N-of-1 (single-patient) trials for statin-related myalgia.

BACKGROUND: Statin-related myalgia is difficult to distinguish from other conditions causing myalgia and may often lead to statin discontinuation. OBJECTIVE: To compare the effect of statin rechallenge with placebo in patients with prior statin-related myalgia and to determine whether patients resumed statin therapy after evaluating the results. DESIGN: N-of-1 trial with 3 double-blind, crossover comparisons separated by 3-week washout periods. (Clinicaltrials.gov: NCT01259791) SETTING: Tertiary care lipid clinic. PATIENTS: Patients with prior statin-related myalgia with or without mild elevation of creatine kinase levels. INTERVENTION: Rechallenge with the statin that was previously associated with myalgia within 3 weeks of open-label use versus matching placebo. MEASUREMENTS: Weekly visual analogue scale (VAS) scores for myalgia and specific symptoms (VAS myalgia score and symptom-specific VAS score, respectively), pain interference scores, and pain severity scores were recorded during the 3-week periods when patients were receiving placebo or statin. The primary outcome was the VAS myalgia score (range, 0 to 100 mm). RESULTS: Eight patients (mean age, 66 years [SD, 8 years]; 88% women, all with high 10-year Framingham cardiovascular risk) participated in n-of-1 trials. Seven patients completed 3 treatment pairs, and 1 completed 2 treatment pairs. For each n-of-1 trial, no statistically significant differences were seen between statin and placebo in the VAS myalgia score, symptom-specific VAS score, pain interference score, and pain severity score. Five patients resumed open-label statin treatment, with a median posttrial follow-up of 10 months. LIMITATION: Results are limited by the small sample size and cannot be extended to patients with longer onset of myalgia after statin initiation. CONCLUSION: In selected patients with a history of statin-related myalgia whose symptoms are difficult to evaluate, n-of-1 trials may be a useful method for determining statin tolerability. PRIMARY FUNDING SOURCE: Western University, London, Ontario, Canada.

Strategies For Enhancing Equity, Diversity, and Inclusion in Medical School Admissions-A Canadian Medical School's Journey.

Background: Medical schools aim to select and train future physicians representative of and able to serve their diverse population needs. Enhancing equity, diversity, and inclusion (EDI) in admissions processes includes identifying and mitigating barriers for those underrepresented in medicine (URM). Summary of Innovations: In 2017, Schulich School of Medicine and Dentistry (Western University, Ontario, Canada) critically reviewed its general Admissions pathways for the Doctor of Medicine (MD) program. Till that time, interview invitations were primarily based on academic metrics rather than a holistic review as for its Indigenous MD Admissions pathway. To help diversify the Canadian physician workforce, Schulich Medicine utilized a multipronged approach with five key changes implemented over 2 years into the general MD Admissions pathways: 1. A voluntary applicant diversity survey (race, socioeconomic status, and community size) to examine potential barriers within the Admissions process; 2. Diversification of the admissions committee and evaluator pool with the inclusion of an Equity Representative on the admissions committee; 3. A biosketch for applicants' life experiences; 4. Implicit bias awareness training for Committee members, file reviewers and interviewers; and 5. A specific pathway for applicants with financial, sociocultural, and medical barriers (termed ACCESS pathway). Diversity data before (Class of 2022) vs. after (Class of 2024) these initiatives and of the applicant pool vs. admitted class were examined. Conclusion: For the Class of 2024, the percentage of admitted racialized students (55.2%), those with socioeconomic challenges (32.3%), and those from remote/rural/small town communities (18.6%) reflected applicant pool demographics (52.8, 29.9, and 17.2%, respectively). Additionally, 5.3% (vs. 5.6% applicant pool) of admitted students had applied through ACCESS. These data suggest that barriers within the admissions process for these URM populations were potentially mitigated by these initiatives. The initiatives broadly improved representation of racialized students, LGBTQ2S+, and those with disability with statistically significant increases in representation of those with socioeconomic challenges (32.3 vs. 19.3%, p = 0.04), and those with language diversity (42.1 vs. 35.0%, p = 0.04). Thus, these changes within the general MD admissions pathways will help diversify the future Canadian physician workforce and inform future initiatives to address health equity and social accountability within Canada.

Evaluation of adipose tissue volume quantification with IDEAL fat-water separation.

PURPOSE: To validate iterative decomposition of water and fat with echo asymmetry and least-squares estimation (IDEAL) for adipose tissue volume quantification. IDEAL allows MRI images to be produced only from adipose-containing tissues; hence, quantifying adipose tissue should be simpler and more accurate than with current methods. MATERIALS AND METHODS: Ten healthy controls were imaged with 1.5 Tesla (T) Spin Echo (SE), 3.0T T1-weighted spoiled gradient echo (SPGR), and 3.0T IDEAL-SPGR. Images were acquired from the abdomen, pelvis, mid-thigh, and mid-calf. Mean subcutaneous and visceral adipose tissue volumes were compared between the three acquisitions for each subject. RESULTS: There were no significant differences (P>0.05) between the three acquisitions for subcutaneous adipose tissue volumes. However, there was a significant difference (P=0.0002) for visceral adipose tissue volumes in the abdomen. Post hoc analysis showed significantly lower visceral adipose tissue volumes measured by IDEAL versus 1.5T (P<0.0001) and 3.0T SPGR (P<0.002). The lower volumes given by IDEAL are due to its ability to differentiate true visceral adipose tissue from other bright structures like blood vessels and bowel content that are mistaken for adipose tissue in non-fat suppressed images. CONCLUSION: IDEAL measurements of adipose tissue are equivalent to established 1.5T measurement techniques for subcutaneous depots and have improved accuracy for visceral depots, which are more metabolically relevant.

Narrative review: statin-related myopathy.

Statin-related myopathy is a clinically important cause of statin intolerance and discontinuation. The spectrum of statin-related myopathy ranges from common but clinically benign myalgia to rare but life-threatening rhabdomyolysis. Observational studies suggest that myalgia can occur in up to 10% of persons prescribed statins, whereas rhabdomyolysis continues to be rare. The mechanisms of statin-related myopathy are unclear. Options for managing statin myopathy include statin switching, particularly to fluvastatin or low-dose rosuvastatin; nondaily dosing regimens; nonstatin alternatives, such as ezetimibe and bile acid-binding resins; and coenzyme Q10 supplementation. Few of these strategies have high-quality evidence supporting them. Because statin-related myopathy will probably become more common with greater numbers of persons starting high-dose statin therapy and the increasing stringency of low-density lipoprotein cholesterol level targets, research to better identify patients at risk for statin myopathy and to evaluate management strategies for statin-related myopathy is warranted.

Emerging antidyslipidemic drugs.

BACKGROUND: Many patients at high risk for coronary heart disease (CHD) fail to reach target lipid levels with currently available medications, and a small but clinically relevant proportion of patients experience adverse effects. Thus, additional pharmaceutical strategies are required to fill these gaps in efficacy and tolerability. OBJECTIVE: To provide an overview of both current and emerging antidyslipidemic drugs. METHODS: For the current antidyslipidemic drugs, we focus primarily on statins, bile acid sequestrants, fibrates, ezetimibe, and niacin. Emerging antidyslipidemic drugs herein discussed were identified by searching the Pharmaprojects database for 'hypercholesterolemia drugs' (Phase II or Phase III), 'HDL-based therapies', and 'PCSK9 inhibition'. RESULTS/CONCLUSIONS: Combinations of currently existing medications are most easily applicable. Meanwhile, strategies to raise HDL-C rely on a deep understanding of the complexity of HDL metabolism. Furthermore, novel approaches to further reduce LDL-C warrant careful evaluation of benefit-risk ratio. Finally, the medical community will have to rely on late-phase CHD outcome studies as the final arbiter of clinical application for any new antidyslipidemia treatment.

Canadian Cardiovascular Society Position Statement on Familial Hypercholesterolemia: Update 2018.

Familial hypercholesterolemia (FH) is the most common monogenic disorder causing premature atherosclerotic cardiovascular disease. It affects 1 in 250 individuals worldwide, and of the approximately 145,000 Canadians estimated to have FH, most are undiagnosed. Herein, we provide an update of the 2014 Canadian Cardiovascular Society position statement on FH addressing the need for case identification, prompt recognition, and treatment with statins and ezetimibe, and cascade family screening. We provide a new Canadian definition for FH and tools for clinicians to make a diagnosis. The risk of atherosclerotic cardiovascular disease in patients with "definite" FH is 10- to 20-fold that of a normolipidemic individual and initiating treatment in youth or young adulthood can normalize life expectancy. Target levels for low-density lipoprotein cholesterol are proposed and are aligned with the Canadian Cardiovascular Society guidelines on dyslipidemia. Recommendation for the use of inhibitors of proprotein convertase kexin/subtilisin type 9 are made in patients who cannot achieve therapeutic low-density lipoprotein cholesterol targets on maximally tolerated statins and ezetimibe. The writing committee used the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology in the preparation of the present document, which offers guidance for practical evaluation and management of patients with FH. This position statement also aims to raise awareness of FH nationally, and to mobilize patient support, promote knowledge translation, and availability of treatment and health care resources for this under-recognized, but important medical condition.

Management Strategies for Statin-Associated Muscle Symptoms: How Useful Is Same-Statin Rechallenge?

BACKGROUND: Statin-associated muscle symptoms (SAMS) are common. Rechallenge with the same statin (same-statin rechallenge) has recently been included as part of a proposed scoring index for diagnosing SAMS, but data regarding tolerability and efficacy of same-statin rechallenge, compared with other strategies, is minimal. In this study we evaluated the tolerability, percent change in low-density lipoprotein cholesterol (LDL-C), and proportion of patients achieving their LDL-C targets among 3 common management strategies-same-statin rechallenge, switching to a different statin (statin switch), and use of nonstatin medications only. METHODS: We performed a retrospective analysis of 118 patients referred to our tertiary care centre for management of SAMS, defined as development of muscle-related symptoms with 2 or more statins. Baseline and last follow-up lipid parameters were documented. Patients were classified as tolerant of a strategy if, at their last follow-up, they remained on that strategy. RESULTS: After a median follow-up of 17 months, most (n = 79; 67%) patients were able to tolerate a statin. Tolerability was similar among the 3 treatment strategies (71% same-statin rechallenge vs 53% statin switch vs 57% for nonstatin therapy only; P = 0.11). Those in the same-statin rechallenge and statin switch groups achieved greater LDL-C reductions compared with those who only tolerated nonstatins (-38.8 ± 3.4% vs -36.4 ± 2.9% vs -17.3 ± 4.5%; P = 0.0007). A greater proportion of patients in the same-statin rechallenge group achieved their target LDL-C compared with those in the nonstatin therapy only group (50% vs 15%; odds ratio, 6.8; 95% confidence interval, 1.5-40.7; P = 0.04). CONCLUSIONS: Among individuals with a history of SAMS, most will tolerate statin therapy. Same-statin rechallenge was highly tolerable and efficacious. Thus, same-statin rechallenge might warrant increased utilization.

Sitagliptin in patients with non-alcoholic steatohepatitis: A randomized, placebo-controlled trial.

AIM: To evaluate the effect of sitagliptin vs placebo on histologic and non-histologic parameters of non-alcoholic steatohepatitis (NASH). METHODS: Twelve patients with biopsy-proven NASH were randomized to sitagliptin (100 mg daily) (n = 6) or placebo (n = 6) for 24 wk. The primary outcome was improvement in liver fibrosis after 24 wk. Secondary outcomes included evaluation of changes in NAFLD activity score (NAS), individual components of NAS (hepatocyte ballooning, lobular inflammation, and steatosis), glycemic control and insulin resistance [including measurements of glycated hemoglobin (HbA1C) and adipocytokines], lipid profile including free fatty acids, adipose distribution measured using magnetic resonance imaging (MRI), and thrombosis markers (platelet aggregation and plasminogen activator inhibitor 1 levels). We also sought to determine the correlation between changes in hepatic fat fraction (%) [as measured using the Iterative Decomposition of water and fat with Echo Asymmetry and Least-squares estimation (IDEAL) MRI technique] and changes in hepatic steatosis on liver biopsy. RESULTS: Sitagliptin was not significantly better than placebo at reducing liver fibrosis score as measured on liver biopsy (mean difference between sitagliptin and placebo arms, 0.40, P = 0.82). There were no significant improvements evident with the use of sitagliptin vs placebo for the secondary histologic outcomes of NAS total score as well as for the individual components of NAS. Compared to baseline, those patients who received sitagliptin demonstrated improved HbA1C (6.7% ± 0.4% vs 7.9% ± 1.0%, P = 0.02), and trended towards improved adiponectin levels (4.7 ± 3.5 µg/mL vs 3.9 ± 2.7 µg/mL, P = 0.06) and triglyceride levels (1.26 ± 0.43 mmol/L vs 2.80 ± 1.64 mmol/L, P = 0.08). However, when compared with placebo, sitagliptin did not cause a statistically significant improvement in HbA1C (mean difference, -0.7%, P = 0.19) nor triglyceride levels (mean difference -1.10 mmol/L, P = 0.19) but did trend towards improved adiponectin levels only (mean difference, 0.60 µg/mL, P = 0.095). No significant changes in anthropometrics, liver enzymes, other adipocytokines, lipid profile, thrombosis parameters, or adipose distribution were demonstrated. The MRI IDEAL procedure correlated well with steatosis scores obtained on liver biopsy in both groups at baseline and post-treatment, and the Spearman correlation coefficients ranged from r = 0.819 (baseline) to r = 0.878 (post-treatment), P = 0.002. CONCLUSION: Sitagliptin does not improve fibrosis score or NAS after 24 wk of therapy. The MRI IDEAL technique may be useful for non-invasive measurement of hepatic steatosis.

Access to nutritious food, socioeconomic individualism and public health ethics in the USA: a common good approach.

Good nutrition plays an important role in the optimal growth, development, health and well-being of individuals in all stages of life. Healthy eating can reduce the risk of chronic diseases, such as heart disease, stroke, diabetes and some types of cancer. However, the capitalist mindset that shapes the food environment has led to the commoditization of food. Food is not just a marketable commodity like any other commodity. Food is different from other commodities on the market in that it is explicitly and intrinsically linked to our human existence. While possessing another commodity allows for social benefits, food ensures survival. Millions of people in United States of America are either malnourished or food insecure. The purpose of this paper is to present a critique of the current food system using four meanings of the common good--as a framework, rhetorical device, ethical concept and practical tool for social justice. The first section of this paper provides a general overview of the notion of the common good. The second section outlines how each of the four meanings of the common good helps us understand public practices, social policies and market values that shape the distal causal factors of nutritious food inaccessibility. We then outline policy and empowerment initiatives for nutritious food access.

Novel HDL-based therapeutic agents.

Reduction in low-density lipoprotein cholesterol (LDL-C) levels has been associated with a 25-30% reduction in cardiovascular disease risk. However, there still remains a significant and quantifiable risk. Since epidemiologic data have demonstrated that low levels of high-density lipoprotein cholesterol (HDL-C) are associated with an increased risk for cardiovascular disease, novel therapeutic agents are currently being developed to either raise HDL-C levels or enhance HDL functionality. This review will highlight some of these therapeutic agents including cholesteryl ester transfer protein inhibitors, apolipoprotein A-I mimetics, RVX-208, and apolipoprotein A-I based infusion therapies. For each therapeutic class, an overview of the mechanism of action, pharmacokinetic data, and efficacy/safety evidence will be provided.

Novel therapeutic agents for lowering low density lipoprotein cholesterol.

Elevated low density lipoprotein cholesterol (LDL-C) levels have been associated with an increased risk for cardiovascular disease (CVD). Despite a 25-30% reduction in CVD risk with LDL-C reducing strategies, there is still a significant residual risk. Moreover, achieving target LDL-C values in individuals at high CVD risk is sometimes limited because of tolerability and/or efficacy. Thus, novel therapeutic agents are currently being developed to lower LDL-C levels further. This review will highlight some of these therapeutic agents including anti-sense oligonucleotides focused on apolipoprotein B, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, microsomal triglyceride transfer protein inhibitors, and thyromimetics. For each therapeutic class, an overview of the mechanism of action, pharmacokinetic data, and efficacy/safety evidence will be provided.

Niacin: another look at an underutilized lipid-lowering medication.

Niacin, or water-soluble vitamin B(3), when given at pharmacologic doses, is a powerful lipid-altering agent. This drug, which lowers the levels of atherogenic, apolipoprotein-B-containing lipoproteins, is one of few medications that can raise the levels of atheroprotective HDL cholesterol. Niacin also has beneficial effects on other cardiovascular risk factors, including lipoprotein(a), C-reactive protein, platelet-activating factor acetylhydrolase, plasminogen activator inhibitor 1 and fibrinogen. Many clinical trials have confirmed the lipid effects of niacin treatment; however, its effects on cardiovascular outcomes have been called into question owing to the AIM-HIGH trial, which showed no benefit of niacin therapy on cardiovascular endpoints. Furthermore, use of niacin has historically been limited by tolerability issues. In addition to flushing, worsened hyperglycaemia among patients with diabetes mellitus has also been a concern with niacin therapy. This article reviews the utility of niacin including its mechanism of action, clinical trial data regarding cardiovascular outcomes, adverse effect profile and strategies to address these effects and improve compliance.

Anacetrapib: hope for CETP inhibitors?

Inhibition of cholesteryl ester transfer protein (CETP), a key protein involved in reverse cholesterol transport, can lead to increases in high-density lipoprotein cholesterol (HDL-C) levels and thus, is under evaluation as an antiatherogenic strategy. Several CETP inhibitors have been under development including anacetrapib, dalcetrapib, and torcetrapib. To date, anacetrapib demonstrates the greatest HDL-C raising and low-density lipoprotein cholesterol (LDL-C) lowering potential. Phase I and phase II trials with anacetrapib have revealed that anacetrapib is well-tolerated and does not seem to possess the pressor effects associated with torcetrapib. This article will briefly review the HDL-C raising through CETP inhibition as an antiatherogenic strategy with a specific focus on anacetrapib.

Epistemological and ethical assessment of obesity bias in industrialized countries.

Bernard Lonergan's cognitive theory challenges us to raise questions about both the cognitive process through which obesity is perceived as a behaviour change issue and the objectivity of such a moral judgment. Lonergan's theory provides the theoretical tools to affirm that anti-fat discrimination, in the United States of America and in many industrialized countries, is the result of both a group bias that resists insights into the good of other groups and a general bias of anti-intellectualism that tends to set common sense against insights that require any thorough scientific analyses. While general bias diverts the public's attention away from the true aetiology of obesity, group bias sustains an anti-fat culture that subtly legitimates discriminatory practices and policies against obese people. Although anti-discrimination laws may seem to be a reasonable way of protecting obese and overweight individuals from discrimination, obesity bias can be best addressed by reframing the obesity debate from an environmental perspective from which tools and strategies to address both the social and individual determinants of obesity can be developed. Attention should not be concentrated on individuals' behaviour as it is related to lifestyle choices, without giving due consideration to the all-encompassing constraining factors which challenge the social and rational blindness of obesity bias.

A translational view of the genetics of lipodystrophy and ectopic fat deposition.

A wide range of lipodystrophy syndromes exist, each with varying clinical presentations, and yet cumulatively they underscore the importance of adipocyte biology in human metabolism. Loss of the ability to retain excess lipids in "classical" adipose tissue stores can lead to the overdevelopment of ectopic fat stores, often creating severe perturbations of both glucose and lipid homeostasis. Linkage analysis and candidate sequencing efforts have successfully identified responsible mutations for multiple forms of lipodystrophy. Recently, the reduction in the cost of DNA sequencing has resulted in discovery of many novel mutations within both known and novel loci. In this review, we present the steps involved in clinical characterization of a suspected lipodystrophy case, an overview of the clinical manifestations, molecular findings, and pathogenic basis of different forms of lipodystrophy, a discussion of therapeutic options for lipodystrophy patients, and an examination of genetic advances that will be used to identify additional pathogenic mechanisms.

Microsomal triglyceride transfer protein inhibition-friend or foe?

This article sets out the clinical context of the research presented by Samaha et al. in an accompanying article in this issue. Hyperlipidemia is a common and important risk factor for cardiovascular disease. Current lipid-lowering therapies, particularly statins, lead to substantial decreases in cardiovascular disease morbidity and mortality, but use has been limited by safety or efficacy issues. The way has, therefore, been paved for the pharmaceutical development and clinical investigation of new lipid-lowering therapies. The clinical trial by Samaha et al. examines the safety and efficacy of microsomal triglyceride transfer protein inhibition for lowering lipids. Joy and Hegele explore the difficulties of translating microsomal triglyceride transfer protein inhibition into clinical practice because of the trade-off between efficacy and potential adverse effects. They also stress the need for outcome studies, rather than biochemical or surrogate studies, as the final arbiter for the clinical use of this new treatment.

Prevalence of reproductive abnormalities among women with familial partial lipodystrophy.

OBJECTIVE: To compare the risk of having polycystic ovary syndrome (PCOS) or ovarian cysts among women with genetically confirmed familial partial lipodystrophy (FPLD) with that in the general population of healthy women. METHODS: Twenty-five women with FPLD who were 18 to 80 years old were interviewed regarding a history of PCOS or ovarian cysts (composite primary outcome) as well as for secondary outcomes of interest including menstrual irregularities, hirsutism, gynecologic surgical procedures, and fertility or obstetric complications. From the 2005 National Ambulatory Medical Care Survey, 3,326 women, aged 18 to 80 years (control subjects), were assessed for the presence of the primary outcome based on appropriate International Classification of Diseases, Ninth Revision, Clinical Modification codes. RESULTS: Four of the 25 patients with FPLD (16%) had a history of PCOS or ovarian cysts, in comparison with 14 of the 3,326 control subjects (0.42%), resulting in an age- and body mass index-adjusted odds ratio of 40.6 (95% confidence interval, 12.1 to 136.7; P<.0001) among the patients with FPLD. Furthermore, 5 women with FPLD (20%) required at least 1 oophorectomy during their lifetime, and 6 (24%) had had hysterectomies at a young age (