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Macrovascular Residual Risk THROUGH LANDMARK STUDY

1 December 2014
New FIELD analysis: Fenofibrate has similar cardioprotective effects in women and men

Treatment with fenofibrate was as effective in reducing cardiovascular outcomes in women and men with type 2 diabetes in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study. Women derived greater lipid-modifying benefit.

d’Emden MC, Jenkins AJ, Li L, Zannino D, Mann KP, Best JD, Stuckey BGA, Park K, Saltevo J, Keech AC on behalf of the FIELD Study Investigators. Favourable effects of fenofibrate on lipids and cardiovascular disease in women with type 2 diabetes: results from the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study. Diabetologia 2014;57:2296–303.
Summary
Comments & References
STUDY SUMMARY
Objective:  To test whether fenofibrate treatment was as effective in women as men with type 2 diabetes enrolled in the FIELD study. 
Study design:  Pre-specified analysis of this randomised, double-blind, placebo-controlled study  
Study population:  Women (n=3,657, 37%) and men (n=6,138) aged 50–75 years with type 2 diabetes not using statins at baseline. All had baseline total cholesterol levels of 3.0–6.5 mmol/l, plus a total cholesterol:HDL-cholesterol ratio ≥4 or a triacylglycerol concentration of 1–5 mmol/l, with no clear indication for lipid-modifying therapy at the time of study initiation. Notably, at baseline a greater proportion of women than men had atherogenic dyslipidaemia (defined as fasting triacylglycerol levels ≥1.7 mmol/L and HDL-C <1.03 mmol/l for men and <1.29 mmol/l for women): 43.1% versus 34.8%, (p<0.001). 
Primary variable:

• The primary pre-specified outcome for all subgroup analyses, including by sex, was total cardiovascular disease (CVD) events, defined as the combination of non-fatal myocardial infarction (MI), death from coronary heart disease (CHD), stroke, other CVD death, plus coronary and carotid revascularisation.

• The effect of fenofibrate on lipid levels measured at baseline, 4 months, 1 year, 2 years and study close was also investigated in each group. 

Methods:  In the FIELD study, eligible patients were randomised to treatment with fenofibrate or placebo for 5 years. In this analysis, data were analysed on an intention to treat basis. The log-rank test and Kaplan–Meier methods were used for time to event analyses, and Hazard ratios (HRs) with 95% confidence intervals (CIs) were analysed using a Cox proportional-hazards models adjusting for demographics, CVD history, conventional cardiovascular risk factors including lipids, microalbuminuria, macroalbuminuria, and use of metformin, sulphonylurea and statins during the trial.  Analysis of variance (ANOVA) was used to assess the treatment-effect difference in the change in lipid and apolipoprotein levels. 
Main results:   Although the magnitude of benefit on total CVD events appeared greater in women than in men (both overall and for those with high triglycerides and low high-density lipoprotein cholesterol [HDL-C]), there was no significant treatment-by-sex interaction (p>0.1) (Table). Fenofibrate reduced low-density lipoprotein by 20.1% in women versus 11.2% in men at study close).

Table 1. Effect of fenofibrate on total CVD events in men and women with type 2 diabetes in the FIELD study.

Data given as adjusted relative risk reduction (95% CI)

Population

Women

Men

P-value for treatment by sex interaction

All patients

30% (8 to 46%)

13% (-1 to 24%)

NS, >0.1

Patients with atherogenic dyslipidaemia*

30% (-7% to 54%)

24% (2 to 42%)

NS >0.1

* As defined above

Authors’ conclusion:   CVD event reductions with fenofibrate were consistently similar in women and men, both overall and among those with elevated triglycerides and low HDL-C.  These data provide reassurance about fenofibrate efficacy in women and men. Both sexes with type 2 diabetes should be considered for fenofibrate therapy for cardioprotection. 

COMMENT

As recommended by the R3i, fibrates are one option for managing atherogenic dyslipidaemia to reduce residual cardiovascular risk.(1) Questions have been raised, however, about the efficacy of fibrates in reducing cardiovascular outcomes in women. Prior to the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, there have been limited data to either support or refute their efficacy. In contrast, the ACCORD Lipid trial included a sizable proportion of women with type 2 diabetes (31%), but showed in subgroup analyses an increased CVD rate in women with fenofibrate (9.1% versus 6.6% in the placebo group), albeit not statistically significant.(2) This finding raised concerns about the efficacy and/or safety of fenofibrate in women, in turn prompting regulatory review of the cardiovascular safety of fenofibrate in women with diabetes.(3)

Thus, it was appropriate to investigate this issue further in a pre-specified analysis of the FIELD study.  The findings from this analysis show that the reduction in risk of CVD events did not differ statistically between women or men allocated fenofibrate. This comparability of effect was also observed in the subgroup of patients with atherogenic dyslipidaemia. Thus, these findings provide reassurance for the cardiovascular safety of fenofibrate in women. Furthermore, there was also evidence that women derived greater lipid and lipoprotein-modifying benefit from fenofibrate than men, which did not appear to be explained by differences in statin uptake or metformin use.(4)

In conclusion, based on the findings of this pre-specified analysis of the FIELD study, fenofibrate is an effective option for improving the dyslipidaemic profile and reducing residual cardiovascular risk in both men and women with type 2 diabetes.

References  
  1. Fruchart JC, Davignon J, Hermans MP et al. Residual macrovascular risk in 2013: what have we learned? Cardiovasc Diabetol 2014;13:26.
  2. ACCORD Study Group.Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med 2010;362:1563–74.
  3. US Food and Drug Administration (2011) FDA drug safety communication: review update of Trilipix (fenofibric acid) and the ACCORD Lipid trial Silver Spring, MD: US FDA (updated 8 Dec 2011). Available from www.fda.gov/Drugs/DrugSafety/
  4. FIELD Study Investigators, Keech A, Simes RJ, Barter P et al. Effects 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; cardiovascular disease; fenofibrate; elevated triglycerides and low HDL-C; atherogenic dyslipidaemia; women