Dyslipidemia: Treatment in Statin – Intolerant Patients

Statins are the mainstay of lipid-lowering therapy because of their well-established efficacy for reducing cardiovascular disease mortality and morbidity in various high risk populations. However, certain patients cannot avail themselves of these beneficial effects due to intolerance in these agents. Statin-induced myopathy is by far the most common side-effect. A less common side-effect of statin therapy is hepatic toxicity. Intolerance to statins is frequently encountered in clinical practice, mostly due to muscular symptoms and/or elevation of hepatic aminotransferases, which overall constitutes approximately two-thirds of reported adverse events during statin therapy. The first step in handling intolerant patients is to rule out any secondary causes of myopathy or liver toxicity. The second step is to determine whether the adverse effects are indeed related to statin therapy by statin dechallenge and rechallenge. Another option is to restart with the same statin at a lower dosage or to switch to another statin with defferent pathways of metabolism. If the symptoms are recurrent, different approaches should be considered, such as unconventional dosing (every other-day or weekly administration) of statins with longer half-life. Another option in patients who cannot tolerate statins is the use of non-lipid lowering drugs, such as ezetimibe, bile acids sequestrants (colesevelam) and fibrates, alone or in combination. Concerning low-risk individuals the use of herbal supplements effective in reducing LDL cholesterol may be considered

Novel Hypolipidemic Agents: the Role of PCSK9 Inhibitors

Hyperlipidemia is a major cause of cardiovascular disease despite the availability of first-line cholesterol lowering agents such as statins. Although statin therapy is very efficient to reduce cholesterol, nearly 10-20% of individuals on statins, experience side effects, such myopathy, which hinder the drugs ability to achieve target low-density lipoprotein (LDL) cholesterol (LDL-C) levels. Statin-intolerant patients require more effective therapies for lowering LDL-C. As proprotein convertase subtilisin kexin type 9 (PCSK9) promotes the degradation of the LDL receptor (LDLR) and prevents it from recycling to the membrane, a new therapeutic approach to lowering LDL-C acts by blocking LDL-receptor degradation by serum PCSK9. Humanized monoclonal antibodies which target PCSK9 and its interaction with the LDL receptor (REGN727/SAR23653, AMG145, and RN316), as well as agents that inhibit PCSK9 synthesis, such as ALN-PCS, are now in clinical trials. The latter is a small interfering RNA (siRNA) that directs sequence-specific messenger RNA for PCSK9 leading to reduced hepatocyte-specific synthesis of PCSK9. Ongoing phase III trials’ results are awaited with great interest in order to define these agents’ long-term safety, tolerability and efficacy for reducing cardiovascular events

Long-term prognostic value of LDL-C, HDL-C, lp(a) and TG levels on cardiovascular disease incidence, by body weight status, dietary habits and lipid-lowering treatment:the ATTICA epidemiological cohort study (2002–2012)

BACKGROUND: The link between blood lipids and cardiovascular disease (CVD) is complex. Our aim was to assess the differential effect of blood lipids on CVD risk according to age, sex, body weight, diet quality, use of lipid-lowering drugs and presence of hypercholesterolemia. METHODS: In this secondary analysis of the ATTICA prospective cohort study, serum blood lipids, i.e., total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG) and liproprotein(a) [Lp(a)], and sociodemographic, anthropometric, lifestyle and clinical parameters were evaluated at baseline (2001/2002) in 2020 CVD-free men and women. CVD incidence was recorded at the 10-year follow-up (2011/2012). RESULTS: All blood lipids assessed were univariately related to CVD risk; however, associations remained significant only for HDL-C and TG in multivariate models adjusted for age, sex, body mass index, smoking, Mediterranean Diet Score, physical activity, presence of hypercholesterolemia, hypertension and diabetes mellitus, use of lipid-lowering drugs, and family history of CVD [RR per 1 mg/dL (95% CI): 0.983 (0.967, 1.000) and 1.002 (1.001, 1.003), respectively]. In stratified analyses, TC and LDL-C predicted CVD risk in younger subjects, normal-weight subjects, and those not on lipid-lowering drugs, while HDL-C and TG were significant predictors in older subjects, those with low adherence to the Mediterranean diet, and hypercholesterolemic subjects; a significant effect on CVD risk was also observed for TG in males, overweight participants and lipid-lowering medication users and for Lp(a) in older subjects and females (all p ≤ 0.050). CONCLUSIONS: The impact of blood lipids on CVD risk differs according to several biological, lifestyle and clinical parameters

Adiponectin circulating levels and 10-year (2002–2012) cardiovascular disease incidence:the ATTICA Study

Purpose: Adiponectin is an adipokine with anti-inflammatory and cardiovascular-protective properties. Existing epidemiological evidence is conflicting on the exact relationship between adiponectin and long-term cardiovascular disease (CVD) risk. Our aim was to prospectively assess whether circulating adiponectin is associated with long-term incident CVD. Methods: A population-based, prospective study in adults (>18 years) without previous CVD history (ATTICA study). Circulating total adiponectin levels were measured at baseline (2001–2002) in a sub-sample (n = 531; women/men: 222/309; age: 40 ± 11 years) of the ATTICA cohort and complete 10-year follow-up data were available in 366 of these participants (women/men: 154/212; age: 40 ± 12 years). Results: After adjusting for multiple factors, including age, sex, body mass index, waist circumference, smoking, physical activity, Mediterranean diet adherence, hypertension, diabetes, and hypercholesterolemia, our logistic regression analysis indicates that an increase in circulating total adiponectin levels by 1 unit was associated with 36% lower CVD risk (relative risk [RR]: 0.64, 95% confidence interval [CI] 0.42–0.96; p = 0.03). Further adjusting for interleukin-6 plasma levels had no significant impact (RR: 0.60, 95% CI 0.38–0.94; p = 0.03), while additional adjustment for circulating C-reactive protein (CRP) modestly attenuated this association (RR: 0.63, 95% CI 0.40–0.99; p = 0.046). Conclusions: In our study, elevated circulating total adiponectin levels were associated with lower 10-year CVD risk in adults without previous CVD, independently of other established CVD risk factors. This association appeared to be modestly attenuated by CRP, yet was not mediated by interleukin-6 which is the main endocrine/circulating pro-inflammatory cytokine

Familial hypercholesterolaemia in children and adolescents from 48 countries: a cross-sectional study

Background: Approximately 450 000 children are born with familial hypercholesterolaemia worldwide every year, yet only 2·1% of adults with familial hypercholesterolaemia were diagnosed before age 18 years via current diagnostic approaches, which are derived from observations in adults. We aimed to characterise children and adolescents with heterozygous familial hypercholesterolaemia (HeFH) and understand current approaches to the identification and management of familial hypercholesterolaemia to inform future public health strategies. Methods: For this cross-sectional study, we assessed children and adolescents younger than 18 years with a clinical or genetic diagnosis of HeFH at the time of entry into the Familial Hypercholesterolaemia Studies Collaboration (FHSC) registry between Oct 1, 2015, and Jan 31, 2021. Data in the registry were collected from 55 regional or national registries in 48 countries. Diagnoses relying on self-reported history of familial hypercholesterolaemia and suspected secondary hypercholesterolaemia were excluded from the registry; people with untreated LDL cholesterol (LDL-C) of at least 13·0 mmol/L were excluded from this study. Data were assessed overall and by WHO region, World Bank country income status, age, diagnostic criteria, and index-case status. The main outcome of this study was to assess current identification and management of children and adolescents with familial hypercholesterolaemia. Findings: Of 63 093 individuals in the FHSC registry, 11 848 (18·8%) were children or adolescents younger than 18 years with HeFH and were included in this study; 5756 (50·2%) of 11 476 included individuals were female and 5720 (49·8%) were male. Sex data were missing for 372 (3·1%) of 11 848 individuals. Median age at registry entry was 9·6 years (IQR 5·8-13·2). 10 099 (89·9%) of 11 235 included individuals had a final genetically confirmed diagnosis of familial hypercholesterolaemia and 1136 (10·1%) had a clinical diagnosis. Genetically confirmed diagnosis data or clinical diagnosis data were missing for 613 (5·2%) of 11 848 individuals. Genetic diagnosis was more common in children and adolescents from high-income countries (9427 [92·4%] of 10 202) than in children and adolescents from non-high-income countries (199 [48·0%] of 415). 3414 (31·6%) of 10 804 children or adolescents were index cases. Familial-hypercholesterolaemia-related physical signs, cardiovascular risk factors, and cardiovascular disease were uncommon, but were more common in non-high-income countries. 7557 (72·4%) of 10 428 included children or adolescents were not taking lipid-lowering medication (LLM) and had a median LDL-C of 5·00 mmol/L (IQR 4·05-6·08). Compared with genetic diagnosis, the use of unadapted clinical criteria intended for use in adults and reliant on more extreme phenotypes could result in 50-75% of children and adolescents with familial hypercholesterolaemia not being identified. Interpretation: Clinical characteristics observed in adults with familial hypercholesterolaemia are uncommon in children and adolescents with familial hypercholesterolaemia, hence detection in this age group relies on measurement of LDL-C and genetic confirmation. Where genetic testing is unavailable, increased availability and use of LDL-C measurements in the first few years of life could help reduce the current gap between prevalence and detection, enabling increased use of combination LLM to reach recommended LDL-C targets early in life

Advancing therapy for hypercholesterolemia

Importance of the field: Hypercholesterolemia holds a key role in the development and progression of atherosclerosis and is a causative factor of coronary artery disease. Current guidelines for cholesterol treatment target low-density cholesterol (LDL-C) as the primary goal of therapy. Despite advances in the pharmacotherapy of atherosclerosis, the most successful agents used to treat this disease - HMG CoA reductase inhibitors - remain ineffective for the primary or secondary prevention of myocardial infarction in 50 - 60% of patients. Advancing therapy for hypercholesterolemia with new-emerging drugs either as monotherapy or in combination will hopefully improve cardiovascular outcomes. Areas covered in this review: The two major sources of cholesterol in the human body are: i) biosynthesis of cholesterol by the liver; and ii) absorption by the intestines. Both play a pivotal role in the overall balance of cholesterol. A recent and more effective therapeutic strategy is to treat both sources of cholesterol simultaneously with a complementary mechanism of action. The present article presents cholesterol metabolism and reviews new emerging lipid-lowering drugs and therapies that: i) lower LDL-C; ii) lower triglycerides; and iii) increase high-density lipoprotein cholesterol. What the reader will gain: This review summarizes the pivotal role of both the liver and intestine in the overall balance of cholesterol in the body and describe the clinical impact and relevance of using new emerging lipid-lowering drugs either alone or co-administered with statins in controlling cholesterol levels. Take-home message: An elevated concentration of LDL-C plays a causal role in the development of cardiovascular disease. The new aggressive cholesterol treatment goals call for a more advanced therapeutic approach to maximize the cardiovascular benefits associated with lower LDL-C levels

Arterial endothelial function and wall thickness in familial hypercholesterolemia and familial combined hyperlipidemia and the effect of statins. A systematic review and meta-analysis

Background: To evaluate the impact of familial hypercholesterolemia (FH) and familial combined hyperlipidemia (FCH) on arterial properties and the effects of statins. Methods: We meta-analyzed 51 studies providing data for 4,057 FH patients and 732 FCH patients with random-effects models, meta-regression analysis and publication bias analysis. The main outcomes of interest were (1) brachial artery flow-mediated dilation (FMD), (2) intima-media thickness (IMT), and (3) change of IMT and FMD after treatment with statins. Results: Compared to normolipidemic controls, FH patients had lower FMD [pooled mean difference (MD): 5.31%, 95% CI 7.09 to 3.53%, P < 0.001] and higher carotid IMT (pooled MD: 0.12 mm, 95% CI 0.09-0.15 mm, P < 0.001) and femoral IMT (pooled MD: 0.35 mm, 95% CI 0.18-0.51 mm, P < 0.001). FCH patients had lower FMD and increased IMT (pooled MD: -3.60%, 95% CI -6.69 to -0.50%, P = 0.023; and 0.06 mm, 95% CI 0.04-0.08 mm, P < 0.001, respectively). Total and LDL-cholesterol was a significant determinant of FMD and carotid IMT in FCH patients and of FMD and femoral IMT in FH patients. In FH patients, statins improved FMD (pooled MD of change: 5.39%, 95% CI 2.86-7.92%, P < 0.001) and decreased carotid IMT (pooled MD of change: -0.025 mm, 95% CI -0.042 to -0.009 mm, P = 0.003). Changes of both FMD and IMT with statins correlated with the duration x treatment intensity product in FH patients (both P < 0.01). Additionally, statins improved FMD in FCH patients (pooled MD of change: 2.06%, 95% CI 0.43-3.69%, P = 0.013). No significant publication bias was detected. Conclusion: Arterial properties are impaired in subjects with FH or FCH. Statins improve arterial function and structure in FH patients in a treatment intensity-related manner. (C) 2010 Elsevier Ireland Ltd. All rights reserved