Statin Safety and Associated Adverse Events: A Scientific Statement From the American Heart Association.

One in 4 Americans >40 years of age takes a statin to reduce the risk of myocardial infarction, ischemic stroke, and other complications of atherosclerotic disease. The most effective statins produce a mean reduction in low-density lipoprotein cholesterol of 55% to 60% at the maximum dosage, and 6 of the 7 marketed statins are available in generic form, which makes them affordable for most patients. Primarily using data from randomized controlled trials, supplemented with observational data where necessary, this scientific statement provides a comprehensive review of statin safety and tolerability. The review covers the general patient population, as well as demographic subgroups, including the elderly, children, pregnant women, East Asians, and patients with specific conditions such as chronic disease of the kidney and liver, human immunodeficiency viral infection, and organ transplants. The risk of statin-induced serious muscle injury, including rhabdomyolysis, is <0.1%, and the risk of serious hepatotoxicity is ≈0.001%. The risk of statin-induced newly diagnosed diabetes mellitus is ≈0.2% per year of treatment, depending on the underlying risk of diabetes mellitus in the population studied. In patients with cerebrovascular disease, statins possibly increase the risk of hemorrhagic stroke; however, they clearly produce a greater reduction in the risk of atherothrombotic stroke and thus total stroke, as well as other cardiovascular events. There is no convincing evidence for a causal relationship between statins and cancer, cataracts, cognitive dysfunction, peripheral neuropathy, erectile dysfunction, or tendonitis. In US clinical practices, roughly 10% of patients stop taking a statin because of subjective complaints, most commonly muscle symptoms without raised creatine kinase. In contrast, in randomized clinical trials, the difference in the incidence of muscle symptoms without significantly raised creatinine kinase in statin-treated compared with placebo-treated participants is <1%, and it is even smaller (0.1%) for patients who discontinued treatment because of such muscle symptoms. This suggests that muscle symptoms are usually not caused by pharmacological effects of the statin. Restarting statin therapy in these patients can be challenging, but it is important, especially in patients at high risk of cardiovascular events, for whom prevention of these events is a priority. Overall, in patients for whom statin treatment is recommended by current guidelines, the benefits greatly outweigh the risks.

Exercise prescription for weight management in obese adults at risk for osteoarthritis: synthesis from a systematic review.

BACKGROUND: The aim of this systematic review was to identify principles of exercise interventions associated with improved physical function, weight management or musculoskeletal pain relief among young and middle-aged adults with obesity and propose an evidence-based exercise prescription that could assist in secondary prevention of osteoarthritis. METHODS: A structured electronic review was conducted using MEDLINE, PubMed, and SPORTDiscus. The search string included 1) "obes*" AND "exercise" AND "interven*" AND "musculoskeletal pain OR knee pain OR hip pain". Studies 1) were randomized controlled trials of humans, with a non-exercise control, 2) included participants aged 18-50 years, and 3) had outcomes that included physical function, musculoskeletal pain, and/or body composition. Studies were excluded if participants had peri-menopausal status, cancer, or obesity-related co-morbidities. A recommended exercise prescription was developed based on common principles used in the included exercise interventions with greatest change in function or pain. RESULTS: Seven studies were included. Similarities in exercise intensity (40-80% VO2max), frequency (three times per week), duration (30-60 min), and exercise mode (treadmill, cross-trainer, stationary bike, aquatic exercise) were observed in exercise interventions that resulted in improved physical function and/or pain, compared to non-exercise control groups. CONCLUSION: Common principles in exercise prescription for improvements in weight management, physical function and pain relief among otherwise healthy people with obesity. Exercise prescription including moderate intensity exercise for 30-60 min, three times per week can be considered an effective treatment for weight management and obesity-related musculoskeletal symptoms. Exercise should be recommended to at-risk individuals as part of secondary prevention of osteoarthritis.

Statin-associated muscle symptoms: impact on statin therapy-European Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management.

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.

Effects of low dose versus high dose human growth hormone on body composition and lipids in adults with GH deficiency: a meta-analysis of placebo-controlled randomized trials.

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.

Inclusion of Sex and Gender Differences in U.S. State Action Plans for Opioid Use and Opioid Use Disorder.

Background: States have developed action plans to address the "opioid crisis" over the past several years. While sex- and gender-based differences have been identified in complications of opioid use, risks of addiction to opioids, barriers to treatment of opioid use disorder, and associated stigma, it is unknown if or to what extent opioid plans consider or account for these differences. The objectives of this study were to analyze U.S. state opioid action plans and their inclusion of sex- and gender-specific concerns. Methods: A content analysis of 49 state plans was conducted in June 2020, assessing their inclusion of 14 variables covering provider education, pregnancy-related, and sex- or gender-based differences in opioid addiction and treatment. Results: Neonatal opioid withdrawal syndrome was the most common variable, noted in 57% of plans. Only 14% included pregnancy-related stigma, and 4% identified gender-specific stigma. Contraceptives and family-planning were included in 12% and 10% of plans, respectively. Two states included more than half of the variables and five plans made no mention of sex or gender differences. Conclusions: Few state plans contained sex- or gender-specific information, and those that did focused almost exclusively on childbearing, excluding other unique considerations of opioid-using-women of all ages. The results of this study could improve the care of women using opioids by informing the strategies of state agencies and impacting legislative efforts for prevention initiatives, substance use disorder treatment, and law enforcement programs.

Reflecting on Progress in and Establishing Benchmarks for Sex and Gender Health Education.

ABSTRACT: Sex and gender influence every aspect of human health; thus, sex- and gender-related topics should be incorporated in all aspects of health education curricula. Sex and gender health education (SGHE) is the rigorous, intersectional, data-driven integration of sex and gender into all elements of health education. A multisectoral group of thought leaders has collaborated to advance SGHE since 2012. This cross-sector collaboration to advance SGHE has been successful on several fronts, primarily developing robust interprofessional SGHE programs, hosting a series of international SGHE summits, developing sex- and gender-specific resources, and broadening the collaboration beyond medical education. However, other deeply entrenched challenges have proven more difficult to address, including accurate and consistent sex and gender reporting in research publications, broadening institutional support for SGHE, and the development and implementation of evaluation plans for assessing learner outcomes and the downstream effects of SGHE on patient care. This commentary reflects on progress made in SGHE over the first decade of the current collaboration (2012-2022), articulates a vision for next steps to advance SGHE, and proposes 4 benchmarks to guide the next decade of SGHE: (1) integrate sex, gender, and intersectionality across health curricula; (2) develop sex- and gender-specific resources for health professionals; (3) improve sex and gender reporting in research publications; and (4) develop evaluation plans to assess learner and patient outcomes.

Effects of endocrine disorders on lipids and lipoproteins.

Endocrine diseases may be associated with dyslipidaemia and may increase atherosclerotic cardiovascular disease (ASCVD) risk. This chapter describes changes in lipids and lipoproteins in diseases of the pituitary, thyroid, adrenal glands, ovaries, and testes, the mechanisms for these changes, ASCVD risk in these endocrine disorders, and whether treatment of the endocrine disorder improves the lipid profile and reduces ASCVD risk. Acromegaly, GH deficiency, Cushing syndrome, chronic glucocorticoid replacement, hypothyroidism, PCOS and male hypogonadism can increase LDL-C and/or TG. Marked reductions in LDL-C are associated with hyperthyroidism, and extremely low HDL-C levels with testosterone and/or other anabolic steroid abuse. Acromegaly, GH deficiency, Cushing syndrome, and chronic glucocorticoid replacement are associated with increased ASCVD risk. Treatment of acromegaly, GH deficiency, hypothyroidism, Cushing syndrome, and testosterone deficiency reduce LDL-C, although statin therapy may still be needed. Effects on ASCVD are not known.

Targeting PCSK9 With Antibodies and Gene Silencing to Reduce LDL Cholesterol.

The discovery of PCSK9 and its role in regulating the low-density lipoprotein (LDL) receptor, and the effect of loss-of-function mutations of its gene, identified it as a therapeutic target in 2006. Fully humanized monoclonal antibodies to PCSK9 (alirocumab and evolocumab) proved effective for lowering LDL cholesterol and subsequently for reducing atherosclerotic events in large outcome trials. Suppressing PCSK9 synthesis via gene silencing using inclisiran, a small interfering RNA, is another approach that effectively reduces LDL cholesterol, and a cardiovascular outcome trial is in progress. These treatments are given subcutaneously on a background of maximally tolerated statin treatment and are long-lasting: dosing is once or twice a month, self-administered, for alirocumab and evolocumab, and every 6 months for inclisiran, in the clinic, with an extra dose at 3 months in the initial year of therapy. These 3 agents produce mean LDL reductions of about 55% with no important adverse effects detectable to date. They are indicated in patients with atherosclerotic vascular disease or familial hypercholesterolemia who cannot achieve LDL cholesterol targets with maximally tolerated statin treatment. Such therapy can produce very low plasma LDL cholesterol and PCSK9, but there is no evidence this is harmful. Introduction into clinical practice has been impeded by economic considerations. The barrier to their use has not been scientific or medical, but rather the impact on healthcare resources. Prices have been reduced, but whether they are now cost-effective varies from country to country.

Evidence-Based Dietary Practices to Improve Osteoarthritis Symptoms: An Umbrella Review.

While there is some research investigating whole foods or diets that are easily understood and accessible to patients with osteoarthritis, specific nutrients or nutraceuticals are more commonly identified. Unfortunately, guidelines and evidence surrounding individual nutrients, extracts, and nutraceuticals are conflicting and are more difficult to interpret and implement for patients with osteoarthritis. The purpose of this umbrella review is to provide a comprehensive understanding of the existing evidence of whole foods and dietary patterns effects on osteoarthritis-related outcomes to inform evidence-based recommendations for healthcare professionals and identify areas where more research is warranted. A literature search identified relevant systematic reviews/meta-analyses using five databases from inception to May 2022. Five systematic reviews/meta-analyses were included in the current umbrella review. Most evidence supported the Mediterranean diet improving osteoarthritis-related outcomes (e.g., pain, stiffness, inflammation, biomarkers of cartilage degeneration). There was little to no evidence supporting the effects of fruits and herbs on osteoarthritis-related outcomes; however, there was some suggestion that specific foods could potentiate symptom improvement through antioxidative mechanisms. The overall lack of homogeneity between the studies limits the conclusions that can be made and highlights the need for quality research that can identify consumer-accessible foods to improve osteoarthritis-related symptoms.

Preventing Osteoarthritis After an Anterior Cruciate Ligament Injury: An Osteoarthritis Action Alliance Consensus Statement.

After an anterior cruciate ligament (ACL) injury, people need secondary prevention strategies to identify osteoarthritis at its earliest stages so that interventions can be implemented to halt or slow the progression toward its long-term burden. The Osteoarthritis Action Alliance formed an interdisciplinary Secondary Prevention Task Group to develop a consensus on recommendations to provide clinicians with secondary prevention strategies that are intended to reduce the risk of osteoarthritis after a person has an ACL injury. The group achieved consensus on 15 out of 16 recommendations that address patient education, exercise and rehabilitation, psychological skills training, graded-exposure therapy, cognitive-behavioral counseling (lacked consensus), outcomes to monitor, secondary injury prevention, system-level social support, leveraging technology, and coordinated care models. We hope this statement raises awareness among clinicians and researchers on the importance of taking steps to mitigate the risk of osteoarthritis after an ACL injury.

Evidence Review for Preventing Osteoarthritis After an Anterior Cruciate Ligament Injury: An Osteoarthritis Action Alliance Consensus Statement.

CONTEXT: The Osteoarthritis Action Alliance formed a secondary prevention task group to develop a consensus on secondary prevention recommendations to reduce the risk of osteoarthritis after a knee injury. OBJECTIVE: Our goal was to provide clinicians with secondary prevention recommendations that are intended to reduce the risk of osteoarthritis after a person has sustained an anterior cruciate ligament injury. Specifically, this manuscript describes our methods, literature reviews, and dissenting opinions to elaborate on the rationale for our recommendations and to identify critical gaps. DESIGN: Consensus process. SETTING: Virtual video conference calls and online voting. PATIENTS OR OTHER PARTICIPANTS: The Secondary Prevention Task Group consisted of 29 members from various clinical backgrounds. MAIN OUTCOME MEASURE(S): The group initially convened online in August 2020 to discuss the target population, goals, and key topics. After a second call, the task group divided into 9 subgroups to draft the recommendations and supportive text for crucial content areas. Twenty-one members completed 2 rounds of voting and revising the recommendations and supportive text between February and April 2021. A virtual meeting was held to review the wording of the recommendations and obtain final votes. We defined consensus as >80% of voting members supporting a proposed recommendation. RESULTS: The group achieved consensus on 15 of 16 recommendations. The recommendations address patient education, exercise and rehabilitation, psychological skills training, graded-exposure therapy, cognitive-behavioral counseling (lacked consensus), outcomes to monitor, secondary injury prevention, system-level social support, leveraging technology, and coordinated care models. CONCLUSIONS: This consensus statement reflects information synthesized from an interdisciplinary group of experts based on the best available evidence from the literature or personal experience. We hope this document raises awareness among clinicians and researchers to take steps to mitigate the risk of osteoarthritis after an anterior cruciate ligament injury.

Safety of Statins and Nonstatins for Treatment of Dyslipidemia.

This article reviews the safety of statins and non-statin medications for management of dyslipidemia. Statins have uncommon serious adverse effects: myopathy/ rhabdomyolysis, which resolve with statin discontinuation, and diabetes, usually in people with risk factors for diabetes. The CVD benefit of statins far exceeds the risk of diabetes. Statin myalgia, without CK elevation, is likely caused by muscle symptoms with another etiology, or the nocebo effect. Notable adverse effects of non-statin medicines include injection site reactions (alirocumab, evolocumab, inclisiran), increased uric acid and gout (bempedoic acid), atrial fibrillation/flutter (omega-3-fatty acids), and myopathy in combination with a statin (gemfibrozil).

Exploring Obesity as a Gendered Contagion: Impact on Lifestyle Interventions to Improve Cardiovascular Health.

PURPOSE: Obesity increases the risk of cardiovascular disease. Lifestyle interventions such as physical activity and diet are important components for reducing the risk of obesity. Data suggest that lifestyle choices differ between men and women, as well as in groups. The purpose of this review was to explore whether obesity can be considered as a gendered social contagion, associated with differences in lifestyle and response to lifestyle interventions in men and women. FINDINGS: There are important sex-based differences of obesity to consider. There is evidence that peers have an influence on lifestyle preferences such as physical activity level and dietary habits, but the evidence is inconclusive if the differences exist between men and women. Similarly, data from lifestyle intervention studies are not conclusive whether there are differences between men and women. There is not enough evidence for the notion that obesity is a gendered social contagion. IMPLICATIONS: More research is needed to understand differences in lifestyle and lifestyle interventions between men and women, especially across the life span, which could have profound public health implications.

Management of dyslipidemia and atherosclerotic cardiovascular risk in prediabetes.

Prediabetes affects at least 1 in 3 adults in the U.S. and 1 in 5 in Europe. Although guidelines advocate aggressive management of lipid parameters in diabetes, most guidelines do not address treatment of dyslipidemia in prediabetes despite the increased atherosclerotic cardiovascular disease (ASCVD) risk. Several criteria are used to diagnose prediabetes: impaired fasting glucose (IFG), impaired glucose tolerance (IGT) and HbA1c of 5.7-6.4%. Individuals with prediabetes have a greater risk of diabetes, a higher prevalence of dyslipidemia with a more atherogenic lipid profile and an increased risk of ASCVD. In addition to calculating ASCVD risk using traditional methods, an OGTT may further stratify risk. Those with 1-hour plasma glucose ≥8.6 mmol/L (155 mg/dL) and/or 2-hour ≥7.8 mmol/L (140 mg/dL) (IGT) have a greater risk of ASCVD. Diet and lifestyle modification are fundamental in prediabetes. Statins, ezetimibe and PCSK9 inhibitors are recommended in people requiring pharmacotherapy. Although high-intensity statins may increase risk of diabetes, this is acceptable because of the greater reduction of ASCVD. The LDL-C goal in prediabetes should be individualized. In those with IGT and/or elevated 1-hour plasma glucose, the same intensive approach to dyslipidemia as recommended for diabetes should be considered, particularly if other ASCVD risk factors are present.

Mind the Gap: Exploring Nutritional Health Compared With Weight Management Interests of Individuals with Osteoarthritis.

Background: For persons with osteoarthritis (OA), nutrition education may facilitate weight and OA symptom management. Objectives: The primary aim of this study was to determine preferred OA-related nutritional and weight management topics and their preferred delivery modality. The secondary aim was to determine whether there is a disconnect between what patients want to know about nutrition and OA management and what information health-care professionals (HCPs) are providing to patients. Methods: The Osteoarthritis Action Alliance surveyed individuals with OA to identify their preferences, categorized in 4 domains: 1) strategies for weight management and a healthy lifestyle; 2) vitamins, minerals, and other supplements; 3) foods or nutrients that may reduce inflammation; and 4) diets for weight loss. HCPs were provided these domains and asked which topics they discussed with patients with OA. Both groups were asked to select currently utilized or preferred formats of nutritional resources. Results: Survey responses from 338 individuals with OA and 104 HCPs were included. The highest preference rankings in each domain were: 1) foods that make OA symptoms worse (65%), foods and nutrients to reduce inflammation (57%), and healthy weight loss (42%); 2) glucosamine (53%), vitamin D (49%), and omega-3 fatty acids (45%); 3) spices and herbs (65%), fruits and vegetables (58%), and nuts (40%); and 4) Mediterranean diet (21%), low-carbohydrate diet (18%), and fasting or intermittent fasting (15%). There was greater than 20% discrepancy between interests reported by individuals with OA and discussions reported by HCPs on: weight loss strategies, general information on vitamins and minerals, special dietary considerations for other conditions, mindful eating, controlling caloric intake or portion sizes, and what foods worsen OA symptoms. Most respondents preferred to receive nutrition information in a passive format and did not want information from social media messaging. Conclusions: There is disparity between the nutrition education content preferred by individuals with OA (which often lacks empirical support) and evidence-based topics being discussed by HCPs. HCPs must communicate evidence-based management of joint health and OA symptoms in patient-preferred formats. This study explored the information gap between what individuals with OA want to know and what HCPs believe they need to know.

Sex and Gender Health Educational Tenets: A Report from the 2020 Sex and Gender Health Education Summit.

Background: Sex as a biological variable and gender as a sociocultural variable influence many health conditions and outcomes. However, they have not been incorporated systematically into education across health professions. Methods: Areas of knowledge and abilities that apply to sex and gender education across health professions were summarized from the 2015 and 2018 Sex and Gender Health Education Summits. Results: Using this summary, draft tenets were developed by facilitated interprofessional discussion groups at the 2020 Summit, and then reviewed, edited, and refined by a writing group who recommended four tenets that health care professionals should be able to do: (1) demonstrate knowledge of sex and gender specific health (SGSH), (2) evaluate literature and the conduct of research for incorporation of sex and gender, (3) incorporate sex and gender considerations into clinical decision making, and (4) demonstrate patient advocacy with respect to sex and gender. Conclusion: These tenets provide the framework for collaborative interprofessional education about SGSH. Individual professions can also use the tenets to develop practice-specific competencies, competency statements, and/or assessment benchmarks within the structures of their respective accrediting bodies to advance the health of women, men, and sex and gender minority persons. Interprofessional collaborations are key for sharing best practices in development, curricular integration, and dissemination.

Mortality in COVID-19: Further Evidence for a Sex-Based Difference in the OpenSAFELY Study.

Although COVID-19 death rates are lower in women compared to men, it is not clear whether this difference in mortality is due to sex (biological) based factors, comorbidities that differ in men and women, or gender influences. New evidence supports a sex-based difference in COVID-19 mortality. Data from the OpenSAFELY cohort study in 17 million adult patients in England demonstrate that COVID-19-related deaths were associated with male sex (hazard ratio 1.59; 95% confidence interval 1.53-1.65) when fully adjusted for age, low income, smoking, pre-existing diseases, and ethnicity. Women have stronger innate and adaptive responses to infection. It is hypothesized that biological differences in the immune system may have a role in the sex-based difference in mortality from COVID-19. The results of OpenSAFELY demonstrate the importance of collection and analysis of sex-disaggregated data in research and public surveillance.

Inequity and Women Physicians: Time to Change Millennia of Societal Beliefs.

Gender inequities date back thousands of years, with women expected to be caregivers at home and men expected to be leaders with occupations outside the home. In more recent history, women have trained in various professions, including medicine. Although the number of female physicians has risen consistently over the past several decades and half of US medical students now are women, gender inequities persist and are due, at least in part, to implicit (unconscious) biases held by doctors, other health care professionals, and patients and their families. Implicit biases negatively affect women in their medical careers and contribute to slower advancement, less favorable evaluations, underrepresentation in leadership positions, fewer invited lectures, lower salaries, impostor syndrome, and burnout. Despite efforts to address gender biases, studies in academic medical centers indicate no major change over a 20-year span. Management of implicit gender bias at the organizational level is imperative. Strategies include implicit bias training for doctors and other staff; development of a transparent and equitable compensation plan; and transparent processes for promotion and hiring, mentorship, and sponsorship of women physicians for grand rounds, lectureships, committees, leadership positions, and awards. Achievement of equity for women physicians requires effort and ultimately a culture change. Gender equity in the medical profession will lead to improved physician wellness, retention of women physicians, and improved access to and quality of health care.