Faculty Bibliography

Testosterone replacement therapy is recommended for men with clinical androgen deficiency with decades of evidence supporting its use for treatment of sexual, physical, and psychological consequences of male hypogonadism. In this updated review, the authors discuss the implications of testosterone deficiency and conflicting evidence regarding testosterone replacement therapy and its effects on the cardiovascular system. Based on mounting evidence, the authors conclude that testosterone therapy can be safely considered in men with appropriately diagnosed clinical androgen deficiency and concurrent cardiovascular risk factors and even manifest cardiovascular disease after a thorough discussion of potential risks and with guideline-recommended safety monitoring.

BACKGROUND: Lomitapide is an orally active selective inhibitor of microsomal triglyceride transfer protein approved as adjunctive therapy for homozygous familial hypercholesterolemia (HoFH). The Lomitapide Observational Worldwide Evaluation Registry (LOWER) is a global, long-term, prospective, observational treatment registry established as a regulatory requirement. OBJECTIVES: LOWER will evaluate the long-term safety and effectiveness of lomitapide in clinical practice. The objectives include evaluation of the occurrence of events of special interest and assessment of the long-term effectiveness of lomitapide in maintaining reduced serum lipid levels. METHODS: LOWER is a noninterventional study open to eligible lomitapide-treated patients. At least 300 patients will be enrolled and followed for at least 10 years. Data will be collected in conjunction with usual care visits and analyzed annually. LOWER includes a cardiovascular imaging substudy; an independent pregnancy exposure registry is also open. RESULTS: Events of special interest include hepatic abnormalities, gastrointestinal events, certain gastrointestinal tumors, major adverse cardiovascular events, and events associated with coagulopathy. Data will be collected on demographics, diagnosis, patient history, lomitapide dosing, concomitant treatment, lipid profile, and other laboratory results. CONCLUSION: LOWER will assess the long-term safety, efficacy, and patterns of use of lomitapide, increase understanding of the benefit-to-risk profile, and add to knowledge of HoFH.

BACKGROUND: Diabetes mellitus (DM) and metabolic syndrome are important targets for secondary prevention in cardiovascular disease. However, the prevalence in patients undergoing elective percutaneous coronary intervention (PCI) is not well defined. We aimed to analyze the prevalence and characteristics of patients undergoing PCI with previously unrecognized prediabetes, diabetes and metabolic syndrome. METHODS: Data were collected from 740 patients undergoing elective PCI between November 2010 and March 2013 at a tertiary referral center. Prevalence of DM and prediabetes was evaluated using Hemoglobin A1c (A1c >/= 6.5% for DM, A1c 5.7-6.4% for prediabetes). A modified definition was used for metabolic syndrome [3 or more of the following criteria: body mass index (BMI) >/=30 kg/m2; triglycerides >/= 150 mg/dL; high density lipoprotein <40 mg/dL in men and <50 mg/dL in women; systolic blood pressure >/= 130 mmHg and/or diastolic >/= 85 mmHg; A1c >/= 5.7% or on therapy]. RESULTS: Mean age was 67 years, median BMI was 28.2 kg/m2 , and 39% had known DM. Of those without known DM, 8.3% and 58.5% met A1c criteria for DM and for prediabetes at time of PCI. Overall, 54.9% met criteria for metabolic syndrome (69.2% of patients with DM and 45.8% of patients without DM). CONCLUSION: Among patients undergoing elective PCI, a substantial number were identified with new DM, prediabetes, and/or metabolic syndrome. Routine screening for an abnormal glucometabolic state at the time of revascularization may be useful for identifying patients who may benefit from additional targeting of modifiable risk factors

The National Lipid Association (NLA) recently released recommendations for the treatment of dyslipidemias. These recommendations have commonalities and differences with those of other major societies with respect to risk assessment, lifestyle therapy, targets of therapy, and the use of non-statin agents. In this review, we compare the basic elements of the guidelines from each major society to provide clinicians with a comprehensive document reviewing the key principles of each.

Introduction: Lomitapide is a microsomal triglyceride transfer protein inhibitor indicated as an adjunctive therapy for adults with homozygous familial hypercholesterolemia (HoFH). LOWER is a global, long-term, prospective, observational registry of the long-term safety and effectiveness of lomitapide in clinical practice. At least 300 adult HoFH patients will be followed for a minimum of 10 years. Enrollment opened in March 2014 for adult HoFH patients with less than 15 months of lomitapide exposure. We present data from the first year of the registry Results: As of March 1, 2015, 84 patients with mean age 55.4 (SD 11.5) years, were enrolled in LOWER; 6 (7%) have since discontinued. Exposure duration was up to 26 months, with 60% of patients receiving the drug for >12 months. Lomitapide dose ranged from 5 to 40 mg; dose increased over time to a median of 13.0 mg (mean 14.4 mg) after 2 years' exposure. Mean LDL-C at baseline was 216.3 (SD 76.9) mg/dL which decreased by 42% at Month 4 and was maintained throughout the reporting period. Fifty-one (61%) and 30 (36%) respectively achieved an LDL-C value <100 mg/dL or <70 mg/dL, at least once while receiving lomitapide. Events of special interest (ESI) include: 1 major adverse cardiovascular event (MACE) resulting in death; 11 hepatic events; and 6 gastrointestinal events. No tumors, pregnancies, or coagulopathy events were reported. Elevated aminotransferase levels >3x upper limit of normal (ULN) were observed in 16 patients (20%); 4 of these patients experienced elevations of >5x - <10x ULN. No cases of Hy's Law were recorded. Diarrhea was the most common adverse event (AE), experienced by 24% of patients, and the only AE reported by >10% of patients. Serious AEs occurred in 6 (7%) patients. Eight (10%) patients discontinued lomitapide because of an AE Conclusions: Data from the first year of the LOWER registry demonstrate both safety and efficacy that are consistent with the product labeling. There were no new safety signals. Discontinuations because of aminotransferase or gastrointestinal ESIs were low. Future data from LOWER will provide further information about the real-world, long-term safety and effectiveness of lomitapide in HoFH

Introduction: Familial hypercholesterolemia (FH) is an autosomal dominant disorder with a prevalence of 1:300 to 1:500 worldwide. FH patients have 20-fold increased risk for premature coronary heart disease (CHD) due to lifelong extreme elevations in LDL-C. Three criteria can be used to diagnose FH: Simon-Broome, Dutch Lipid Clinic Network (DLCN) or United States (US) Make Early Diagnosis to Prevent Early Deaths (MEDPED). In the Netherlands the DLCN criteria was a critical component of a public health strategy to identify FH patients for genetic testing, early treatment, and CHD prevention. The consistent application of these criteria resulted in identification of 71% of estimated cases (1). In the US, however, < 10% of FH patients are identified, perhaps due to a lack of a nationwide consensus on diagnostic criteria. We lack contemporary data regarding diagnostic strategies and patient outcomes in the US. Objectives: To characterize the FH diagnostic criteria applied by US lipid specialists participating in the FH Foundation's CASCADE FH (CAscade SCreening for Awareness and DEtection of Familial Hypercholesterolemia) patient registry - a US registry that became active in September 2013 and currently has data on FH patients treated at 11 specialty lipid clinics (2). Methods: We queried the CASCADE FH database for the diagnostic criteria chosen for each patient and baseline patient characteristics. Diagnostic criteria were divided into 5 non-exclusive categories: "clinical diagnosis," MEDPED, Simon-Broome, DLCN, and/or other. Only adults (age >18) were included since the diagnostic criteria cannot be applied to pediatric populations. Results: 876 FH adults had available data entered from clinical sites. 57% were female; mean (SD) age 53 (17) yrs; and BMI 28 (6) kg/m². Ethnicity/race was 78% white, 6% African American, 3% Hispanic, 12% other. Mean age at FH diagnosis was 43 (19) yrs. 38% had prior CHD, 16% had tendon xanthomas, and 45% had a family history of myocardial infarction. Mean pre-treatment LDL-C was 269 (87) mg/dL. Most adults enrolled in CASCADE FH received a "clinical diagnosis" of FH: 64% "clinical diagnosis" (n = 560) vs. 11 % MEDPED (n = 105) vs. 4% Simon-Broome (n = 32) vs. 1% DLCN (n = 7) vs. 1% other (n = 9) vs. 19% "multiple diagnostic criteria" (n = 163), p = 0.01. For patients with "multiple diagnostic criteria", 57% were diagnosed using two or more of the established criteria (Simon-Broome, MEDPED, DLCN); the remainder had one of the established criteria and "clinical diagnosis." Summary: Among US lipid clinics participating in the CASCADE FH registry, most did not report utilizing one of the existing diagnostic tools. Conclusions: Our findings imply that established FH criteria are not regularly utilized to diagnose FH in the US. A need exists to develop a nationwide consensus, which will lead to better identification, earlier treatment, and ultimately prevention of CHD events

BACKGROUND: The drug-drug interactions between pitavastatin and darunavir/ritonavir (DRV/r) as well as pitavastatin and efavirenz (EFV) were examined in an open-label, parallel-arm, pharmacokinetic (PK) study in HIV-uninfected healthy volunteers. METHODS: Subjects received a pitavastatin dose of 2 mg for 4 days, followed by either EFV 600 mg (n = 14) or DRV/r 800/100 mg (n = 14) daily for 10 days, and pitavastatin 2 mg coadministered with EFV 600 mg or DRV/r 800/100 mg for 4 days. Full PK profiles were determined for pitavastatin and its lactone metabolite on days 4 and 18 and for EFV or DRV on days 14 and 18. RESULTS: In the EFV arm, the geometric mean area under the concentration time curve (AUC0-tau) and Cmax of pitavastatin were 85.3 ng.h.mL and 15.6 ng/mL, respectively, when given alone, versus 76 ng.h.mL and 18.8 ng/mL when coadministered with EFV. The geometric mean ratio for pitavastatin with EFV versus alone was 0.89 [90% confidence interval (CI): 0.73 to 1.09] for AUC0-tau and 1.20 (90% CI: 0.79 to 1.83) for Cmax. In the DRV/r arm, AUC0-tau and Cmax were 62.8 ng.h.mL and 24.0 ng/mL, respectively, when pitavastatin was administered alone, versus 56.9 ng.h.mL and 23.2 ng/mL when coadministered with DRV/r. The geometric mean ratio for pitavastatin with DRV/r versus alone was 0.91 (90% CI: 0.78 to 1.06) for AUC0-tau and 0.93 (90% CI: 0.72 to 1.19) for Cmax. CONCLUSIONS: There were no significant PK interactions between pitavastatin and EFV or DRV/r. No significant safety issues or lipid changes were noted.

BACKGROUND: Obesity, metabolic syndrome (MS) and dyslipidemia are independent risk factors for cardiovascular disease. Bariatric surgery is increasingly recognized as an effective intervention for improving each of these risk factors. There are sparse data on the long-term durability of metabolic changes associated with bariatric surgery, in particular with laparoscopic gastric banding (LGB). Our objective was to evaluate the durability of metabolic changes associated with LGB in nonmorbid obesity. METHODS: Fifty obese patients (BMI 30-40) with >/=1 obesity-related comorbidity were prospectively followed for five years. At follow-up, subjects underwent fasting blood measures, including lipid NMR spectroscopy and standard lipid profile. RESULTS: Forty-seven patients (45 female, mean age 43.8 years) completed four years follow-up (46 completed five years). Baseline BMI was 35.1 +/- 2.6. Subjects exhibited mean weight loss of 22.3 +/- 7.9 kg (22.9 +/- 7.4%) at year one and maintained this (19.8 +/- 10.2%) over five years. At baseline, 43% (20/47) of subjects met criteria for MS. This was reduced to 15% (7/47) at year one and remained reduced over five years (13%, 6/46) (p < 0.001). There were reductions in triglycerides (p < 0.001) and increases in HDL cholesterol (HDL-C, p < 0.001) and HDL particle concentration (p = 0.02), with a trend toward increased HDL particle size (p = 0.06) at year five. Changes in triglycerides and HDL-C were more prominent in patients with MS at baseline, but unassociated with weight loss or waist circumference. Changes in HDL particle size and concentration were not associated with MS status, weight loss, waist circumference, or statin use. CONCLUSIONS: LGB produces significant weight loss, resolution of MS and changes in lipid profile suggestive of beneficial HDL remodeling. These changes persist five years following LGB.

BACKGROUND: The American Heart Association recommends targeting 7 cardiovascular (CV) health metrics to reduce morbidity and mortality. Control of these targets in patients undergoing CV intervention is uncertain. METHODS: We prospectively studied patients undergoing elective percutaneous coronary or peripheral intervention from November 2010 to May 2012. We recorded data on patient demographics, clinical characteristics, and social history. Risk factor control was categorized as ideal, intermediate, or poor according to the 7 American Heart Association-defined CV health metrics (smoking status, body mass index, physical activity, diet, cholesterol, blood pressure, and metabolic control). Linear regression model was used to evaluate the association between baseline characteristics and poor CV health. RESULTS: Among 830 consecutive patients enrolled, mean age is 67.3 +/- 10.8 years, 74.2% are male, and 62.1% are white. The adequacy of achievement of ideal CV health is suboptimal in our cohort; the mean number of ideal CV metrics is 2.15 +/- 1.06. Less than 1 in 10 (9.7%) met >/=4 ideal CV health metrics. After multivariate analysis, male sex (P = .04), nonwhite race (P = .01), prior coronary artery disease (P < .01), prior peripheral arterial disease (P < .01), and history of depression (P = .01) were significantly associated with poor CV health. CONCLUSIONS: Among patients referred for elective CV intervention, achievement of ideal CV health is poor. Elective interventions represent an opportunity to identify and target CV health for risk factor control and secondary prevention.

BACKGROUND: Familial hypercholesterolemia (FH) is a hereditary condition caused by various genetic mutations that lead to significantly elevated low-density lipoprotein cholesterol levels and resulting in a 20-fold increased lifetime risk for premature cardiovascular disease. Although its prevalence in the United States is 1 in 300 to 500 individuals, <10% of FH patients are formally diagnosed, and many are not appropriately treated. Contemporary data are needed to more fully characterize FH disease prevalence, treatment strategies, and patient experiences in the United States. DESIGN: The Familial Hypercholesterolemia Foundation (a patient-led nonprofit organization) has established the CAscade SCreening for Awareness and DEtection of Familial Hypercholesterolemia (CASCADE FH) Registry as a national, multicenter initiative to identify US FH patients, track their treatment, and clinical and patient-reported outcomes over time. The CASCADE FH will use multiple enrollment strategies to maximize identification of FH patients. Electronic health record screening of health care systems will provide an efficient mechanism to identify undiagnosed patients. A group of specialized lipid clinics will enter baseline and annual follow-up data on demographics, laboratory values, treatment, and clinical events. Patients meeting prespecified low-density lipoprotein or total cholesterol criteria suspicious for FH will have the opportunity to self-enroll in an online patient portal with information collected directly from patients semiannually. Registry patients will be provided information on cascade screening and will complete an online pedigree to assist with notification of family members. SUMMARY: The Familial Hypercholesterolemia Foundation CASCADE FH Registry represents a novel research paradigm to address gaps in knowledge and barriers to comprehensive FH screening, identification, and treatment.