Regional Variations in Alirocumab Dosing Patterns in Patients with Heterozygous Familial Hypercholesterolemia During an Open-Label Extension Study.

PURPOSE: During the alirocumab open-label extension study ODYSSEY OLE (open-label extension; NCT01954394), physicians could adjust alirocumab dosing for enrolled patients, who were diagnosed with heterozygous familial hypercholesterolemia (HeFH) and who had completed previous phase III clinical trials with alirocumab. This post hoc analysis evaluated the differences in physician-patient dosing decisions between the regions of Western Europe, Eastern Europe, North America, and the rest of the world (ROW). METHODS: Patients (n = 909) who received starting dose alirocumab 75 mg every 2 weeks (Q2W) during ODYSSEY OLE (patients from FH I, FH II, and LONG TERM parent studies) were included. Low-density lipoprotein cholesterol (LDL-C) levels were blinded until week 8; subsequently, LDL-C values were communicated to physicians. From week 12, dose adjustment from 75 to 150 mg Q2W, or vice versa, was possible. RESULTS: Mean LDL-C values used for the decision to increase dose from 75 to 150 mg Q2W were higher in Eastern Europe (3.7 mmol/L; 144.0 mg/dL) and ROW (3.8 mmol/L; 145.2 mg/dL) compared with Western Europe (3.1 mmol/L; 118.6 mg/dL) and North America (3.3 mmol/L; 126.6 mg/dL). Irrespective of region, the mean LDL-C at the time of decision to maintain at 75 mg Q2W was approximately 1.8 mmol/L (70 mg/dL). During ODYSSEY OLE (median treatment duration of 131.7 weeks), alirocumab was shown to have no unexpected long-term safety concerns. CONCLUSIONS: In this OLE study, the observed variations in clinical treatment decisions suggest that physicians may perceive the severity of HeFH and/or the treatment of HeFH differently depending on their region.

Triglycerides: Emerging Targets in Diabetes Care? Review of Moderate Hypertriglyceridemia in Diabetes.

PURPOSE OF REVIEW: Moderate hypertriglyceridemia is exceedingly common in diabetes, and there is growing evidence that it contributes to residual cardiovascular risk in statin-optimized patients. Major fibrate trials yielded inconclusive results regarding the cardiovascular benefit of lowering triglycerides, although there was a signal for improvement among patients with high triglycerides and low high-density lipoprotein (HDL)-the "diabetic dyslipidemia" phenotype. Until recently, no trials have examined a priori the impact of triglyceride lowering in patients with diabetic dyslipidemia, who are likely among the highest cardiovascular-risk patients. RECENT FINDINGS: In the recent REDUCE IT trial, omega-3 fatty acid icosapent ethyl demonstrated efficacy in lowering cardiovascular events in patients with high triglycerides, low HDL, and statin-optimized low-density lipoprotein (LDL). The ongoing PROMINENT trial is examining the impact of pemafibrate in a similar patient population. Emerging evidence suggests that lowering triglycerides may reduce residual cardiovascular risk, especially in high-risk patients with diabetic dyslipidemia.

Efficacy and Safety of Alirocumab in Patients with Heterozygous Familial Hypercholesterolemia and LDL-C of 160 mg/dl or Higher.

PURPOSE: Even with statins and other lipid-lowering therapy (LLT), many patients with heterozygous familial hypercholesterolemia (heFH) continue to have elevated low-density lipoprotein cholesterol (LDL-C) levels. ODYSSEY HIGH FH (NCT01617655) assessed the efficacy and safety of alirocumab, a proprotein convertase subtilisin/kexin type 9 monoclonal antibody, versus placebo in patients with heFH and LDL-C ≥ 160 mg/dl despite maximally tolerated statin ± other LLT. METHODS: Patients were randomized to subcutaneous alirocumab 150 mg or placebo every 2 weeks (Q2W) for 78 weeks. The primary endpoint was percent change in LDL-C from baseline to week 24. RESULTS: Mean baseline LDL-C levels were 196.3 mg/dl in the alirocumab (n = 71) and 201.0 mg/dl in the placebo groups (n = 35). Significant mean (standard error [SE]) reductions in LDL-C from baseline to week 24 were observed with alirocumab (-45.7 [3.5] %) versus placebo (-6.6 [4.9] %), a difference of -39.1 (6.0) % (P < 0.0001). Absolute mean (SE) LDL-C levels were reduced from baseline by 90.8 (6.7) mg/dl with alirocumab at week 24, with reductions maintained to week 78. Treatment-emergent adverse events were generally comparable between groups. Injection-site reactions were more frequent in the alirocumab group (8.3 %) versus placebo (5.7 %); most were mild in severity and did not result in study medication discontinuation. CONCLUSIONS: In patients with heFH and very high LDL-C baseline levels despite maximally tolerated statin ± other LLT, alirocumab 150 mg Q2W demonstrated significant reductions in LDL-C levels with 41 % of patients achieving predefined LDL-C goals. Alirocumab was generally well tolerated.

Long-term efficacy and safety of mipomersen in patients with familial hypercholesterolaemia: 2-year interim results of an open-label extension.

AIMS: To evaluate the efficacy and safety of extended dosing with mipomersen in patients with familial hypercholesterolaemia (HC) taking maximally tolerated lipid-lowering therapy. METHODS AND RESULTS: A planned interim analysis of an ongoing, open-label extension trial in patients (n = 141) with familial HC receiving a subcutaneous injection of 200 mg mipomersen weekly plus maximally tolerated lipid-lowering therapy for up to 104 weeks. The mean changes in low-density lipoprotein cholesterol (LDL-C) from baseline to weeks 26 (n = 130), 52 (n = 111), 76 (n = 66), and 104 (n = 53) were -28, -27, -27, and -28%; and in apolipoprotein B -29, -28, -30, and -31%, respectively. Reductions in total cholesterol, non-high-density lipoprotein-cholesterol, and lipoprotein(a) were comparable with decreases in LDL-C and apolipoprotein B levels. Mean high-density lipoprotein cholesterol increased from baseline by 7 and 6% at weeks 26 and 52, respectively. The long-term safety profile of mipomersen was similar to that reported in the associated randomized placebo-controlled Phase 3 trials. Adverse events included injection site reactions and flu-like symptoms. There was an incremental increase in the median liver fat during the initial 6-12 months that appeared to diminish with continued mipomersen exposure beyond 1 year and returned towards baseline 24 weeks after last drug dose suggestive of adaptation. The median alanine aminotransferase level showed a similar trend over time. CONCLUSION: Long-term treatment with mipomersen for up to 104 weeks provided sustained reductions in all atherosclerotic lipoproteins measured and a safety profile consistent with prior controlled trials in these high-risk patient populations. CLINICALTRIALS.GOV: NCT00694109.

JCL roundtable: Evolution of preventive cardiology and clinical lipidology.

It's a privilege to discuss preventive cardiology with 3 of the foremost U.S. leaders in this growing subspecialty. Preventive cardiology is the practice of primordial, primary, and secondary prevention of cardiovascular disease. It employs an integrated team of clinicians committed to preventing all forms of cardiovascular disease, including ischemic heart disease, heart failure, atrial fibrillation, and other conditions. Thus, contemporary preventive cardiology extends management beyond dyslipidemic risk reduction and now commonly includes treatment of hypertension, diabetes and other related cardiometabolic disorders, novel cardiovascular risk factors, thrombotic risk, some cardiac genetic disorders, and cardiac disorders specific to women's health, as well as attention to tobacco- and drug-related risks. Preventive cardiologists may simultaneously manage cardiac rehabilitation programs. Among significant innovations are the launch of the American Journal of Preventive Cardiology in 2020, increasing validation and use of coronary artery calcium scoring, prescription of obesity and diabetes pharmaceuticals by cardiologists, and focus on pregnancy as a natural cardiovascular stress test for women with implications for future cardiovascular events. A continuing major barrier is that reimbursement for preventive cardiology services currently does not match the value benefit which accrues to patients and society. Preventive care too often is added late in the course of disease management. In addition to ongoing pharmaceutical and lifestyle research, future directions include incorporation of specific training goals for preventive cardiology in general clinical cardiology training programs and support for registered dietitian reimbursement for services to patients with clinically manifest atherosclerosis.

Intermittent nondaily dosing strategies in patients with previous statin-induced myopathy.

OBJECTIVE: To review the safety and efficacy of alternative intermittent statin dosing regimens in patients with previous intolerance due to myopathy. DATA SOURCES: Literature was accessed through MEDLINE (1946 -December 2012) and EMBASE (1966-December 2012) using relevant MeSH and Emtree search terms, including statins, HMG Co-A reductase inhibitors, simvastatin, atorvastatin, lovastatin, fluvastatin, pravastatin, pitavastatin, rosuvastatin, myopathy, and myalgias. Web of Science (1955-December 2012) and the aforementioned databases were additionally searched using combinations of the following text words: statin intolerance, alternate dosing, nondaily dosing, weekly dosing, statin-induced myopathy, and intermittent statin dosing. References of identified articles were reviewed for additional citations. STUDY SELECTION AND DATA EXTRACTION: All identified English-language peer-reviewed publications were evaluated. Articles (excluding meeting abstracts) specifically addressing nondaily statin use in patients with previous statin-induced myopathy were reviewed. DATA SYNTHESIS: Although statins have achieved significant reductions in cardiovascular morbidity and mortality, as many as 10% of patients prescribed these therapies experience myopathies. Intermittent statin regimens ranging from every-other-day to once-weekly dosing have emerged in an attempt to maintain efficacy while moderating the incidence of adverse effects. The results reported in 10 publications investigating varying regimens with atorvastatin and/or rosuvastatin revealed that at least 70% of patients were able to tolerate an intermittent dosing strategy without a recurrence of previous treatment-limiting adverse effects. Although the degree of low-density lipoprotein cholesterol-lowering varied appreciably among studies (12-38%), the addition of a nondaily statin regimen facilitated attainment of National Cholesterol Education Program goals for some. CONCLUSIONS: Although areas of uncertainty remain, intermittent dosing (particularly with rosuvastatin and atorvastatin) in previously intolerant patients is a useful strategy to capitalize on the benefits of this therapy. Larger scale randomized trials are necessary to more clearly define the role of this strategy and the optimal choice of regimen.

Genome-wide association study of Lp-PLA(2) activity and mass in the Framingham Heart Study.

Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) is an emerging risk factor and therapeutic target for cardiovascular disease. The activity and mass of this enzyme are heritable traits, but major genetic determinants have not been explored in a systematic, genome-wide fashion. We carried out a genome-wide association study of Lp-PLA(2) activity and mass in 6,668 Caucasian subjects from the population-based Framingham Heart Study. Clinical data and genotypes from the Affymetrix 550K SNP array were obtained from the open-access Framingham SHARe project. Each polymorphism that passed quality control was tested for associations with Lp-PLA(2) activity and mass using linear mixed models implemented in the R statistical package, accounting for familial correlations, and controlling for age, sex, smoking, lipid-lowering-medication use, and cohort. For Lp-PLA(2) activity, polymorphisms at four independent loci reached genome-wide significance, including the APOE/APOC1 region on chromosome 19 (p = 6 x 10(-24)); CELSR2/PSRC1 on chromosome 1 (p = 3 x 10(-15)); SCARB1 on chromosome 12 (p = 1x10(-8)) and ZNF259/BUD13 in the APOA5/APOA1 gene region on chromosome 11 (p = 4 x 10(-8)). All of these remained significant after accounting for associations with LDL cholesterol, HDL cholesterol, or triglycerides. For Lp-PLA(2) mass, 12 SNPs achieved genome-wide significance, all clustering in a region on chromosome 6p12.3 near the PLA2G7 gene. Our analyses demonstrate that genetic polymorphisms may contribute to inter-individual variation in Lp-PLA(2) activity and mass.

JCL Roundtable: Lipidology and Women's Health.

In this JCL Roundtable, we bring together three experts to discuss women's cardiovascular health throughout the lifespan, viewed from the standpoint of clinical lipidology. Overall, heart disease leads to one out of every 3 deaths of American women, but unfortunately patient awareness of cardiovascular risk actually has declined since 2009. Younger women are not exempt, since their risk can be increased by smoking, birth control, adverse lifestyle and diet, and genetic disorders. Age at menarche can influence lifetime risk. Polycystic ovary syndrome, noted in 5-13% of women of reproductive age, has been linked to increased cardiovascular risk, partly through atherogenic dyslipidemia. Oral contraception has improved greatly since its introduction, but remains a risk for venous thromboembolism and stroke, particularly in smokers. Fetal nutritional and metabolic requirements in pregnancy impose high vascular demand on the placenta and lead to escalating maternal triglycerides and cholesterol especially in the 3rd trimester. Triglycerides may require special management. Adverse pregnancy outcomes associated with placental dysfunction signal subsequent increased risk for maternal atherosclerotic disease. Early menopause has long been recognized as a risk enhancing factor for atherosclerosis with pathophysiology remaining unclear. The menopause transition represents a period when cardiovascular risk for women increases rapidly and approaches that of men. Current studies are evaluating hormonal changes and even clonal hematopoiesis as potential causes. At the same time, lifestyle habits and routine chronic conditions such as hypertension and obesity/diabetes/metabolic syndrome play a large role and need attention.

JCL Roundtable: From Gen Med to Clinical Lipidology.

The prevalence of lipid-related risk for atherosclerotic cardiovascular disease surpasses half the population as individuals age, and thus generalists and primary care providers manage by far the bulk of treatment of lipid disorders. It should come as no surprise that many individuals who practice clinical lipidology, focusing on the care of patients with resistant or perplexing lipid disorders, come from a background of general or primary care medicine. Among 429 providers responding to a survey of National Lipid Association (NLA) members in 2010, 50% were internal medicine or family medicine practitioners, 32% cardiologists, 11% endocrinologists, and 7% with a variety of other specialty training. This JCL Roundtable brings together 3 NLA physician leaders who came from primary care. We discuss their career pathways, their blend of practice, teaching, research, and administration, and the settings in which they carry out the lipidology mission.

Assessment and management of statin-associated muscle symptoms (SAMS): A clinical perspective from the National Lipid Association.

Statin-associated muscle symptoms (SAMS) are the most common form of statin intolerance and are associated with increased risk of cardiovascular events that manifest from statin underutilization and discontinuation. The reported frequencies of SAMS are divergent in the literature. The writing group estimates the prevalence of SAMS, namely all muscle symptoms temporally related to statin use but without regard to causality, to be about 10% (range 5% to 25%), and the prevalence of pharmacological SAMS, specifically muscle symptoms resulting from pharmacological properties of the statin, to be about 1-2% (range 0.5% to 4%). In clinical practice, SAMS are likely to result from a combination of pharmacological and nonpharmacological effects, however this does not make the symptoms any less clinically relevant. Regardless of the etiology, SAMS need to be addressed in accordance with patients' preferences and experiences. This clinical perspective reviews the epidemiology and underlying pathophysiology of SAMS, and the cardiovascular consequences resulting from statin discontinuation. We present patient-centered clinical and communication strategies to mitigate SAMS and improve medication adherence and outcomes among statin users. Treatment strategies include 1) optimizing lifestyle interventions, 2) modulating risk factors that may contribute to muscle symptoms, 3) optimizing statin tolerability by dose reduction, decreased dosing frequency, or use of an alternate statin with more favorable pharmacokinetic properties, and 4) use of non-statins, emphasizing those with evidence for atherosclerotic risk reduction, either in combination with or in place of statin therapy depending on the patient's circumstances. The focus of this clinical perspective is sustainable lipoprotein goal achievement, which is important for cardiovascular risk reduction.