Faculty Bibliography

BACKGROUND: Statin intolerance is a barrier to effective lipid-lowering treatment. A significant number of patients stop prescribed statins, or can take only a reduced dose, because of adverse events attributed to the statin, and are then considered statin-intolerant. METHODS: Examination of differences between statin and placebo in withdrawal rates due to adverse events - a good measure of tolerability - in statin cardiovascular outcome trials in patients with advanced disease and complex medical histories, who may be more vulnerable to adverse effects. The arguments commonly used to dismiss safety and tolerability data in statin clinical trials are examined. RESULTS: Rates of withdrawal due to adverse events in trials in patients with advanced disease and complex medical histories are consistently similar in the statin and placebo groups. We find no support for arguments that statin cardiovascular outcome trials do not translate to clinical practice. CONCLUSIONS: Given the absence of any signal of intolerance in clinical trials, it appears that statin intolerance in the clinic is commonly due to the nocebo effect causing patients to attribute background symptoms to the statin. Consistent with this, over 90% of patients who have stopped treatment because of an adverse event can tolerate a statin if re-challenged. Consequently, new agents, including monoclonal antibodies to proprotein convertase subtilisin/kexin type 9, will be useful when added to statin therapy but should rarely be used as a statin substitute.

PURPOSE: Doses of growth hormone in adults with growth hormone deficiency are now lower than previously. However, it is not clear they are as effective as higher doses. The objective of this meta-analysis was to assess efficacy of low to moderate dose (LD) GH replacement on standard endpoints of GH compared to higher doses. METHODS: A meta-analysis was carried out using PubMed, Cochrane and Embase databases from 1960 to 9/23/12. Three reviewers identified randomized double-blind, placebo-controlled trials of 6 months duration. Of 173 publications, 28 representing 22 trials (591 GH-treated patients and 562 placebo) were included. Data were independently extracted by three reviewers. Endpoints were analyzed if >/=4 studies per dose group reported baseline and 6 month data. RESULTS: Mean lean body mass (LBM) increased by 2.61 kg in GH-treated subjects versus 0.04 in the placebo group (P < 0.0001). Fat mass (FM) was reduced by -2.19 kg versus 0.31 (GH vs. placebo) (P = 0.0002). Changes in LBM and FM were dose-related (P = 0.02 and 0.007, respectively), high dose (HD) being more effective than low dose (LBM P = 0.03 and FM P = 0.04). In contrast, treatment with GH reduced total cholesterol -0.38 mmol/L versus. 0.01 (placebo) (P < 0.0001), and low density lipoprotein cholesterol (LDL-C) -0.42 mmol/L versus -0.1 (P = 0.0009), but there were no differences between LD and HD GH. CONCLUSIONS: LDs of hGH improve total- and LDL-C, and body composition. Higher doses are more effective on body composition, but not lipids.

Statin-associated muscle symptoms (SAMS) are one of the principal reasons for statin non-adherence and/or discontinuation, contributing to adverse cardiovascular outcomes. This European Atherosclerosis Society (EAS) Consensus Panel overviews current understanding of the pathophysiology of statin-associated myopathy, and provides guidance for diagnosis and management of SAMS. Statin-associated myopathy, with significant elevation of serum creatine kinase (CK), is a rare but serious side effect of statins, affecting 1 per 1000 to 1 per 10 000 people on standard statin doses. Statin-associated muscle symptoms cover a broader range of clinical presentations, usually with normal or minimally elevated CK levels, with a prevalence of 7-29% in registries and observational studies. Preclinical studies show that statins decrease mitochondrial function, attenuate energy production, and alter muscle protein degradation, thereby providing a potential link between statins and muscle symptoms; controlled mechanistic and genetic studies in humans are necessary to further understanding. The Panel proposes to identify SAMS by symptoms typical of statin myalgia (i.e. muscle pain or aching) and their temporal association with discontinuation and response to repetitive statin re-challenge. In people with SAMS, the Panel recommends the use of a maximally tolerated statin dose combined with non-statin lipid-lowering therapies to attain recommended low-density lipoprotein cholesterol targets. The Panel recommends a structured work-up to identify individuals with clinically relevant SAMS generally to at least three different statins, so that they can be offered therapeutic regimens to satisfactorily address their cardiovascular risk. Further research into the underlying pathophysiological mechanisms may offer future therapeutic potential.

BACKGROUND: Previous large trials of vitamin D for prevention of fractures and other disease outcomes have reported conflicting results, possibly because the doses tested were insufficient to maintain optimum blood levels of vitamin D (25[OH]D) predicted by the observational studies. This report describes the design and baseline characteristics of the BEST-D (Biochemical Efficacy and Safety Trial of vitamin D) trial which aims to establish the best dose of vitamin D to assess in a future large outcome trial. METHODS: The BEST-D trial will compare the biochemical and other effects of daily dietary supplementation with 100mug or 50mug vitamin D3 or placebo, when administered for 12 months, in 305 ambulant community-dwelling older people living in Oxfordshire, England. The primary analyses will compare 12-month mean plasma concentrations of 25(OH)D as well as the proportion of participants with a 12-month concentration >90nmol/L between participants allocated 100mug and participants allocated 50mug daily. Secondary analyses will compare the two active doses (both separately and when combined) with placebo. Additional end-points include biochemical assessments of safety, blood pressure, arterial stiffness, falls, fractures, heel and wrist bone density, grip strength and physical performance and echocardiographic assessments of cardiac function in a random sample of participants. RESULTS: About one-third of eligible participants agreed to participate in the trial. The mean age was 72 (SD 6) years with equal numbers of men and women. About one third reported a prior history of fracture or hypertension, one-fifth reported a prior cardiovascular event, and one tenth reported diabetes or a fall in the previous 6 months. CONCLUSIONS: The results of this trial will help determine the optimum dose of vitamin D to test in a larger trial investigating whether vitamin D supplementation can reduce the risk of fractures, cardiovascular disease or cancer.

Background Observational studies indicate that plasma levels of vitamin D (25[OH]D) are inversely associated with risk of fracture, cardiovascular and non-cardiovascular diseases, with the lowest risks associated with plasma levels >90 nmol/L (36ng/ml). (1) Previous large trials of vitamin D3 supplementation for prevention of fracture or other disease outcomes have reported conflicting results, possibly because the doses tested were insufficient to maintain optimum levels of 25(OH)D. (2) Methods With the aim of establishing the most appropriate dose of vitamin D to assess in a large outcome trial, the BEST-D (Biochemical Efficacy and Safety Trial of vitamin D) trial compared the biochemical and other effects of 100 mug (4000 IU) vs 50 mug (2000 IU) D3 daily vs placebo administered for 12 months in ambulant community-dwelling people >65 years living in Oxfordshire, England. The co-primary outcomes were mean plasma 25(OH)D levels at 12 months and the proportion of participants with plasma 25(OH)D >90 nmol/L, by allocated treatment. Results Mean age of the 305 randomized individuals was 72 years, 51% were male and mean body mass index was 27 kg/m². At baseline, the mean (SE) plasma 25(OH)D concentrations were 49 (1.5) nmol/L, 55 (2.3) nmol/L and 47 (1.5) nmol/L, among those allocated 100 mug daily, 50 mug daily or placebo, respectively. By 12 months, the baseline-adjusted mean (SE) levels of 25(OH)D were 137 (2.4) nmol/L, 102 (2.4) nmol/L and 53 (2.4) nmol/L, respectively. Plasma 25(OH)D >90 nmol/L at 12 months was seen in 88% of participants allocated 100 mug daily and 70% of those allocated 50 mug daily (p<0.0001). There were no significant differences in the percent outside the normal range for parathyroid hormone or albumin-corrected calcium (p=0.36 and p=0.21 for 100 mug vs placebo, respectively). Allocation to either dose of vitamin D compared with placebo had no significant effects on muscle or joint pains, physical activity, grip strength or a short physical battery. Conclusions Significantly more participants allocated 100 mug vitamin D3 daily achieved plasma levels of 25(OH)D >90 nmol/L than with 50 mug daily and mean levels were also significantly higher. Neither dose was associated with any significant adverse effects. Large, long-term trials of 100 mug vitamin D daily are now required to assess whether the associations of vitamin D with risk of fracture, cardiovascular disease and cancer seen in the observational studies are causal and whether such events are preventable by vitamin D supplementation

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