Damon A. Bell

Mipomersen, an antisense apolipoprotein B synthesis inhibitor

Introduction: Mipomersen is a second-generation antisense oligonucleotide (ASO) targeted to human apolipoprotein (apo) B-100, a large protein synthesized by the liver that plays a fundamental role in human lipoprotein metabolism. Mipomersen predominantly distributes to the liver and decreases the production of apoB-100, the primary structural protein of the atherogenic lipoproteins including low density lipoprotein (LDL), thereby reducing plasma LDL-cholesterol and apoB-100 concentrations. Areas covered: The mode of action, preclinical development and clinical trials of mipomersen, an antisense apoB synthesis inhibitor. The paper provides an understanding of the pharmacokinetic and pharmacodynamic characteristics of mipomersen and insight into its clinical efficacy and safety. In clinical trials, mipomersen produced dose-dependent and prolonged reductions in LDL-cholesterol and other apoB-containing lipoproteins, including lipoprotein (a) [Lp(a)] in healthy volunteers and in patients with mild to moderate hypercholesterolemia. Mipomersen has been shown to decrease apoB, LDL-cholesterol and Lp(a) in patients with heterozygous and homozygous familial hypercholesterolemia on maximally tolerated lipid-lowering therapy. Expert opinion: Mipomersen shows promise as an adjunctive agent by reducing apoB-containing lipoproteins in patients at high risk of atherosclerotic cardiovascular disease who are not at target or are intolerant of statins. Although the short-term efficacy and safety of mipomersen has been established, concern exists regarding the long-term potential for hepatic steatosis with this ASO.

Optimising the Detection and Management of Familial Hypercholesterolaemia: Central Role of Primary Care and its Integration with Specialist Services

Familial hypercholesterolaemia (FH) is the most common monogenic lipid disorder associated with premature coronary heart disease (CHD). However, the majority of people with FH are undiagnosed or undertreated. Early cholesterol lowering therapy reduces cardiovascular disease mortality in FH. Low awareness and knowledge of FH in specialty and general practice highlights the need for strategies to improve the detection and management of FH. We present an algorithm describing a multidisciplinary approach to FH detection and management. We highlight the role of primary care, and where GPs can work with preventive cardiologists to improve care of FH. Novel strategies to detect index cases with FH are presented including the community laboratory, highlighting patients at high risk of FH, and targeted FH detection through searching the general practice database. General practitioners request over 90% of LDL cholesterol measurements in the community. Once an individual with FH is detected only a small proportion of patients require specialty management with the majority of patients suitably managed in primary care. However, it is crucial to screen family members, as 50% of first-degree family members are expected to have FH due to the autosomal dominant inheritance.

Mipomersen and other therapies for the treatment of severe familial hypercholesterolemia

Familial hypercholesterolemia (FH) is an autosomal dominant condition with a population prevalence of one in 300–500 (heterozygous) that is characterized by high levels of low-density lipoprotein (LDL) cholesterol, tendon xanthomata, and premature atherosclerosis and coronary heart disease (CHD). FH is caused mainly by mutations in the LDLR gene. However, mutations in other genes including APOB and PCSK9, can give rise to a similar phenotype. Homozygous FH with an estimated prevalence of one in a million is associated with severe hypercholesterolemia with accelerated atherosclerotic CHD in childhood and without treatment, death usually occurs before the age of 30 years. Current approaches for the treatment of homozygous FH include statin-based lipid-lowering therapies and LDL apheresis. Mipomersen is a second-generation antisense oligonucleotide (ASO) targeted to human apolipoprotein B (apoB)-100. This review provides an overview of the pathophysiology and current treatment options for familial hypercholesterolemia and describes novel therapeutic strategies focusing on mipomersen, an antisense apoB synthesis inhibitor. Mipomersen is distributed mainly to the liver where it silences apoB mRNA, thereby reducing hepatic apoB-100 and giving rise to reductions in plasma total cholesterol, LDL-cholesterol, and apoB concentrations in a dose-and time-dependent manner. Mipomersen has been shown to decrease apoB, LDL-cholesterol and lipoprotein(a) in patients with heterozygous and homozygous FH on maximally tolerated lipid-lowering therapy. The short-term efficacy and safety of mipomersen has been established, however, injection site reactions are common and concern exists regarding the long-term potential for hepatic steatosis with this ASO. In summary, mipomersen given alone or in combination with standard lipid-lowering medications shows promise as an adjunct therapy in patients with homozygous or refractory heterozygous FH at high risk of atherosclerotic CHD, who are not at target or are intolerant of statins.

Frequency of familial hypercholesterolemia in patients with early-onset coronary artery disease admitted to a coronary care unit

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. OBJECTIVE To investigate the point prevalence of FH in a coronary care unit (CCU) among patients with early-onset CAD. METHODS 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. RESULTS 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. CONCLUSIONS 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.

Opportunistic screening for familial hypercholesterolaemia via a community laboratory

Background Familial hypercholesterolaemia (FH) is an inherited disorder characterized by increased serum low-density lipoprotein (LDL)-cholesterol concentrations and premature atherosclerotic cardiovascular disease. The majority of people with FH are currently undiagnosed. We sought to determine the ability of a community laboratory to screen for individuals with potential FH. Methods Serum LDL-cholesterol concentrations issued by a private community laboratory in Western Australia were reviewed over a one-year period (1 May 2010 to 31 April 2011). We assessed the prevalence of possible FH based on LDL-cholesterol thresholds employed by the Make Early Diagnosis-Prevent Early Death (MED-PED), the Simon Broome Registry and the Dutch Lipid Clinic Network criteria. Results During this period, 84,823 people had 99,467 serum LDL-cholesterol measurements, with 91.8% requested by general practitioners. A secondary cause of hypercholesterolaemia was identified in 8.3% of subjects with an LDL-cholesterol ≥5.0 mmol/L. The prevalence of FH based on an LDL-cholesterol ≥6.5 mmol/L, the 99.75th percentile, was 1:398 in this sample population; similarly, the MED-PED LDL-cholesterol criteria gave a prevalence of 1:482. Conclusions The community laboratory is well placed to screen opportunistically for subjects with potential FH. This may be achieved using either the MED-PED criteria or a serum LDL-cholesterol cut-off point of ≥6.5 mmol/L, irrespective of age. Further investigation is required to determine the most effective method of identifying these individuals and, thereby, ensuring referral to a specialist lipid clinic.

Improvements in Glucose Metabolism and Insulin Sensitivity with a Low-Carbohydrate Diet in Obese Patients with Type 2 Diabetes

Objective: The optimal diet for weight loss in type 2 diabetes remains controversial. This study examined a low-carbohydrate, high-fat diet with detailed physiological assessments of insulin sensitivity, glycemic control, and risk factors for cardiovascular disease. Methods: Fourteen obese patients (body mass index [BMI] 40.6 ± 4.9 kg/m2) with type 2 diabetes were recruited for an “Atkins”-type low-carbohydrate diet. Measurements were made at 0, 12, and 24 weeks of weight, insulin sensitivity, HbA1c, lipids, and blood pressure. Results: Twelve completers lost a mean of 9.7 ± 1.8 kg over 24 weeks attributable to a major reduction in carbohydrates and resultant reduction in total energy intake. Glycemic control significantly improved (HbA1c −1.1 ± 0.25%) with reductions in hypoglycemic medication. Fasting glucose, homeostasis model assessment (HOMA), and area under the curve (AUC) glucose (intravenous glucose tolerance test [IVGTT]) were significantly reduced by week 12 ( p < 0.05). There were nonsignificant improvements in insulin sensitivity (SI) at week 12 ( p = 0.19) and week 24 ( p = 0.31). Systolic blood pressure was reduced (mean −10.0 mmHg between weeks 0 and 24, p = 0.13). Mean high-density lipoprotein (HDL), low-density lipoprotein (LDL), and total cholesterol all increased. The ratio of total: HDL cholesterol and triglycerides was reduced. Conclusion: A low-carbohydrate diet was well tolerated and achieved weight loss over 24 weeks in subjects with diabetes. Glycemic control improved with a reduction in requirements for hypoglycemic agents.

Screening for familial hypercholesterolaemia

Summary Familial hypercholesterolaemia (FH) is an autosomal dominant disorder characterised by increased plasma concentrations of low density lipoprotein (LDL) cholesterol leading to atherosclerosis and premature coronary heart disease (CHD) and death. The clinical diagnosis of FH is based on a personal and family history, physical examination findings and LDL-cholesterol concentrations. FH is primarily caused by mutations in the LDL-receptor gene (LDLR), and less frequently by mutations in genes for APOB and the more recently identified PCSK9. Lifestyle modification and pharmacotherapy can delay or prevent the onset of CHD in FH. It is estimated that only 20% of cases have been diagnosed in Australia and that the majority are inadequately treated. Screening options for FH include population screening (of children or adults), targeted screening of patients with premature CHD and their relatives, or opportunistic screening such as flagging laboratory lipid reports. Cascade screening, a form of targeted screening, is an ethically acceptable, cost-effective strategy for the identification of FH. However, for screening to be successful, medical practitioners need to be aware of the signs and diagnosis of FH and the benefits of early treatment.

Lipoprotein apheresis and new therapies for severe familial hypercholesterolemia in adults and children

Familial hypercholesterolemia (FH), the most common and severe monogenic form of hypercholesterolemia, is an autosomal co-dominant disease characterized by an increased plasma low density lipoprotein (LDL)-cholesterol concentration and premature coronary heart disease (CHD). The clinical phenotype depends on the gene involved and severity of mutation (or mutations) present. Patients with homozygous or compound heterozygous FH have severe hypercholesterolemia (LDL-cholesterol >13 mmol/L) due to a gene dosing effect and without treatment have accelerated atherosclerotic CHD from birth, and frequently die of CHD before age 30. Cholesterol-lowering therapies have been shown to reduce both mortality and major adverse cardiovascular events in individuals with FH. Lipoprotein apheresis concomitant with lipid-lowering therapy is the treatment of choice for homozygous FH. This article describes the rationale and role of lipoprotein apheresis in the treatment of severe FH and outlines the recent advances in new pharmacotherapies for this condition.

Elevated lipoprotein(a), hypertension and renal insufficiency as predictors of coronary artery disease in patients with genetically confirmed heterozygous familial hypercholesterolemia ☆

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. METHODS 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. RESULTS 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. CONCLUSIONS 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.

Impact of interpretative commenting on lipid profiles in people at high risk of familial hypercholesterolaemia

BACKGROUND Familial hypercholesterolaemia (FH) is an autosomal dominant condition characterised by increased low density lipoprotein cholesterol (LDL-c), xanthomata and premature cardiovascular disease. However, it is currently underdiagnosed and undertreated in Australasia. We sought to investigate whether interpretative commenting on lipid profiles could improve FH detection and treatment. METHODS A case-historical control study of individuals with serum LDL-c concentrations ≥6.5 mmol/L; 96 cases receiving an interpretative comment suggesting FH compared with 100 controls not receiving a comment. RESULTS Serum LDL-c was repeated in 63 (66%) cases and 70 (70%) controls within 12 months. LDL-c decreased in 59 (94%) cases and in 61 (87%) controls. In individuals with a repeat LDL-c, a mean LDL-c reduction of 2.3 mmol/L (32%; p<0.0001) was demonstrated in controls, compared with 3.0 mmol/L (42%; p<0.0001) in cases; significantly greater than that of controls (p<0.005). Interpretative comments suggesting specialist review were associated with a higher referral rate compared with controls (11.5% vs 1%, p<0.05). CONCLUSION Interpretative commenting was associated with a significant additional LDL-c reduction and increased specialist referrals compared with controls. However, only a minority of individuals received a specialist referral. Interpretative commenting may play an important role in the detection and management of FH.