Impact of cardiometabolic risk factors on major cardiovascular events in patients with familial combined hyperlipidemia.

BACKGROUND: Familial combined hyperlipidemia (FCH) is an inherited lipid disorder associated with premature cardiovascular disease. It has not been established whether the cardiometabolic risk factors, which frequently accompany FCH, such as diabetes, metabolic syndrome (MetS) and hypertension, modulate cardiovascular risk in FCH patients. METHODS AND RESULTS: In this single-center, retrospective study, 695 FCH patients with adequate follow-up were enrolled (mean age, 48.9 years; 455 male). Risk factors including lipid levels were evaluated before the initiation of treatment. Acute myocardial infarction (AMI) and cardiovascular death were recorded during a mean follow-up of 9 years. The combined endpoint (AMI and/or cardiovascular death) occurred in 41 patients (5.9% of the total). Those FCH patients who reached the combined endpoint had lower high-density lipoprotein cholesterol (HDL-C) than those who did not, but levels of other lipid variables were similar. Presence of hypertension, diabetes or MetS was a predictor of the combined endpoint on univariate Kaplan-Meier analysis (all P<0.005). Multivariate Cox proportional analysis showed that hypertension and MetS were associated with the combined endpoint independently of age, gender, HDL-C and presence of coronary artery disease at enrollment (adjusted hazard ratios [HRs], 3.00; 95% confidence interval [CI]: 1.46-6.17, P=0.003; HR, 2.43; 95CI%: 1.11-5.33, P=0.026, respectively). CONCLUSIONS: Cardiometabolic risk factors such as hypertension and MetS are independent predictors of major cardiovascular events in FCH patients.

Familial-combined hyperlipidaemia in very young myocardial infarction survivors (< or =40 years of age).

AIMS: Myocardial infarction (MI) in very young individuals is a rare disease associated with an unfavourable prognosis. Familial-combined hyperlipidaemia (FCHL) increases the risk for MI in individuals below 60 years; however, its role in very young MI patients below 40 years is not as well established. We investigated the prevalence and impact of FCHL in these very young MI patients. METHODS AND RESULTS: We prospectively enrolled 102 consecutive MI survivors (< or =40 years) from two high-volume cardiac catheterization centres. Patients were frequency-matched for age, gender, and centre to 200 hospital controls free from coronary heart disease. Myocardial infarction patients were invited to send family members for FCHL screening. Overall, 37 families were screened. Familial-combined hyperlipidaemia was diagnosed using a nomogram, which takes into account total cholesterol, triglycerides, and Apo B(100) levels. Thirty-eight acute myocardial infarction (AMI) patients (38%) and five controls (2.5%) displayed the FCHL phenotype, 21 of these MI patients sent family members for screening, and FCHL was confirmed in 16 families (76%). The FCHL phenotype was associated with a 24-fold increased adjusted risk for MI (95% CI 7.5-81, P < 0.001). Of all lipid parameters, VLDL-cholesterol, and non-HDL-cholesterol were most strongly associated with MI. CONCLUSIONS: The present study suggests that the FCHL phenotype seems to be a major risk factor for the occurrence of MI at a very young age. It remains to be determined whether this excessively increased risk can be favourably modified by therapeutic interventions.

Meta-analysis of safety of the coadministration of statin with fenofibrate in patients with combined hyperlipidemia.

Addition of fenofibrate to statin therapy might represent a viable treatment option for patients whose high risk for coronary heart disease is not controlled by a statin alone. However, safety of coadministration of statin with fenofibrate has been a great concern. The present study tested the safety of coadministration of statin with fenofibrate. We systematically searched the literature to identify randomized controlled trials examining safety of coadministration of statin with fenofibrate. A meta-analysis was performed to estimate safety of coadministration of statin with fenofibrate using fixed-effects models. There were 1,628 subjects in the identified 6 studies. Discontinuation attributed to any adverse events (4.5% vs 3.1%, p = 0.20), any adverse events (42% vs 41%, p = 0.82), adverse events related to study drug (10.9% vs 11.0%, p = 0.95), and serious adverse events (2.0% vs 1.5%, p = 0.71) were not significantly different in the 2 arms. Incidence of alanine aminotransferase and/or aspartate aminotransferase ≥3 times upper limit of normal in the combination therapy arm was significantly higher than in the statin monotherapy arm (3.1% vs 0.2%, p = 0.0009). In the 6 trials with 1,628 subjects no case of myopathy or rhabdomyolysis was reported. In conclusion, statin-fenofibrate combination therapy was tolerated as well as statin monotherapy. Physicians should consider statin-fenofibrate combination therapy to treat patients with mixed dyslipidemia.

Vascular and metabolic effects of treatment of combined hyperlipidemia: focus on statins and fibrates.

Combined hyperlipidemia results from overproduction of hepatically synthesized apolipoprotein B in very low-density lipoproteins in association with reduced lipoprotein lipase activity. Thus, this condition is typically characterized by concurrent elevations in total cholesterol and triglycerides with decreased high-density lipoprotein cholesterol. High levels of apolipoprotein B-containing lipoproteins, most prominently carried by low-density lipoprotein (LDL) particles, are an important risk factor for coronary heart disease. Statin therapy is highly effective at lowering LDL cholesterol. Despite the benefits of statin treatment for lowering total and LDL cholesterol, many statin-treated patients still have initial or recurrent coronary heart disease events. In this regard, combined therapy with statins and fibrates is more effective in controlling atherogenic dyslipidemia in patients with combined hyperlipidemia than either drug alone. Furthermore, statins and fibrates activate PPARalpha in a synergistic manner providing a molecular rationale for combination treatment in coronary heart disease. Endothelial dysfunction associated with cardiovascular diseases may contribute to insulin resistance so that there may also be additional beneficial metabolic effects of combined statin/fibrates therapy. However, there has been little published evidence that combined therapy is synergistic or even better than monotherapy alone in clinical studies. Therefore, there is a great need to study the effects of combination therapy in patients. When statins are combined with gemfibrozil therapy, this is more likely to be accompanied by myopathy. However, this limitation is not observed when fenofibrate, bezafibrate, or ciprofibrate are used in combination therapy.

Rosuvastatin: a highly potent statin for the prevention and management of coronary artery disease.

Since the identification of a fungal metabolite that inhibits HMG-CoA reductase in 1976, statins have emerged rapidly as the global leader in pharmacotherapeutics designed to lower low-density lipoprotein cholesterol (LDL-C). In conjunction, practice guidelines have recommended increasingly aggressive measures to improve coronary heart disease (CHD) outcomes by lowering LDL-C. By virtue of unique chemical characteristics, enhanced binding thermodynamics and limited cytochrome P450 3A4 metabolism, rosuvastatin calcium has a safety profile in line with currently marketed statins, but a different efficacy profile. Mirroring this chemical profile, the GALAXY program represents a comprehensive evaluation of the efficacy, safety and cost-effectiveness of rosuvastatin in individuals representing various clinical diagnoses, pathophysiological states and ethnicities. Also results from the Justification for the Use of statins in Primary prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) study could provide further evidence for the use of rosuvastatin in individuals with traditional and emerging CHD risk factors, such as an elevated high sensitivity C-reactive protein level. This review will provide a comprehensive evaluation of the chemistry, clinical efficacy, safety and tolerability of rosuvastatin, and discuss the future role in the management of CHD and atherosclerosis.

Lipoprotein(a) as a risk factor for maternal cardiovascular disease mortality in kindreds with familial combined hyperlipidemia or familial hypertriglyceridemia.

Most but not all epidemiologic studies have shown that lipoprotein(a) [Lp(a)] is a risk factor for cardiovascular disease (CVD). Lp(a) levels are also strongly genetically influenced. The purpose of this study was to evaluate the association between Lp(a) levels in adult offspring and parental CVD mortality in 61 kindreds with familial forms of hyperlipidemia. The study sample consisted of offspring-parent pairs in which offspring had fasting Lp(a) measurements and parents had 20-year vital status data and standardized cause-of-death classification if deceased. Linear regression analyses, using a robust variance estimator, were performed separately for 241 offspring with known maternal history (114 mothers) and 194 offspring with known paternal history (93 fathers). Maternal history of CVD mortality was significantly (p=0.004) associated with 2.4-fold higher median Lp(a) levels in offspring compared with those with no maternal history, independent of diabetes, lipid-lowering medications and hormone use. No association was observed between paternal CVD mortality and offspring Lp(a) levels (p=0.505). Adjusting for apolipoprotein(a) kringle 4 number did not alter these parent-specific associations. In conclusion, Lp(a) levels in offspring may be associated with maternal but not paternal history of CVD mortality. This parent-specific finding needs to be confirmed in other samples of high-risk families.