RNA-based therapy in the management of lipid disorders: a review.

This review focuses on antisense oligonucleotides and small interfering ribonucleic acid therapies approved or under development for the management of lipid disorders. Recent advances in RNA-based therapeutics allow tissue-specific targeting improving safety. Multiple potential target proteins have been identified and RNA-based therapeutics have the potential to significantly improve outcomes for patients with or at risk for atherosclerotic cardiovascular disease. The advantages of RNA-based lipid modifying therapies include the ability to reduce the concentration of almost any target protein highly selectively, allowing for more precise control of metabolic pathways than can often be achieved with small molecule-based drugs. RNA-based lipid modifying therapies also make it possible to reduce the expression of target proteins for which there are no small molecule inhibitors. RNA-based therapies can also reduce pill burden as their administration schedule typically varies from weekly to twice yearly injections. The safety profile of most current RNA-based lipid therapies is acceptable but adverse events associated with various therapies targeting lipid pathways have included injection site reactions, inflammatory reactions, hepatic steatosis and thrombocytopenia. While the body of evidence for these therapies is expanding, clinical experience with these therapies is currently limited in duration and the results of long-term studies are eagerly awaited.

The therapeutic management of South African dyslipidaemic patients at very high cardiovascular risk (CARDIO TRACK): a cross-sectional study.

BACKGROUND: Dyslipidaemia is a major modifiable risk factor for atherosclerotic cardiovascular disease. At the time the study was conducted, guidelines recommended a low-density lipoprotein cholesterol (LDL-C) target of less than 1.8 mmol/l and a reduction of at least 50% if the baseline LDL-C was between 1.8 and 3.5 mmol/l in patients with either very high cardiovascular risk or established atherosclerosis. In South Africa, there is a paucity of data on attainment of LDL-C goal in patients with very high cardiovascular risk who are on maximum tolerated statin with or without ezetimibe. OBJECTIVE: The aim was to assess the percentage of very high cardiovascular risk South African patients with dyslipidaemia not reaching an LDL-C goal of less than 1.8 mmol/l, despite maximum tolerated statin with or without ezetimibe. METHODS: This was a multi-centre, observational, cross-sectional study conducted at 15 private healthcare sector sites and one public sector site. Adults (> 18 years) with very high cardiovascular risk of familial hypercholesterolaemia receiving stable, maximum-tolerated statin therapy for at least four weeks prior to their latest lipid profile were enrolled into the study, and electronic case report forms were completed after written informed consent was provided. LDL-C goal attainment was modelled, first assuming an increase in the statin dose to the registered maximum, followed by the addition of ezetimibe or a PCSK9-inhibitor. RESULTS: In total, 507 patients were screened, of whom 492 were eligible for study participation. One patient was excluded from the analysis because of a missing LDL-C value. Most participants were male (male 329, 67%; female 162, 33%). Most patients were either obese (223, 46.0%) or overweight (176, 36.3%). Hypertension and diabetes mellitus were frequent co-morbidities and were found in 381 (77.6%) and 316 (64.4%) patients, respectively. Eighty (16.3%) patients reported current smoking. Only 68 (13.8%) patients were taking ezetimibe in addition to a statin. Reasons for not using ezetimibe included no requirement for ezetimibe in the opinion of the treating physician (229, 48.7%), cost (149, 31.7%), Physician's choice (39, 8.3%), or other (53, 11.3%). Only 161 (32.8%) of the patients attained their goal LDL-C level. In our modelling analysis, increasing the statin dose to the registered maximum and adding ezetimibe brought an additional 34.5% of patients to goal, while adding a PCSK9-inhibitor, irrespective of any other changes to lipid-lowering therapy brought over 90% of not-at-goal patients to goal. CONCLUSIONS: Most study participants were not at LDL-C goal despite maximum-tolerated statin, highlighting the need for treatment intensification in this high-risk population. Although intensifying treatment by adding a PCSK9-inhibitor brought more patients to goal, the initial addition of ezetimibe would be more reasonable, given the cost of PCSK9-inhibitors.

Therapeutic Management of Dyslipidemia Patients at Very High Cardiovascular Risk (CARDIO TRACK): Protocol for the Observational Registry Study.

BACKGROUND: Dyslipidemia is a major modifiable risk factor for atherosclerotic cardiovascular disease. Current South African guidelines recommend titrating lipid-lowering therapy (LLT) to low-density lipoprotein cholesterol (LDL-C) targets stratified by cardiovascular risk. The LDL-C goal for very high-risk patients is <1.8 mmol/L. In international studies, approximately 30% of patients do not achieve this goal despite receiving maximally tolerated statin doses. There is, however, a paucity of data on LDL-C goal achievement in very high-risk South African patients receiving maximal statin doses. OBJECTIVE: The goal of the research it to assess LDL-C goal achievement in, and clinical characteristics of, very high cardiovascular risk dyslipidemic patients receiving maximal tolerated statin doses with or without ezetimibe. METHODS: This is an observational, cross-sectional South African registry study that plans to include up to 30 sites and 500 study participants. Adult patients with very high cardiovascular risk status receiving stable, maximally tolerated statin doses (with or without ezetimibe) will be eligible for inclusion. RESULTS: Funding has been awarded and enrollment began on November 15, 2017, and was completed on April 13, 2018, with 507 participants. Database lock was done on June 21, 2018. The statistical analysis has commenced and we expect the final clinical study report to be completed by October 2018. CONCLUSIONS: This study will document the adequacy of LLT in those at highest risk and will thus fill an important data gap in South Africa. This data may be useful in assessing the need for novel LLTs like proprotein convertase subtilisin/kexin 9 inhibitors that substantially lower cholesterol levels in addition to optimal statin therapy. REGISTERED REPORT IDENTIFIER: RR1-10.2196/9248.

9ß Polymorphism of the glucocorticoid receptor gene appears to have limited impact in patients with Addison's disease.

BACKGROUND: Addison's disease (AD) has been associated with an increased risk of cardiovascular disease. Glucocorticoid receptor polymorphisms that alter glucocorticoid sensitivity may influence metabolic and cardiovascular risk factors in patients with AD. The 9ß polymorphism of the glucocorticoid receptor gene is associated with relative glucocorticoid resistance and has been reported to increase the risk of myocardial infarction in the elderly. We explored the impact of this polymorphism in patients with AD. MATERIALS AND METHODS: 147 patients with AD and 147 age, gender and ethnicity matched healthy controls were recruited. Blood was taken in a non-fasted state for plasma lipid determination, measurement of cardiovascular risk factors and DNA extraction. RESULTS: Genotype data for the 9ß polymorphism was available for 139 patients and 146 controls. AD patients had a more atherogenic lipid profile characterized by an increase in the prevalence of small dense LDL (p = 0.003), increased triglycerides (p = 0.002), reduced HDLC (p<0.001) an elevated highly sensitive C-reactive protein (p = 0.01), compared with controls. The 9ß polymorphism (at least one G allele) was found in 28% of patients and controls respectively. After adjusting for age, gender, ethnicity, BMI and hydrocortisone dose per metre square of body surface area in patients, there were no significant metabolic associations with this polymorphism and hydrocortisone doses were not higher in patients with the polymorphism. CONCLUSIONS: This study did not identify any associations between the 9ß polymorphism and cardiovascular risk factors or hydrocortisone dose and determination of this polymorphism is therefore unlikely to be of clinical benefit in the management of patients with AD.

Gender and ethnic differences in the control of hyperlipidaemia and other vascular risk factors: insights from the CEntralised Pan-South African survey on tHE Under-treatment of hypercholeSterolaemia (CEPHEUS SA) study.

AIM: The aim of the CEntralised Pan-South African survey on tHE Under-treatment of hypercholeSterolaemia (CEPHEUS SA) was to evaluate the current use and efficacy of lipid-lowering drugs (LLDs) in urban patients of different ethnicity with hyperlipidaemia, and to identify possible patient characteristics associated with failure to achieve low-density lipoprotein cholesterol (LDL-C) targets. There is little published data on LDL-C attainment from developing countries. METHOD: The survey was conducted in 69 study centres in South Africa and recruited consecutive patients who had been prescribed LLDs for at least three months with no dose adjustment for six weeks. All patients provided written consent. One visit was scheduled for data collection, including fasting lipid and glucose, and HbA1c levels. RESULTS: Of the 3 001 patients recruited, 2 996 were included in the final analyses; 1 385 subjects were of Caucasian origin (818 male), 510 of African ancestry (168 male), 481 of mixed ancestry (222 male) and 620 of Asian origin (364 male). Only 60.5% of patients on LLDs for at least three months achieved the LDL-C targets recommended by the NCEP ATP III/2004 updated NCEP ATP III guidelines and 52.3% the fourth JETF/South African guidelines. African females were on average younger than females of other ethnic origins, and had the lowest smoking rates but the highest prevalence of obesity, hypertension, the metabolic syndrome and diabetes mellitus (DM), with the worst glycaemic control. Although women were less likely than men to reach goal [OR 0.65 (CI 0.54-0.77), p < 0.001 for NCEP ATP III guidelines and OR 0.76 (CI 0.64-0.91), p < 0.003 for fourth JETF guidelines], women of African ancestry were just as likely not to reach goal as their Caucasian counterparts. CONCLUSION: The results of this survey highlight the sub-optimal lipid control achieved in many South African patients, and profile important gender and ethnic differences. Control of cardiovascular disease risk factors across gender and ethnic groups remains poor.

Homozygous familial hypercholesterolemia and its management.

Mutations in the low-density lipoprotein (LDL) receptor gene cause familial hypercholesterolemia. In homozygous familial hypercholesterolemia, both genes for the LDL- receptor are mutated and LDL levels are markedly elevated. High-density lipoprotein cholesterol concentration is often reduced and lipoprotein(a) levels are high when corrected for apolipoprotein(a) isoforms. Cutaneous and tendinous xanthomata develop in childhood and are the most common reason for initial presentation. The diagnosis can be confirmed by analysis of LDL-receptor genes or studies of LDL receptor function in cultured cells. Severe aortic and coronary atherosclerosis usually occurs within the first or second decades of life. Left ventricular outflow tract obstruction may be at the level of the aortic valve or the supravalvar aorta. Treatment for the hyperlipidemia is with plasmapheresis, high-dose statins, and ezetimibe. Liver transplantation reverses the metabolic defect but requires chronic immunosupression, and rejection may still occur. Liver transplantation is indicated if cardiac transplantation becomes necessary. Portocaval shunt may still play a role in patients with coronary artery disease who do not have access to plasmapheresis. Gene therapy is currently not practicable but is being actively developed.

Familial hypercholesterolemia in South Africa.

South Africa, especially the Caucasian part of the population, has one of the highest incidences of familial hypercholesterolemia in the world. The founder effect in this region has led to this high incidence and to a limited number of mutations in the low-density lipoprotein-receptor gene. This chapter describes current situation concerning the management of familial hypercholesterolemia in South Africa.