[Show abstract][Hide abstract] ABSTRACT: Background:
Familial hypercholesterolemia (FH) is the most common dominantly inherited cause of premature coronary artery disease (CAD). However, the diagnosis of FH in patients who have premature CAD in hospital settings is under-recognized, this also represents a missed opportunity for screening their close family members and implementing primary prevention.
To investigate the point prevalence of FH in a coronary care unit (CCU) among patients with early-onset CAD.
The prevalence of FH, based on modified phenotypic Dutch Lipid Clinic Network Criteria, and the spectrum of associated CAD risk factors, were investigated in a CCU setting. Data were collected on 175 coronary care patients with onset of CAD at age <60 years.
The prevalence of probable/definite FH was 14.3% (95% confidence interval, 9.0%-19.5%); 46.3% of the patients gave a family history of premature CAD and 20.6% had an untreated low-density lipoprotein cholesterol >5.0 mmol/L. Diabetes, hypertension, obesity, and smoking were common and equally prevalent in patients with and without FH.
FH is relatively frequent among patients with a history of early-onset CAD in the CCU. Every effort should be made to detect FH in these patients and to initiate cascade testing of available family members to prevent the development of CAD in those who may be unaware that they also have the condition.
[Show abstract][Hide abstract] ABSTRACT: Background:
Familial hypercholesterolemia (FH) is characterized by elevated LDL-cholesterol and increased risk of premature coronary artery disease (CAD). Lipoprotein(a) [Lp(a)] increases CAD in FH, although the independence of this association relative to other CAD risk factors remains unclear. In this study, we examined the association between Lp(a) and other cardiovascular risk factors and prevalent CAD in patients with FH.
A cross-sectional study of 390 patients with genetically confirmed FH were studied. Clinical and biochemical parameters of FH patients with and without CAD were compared.
FH patients with CAD were older and more often male and had a higher prevalence of hypertension, smoking, diabetes, obesity, reduced eGFR, and elevated plasma Lp(a) and pre-treatment LDL-cholesterol and triglyceride (or low HDL-cholesterol) than FH patients without CAD (P<0.05 for all). In univariate analyses, age, male gender, smoking, hypertension, reduced eGFR, diabetes, obesity, plasma creatinine, Lp(a) and pretreatment LDL-cholesterol, triglycerides and HDL-cholesterol levels were significant predictors of CAD in the FH patients (P<0.05 for all). Elevated LDL-cholesterol, raised Lp(a), hypertension and reduced eGFR remained significant independent predictors of CAD (P<0.05 for all) in FH after adjusting for other modifiable risk factors.
Elevated Lp(a), hypertension and renal insufficiency are independent risk factors beyond elevated pretreatment LDL-cholesterol which predict CAD in patients with FH. In spite of the cross-sectional design of our study, we propose the need for identifying and managing these abnormalities to reduce excess CAD risk in FH patients. However, this proposal remains to be formally tested in a prospective study.
International journal of cardiology 09/2015; 201:633-638. DOI:10.1016/j.ijcard.2015.08.146 · 4.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Familial hyperchoelsterolaemia (FH) remains under-diagnosed and under-treated in the community setting. Earlier evidence suggested a prevalence of 1:500 worldwide but newer evidence suggests it is more common. Less than 15% of FH patients are ever diagnosed, with children and young adults rarely tested despite having the most to gain given their lifetime exposure. Increasing awareness among primary care teams is critical to improve the detection profile for FH. Cascade testing in the community setting needs a sustainable approach to be developed to facilitate family tracing of index cases. The use of the Dutch Lipid Clinic Network Criteria score to facilitate a phenotypic diagnosis is the preferred approach adopted in Australia and eliminates the need to undertake genetic testing for all suspected FH cases.
Expert Review of Cardiovascular Therapy 08/2015; 13(10):1-10. DOI:10.1586/14779072.2015.1082907
[Show abstract][Hide abstract] ABSTRACT: Statins are the mainstay of lipid-lowering therapies targeted at reducing cardiovascular risk. However, they do not completely obviate risk, not all patients tolerate them, and they are not sufficiently effective in patients with very high plasma levels of low-density lipoprotein-cholesterol (LDL-C) such as those with familial hypercholesterolemia (FH) or patients with elevated plasma levels of lipoprotein(a) [Lp(a)]. Recent advances in the understanding of lipoprotein metabolism have led to the development of the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors including evolocumab , which lowers plasma levels of LDL-C by 50 - 75% as monotherapy or in combination with statin therapy.
We discuss in this review the rationale and background behind the development of evolocumab, and its pharmacodynamics and pharmacokinetics. We then discuss the current state-of-play of relevant clinical trials.
The dramatic reduction in plasma levels of LDL-C attributable to evolocumab is anticipated to translate into lower rates of atherosclerotic cardiovascular disease, but this hypothesis remains to be proven. Also to be established are the long-term safety and economic benefits of evolocumab. PCSK9 inhibitors will also probably provide a valuable option for patients with statin intolerance, those with FH and patients with elevated plasma levels of Lp(a).
Expert Opinion on Drug Metabolism & Toxicology 08/2015; 11(9). DOI:10.1517/17425255.2015.1073712 · 2.83 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Statin therapy may lower plasma coenzyme Q10 (CoQ10) concentrations, but the evidence as to the significance of this effect is unclear. We assessed the impact of statin therapy on plasma CoQ10 concentrations through the meta-analysis of available RCTs.
The literature search included selected databases up to April 30, 2015. The meta-analysis was performed using either a fixed-effects or random-effect model according to I2 statistic. Effect sizes were expressed as weighted mean difference (WMD) and 95% confidence interval (CI).
The data from 8 placebo-controlled treatment arms suggested a significant reduction in plasma CoQ10 concentrations following treatment with statins (WMD: −0.44 μmol/L, 95%CI: −0.52, −0.37, p < 0.001). The pooled effect size was robust and remained significant in the leave-one-out sensitivity analysis. Subgroup analysis suggested that the impact of statins on plasma CoQ10 concentrations is significant for all 4 types of statins studied i.e. atorvastatin (WMD: −0.41 μmol/L, 95%CI: −0.53, −0.29, p < 0.001), simvastatin (WMD: −0.47 μmol/L, 95% CI: −0.61, −0.33, p < 0.001), rosuvastatin (WMD: −0.49 μmol/L, 95%CI: −0.67, −0.31, p < 0.001) and pravastatin (WMD: −0.43 μmol/L, 95%CI: −0.69, −0.16, p = 0.001). Likewise, there was no differential effect of lipophilic (WMD: −0.43 μmol/L, 95%CI: −0.53, −0.34, p < 0.001) and hydrophilic statins (WMD: −0.47 μmol/L, 95%CI: −0.62, −0.32, p < 0.001). With respect to treatment duration, a significant effect was observed in both subsets of trials lasting <12 weeks (WMD: −0.51 μmol/L, 95%CI: −0.64, −0.39, p < 0.001) and ≥12 weeks (WMD: −0.40 μmol/L, 95%CI: −0.50, −0.30, p < 0.001).
The meta-analysis showed a significant reduction in plasma CoQ10 concentrations following treatment with statins. Further well-designed trials are required to confirm our findings and elucidate their clinical relevance.
Pharmacological Research 07/2015; 99. DOI:10.1016/j.phrs.2015.07.008 · 4.41 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The aim of this meta-analysis was to evaluate the magnitude of effect of statin therapy on plasma proprotein convertase subtilisin kexin 9 (PCSK9) levels through a systematic review and meta-analysis of clinical trials.
A random-effects model (using DerSimonian-Laird method) and the generic inverse variance method were used for quantitative data synthesis. Heterogeneity was quantitatively assessed using I(2) index. Sensitivity analyses were conducted using the one-study remove approach. Random-effects meta-regression was performed using unrestricted maximum likelihood method to evaluate the association between statin-induced elevation of plasma PCSK9 concentrations with duration of treatment and magnitude of low-density lipoprotein cholesterol reduction.
A total of 15 clinical trials examining the effects of statin therapy on plasma PCSK9 levels were included. Meta-analysis of data from single-arm statin treatment arms (weighted mean difference [WMD]: 40.72 ng/mL, 95% confidence interval [CI]: 34.79, 46.65, p<0.001) and randomized placebo-controlled trials ([randomized controlled trials] RCTs; WMD: 22.98 ng/mL, 95% CI: 17.95, 28.01, p<0.001) revealed a significant increase in plasma PCSK9 concentrations following statin therapy, irrespective of the type of statin administered in either of the analyses (single-arm or RCT). There was no significant elevation of plasma PCSK9 levels with statin/ezetimibe combination compared with statin monotherapy (WMD: 23.14 ng/mL, 95% CI: -1.97, 48.25, p=0.071), however, removal of one study in the meta-analysis yielded a significant result in the sensitivity analysis (WMD: 31.41 ng/mL, 95% CI: 7.86, 54.97, p=0.009).
This meta-analysis suggests that statin therapy causes a significant increase in plasma PCSK9 concentrations.
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Diabetes Obesity and Metabolism 07/2015; DOI:10.1111/dom.12536 · 6.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Introduction:
Circulating lipoprotein (a) (Lp(a)) is a recognized risk factor for cardiovascular disease (CVD). Tibolone, a synthetic steroid, may lower Lp(a) levels; however, evidence of the effects of tibolone on Lp(a) still remain to be defined. Therefore, we investigated the effects of tibolone treatment on circulating Lp(a) levels in postmenopausal women.
The search included PUBMED, Web of Science, Scopus, and Google Scholar (up to January 31st, 2015) to identify controlled clinical studies investigating the effects of oral tibolone treatment on Lp(a) levels in postmenopausal women. Random-effects meta-regression was performed using unrestricted maximum likelihood method for the association between calculated weighted mean difference (WMD) and potential moderators.
Meta-analysis of data from 12 trials (16 treatment arms) suggested a significant reduction of Lp(a) levels following tibolone treatment (WMD: -25.28%, 95% confidence interval [CI]: -36.50, -14.06; p < 0.001). This result was robust in the sensitivity analysis and its significance was not influenced after omitting each of the included studies from the meta-analysis. When the studies were categorized according to the tibolone dose, there were consistent significant reductions of Lp(a) in the subsets of studies with doses <2.5 mg/day (WMD: -17.00%, 95%CI: -30.22, -3.77; p < 0.012) and 2.5 mg/day (WMD: -29.18%, 95%CI: -45.02, -13.33; p < 0.001). Likewise, there were similar reductions in the subsets of trials with follow-up either <24 months (WMD: -26.79%, 95%CI: -38.40, -15.17; p < 0.001) or ≥24 months (WMD: -23.10%, 95%CI: -40.17, -6.03; p = 0.008).
This meta-analysis shows that oral tibolone treatment significantly lowers circulating Lp(a) levels in postmenopausal women. Further studies are warranted to explore the mechanism of this effect and the potential value and place of tibolone or its analogues in the treatment of elevated Lp(a) in individuals at risk of CVD.
[Show abstract][Hide abstract] ABSTRACT: Familial hypercholesterolaemia (FH) is an autosomal co-dominant disorder that markedly raises plasma low-density lipoprotein-cholesterol (LDL-C) concentration, causing premature atherosclerotic coronary artery disease (CAD). FH has recently come under intense focus and while there is general consensus in recent international guidelines as to diagnosis and treatment, there is debate concerning the value of genetic studies. Genetic testing can be cost-effective as part of cascade screening in dedicated centres, but the full mutation spectrum responsible for FH has not been established in many populations and its use in primary care is not at present logistically feasible. Whether employing genetic testing or not, cholesterol screening of family members of index patients with an abnormally raised LDL-C must be employed to determine the need for early treatment to prevent the development of CAD.
The metabolic defects in FH extend beyond low-density lipoprotein (LDL) and may affect triglyceride-rich and high-density lipoproteins, lipoprotein(a) and oxidative stress. Achieving recommended targets for LDL-cholesterol with current treatments is difficult, but this may be resolved by new drug therapies. Lipoprotein apheresis remains an effective treatment for severe FH and, whilst expensive, its cost is less than that of the two recently introduced orphan drugs (lomitapide and mipomersen) for homozygous FH. Recent advances in understanding the biology of proprotein convertase subtilisin/kexin type 9 (PCSK9) have further elucidated the regulation of lipoprotein metabolism and led to new drugs for effectively treating hypercholesterolaemia in FH and related conditions, as well as many patients with statin intolerance. The mechanisms of action of PCSK9 inhibitors on lipoprotein metabolism and atherosclerosis, as well as their impact on cardiovascular outcomes and cost-effectiveness remain to be established.