaths (both all-cause and CV) in the group receiving the combination therapy. Clearly there will be further analysis of the gender interaction in the total study population. It is, however, notable that this interaction disappeared in the subgroup with atherogenic dyslipidemia, reaffirming the benefit of fenofibrate-statin combination therapy in both men and women with type 2 diabetes and atherogenic dyslipidemia.

Adding fenofibrate beneficially impacts on incidence / progression of diabetic renal disease

ACCORD Lipid also evaluated treatment effects 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).9 Results for this outcome have not yet been reported., However, insights were provided by the current paper. Adding fenofibrate significantly reduced incidence of microalbuminuria (p=0.01) and macroalbuminuria (p=0.03) versus simvastatin monotherapy. These findings are supported by evidence from other trials.10,11

What have we learned from ACCORD Lipid about managing residual CV risk?

The implications of ACCORD Lipid support the value of a targeted approach to reducing residual CV risk due to atherogenic dyslipidemia in high-risk type 2 diabetes patients, consistent with current guidelines. Although the prevalence of atherogenic dyslipidemia in ACCORD Lipid was only 17%, it is reckoned to be actually substantially higher in a real-life clinical setting, especially given that the HDL‑C criterion in the study was below recommended minimum targets1,2. The REsiduAl risk Lipids and Standard Therapies (REALIST), a R3i-sponsored research initiative, will provide information on a worldwide and regional basis on the current prevalence of residual risk associated with atherogenic dyslipidemia in high-risk type 2 diabetes patients, a group likely to benefit from adding fenofibrate to reduce residual CV risk according to the ACCORD Lipid results.

1. Grundy SM, Cleeman JI, Merz NB et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. Arterioscler Thromb Vasc Biol 2004;24:e149-e161.
2. Graham I, Atar D, Borch-Johnsen K et al. European guidelines on cardiovascular disease prevention in clinical practice. Fourth Joint Task Force of the European Society of Cardiology and other Societies on Cardiovascular Disease Prevention in Clinical Practice. Executive summary. Eur Heart J 2007;28:2375-414.
3. Scott R, O’Brien 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.
4. 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;162:2597-604.
5. 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.
6. The ACCORD Study Group. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med 2010;DOI: 10.1056/NEJMoa1001286.
7. Fruchart JC, Sacks FM, Hermans MP et al. The Residual Risk Reduction Initiative: a call to action to reduce residual vascular risk in dyslipidaemic patients. Diab Vasc Dis Res 2008;5:319-35.
8. Fruchart JC, Sacks FM, Hermans MP et al. The Residual Risk Reduction Initiative: a call to action to reduce residual vascular risk in dyslipidemic patients. Am J Cardiol 2008;102:suppl 10A;1K-34K.
9. 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
10. Ansquer JC, Foucher C, Rattier S et al. Fenofibrate reduces progression to microalbuminuria over 3 years in a placebo‐controlled study in type 2 diabetes: results from the Diabetes Atherosclerosis Intervention Study (DIAS). Am J Kidney Dis 2005;45:485‐93.
11. Keech A, Simes RJ, Barter P et al. The FIELD study investigators. Effect of long‐term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet 2005;366:1849‐61.

Key words Type 2 Diabetes – Macrovascular Residual Risk – Atherogenic Dyslipidemia - Fenofibrate