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Macrovascular Residual Risk THROUGH LANDMARK STUDY

15 November 2012
New insights from ACCORD Lipid

Effect of combination therapy with fenofibrate and simvastatin on postprandial lipemia in the ACCORD Lipid Trial. Diabetes Care 2012 Oct 1. [Epub ahead of print].

Reyes-Soffer G, Ngai CI, Lovato L et al.
Summary
Comments & References
STUDY SUMMARY
Objective: To investigate the effect of fenofibrate-simvastatin on postprandial (PP) lipid and lipoprotein levels in a subgroup of patients in ACCORD Lipid.
Study design: Ancillary study of ACCORD Lipid, a randomized, double-blind placebo controlled trial
Study population:

139 individuals with type 2 diabetes enrolled in ACCORD Lipid were included, 66 on fenofibrate-simvastatin and 73 on placebo-simvastatin. All patients had received the study treatment for at least 4 months. Exclusion criteria were as for the main study.1 Overall, the mean age of patients was 61 years, 40% were female, and the mean duration of diabetes was 10.3 years. 52% of patients had been previously assigned to intensive glycaemic treatment. There were no differences in baseline characteristics between the two groups.

Primary variable: Postprandial triglyceride response after an oral fat load
Secondary variables: Postprandial apolipoprotein (apo) B48 and apoCIII responses after an oral fat load
Method:
  • After fasting for 12 hours (h), patients received a standardized high-fat drink
  • Sequential blood samples were obtained before administration and up to 10 h later
  • PP incremental area under the curve (IAUC) for triglycerides, apoB48 and apoCIII was calculated using the trapezoidal method
  • The effect of fenofibrate on IAUC was tested using a multiple regression model.
Main results:
  • Compared with simvastatin alone, fenofibrate significantly reduced:

    - the PP triglyceride IAUC response
    - the PP apoB48 IAUC response
    There was no significant difference between the groups for the PP apoCIII IAUC response.

Table. Incremental AUC above fasting


Variable

Fenofibrate + simvastatin

Placebo + simvastatin

Adjusted p-value

PP TG IAUC (mg/dL/h)

572 (352-907)

770 (429-1420)

0.008

PP apoB48 (mg/mL/h)

23.2 ± 16.3

35.2 ± 28.6

0.008

PP apoCIII (mg/dL/h)

10.1 (2-30)

4.7 (-1 to 27)

0.47

Data are given as median (interquartile range) except for apoB48 (mean ±SD)

  • The effect of fenofibrate on PP TG IAUC was consistent across the range of fasting TG levels.
  • However, PPapoB48 was only reduced when fasting TG were increased I.e., at or above the median (131 mg/dL or 1.5 mmol/L).

 

Author's conclusion : Levels of atherogenic apoB particles were reduced by fenofibrate only in patients with elevated TG levels at baseline. This may explain why the benefit of fenofibrate in ACCORD Lipid was specific to patients with atherogenic dyslipidaemia.

COMMENT

The ACCORD Lipid trial failed to show a statistically significant benefit with fenofibrate-simvastatin combination therapy versus simvastatin monotherapy for the total study population. However, a pre-defined subgroup analysis showed clinical benefit in high-risk patients with atherogenic dyslipidaemia (baseline triglycerides ≥204 mg/dL or 2.3 mmol/L and baseline HDL cholesterol levels ≤34 mg/dL or 0.88 mmol/L). In this group, adding fenofibrate to simvastatin resulted in a 31% reduction in cardiovascular events (from 17.3% to 12.4%, absolute risk reduction 4.9%).(1)

Consistent with other fibrate trials, patients in ACCORD Lipid were categorised on the basis of fasting blood lipids. However, there is increasing evidence that nonfasting triglycerides may be of greater relevance. Studies have shown that nonfasting triglycerides are independently predictive of cardiovascular disease events, even after adjustment for other factors including HDL cholesterol.(2,3)

This ancillary ACCORD Lipid study showed that although PP triglycerides were consistently reduced by fenofibrate irrespective of baseline fasting triglycerides, fenofibrate only reduced PP apoB48 levels in patients with elevated triglycerides (³130 mg/dL). In patients with fasting triglycerides ³the 75th percentile (³139 mg/dL or 1.8 mmol/L), fenofibrate treatment was associated with almost 50% reduction in the apoB48 AUC. From a mechanistic perspective, these findings suggest that fenofibrate promotes lipolysis and release of triglycerides from chylomicrons leading in turn to improved clearance of atherogenic triglyceride-rich remnant lipoproteins, only if fasting levels are sufficiently increased at baseline. Thus, it would be expected that the greatest benefits with fenofibrate would be observed in those patients with the highest levels of triglyceride-rich remnant lipoproteins at baseline, consistent with findings of the main ACCORD Lipid trial. Indeed, a critical appraisal of evidence,(4) supports the view that increased levels of remnant triglyceride-rich lipoproteins in type 2 diabetes is a key factor contributing to increased atherogenicity, and therefore a preferable therapeutic target for reducing residual macrovascular risk in type 2 diabetes.

The authors acknowledge that this ancillary study included only ~2.5% of the total ACCORD Lipid population. Despite this limitation, the data provide an explanation of why the benefit of fenofibrate was specific to the subgroup of patients with atherogenic dyslipidaemia.

References

1. Ginsberg HN, Elam MB, Lovato LC et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med 2010;362:1563-74.
2. Bansal S, Buring JE, Rifai N et al. Fasting compared with nonfasting triglycerides and risk of cardiovascular events in women. JAMA 2007;298:309-16.
3. Nordestgaard BG, Benn M, Schnohr P, Tybjaerg-Hansen A. Nonfasting triglycerides and risk of myocardial infarction, ischemic heart disease, and death in men and women. JAMA 2007;298:299-308.
4. Chapman MJ, Ginsberg HN, Amarenco P et al. Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease: evidence and guidance for management. Eur Heart J 201132:1345-61.

This study was partly funded by a grant from the R3i.

Key words

fenofibrate; postprandial lipaemia; atherogenic dyslipidaemia; ACCORD Lipid