Mary McGowan

Familial Hypercholesterolemia: Screening, diagnosis and management of pediatric and adult patients: Clinical guidance from the National Lipid Association Expert Panel on Familial Hypercholesterolemia

The familial hypercholesterolemias (FH) are a group of genetic defects resulting in severe elevations of blood cholesterol levels and increased risk of premature coronary heart disease. FH is among the most commonly occurring congenital metabolic disorders. FH is a treatable disease. Aggressive lipid lowering is necessary to achieve the target LDL cholesterol reduction of at least 50% or more. Even greater target LDL cholesterol reductions may be necessary for FH patients who have other CHD risk factors. Despite the prevalence of this disease and the availability of effective treatment options, FH is both underdiagnosed and undertreated, particularly among children. Deficiencies in the diagnosis and treatment of FH indicate the need for greatly increased awareness and understanding of this disease, both on the part of the public and of healthcare practitioners. This document provides recommendations for the screening, diagnosis and treatment of FH in pediatric and adult patients developed by the National Lipid Association Expert Panel on Familial Hypercholesterolemia. This report goes beyond previously published guidelines by providing specific clinical guidance for the primary care clinician and lipid specialist with the goal of improving care of patients with FH and reducing their elevated risk for CHD.

Apolipoprotein B Synthesis Inhibition with Mipomersen in Heterozygous Familial Hypercholesterolemia: Results of a Randomized, Double-Blind, Placebo Controlled Trial to Assess Efficacy and Safety as Add-on Therapy in Patients with Coronary Artery Disease

Background— Heterozygous familial hypercholesterolemia (HeFH) is a common genetic disorder leading to premature coronary artery disease. Despite statins and additional lipid-lowering therapies, many HeFH patients fail to achieve low-density lipoprotein cholesterol (LDL-C) goals. We evaluated mipomersen, an apolipoprotein B synthesis inhibitor, to further lower LDL-C in HeFH patients with coronary artery disease. Methods and Results— This double-blind, placebo-controlled, phase 3 trial randomized patients with HeFH and coronary artery disease on maximally tolerated statin and LDL-C ≥2.6 mmol/L (≥100 mg/dL) to weekly subcutaneous mipomersen 200 mg or placebo (2:1) for 26 weeks. The primary end point was percent change in LDL-C from baseline at week 28. Safety assessments included adverse events, laboratory tests, and magnetic resonance imaging assessment of hepatic fat. Of 124 randomized patients (41 placebo, 83 mipomersen), 114 (41 placebo, 73 mipomersen) completed treatment. Mean (95% confidence interval) LDL-C decreased significantly with mipomersen (−28.0% [−34.0% to −22.1%] compared with 5.2% [−0.5% to 10.9%] increase with placebo; P <0.001). Mipomersen significantly reduced apolipoprotein B (−26.3%), total cholesterol (−19.4%), and lipoprotein(a) (−21.1%) compared with placebo (all P <0.001). No significant change occurred in high-density lipoprotein cholesterol. Adverse events included injection site reactions and influenza-like symptoms. Five mipomersen patients (6%) had 2 consecutive alanine aminotransferase values ≥3 times the upper limit of normal at least 7 days apart; none were associated with significant bilirubin increases. Hepatic fat content increased a median of 4.9% with mipomersen versus 0.4% with placebo ( P <0.001). Conclusions— Mipomersen is an effective therapy to further reduce apolipoprotein B–containing lipoproteins, including LDL and lipoprotein(a), in HeFH patients with coronary artery disease on statins and other lipid-lowering therapy. The significance of hepatic fat and transaminase increases remains uncertain at this time. Clinical Trial Registration— URL: . Unique identifier: [NCT00706849][1]. # Clinical Perspective {#article-title-34} [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00706849&atom=%2Fcirculationaha%2F126%2F19%2F2283.atomBackground— Heterozygous familial hypercholesterolemia (HeFH) is a common genetic disorder leading to premature coronary artery disease. Despite statins and additional lipid-lowering therapies, many HeFH patients fail to achieve low-density lipoprotein cholesterol (LDL-C) goals. We evaluated mipomersen, an apolipoprotein B synthesis inhibitor, to further lower LDL-C in HeFH patients with coronary artery disease. Methods and Results— This double-blind, placebo-controlled, phase 3 trial randomized patients with HeFH and coronary artery disease on maximally tolerated statin and LDL-C ≥2.6 mmol/L (≥100 mg/dL) to weekly subcutaneous mipomersen 200 mg or placebo (2:1) for 26 weeks. The primary end point was percent change in LDL-C from baseline at week 28. Safety assessments included adverse events, laboratory tests, and magnetic resonance imaging assessment of hepatic fat. Of 124 randomized patients (41 placebo, 83 mipomersen), 114 (41 placebo, 73 mipomersen) completed treatment. Mean (95% confidence interval) LDL-C decreased significantly with mipomersen (−28.0% [−34.0% to −22.1%] compared with 5.2% [−0.5% to 10.9%] increase with placebo; P<0.001). Mipomersen significantly reduced apolipoprotein B (−26.3%), total cholesterol (−19.4%), and lipoprotein(a) (−21.1%) compared with placebo (all P<0.001). No significant change occurred in high-density lipoprotein cholesterol. Adverse events included injection site reactions and influenza-like symptoms. Five mipomersen patients (6%) had 2 consecutive alanine aminotransferase values ≥3 times the upper limit of normal at least 7 days apart; none were associated with significant bilirubin increases. Hepatic fat content increased a median of 4.9% with mipomersen versus 0.4% with placebo (P<0.001). Conclusions— Mipomersen is an effective therapy to further reduce apolipoprotein B–containing lipoproteins, including LDL and lipoprotein(a), in HeFH patients with coronary artery disease on statins and other lipid-lowering therapy. The significance of hepatic fat and transaminase increases remains uncertain at this time. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00706849.

Management of Familial Hypercholesterolemias in adult patients: Recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia

Cardiovascular disease is the leading cause of morbidity and mortality in the United States. Hypercholesterolemia, specifically elevated level of low-density lipoprotein (LDL) cholesterol, is a major coronary heart disease (CHD) risk factor.While environmental factors such as diet and physical activity have important roles in determining an individual’s level of circulating cholesterol, there is also a genetic component. The familial hypercholesterolemias (FH) are a group of inherited genetic defects resulting in severely elevated serum cholesterol concentrations. The genetic defects in FH arise from mutations affecting the LDL receptor, apolipoprotein (Apo) B or proprotein convertase subtilisin kexin type 9

There Is No Evidence for an Increase in Acute Coronary Syndromes After Short-Term Abrupt Discontinuation of Statins in Stable Cardiac Patients

Background—For a variety of reasons, many patients abruptly discontinue statin therapy. The present analysis was conducted to determine whether the risk of cardiovascular outcomes increases after withdrawal of statin therapy in a stable cardiac population. Methods and Results—In the Treating to New Target (TNT) study, 2 doses of atorvastatin (10 and 80 mg once daily) are being used in a double-blind parallel-group design. Of the 18 468 patients screened for study participation, 16 619 entered a dietary lead-in/drug-washout period, and of these, 15 432 eligible participants began treatment with atorvastatin 10 mg/d on an open-label basis. Of the subjects who entered the dietary lead-in/drug-washout period, 57% were receiving prior statin therapy. During the 6-week drug-washout period, there were 24 primary events (defined as coronary heart disease death, nonfatal myocardial infarction, resuscitated cardiac arrest, and fatal or nonfatal stroke); throughout the subsequent 8-week open-label period, there were 31 primary events. This equated to monthly Kaplan-Meier event rates of 0.20% during washout and 0.26% in the open-label phase. Event rates were therefore similar during the 2 phases. Conclusions—The present analysis demonstrates that short-term discontinuation of statin therapy in stable cardiac patients apparently does not lead to a clinically important increased risk of acute coronary syndromes.

The effects of mipomersen, a second-generation antisense oligonucleotide, on atherogenic (apoB-containing) lipoproteins in the treatment of homozygous familial hypercholesterolemia

Abstract Mipomersen (Kynamro® [mipomersen sodium injection]; Genzyme, a Sanofi Company, MA, USA) is indicated as an adjunct to lipid-lowering medications and diet to reduce LDL-C, apoB, total cholesterol and non-HDL cholesterol in patients with homozygous familial hypercholesterolemia. In a 6-month Phase III trial (n = 51), mean percent change in LDL-C was -25% (95% CI: -32 to -18) versus placebo -3% (95% CI: -12 to 5; p < 0.001). The absolute mean LDL-C reduction was 113 mg/dl (2.92 mmol/l). Lipoprotein(a) was also significantly lowered by -31% (95% CI: -39 to -23) versus placebo -8% (95% CI: -19 to 3; p < 0.01). Some patients experienced transient and generally reversible hepatic effects, mild-to-moderate injection site reactions and flu-like symptoms. The mechanism of action and metabolism of mipomersen makes drug–drug interactions unlikely.

NLA Symposium screening and treatment of familial hypercholesterolemia: How can we do better? Opening and introductions

Heterozygous familial hypercholesterolemia is an autosomal dominant disorder characterized by half the normal number of low density lipoprotein (LDL) receptors and markedly elevated LDL cholesterol levels. FH is a very common disorder, affecting about one in 500 in the general population and occurring more frequently in certain ethnic groups. Untreated, roughly 50% of men and 25% of women who have FH will have had their first myocardial infarction or other cardiovascular event by the age of 50. Since roughly half of an affected individuals first degree relatives will also have FH, Cascade Screening represents an important tool for patient identification. Although treating FH represents a clinical challenge, most affected patients can be managed with currently available treatment modalities including statins, resins, cholesterol absorption inhibitors, and niacin. LDL apheresis is an option for individuals who fail currently available oral prescription therapies. And mipomersen is an antisense therapy designed to inhibit apolipoprotein B (apo B) synthesis. This agent is currently being studied in FH patients who fail to achieve target LDL cholesterol levels with the aforementioned prescription therapies.

Question-and-answer session

Dr. Mary McGowan: I have a quick question for Dr. Defesche:My partner, Dr. Susan Lynch, who is here in the audience and, I have begun initiating statin treatment in kidswith familial hypercholesterolemia (FH) according to the new American Academy of Pediatrics guidelines. We are beginning treatment in children at 8 years of agewho cannot achieve low-density lipoprotein (LDL) less than 160 mg/dL. Are you doing the same? Dr. Defesche: Yes. I am. Tom Whayne: Tom Whayne, University of Kentucky. I just have two comments. The speakers can then respond. First, in terms of your guest, Dr. McGowan, that is an appalling problem. To me as a cardiologist, any young woman, no matter how young, her chest pain has to be explained, and most likely, she will end up with a stress test unless it is definitely chest tenderness. If she is a little bit older, if I can’t explain it, a cath as indicated. Dr. McGowan: Let’s see, over here? Dr. J. Ross Tanner: Hi,my question is regarding qualifying patients for LDL apheresis. I live in Anchorage, Alaska. We are the only center in the state that provides apheresis patients. We seem to live and die by standards that are set by somebody else, and one of the difficulties that I have is that wewill havepatients thatmaybeonmaximumtherapy,maybe combination therapy, we may take an LDL of, say, 250 to 350 mg/dL down to 180 mg/dL, or maybe they may be a patient that has an LDL of 250 and they don’t have coronary disease, ormaybe they have highLP(a). These people don’t qualify for LDL apheresis. How do we get the standards changed? Was this set by Centers for Medicare and Medicaid Services with the 200-mg/dL and 300-mg/dL mark? Or I mean, how did that evolve and what can we do as an organization to change