Statin-Associated Side Effects Thompson, Paul D., MD; Panza, Gregory, MS; Zaleski, Amanda, MS ...
Journal of the American College of Cardiology,
05/2016, Volume:
67, Issue:
20
Journal Article
Peer reviewed
Open access
Abstract Hydroxy-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors or statins are well tolerated, but associated with various statin-associated symptoms (SAS), including statin-associated ...muscle symptoms (SAMS), diabetes mellitus (DM), and central nervous system complaints. These are “statin-associated symptoms” because they are rare in clinical trials, making their causative relationship to statins unclear. SAS are, nevertheless, important because they prompt dose reduction or discontinuation of these life-saving mediations. SAMS is the most frequent SAS, and mild myalgia may affect 5% to 10% of statin users. Clinically important muscle symptoms, including rhabdomyolysis and statin-induced necrotizing autoimmune myopathy (SINAM), are rare. Antibodies against HMG-CoA reductase apparently provoke SINAM. Good evidence links statins to DM, but evidence linking statins to other SAS is largely anecdotal. Management of SAS requires making the possible diagnosis, altering or discontinuing the statin treatment, and using alternative lipid-lowering therapy.
New Scope of the Document Although reports on cardiovascular screening efficacy have predominantly involved populations of adolescents and young adults participating in competitive athletics, the ...context of the present discussion is intentionally (and necessarily) much more expansive. ...it is underscored that the present report is not limited in scope to universal mass screening for athlete populations but importantly includes considerations for screening large, young, and truly general populations (school-aged, 12-25 years old, of both sexes) with respect to relevant logistical, ethical, legal, and societal issues (e.g., in the United States or other countries or communities of various sizes, in schools, or in regional or military populations).
Statin therapy is associated with muscle problems in approximately 10% to 25% of patients treated in clinical practice, but muscle problems have rarely been reported in controlled clinical trials. We ...performed a systematic search and review of statin clinical trials to examine how these studies evaluated muscle problems and to determine why there are apparent differences in muscle problems between clinical trials and practice. We initially identified 1,012 reports related to clinical trials of statin therapy, 42 of which qualified for analysis. Fifteen, 4, and 22 trials reported creatine kinase values only >10, 5, and 3 times the upper limits of normal, respectively, in both statin- and placebo-treated participants. Four trials reported average creatine kinase values, which increased with statin treatment in 3 instances. Twenty-six trials reported muscle problems, with an average incidence in statin- and placebo-treated participants of 13%, but only one trial specifically queried about muscle problems. Three trials used a run-in period to eliminate participants with statin intolerance and noncompliance. The percentage of muscle problems tended to be higher with statin treatment (12.7%) than with placebo group (12.4%, P = .06). This small difference probably reflects a high background rate of nonspecific muscle problems in both groups that could not be distinguished from statin-associated myalgia because most clinical trials did not use a standard definition for statin myalgia.
Moderate to vigorous physical activity (MVPA) is strongly associated with risk reductions of noncommunicable diseases and mortality. Cardiovascular health status may influence the benefits of MVPA. ...We compare the association between MVPA and incident major adverse cardiovascular events (MACE) and mortality between healthy individuals, individuals with elevated levels of cardiovascular risk factors (CVRF), and cardiovascular disease (CVD).
A cohort study was performed in the 3 northern provinces of the Netherlands, in which data were collected between 2006 and 2018, with a median follow-up of 6.8 years (Q25 5.7; Q75 7.9). A total of 142,493 participants of the Lifelines Cohort Study were stratified at baseline as (1) healthy; (2) CVRF; or (3) CVD. Individuals were categorized into "inactive" and 4 quartiles of least (Q1) to most (Q4) active based on self-reported MVPA volumes. Primary outcome was a composite of incident MACE and all-cause mortality during follow-up. Cox regression was used to estimate hazard ratios (HRs), 95% confidence intervals (CIs) and P values. The main analyses were stratified on baseline health status and adjusted for age, sex, income, education, alcohol consumption, smoking, protein, fat and carbohydrate intake, kidney function, arrhythmias, hypothyroid, lung disease, osteoarthritis, and rheumatoid arthritis. The event rates were 2.2% in healthy individuals (n = 2,485 of n = 112,018), 7.9% in those with CVRF (n = 2,214 of n = 27,982) and 40.9% in those with CVD (n = 1,019 of n = 2,493). No linear association between MVPA and all-cause mortality or MACE was found for healthy individuals (P = 0.36) and individuals with CVRF (P = 0.86), but a linear association was demonstrated for individuals with CVD (P = 0.04). Adjusted HRs in healthy individuals were 0.81 (95% CI 0.64 to 1.02, P = 0.07), 0.71 (95% CI 0.56 to 0.89, P = 0.004), 0.72 (95% CI 0.57 to 0.91, P = 0.006), and 0.76 (95% CI 0.60 to 0.96, P = 0.02) for MVPA Q1 to Q4, respectively, compared to inactive individuals. In individuals with CVRF, HRs were 0.69 (95% CI 0.57 to 0.82, P < 0.001), 0.66 (95% CI 0.55 to 0.80, P < 0.001), 0.64 (95% CI 0.53 to 0.77, P < 0.001), and 0.69 (95% CI 0.57 to 0.84, P < 0.001) for MVPA Q1 to Q4, respectively, compared to inactive individuals. Finally, HRs for MVPA Q1 to Q4 compared to inactive individuals were 0.80 (95% CI 0.62 to 1.03, P = 0.09), 0.82 (95% CI 0.63 to 1.06, P = 0.13), 0.74 (95% CI 0.57 to 0.95, P = 0.02), and 0.70 (95% CI 0.53 to 0.93, P = 0.01) in CVD patients. Leisure MVPA was associated with the most health benefits, nonleisure MVPA with little health benefits, and occupational MVPA with no health benefits. Study limitations include its observational nature, self-report data about MVPA, and potentially residual confounding despite extensive adjustment for lifestyle risk factors and health-related factors.
MVPA is beneficial for reducing adverse outcomes, but the shape of the association depends on cardiovascular health status. A curvilinear association was found in healthy and CVRF individuals with a steep risk reduction at low to moderate MVPA volumes and benefits plateauing at high(er) MVPA volumes. CVD patients demonstrated a linear association, suggesting a constant reduction of risk with higher volumes of MVPA. Therefore, individuals with CVDs should be encouraged that "more is better" regarding MVPA. These findings may help to optimize exercise prescription to gain maximal benefits of a physically active lifestyle.
To test whether equivalent energy expenditure by moderate-intensity (eg, walking) and vigorous-intensity exercise (eg, running) provides equivalent health benefits.
We used the National Runners' ...(n=33 060) and Walkers' (n=15 945) Health Study cohorts to examine the effect of differences in exercise mode and thereby exercise intensity on coronary heart disease (CHD) risk factors. Baseline expenditure (metabolic equivant hours per day METh/d) was compared with self-reported, physician-diagnosed incident hypertension, hypercholesterolemia, diabetes mellitus, and CHD during 6.2 years follow-up. Running significantly decreased the risks for incident hypertension by 4.2% (P<10(-7)), hypercholesterolemia by 4.3% (P<10(-14)), diabetes mellitus by 12.1% (P<10(-5)), and CHD by 4.5% per METh/d (P=0.05). The corresponding reductions for walking were 7.2% (P<10(-6)), 7.0% (P<10(-8)), 12.3% (P<10(-4)), and 9.3% (P=0.01). Relative to <1.8 METh/d, the risk reductions for 1.8 to 3.6, 3.6 to 5.4, 5.4 to 7.2, and ≥7.2 METh/d were as follows: (1) 10.1%, 17.7%, 25.1%, and 34.9% from running and 14.0%, 23.8%, 21.8%, and 38.3% from walking for hypercholesterolemia; (2) 19.7%, 19.4%, 26.8%, and 39.8% from running and 14.7%, 19.1%, 23.6%, and 13.3% from walking for hypertension; and (3) 43.5%, 44.1%, 47.7%, and 68.2% from running, and 34.1%, 44.2% and 23.6% from walking for diabetes mellitus (walking >5.4 METh/d excluded for too few cases). The risk reductions were not significantly different for running than walking for diabetes mellitus (P=0.94), hypertension (P=0.06), or CHD (P=0.26), and only marginally greater for walking than running for hypercholesterolemia (P=0.04).
Equivalent energy expenditures by moderate (walking) and vigorous (running) exercise produced similar risk reductions for hypertension, hypercholesterolemia, diabetes mellitus, and possibly CHD.
The purpose of the American College of Sports Medicine's (ACSM) exercise preparticipation health screening process is to identify individuals who may be at elevated risk for exercise-related sudden ...cardiac death and/or acute myocardial infarction. Recent studies have suggested that using the current ACSM exercise preparticipation health screening guidelines can result in excessive physician referrals, possibly creating a barrier to exercise participation. In addition, there is considerable evidence that exercise is safe for most people and has many associated health and fitness benefits; exercise-related cardiovascular events are often preceded by warning signs/symptoms; and the cardiovascular risks associated with exercise lessen as individuals become more physically active/fit. Consequently, a scientific roundtable was convened by the ACSM in June 2014 to evaluate the current exercise preparticipation health screening recommendations. The roundtable proposed a new evidence-informed model for exercise preparticipation health screening on the basis of three factors: 1) the individual's current level of physical activity, 2) presence of signs or symptoms and/or known cardiovascular, metabolic, or renal disease, and 3) desired exercise intensity, as these variables have been identified as risk modulators of exercise-related cardiovascular events. Identifying cardiovascular disease risk factors remains an important objective of overall disease prevention and management, but risk factor profiling is no longer included in the exercise preparticipation health screening process. The new ACSM exercise preparticipation health screening recommendations reduce possible unnecessary barriers to adopting and maintaining a regular exercise program, a lifestyle of habitual physical activity, or both, and thereby emphasize the important public health message that regular physical activity is important for all individuals.
Isopentenyl pyrophosphate (IPP) toxicity presents a challenge in engineered microbial systems since its formation is unavoidable in terpene biosynthesis. In this work, we develop an experimental ...platform to study IPP toxicity in isoprenol-producing Escherichia coli. We first characterize the physiological response to IPP accumulation, demonstrating that elevated IPP levels are linked to growth inhibition, reduced cell viability, and plasmid instability. We show that IPP toxicity selects for pathway “breakage”, using proteomics to identify a reduction in phosphomevalonate kinase (PMK) as a probable recovery mechanism. Next, using multi-omics data, we demonstrate that endogenous E. coli metabolism is globally impacted by IPP accumulation, which slows nutrient uptake, decreases ATP levels, and perturbs nucleotide metabolism. We also observe the extracellular accumulation of IPP and present preliminary evidence that IPP can be transported by E. coli, findings that might be broadly relevant for the study of isoprenoid biosynthesis. Finally, we discover that IPP accumulation leads to the formation of ApppI, a nucleotide analog of IPP that may contribute to observed toxicity phenotypes. This comprehensive assessment of IPP stress suggests potential strategies for the alleviation of prenyl diphosphate toxicity and highlights possible engineering targets for improved IPP flux and high titer isoprenoid production.
•Three strains at various IPP accumulation levels were comparatively analyzed.•IPP accumulation was linked to decreased cell viability and nutrient uptake.•IPP-induced pathway “breakage” was characterized using multi-omics data.•Nucleotide metabolism and ATP synthesis were perturbed by IPP accumulation.•A nucleotide analog of IPP was identified as a possible contributor to toxicity.
Test whether: 1) walking intensity predicts mortality when adjusted for walking energy expenditure, and 2) slow walking pace (≥24-minute mile) identifies subjects at substantially elevated risk for ...mortality.
Hazard ratios from Cox proportional survival analyses of all-cause and cause-specific mortality vs. usual walking pace (min/mile) in 7,374 male and 31,607 female recreational walkers. Survival times were left censored for age at entry into the study. Other causes of death were treated as a competing risk for the analyses of cause-specific mortality. All analyses were adjusted for sex, education, baseline smoking, prior heart attack, aspirin use, diet, BMI, and walking energy expenditure. Deaths within one year of baseline were excluded.
The National Death Index identified 1968 deaths during the average 9.4-year mortality surveillance. Each additional minute per mile in walking pace was associated with an increased risk of mortality due to all causes (1.8% increase, P=10(-5)), cardiovascular diseases (2.4% increase, P=0.001, 637 deaths), ischemic heart disease (2.8% increase, P=0.003, 336 deaths), heart failure (6.5% increase, P=0.001, 36 deaths), hypertensive heart disease (6.2% increase, P=0.01, 31 deaths), diabetes (6.3% increase, P=0.004, 32 deaths), and dementia (6.6% increase, P=0.0004, 44 deaths). Those reporting a pace slower than a 24-minute mile were at increased risk for mortality due to all-causes (44.3% increased risk, P=0.0001), cardiovascular diseases (43.9% increased risk, P=0.03), and dementia (5.0-fold increased risk, P=0.0002) even though they satisfied the current exercise recommendations by walking ≥7.5 metabolic equivalent (MET)-hours per week.
The risk for mortality: 1) decreases in association with walking intensity, and 2) increases substantially in association for walking pace ≥24 minute mile (equivalent to <400 m during a six-minute walk test) even among subjects who exercise regularly.
PDF
