Remnant-c and TG associated with MACE in high CV risk overweight or obese subjects
Remnant Cholesterol, Not LDL Cholesterol, Is Associated With Incident Cardiovascular Disease
Introduction and methods
Dyslipidemia is considered a cause of lipid-dependent residual risk, regardless of LDL-c [1-4]. It is present in patients with diabetes, overweight and obesity, metabolic syndrome and renal failure. The lipid profile of patients with atherogenic dyslipidemia is characterized by: 1) increase in triglycerides contained in triglyceride-rich lipoproteins (TRLs); 2) low concentration of HDL-c; 3) high concentration of small dense LDLs. All these factors are associated with increased CVD risk [5-7].
It is suggested that accumulation in the arterial wall of remnant cholesterol (and not triglycerides – these can be easily metabolized) may play a causal role in atherosclerotic CVD, similar to LDL-c . In atherogenic dyslipidemia, TRLs are more abundant, larger and contain more cholesterol in absolute terms than LDL-c. In observational and genetic studies, remnant-cholesterol (remnant-C) content has been associated with CV events and total mortality [6,8,9]. But data on populations with overweight, obesity and diabetes are limited, as well as data from Mediterranean cohorts.
This study examined the association of triglycerides and TRLs with CV outcomes in the PREDIMED cohort. The PREDIMED study was a multicenter, randomized clinical trial that evaluated the efficacy of MedDiets enriched with extra-virgin olive oil or mixed nuts compared to a control diet for the primary prevention of CVD.
Participants in the PREDIMED (Prevención con Dieta Mediterránea) trial  had a high prevalence of diabetes, obesity and metabolic syndrome. The present study enrolled 6901 community-dwelling men 55-80 years and women 60-80 years with T2DM diagnosis or ≥3 CVD risk factors: current smoking; hypertension; LDL-c levels >4.14 mmol/L or use of hypolipidemic agents, HDL-c <1.29 mmol/L for women of <1.03 for men; BMI >25 kg/m2; of family history of CHD. Samples of fasting blood and urine were obtained at baseline. Remnant-c was estimated as total cholesterol minus LDL-c minus HDL-c. Primary endpoint was a composite of major adverse cardiovascular events (MACEs), consisting of myocardial infarction, stroke, or CV death. Median follow-up was 4.8 years.
- Mean age was 67 years, mean BMI was 30.0 kg/m2, 48.3% had diabetes, 40.6% were on statins and 3.8% on fibrates.
- Serum triglyceride levels were associated with a 4% increased risk of MACE per every 10 mg/dL increase (HR 1.04, 95%CI: 1.02-1.06, P<0.001), non-HDL-c with a 5% increased risk of MACE (HR 1.05, 95%CI: 1.01-1.10, P=0.026) and remnant-C was associated with a 21% higher risk per 10 mg/dL increase (HR 1.21, 95%CI: 1.10-1.33, P<0.001). LDL-c and HDL-c were not associated with MACE.
- Characteristics of atherogenic dyslipidemia (triglycerides >150 mg/dL and HDL-c <40 mg/dL in men or <50 mg/dL in women) were associated with a 44% increased risk of MACE (HR 1.44, 95%CI: 1.04-2.00, P=0.030). No interactions were observed between lipid variables and dietary intervention groups or sex.
- Incidence of MACE was highest in participants in the upper quartiles of triglycerides, non-HDL-c and remnant-C compared to the lowest quartiles.
- Those with remnant-C ≥75th percentile of the cohort (~30 mg/dL) were defined as to have abnormally high levels of remnant-C. These subjects had higher CV risk, regardless of LDL-c. For those with LDL-c ≤100 mg/dL and remnant-c >30 mg/dL, HR was 2.69 (95%CI: 1.52-4.75, P=0.001), for those with LDL-c >100 mg/dL and remnant-c ≤ 30 mg/dL HR was 1.36 (95%CI: -0.85 to 2.16) and those with LDL-c> 100 mg/dL and remnant-c >30 mg/dL HR was 1.89 (95%CI: 1.16-3.08, P=001).
In a primary prevention trial with high prevalence of diabetes and obesity in high CV risk participants, triglycerides and remnant-C, but not LDL-c and HDL-c, were associated with MACE. The authors concluded: ‘Remnant-c should be considered a preferential treatment target in this population. Randomized controlled trials with hard CVD outcomes are warranted to compare the benefit of interventions directed at lowering remnant-C against standard cholesterol-lowering therapy, particularly when LDL-c target levels have been achieved’.