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|Objective:||To evaluate the effects of IPE on lipid, lipoprotein and inflammatory biomarkers in patients with diabetes in the ANCHOR (AMR101 [Ethyl Icosapentate] on Triglyceride Levels in Patients on Statins With High Triglyceride Levels)|
|Study design:||Post hoc subgroup analysis of patients with diabetes in ANCHOR, a 12-week, randomized, placebo-controlled phase III study of IPE (4 g/day or 2 g/day) in patients with residual hypertriglyceridaemia (≥200 and|
|Study population:||514 patients with diabetes; all except one had type 2 diabetes. The intention to treat (ITT) population comprised 501 patients, 165 allocated to IPE 4 g/day, 171 allocated to IPE 2 g/day and 165 allocated to placebo. Overall, median HbA1c was 6.8% at baseline; median HbA1c was 6.2% in patients with better controlled diabetes (n=253) and 7.6% in patients with less well-controlled diabetes (n=261)|
|Primary variable:||• Median placebo-adjusted percent change from baseline to week 12 in fasting triglycerides (TG) levels
• Secondary variables included LDL-C, non-high-density lipoprotein cholesterol (non-HDL-C), very low-density lipoprotein cholesterol (VLDL-C), apolipoprotein B100 (apoB), and lipoprotein-associated phospholipase A2.
• Exploratory variables included total cholesterol, HDL-C, VLDL-TG, high-sensitivity C-reactive protein (hs-CRP), oxidized LDL, and remnant-like particle cholesterol.
|Methods:||In the ANCHOR trial, patients initially entered a 4-6 week lead-in period to stabilize diet and lifestyle and washout non-statin lipid-modifying therapy, followed by a 2-3 week lipid-qualifying period in which patients were required to satisfy the criteria of TG≥200 mg/dL and
The analysis of TG levels was pre-specified; all other analyses were post hoc. All analyses were based on the ITT population, defined as all randomized patients who took at least one dose of study drug, and had valid baseline and at least one post-baseline efficacy measurement. The effects of treatment were evaluated overall and for patients with better or less well-controlled diabetes.
|Main results:||Compared with placebo, IPE 4 g/day significantly reduced TG, for all patients and those with better or less well-controlled diabetes (Table 1). In addition, this IPE dose also significantly reduced non-HDL-C, VLDL-C, lipoprotein-associated phospholipase A2, apoB, total cholesterol, HDL-C, VLDL-TG, oxidized LDL and remnant-like particle cholesterol in all three diabetes groups. There was no evidence to suggest deterioration in glycaemic control with either IPE dose regimen.
Table 1. Triglycerides (mg/dL) at baseline, 12 weeks and median placebo-adjusted percent change from baseline to week 12
* p<0.01, **p<0.0001
|Authors’ conclusion:||IPE 4 g/day significantly improved lipid parameters, including TG-rich remnant lipoproteins, without worsening glycaemic control in patients with diabetes and mixed dyslipidaemia.|
Atherogenic dyslipidaemia, i.e. the combination of elevated TG (a marker of TG-rich apoB-containing lipoproteins [TRL]) and low plasma concentrations of HDL-C, is commonly exhibited by patients with type 2 diabetes. While statin therapy is effective in managing LDL-C plasma levels, a considerable proportion of patients often have residual hypertriglyceridaemia. For example, data from the Dyslipidaemia International Study (DYSIS) study in Europe and Canada showed that nearly one-half (44%) of patients with diabetes have persistently elevated TG (³1.7 mmol/L or 150 mg/dL) despite statin therapy.(1) This is clearly clinically relevant, given re-consideration of the role of TRL and their remnants in atherosclerosis and CVD.(2,3) Indeed, a recent Mendelian randomisation study showed that lifelong exposure to elevated remnant cholesterol, carried in TRL, is causal for ischaemic heart disease. Each 1 mmol/L (39 mg/dL) increase in levels of non-fasting remnant cholesterol (a measure of TRL cholesterol) due to genetic variants affecting remnant cholesterol metabolism was associated with a 2.8-fold increase in causal risk for ischaemic heart disease, independent of HDL-C.(3)
Therapeutic options for the management of residual hypertriglyceridaemia in statin-treated patients includes fibrates and omega-3 fatty acids.(4) The formulation of omega-3 fatty acids tested in the ANCHOR trial is a high purity formulation of EPA, which is currently approved in the USA as an adjunct to diet to lower severe hypertriglyceridaemia (³500 mg/dL). In the primary publication of the ANCHOR study,(5) IPE 4 g/day was shown to significantly improve residual hypertriglyceridaemia in high-risk patients at LDL-C goal with statin treatment, and was well tolerated. Despite the limitations inherent in a post hoc analysis, the current report extends the evidence-base for this EPA formulation as a therapeutic option for managing residual hypertriglyceridaemia that persists in high-risk patients with or without type 2 diabetes. Whether this strategy confers clinical benefits is contentious, with conflicting conclusions from recent trials, and meta-analyses.(6-10) The ongoing REDUCE-IT (Reduction of Cardiovascular Events with EPA-Intervention) primary prevention trial (11) in about 8000 high-risk patients with residual hypertriglyceridaemia will provide important insights into the appropriateness of this therapeutic strategy for reducing residual cardiovascular risk.
1. Gitt AK, Drexel H, Feely J et al, (on behalf of the DYSIS Investigators). Persistent lipid abnormalities in statin-treated patients and predictors of LDL-cholesterol goal achievement in clinical practice in Europe and Canada. Eur J Prevent Cardiol 2012;19: 221-30.
|Key words||triglycerides; residual hypertriglyceridemia; residual cardiovascular risk; omega-3 fatty acids; icosapent ethyl; eicosapentoic acid; diabetes|