Rs964184 (APOA5-A4-C3-A1) Is Related to Elevated Plasma Triglyceride Levels, but Not to an Increased Risk for Vascular Events in Patients with Clinically Manifest Vascular Disease

Background: Single nucleotide polymorphisms in the APOA5-A4-C3-A1 gene complex are associated with elevated plasma triglycerides and elevated vascular risk in healthy populations. In patients with clinically manifest vascular disease, hypertriglyceridemia and metabolic syndrome are frequently present, but the contribution of these single nucleotide polymorphisms to plasma triglycerides, effect modification by obesity and risk of recurrent vascular events is unknown in these patients. Methods: Prospective cohort study of 5547 patients with vascular disease. Rs964184 (APOA5-A4-C3-A1 gene complex) was genotyped, and we evaluated the relation with plasma lipid levels, presence of metabolic syndrome and the risk for new vascular events. Results: The minor allele of rs964184 was strongly associated with log plasma triglycerides (β 0.12; 95%CI 0.10-0.15, p = 1.1*10−19), and was also associated with 0.03 mmol/L lower high-density lipoprotein-cholesterol (95%CI 0.01–0.04), and 0.14 mmol/L higher non-high-density lipoprotein-cholesterol (95%CI 0.09–0.20). The minor allele frequency increased from 10.9% in patients with plasma triglycerides 27 kg/m2, p for interaction = 0.02). The prevalence of the metabolic syndrome increased from 52% for patients with two copies of the major allele to 62% for patients with two copies of the minor allele (p = 0.01). Rs964184 was not related with recurrent vascular events (HR 0.99; 95%CI 0.86–1.13). Conclusion: The single nucleotide polymorphism rs964184 (APOA5-A4-C3-A1) is associated with elevated plasma triglycerides concentrations in patients with clinically manifest vascular disease. In carriers of one minor allele, the effect on plasma triglycerides was modified by body mass index. There is no relation between rs964184 and recurrent vascular events in these patients

Effect of Statin Therapy on Incident Type 2 Diabetes Mellitus in Patients With Clinically Manifest Vascular Disease

Several trials and cohort studies have shown an increased incidence of type 2 diabetes mellitus (T2DM) in patients using statins. Whether this only applies to patients at already high risk for the development of T2DM or for all patients is still a matter of debate. In the present prospective cohort study of 4,645 patients with established vascular disease without DM at baseline, 3,057 patients used statins at baseline, of whom 1,608 used intensive statin therapy, defined as statin therapy theoretically lowering low-density lipoprotein cholesterol with ≥40%. Cox proportional hazards models were used to estimate the risk of incident T2DM with (intensive) statin therapy. Statin therapy was associated with increased risk of incident T2DM (hazard ratio 1.63; 95% confidence interval 1.15 to 2.32) when adjusted for age, gender, body mass index, plasma high-density lipoprotein cholesterol, and plasma triglyceride levels. Intensive statin therapy tended to be related to a higher risk of T2DM compared with moderate statin therapy (hazard ratio 1.22; 95% confidence interval 0.92 to 1.61, adjusted for age, gender, body mass index, plasma high-density lipoprotein cholesterol, and plasma triglyceride levels). The increase in risk was regardless of the number of metabolic syndrome characteristics or insulin resistance but was particularly present in patients with low baseline glucose levels (<5.6 mmol/L; p for interaction 2.9 × 10-7). In conclusion, statin use increases the risk of incident T2DM in patients with clinically manifest vascular disease. The increase in risk was independent of the number of metabolic syndrome criteria and was even more pronounced in patients with low baseline glucose levels

Effect of Statin Therapy on Incident Type 2 Diabetes Mellitus in Patients With Clinically Manifest Vascular Disease

Several trials and cohort studies have shown an increased incidence of type 2 diabetes mellitus (T2DM) in patients using statins. Whether this only applies to patients at already high risk for the development of T2DM or for all patients is still a matter of debate. In the present prospective cohort study of 4,645 patients with established vascular disease without DM at baseline, 3,057 patients used statins at baseline, of whom 1,608 used intensive statin therapy, defined as statin therapy theoretically lowering low-density lipoprotein cholesterol with ≥40%. Cox proportional hazards models were used to estimate the risk of incident T2DM with (intensive) statin therapy. Statin therapy was associated with increased risk of incident T2DM (hazard ratio 1.63; 95% confidence interval 1.15 to 2.32) when adjusted for age, gender, body mass index, plasma high-density lipoprotein cholesterol, and plasma triglyceride levels. Intensive statin therapy tended to be related to a higher risk of T2DM compared with moderate statin therapy (hazard ratio 1.22; 95% confidence interval 0.92 to 1.61, adjusted for age, gender, body mass index, plasma high-density lipoprotein cholesterol, and plasma triglyceride levels). The increase in risk was regardless of the number of metabolic syndrome characteristics or insulin resistance but was particularly present in patients with low baseline glucose levels (<5.6 mmol/L; p for interaction 2.9 × 10-7). In conclusion, statin use increases the risk of incident T2DM in patients with clinically manifest vascular disease. The increase in risk was independent of the number of metabolic syndrome criteria and was even more pronounced in patients with low baseline glucose levels

Relation between rs964184 (per minor allele) and lipid levels.

<p>Linear regression adjusted for age and sex.</p><p>*Additionally adjusted for lipid-lowering medication.</p

Association between body mass index and plasma log(TG), stratified by rs964184 genotype.

<p>Black line: CC genotype, red line: CG genotype, blue line: GG genotype. Dotted lines indicate 95% confidence interval.</p

Relation between minor allele frequencies and levels of plasma TG.

<p>Rs964184 minor allele frequency (95% confidence interval) at increasing levels of TG. N indicates the number of patients with a plasma TG level in this category.</p

Relation between rs964184 and risk of new vascular events.

<p>Hazard ratio (95% confidence interval) estimated with Cox proportional hazard models.</p><p>Model 1: adjusted for age and sex.</p><p>Model 2: Model 1 + triglyceride plasma level.</p

Relation between rs964184 genotype and presence of metabolic syndrome or being not at lipid treatment target.

<p>Logistic regression model, adjusted for age and sex.</p><p>*Number of patients with metabolic syndrome or LDL-cholesterol/nonHDL-cholesterol/apoB not at target level.</p><p>**Only in patients using lipid lowering medication.</p

Effect of EPO administration on myocardial infarct size in patients with non-STE acute coronary syndromes; results from a pilot study

A pilot study was performed to determine the effect of 40,000 IU Epo on myocardial damage in 51 patients with non-ST segment elevation acute coronary syndrome (non-STE ACS). No significant difference in myocardial damage was found, but an increased systolic blood pressure was notice