Browsing by Department "Division of Lipidology"

Now showing 1 - 11 of 11
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    Alcohol - foe or friend?
    (2005) Blackhurst, D M; Marais, A D
    In the same month that this manuscript was prepared, newspapers had twice warned the public about the negative aspects of alcohol consumption. South African drinkers consume among the highest volumes of alcoholic beverages in the world, at approximately 50 ml ethanol per drinker per day, making alcohol abuse one of South Africa’s top ten health and social problems.
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    Cardiovascular risk assessment
    (South African Academy of Family Physicians, 2011) Blom, D J
    Cardiovascular disease remains the leading cause of mortality in the Westernised world. Lifestyle changes and drug therapy can reduce cardiovascular risk. Many interventions such as lipid-lowering therapy reduce relative risk to the same extent irrespective of baseline risk, but the absolute benefit is still highest in those with the highest absolute risk. Cardiovascular risk assessment is a tool to determine absolute cardiovascular risk in asymptomatic patients and to select those most likely to benefit from intervention. Conventional risk assessment (Framingham) requires age, gender, blood pressure, smoking status, total cholesterol and high-density lipoprotein cholesterol (HDLC) to determine risk. This is usually expressed as the 10-year risk of coronary heart disease. The accuracy and predictive ability of conventional risk assessment have limitations. Many biomarkers, genetic tests and vascular imaging procedures correlate statistically with vascular risk. Adding these tests to conventional risk assessment (expanded risk assessment) may therefore improve our ability to predict risk. It has, however, been difficult to conclusively demonstrate that expanded risk assessment outperforms conventional risk assessment. Many tests and procedures require further validation before they become part of routine clinical practice. Additional testing may be useful in patients with intermediate risk or where risk is difficult to determine for other reasons.
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    Dyslipidaemia in South Africa
    (2004) Marais, A David
    Dyslipidaemia refers to the abnormal metabolism of lipids, as measured in the blood. Triglycerides (triacylglycerol) and total cholesterol (free and esterified cholesterol) are commonly implicated in hyperlipidaemias. These lipids are transported together with proteins as lipoproteins, which are named according to their ultracentrifugal properties: very low-density lipoprotein (VLDL), low-density lipoprotein (LDL), high-density lipoprotein (HDL) and chylomicrons. Dyslipoproteinaemia refers to abnormalities of the lipoproteins. Understanding metabolism at a molecular level has made it possible to better define dyslipidaemias, their prevalences and phenotypes as recently described in the South African context.
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    Efficacy and safety of alirocumab, a fully human PCSK9 monoclonal antibody, in high cardiovascular risk patients with poorly controlled hypercholesterolemia on maximally tolerated doses of statins: rationale and design of the ODYSSEY COMBO I and II trials
    (2014-09-20) Colhoun, Helen M; Robinson, Jennifer G; Farnier, Michel; Cariou, Bertrand; Blom, Dirk; Kereiakes, Dean J; Lorenzato, Christelle; Pordy, Robert; Chaudhari, Umesh
    Abstract Background Alirocumab is a fully human monoclonal antibody to proprotein convertase subtilisin kexin type 9 (PCSK9) under investigation for treatment of hypercholesterolemia and reduction of cardiovascular events. Methods/design The COMBO studies, part of the Phase 3 ODYSSEY clinical trial program, are designed to evaluate the efficacy and safety of alirocumab as add-on therapy to stable, maximally tolerated daily statin, with or without other lipid-lowering therapy (LLT), in a planned 966 patients with hypercholesterolemia at high cardiovascular risk. COMBO I ( http://clinicaltrials.gov/show/NCT01644175 ) is placebo-controlled, with a double-blind treatment period of 52 weeks, and 306 planned patients who may receive other LLTs in addition to statin therapy. COMBO II ( http://clinicaltrials.gov/show/NCT01644188 ) has a double-blind treatment period of 104 weeks, comparing alirocumab with ezetimibe in 660 planned patients receiving statin therapy (but no other LLTs). The primary efficacy endpoint is the difference between treatment arms in percent change in low-density lipoprotein cholesterol (LDL-C) from baseline to week 24. Both studies utilized a starting dose of alirocumab 75 mg every 2 weeks (Q2W; administered as 1 mL solution via auto-injector). Patients with LDL-C levels ≥70 mg/dL after 8 weeks of treatment were up-titrated in a blinded manner at week 12 to alirocumab 150 mg Q2W (also 1 mL auto-injector). Discussion In conclusion, the COMBO studies will provide information on the long-term efficacy and safety of alirocumab in high-risk patients when administered in addition to maximally tolerated statin therapy, with a flexible dosing strategy which allows for individualized therapy based on the degree of LDL-C lowering needed to achieve the desired treatment response. Trial registrations COMBO I: NCT01644175 ( NCT01644175 ). COMBO II: NCT01644188 ( NCT01644188 ).
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    Familial hypercholesterolaemia
    (South African Academy of Family Physicians, 2011) Blom, D J
    amilial hypercholesterolaemia (FH) is a monogenic disorder of low-density lipoprotein (LDL) metabolism. It is characterised by markedly elevated LDL cholesterol, autosomal dominant inheritance, premature cardiovascular disease and tendon xanthomata. FH is a genetically heterogeneous disorder, but the most common underlying molecular cause is mutation of the LDL receptor gene. The worldwide prevalence of FH is 1:500. South Africa has three founder populations in which the prevalence of FH may be as high as 1:70. FH is diagnosed clinically, but the diagnosis can be confirmed by DNA analysis. DNA testing cannot always identify the causative mutation because there are several genes to examine and more than 1 500 different mutations have been identified in the LDL receptor alone. Statins are the treatment of choice for patients with FH. Ezetimibe or cholestyramine can be added if additional LDL lowering is required, or if patients are unable to tolerate high statin doses.
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    Familial hypercholesterolaemia: the Cape Town experience
    (Health and Medical Publishing Group, 2008) Firth, Jean C; Marais, A David
    Familial hypercholesterolaemia (FH), an autosomal dominantly inherited disorder characterised by elevated plasma low-density lipoprotein (LDL) cholesterol levels, tendon xanthomata and premature ischaemic heart disease, is amenable to treatment with modern medication. The clinical and biochemical details of 1 031 patients with FH were analysed. FH is the most common monogenic disorder of lipoprotein metabolism presenting to the Lipid Clinic at Groote Schuur Hospital, accounting for about 20% of consultations. The hospital classified 55% of the FH patients as white, 43% as coloured, 1.5% as Asian and 0.5% as black. In the FH cohort (whose mean age at presentation was 44 years), 80% had tendon xanthomata, 36% had arcus cornealis, and 14% had xanthelasma. Tendon xanthomata was present in almost 90% of patients by the age of 50 years. Arcus cornealis was present in about 45% by the age of 40 years, further increasing in frequency with age. Cardiovascular complications included ischaemic heart disease (43%), stroke (1.5%), transient ischaemic attacks (1.3%), and peripheral vascular disease (3.7%). The mean age of death was 55 (+13) years; 51 (+10) years in men and 61 (+12) years in women. In 46% of the cohort, a defective gene was identified by testing for locally prevalent mutations.
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    Lipoprotein metabolism and its derangements
    (2003) Marais, David
    The purpose of this article is to provide the medical practitioner with an understanding of lipids, lipoproteins and their metabolism and disorders. Such an understanding would enhance the assimilation of the sections on clinical assessment and treatment of dyslipoproteinaemia. Lipids may be defined as organic chemicals that are insoluble in water. In the biological context lipids are either carboxylic acids (fatty acids) or sterols, and their derivatives. Lipids are less dense than water and will float spontaneously or under centrifugal force. Cholesterol is the principal sterol in the animal kingdom and promotes the impenetrability of the phospholipid bilayer that constitutes the cell membrane. Additionally cholesterol is found in lipoproteins and in bile and is used to synthesise hormones and bile acids.
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    RNA-based therapy in the management of lipid disorders: a review
    (2022-04-23) Blom, Dirk J; Marais, Adrian D; Moodley, Rajen; van der Merwe, Nico; van Tonder, Alet; Raal, Frederick J
    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.
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    Statin therapy for the octogenarian?
    (2012) Blom, D J
    Cardiovascular risk increases progressively with age. Statins in octogenarians may therefore potentially bring about large reductions in absolute risk. Epidemiological studies, however, show that statin prescription declines with age and is lowest in the oldest patients with the highest cardiovascular risk. Reasons for low statin utilisation in the elderly include safety concerns, doubts about the utility of statin therapy in those of advanced age and a paucity of definite trial evidence supporting statin prescription in octogenarians. Some of the more recently completed statin outcome trials have randomised patients as old as 82 years. A meta-analysis of secondary prevention, with patients aged 65–82 years at randomisation, supported statin prescription in this age group, as statin therapy was associated with relative risk reduction similar to that observed in younger patients. A Swedish registry study showed improved survival in octogenarians prescribed a statin following hospitalisation with an acute myocardial infarction. Currently there is no definite evidence that statin therapy prevents or ameliorates cognitive impairment or dementia. Statin therapy should be considered in octogenarians at high cardiovascular risk, taking into account factors such as biological vs. chronological age, life expectancy, quality of life, risk of interaction with medications taken for co-morbidities and the ability of the patient to take the statin safely.
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    Statins: Adherence and side-effects
    (South African Academy of Family Physicians, 2011) Blom, D J
    Many patients either do not adhere to, or fail to persist with, long-term lipid-lowering therapy. This unfavourable medication utilisation behaviour compromises potential treatment benefit. In retrospective studies, patients aged 50-65 had the highest adherence rates, while both younger and older patients had lower rates. Patients with pre-existing cardiovascular disease adhere better than those in primary prevention. Financial barriers may impair adherence. At the individual patient level, health beliefs, perceptions of own cardiovascular risk and need for medication, concerns about side-effects and inconvenience of treatment may influence adherence. In clinical trials, regular reminders to patients have been shown to improve adherence, but each patient will require an individually tailored treatment strategy. Myopathy is the most common clinically relevant adverse effect of statins. The clinical severity of statin myopathy is highly variable, ranging from mild muscle ache to rare instances of rhabdomyolysis. Risk factors for statin myopathy include age, statin dose, hypothyroidism, medications that inhibit statin metabolism, combined statin and fibrate therapy, and renal impairment. Alternative causes of myopathy should be excluded before muscular symptoms are ascribed to statins. The management of statin myopathy is guided by the severity of symptoms and the creatine kinase level. Potential management strategies include statin dechallenge and rechallenge, statin dose reduction, statin switching, non-daily dosing and use of alternative lipid-lowering agents, such as ezetimibe. Statins rarely cause severe liver disease. Mild liver enzyme elevations are seen relatively frequently in patients starting statins, but are usually not clinically important. Patients with persistently elevated liver enzymes should be investigated to determine the cause of liver disease. Patients with stable, well-compensated liver disease can be prescribed statins, provided they are closely monitored.
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    Target achievement and cardiovascular event rates with Lomitapide in homozygous Familial Hypercholesterolaemia
    (BioMed Central, 2018-06-20) Blom, Dirk J; Cuchel, Marina; Ager, Miranda; Phillips, Helen
    Background Homozygous familial hypercholesterolaemia (HoFH) is characterized by a markedly increased risk of premature cardiovascular (CV) events and cardiac death. Lomitapide reduces low-density lipoprotein cholesterol (LDL-C) levels; however, the probable impact on LDL-C goals and CV events is unknown. Methods We used data collected in the first 26 weeks of the lomitapide pivotal phase 3 study (NCT00730236) to evaluate achievement of European Atherosclerosis Society (EAS) LDL-C targets. We used publicly available data reporting major adverse CV events (MACE) rates from other cohorts of HoFH patients to compare event rates for an equivalent number of patient years of exposure (98) in the lomitapide extension trial (NCT00943306). Results Twenty-nine patients were included in the phase 3 study. During the first 26 weeks, 15 (51%) and eight (28%) reached LDL-C targets of 100 mg/dL and 70 mg/dL, respectively, at least once. Fourteen (74%) and 11 (58%) of the 19 patients who remained in the extension study after week 126 reached LDL-C targets of 100 mg/dL and 70 mg/dL at least once during the entire study period. Only two MACE were reported in the lomitapide trials (one cardiac death and one coronary artery bypass graft (CABG)) – equivalent to 1.7 events per 1000 patient months of treatment. MACE rates were 21.7, 9.5 and 1.8 per 1000 patient-months respectively in cohorts of HoFH patients pre- and post-mipomersen, and receiving evolocumab. On treatment LDL-C levels were 166, 331 and 286 mg/dL for lomitapide, mipomersen and evolocumab, respectively. Conclusions Approximately three quarters and half of patients who took lomitapide for at least 2 years reached LDL-C goals of 100 mg/dL and 70 mg/dL, respectively. There were fewer major CV events per 1000 patient months of treatment in patients taking lomitapide, mipomersen or evolocumab than reported in the mipomersen cohort prior to starting mipomersen. These results support the hypothesis that novel lipid-lowering therapies may reduce CV events in HoFH patients by lowering LDL-C further. Trial registration NCT00730236 (registered 8 Aug 2008) and NCT00943306 (registered 22 July 2009).