Connie B. Newman

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.

Lack of effect of lowering LDL cholesterol on cancer: meta-analysis of individual data from 175,000 people in 27 randomised trials of statin therapy.

Background Statin therapy reduces the risk of occlusive vascular events, but uncertainty remains about potential effects on cancer. We sought to provide a detailed assessment of any effects on cancer of lowering LDL cholesterol (LDL-C) with a statin using individual patient records from 175,000 patients in 27 large-scale statin trials. Methods and Findings Individual records of 134,537 participants in 22 randomised trials of statin versus control (median duration 4.8 years) and 39,612 participants in 5 trials of more intensive versus less intensive statin therapy (median duration 5.1 years) were obtained. Reducing LDL-C with a statin for about 5 years had no effect on newly diagnosed cancer or on death from such cancers in either the trials of statin versus control (cancer incidence: 3755 [1.4% per year [py]] versus 3738 [1.4% py], RR 1.00 [95% CI 0.96-1.05]; cancer mortality: 1365 [0.5% py] versus 1358 [0.5% py], RR 1.00 [95% CI 0.93–1.08]) or in the trials of more versus less statin (cancer incidence: 1466 [1.6% py] vs 1472 [1.6% py], RR 1.00 [95% CI 0.93–1.07]; cancer mortality: 447 [0.5% py] versus 481 [0.5% py], RR 0.93 [95% CI 0.82–1.06]). Moreover, there was no evidence of any effect of reducing LDL-C with statin therapy on cancer incidence or mortality at any of 23 individual categories of sites, with increasing years of treatment, for any individual statin, or in any given subgroup. In particular, among individuals with low baseline LDL-C (<2 mmol/L), there was no evidence that further LDL-C reduction (from about 1.7 to 1.3 mmol/L) increased cancer risk (381 [1.6% py] versus 408 [1.7% py]; RR 0.92 [99% CI 0.76–1.10]). Conclusions In 27 randomised trials, a median of five years of statin therapy had no effect on the incidence of, or mortality from, any type of cancer (or the aggregate of all cancer).

MEDICAL THERAPY FOR ACROMEGALY

Both somatostatin analogues, which bind to the somatostatin receptor subtypes 2 and 5, and dopamine agonists, which are specific for the D2 receptor, have been used to treat acromegaly. Each of these classes of drugs contains several compounds that vary in duration of action, efficacy, and side effect profile. Although somatostatin analogues reduce GH levels and alleviate symptoms in most patients and restore IGF-1 levels to normal in 60% to 65% of patients, tumor shrinkage is limited to 40% of patients. evidence in the literature supports the use of these medications as secondary therapy in patients with acromegaly who have had surgery and who continue to have elevated GH levels (above 2 ng/mL during an oral glucose tolerance test) with or without IGF-1 concentrations that are above the upper limit of normal for age. In addition, medical therapy indicated in patients who refuse surgery and in patients who are poor surgical candidates. The controversial question is whether medical therapy should be an option for primary treatment of the acromegalic patient. Currently, ther are no data from prospective randomized trials comparing the effects of surgery versus somatostatin analogues as first-line therapy for for newly diagnosed acromegalic patients. Limited data from nonrandomized studies demonstrate that somatostatin analogues are effective long-term in suppressing GH and reducing IGF-1 into the normal range in approximately two-thirds of patients who have never undergone previous treatment. It is still the consensus that patients with GH-secreting microadenomas should undergo surgical resection, because the likelihood of complete cure by an experience neurosurgeon is high, at least 70% or greater. Successful surgical treatment has the advantage of completely removing the tumor in contrast to medical therapy, which rarely produces shrinkage greater than 50% despite the fact that IGF-1 and GH levels may be normal. In patients with macroadenomas of a size and location that suggest that the chance of complete resection is 40% or less, primary treatment with a somatostatin analogue should be considered as one option in the initial management of the patient. Another option in such an individual would be surgical debulking followed by medical therapy, because it is theoretically possible that biochemical cure with medical therapy after surgical debulking might be achieved with lower doses. The cost-effectiveness of these approaches has not yet been determined. Once the decision has been made to begin medical therapy, a choice must be made between dopamine agonists and somatostatin analogues. Most evidence suggests that somatostatin analogues are more effective than dopamine agonists and therefore would be the therapy of choice. In select patients, dopamine agonists, particularly the long-acting agonist cabergoline, may be preferred initially if the patient is unwilling to take injections or if the GH elevations are relatively modest (< 10 ng/mL). Biochemical cure should be assessed by measurement of GH (which can be performed 2 hours after an octreotide injection) and IGF-1 concentrations. The goal of treatment include reduction of of GH below 2 ng/mL and reduction of IGF-1 into the normal range. In patients who do not reach these goals, the dose or frequency of injection of the somatostatin analogue or both should be increased. If such measures are unsuccessful, a dopamine agonist may be added to the medical regimen because some studies suggest that combination therapy may be more effective in select cases than octreotide therapy alone. If such measures are still unsuccessful, other options should be considered, including surgery, pituitary radiation, and medical treatment with investigational drugs.

Targets of Statin Therapy : LDL Cholesterol, Non-HDL Cholesterol, and Apolipoprotein B in Type 2 Diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS)

BACKGROUND LDL can vary considerably in its cholesterol content; thus, lowering LDL cholesterol (LDLC) as a goal of statin treatment implies the existence of considerable variation in the extent to which statin treatment removes circulating LDL particles. This consideration is particularly applicable in diabetes mellitus, in which LDL is frequently depleted of cholesterol. METHODS Type 2 diabetes patients randomly allocated to 10 mg/day atorvastatin (n = 1154) or to placebo (n = 1196) for 1 year were studied to compare spontaneous and statin-induced apolipoprotein B (apo B) concentrations (a measure of LDL particle concentration) at LDLC and non-HDL cholesterol (non-HDLC) concentrations proposed as statin targets in type 2 diabetes. RESULTS Patients treated with atorvastatin produced lower serum apo B concentrations at any given LDLC concentration than patients on placebo. An LDLC concentration of 1.8 mmol/L (70 mg/dL) during atorvastatin treatment was equivalent to a non-HDLC concentration of 2.59 mmol/L (100 mg/dL) or an apo B concentration of 0.8 g/L. At the more conservative LDLC targets of 2.59 mmol/L (100 mg/dL) and 3.37 mmol/L (130 mg/dL) for non-HDLC, however, the apo B concentration exceeded the 0.9-g/L value anticipated in the recent Consensus Statement from the American Diabetes Association and the American College of Cardiology. CONCLUSIONS The apo B concentration provides a more consistent goal for statin treatment than the LDLC or non-HDLC concentration.

Treatment Gaps in Adults with Heterozygous Familial Hypercholesterolemia in the United States: Data from the CASCADE-FH Registry

Background— Cardiovascular disease burden and treatment patterns among patients with familial hypercholesterolemia (FH) in the United States remain poorly described. In 2013, the FH Foundation launched the Cascade Screening for Awareness and Detection (CASCADE) of FH Registry to address this knowledge gap. Methods and Results— We conducted a cross-sectional analysis of 1295 adults with heterozygous FH enrolled in the CASCADE-FH Registry from 11 US lipid clinics. Median age at initiation of lipid-lowering therapy was 39 years, and median age at FH diagnosis was 47 years. Prevalent coronary heart disease was reported in 36% of patients, and 61% exhibited 1 or more modifiable risk factors. Median untreated low-density lipoprotein cholesterol (LDL-C) was 239 mg/dL. At enrollment, median LDL-C was 141 mg/dL; 42% of patients were taking high-intensity statin therapy and 45% received >1 LDL-lowering medication. Among FH patients receiving LDL-lowering medication(s), 25% achieved an LDL-C <100 mg/dL and 41% achieved a ≥50% LDL-C reduction. Factors associated with prevalent coronary heart disease included diabetes mellitus (adjusted odds ratio 1.74; 95% confidence interval 1.08–2.82) and hypertension (2.48; 1.92–3.21). Factors associated with a ≥50% LDL-C reduction from untreated levels included high-intensity statin use (7.33; 1.86–28.86) and use of >1 LDL-lowering medication (1.80; 1.34–2.41). Conclusions— FH patients in the CASCADE-FH Registry are diagnosed late in life and often do not achieve adequate LDL-C lowering, despite a high prevalence of coronary heart disease and risk factors. These findings highlight the need for earlier diagnosis of FH and initiation of lipid-lowering therapy, more consistent use of guideline-recommended LDL-lowering therapy, and comprehensive management of traditional coronary heart disease risk factors.

Statin Intolerance: Reconciling Clinical Trials and Clinical Experience

Since their introduction in 1987, statins have accumulated an extensive amount of data in randomized clinical trials and clinical use. The studies included in the Cholesterol Treatment Trialists’ (CTT) Collaboration meta-analyses have shown that statins are clearly effective in reducing the risk of major atherosclerotic cardiovascular events1 and that the cardiovascular benefits outweigh the risks of treatment. Several statins are available in generic form and are therefore cost-effective. However, for a significant number of patients statin therapy is discontinued because of intolerance, ie, adverse events perceived to be caused by the statin, most commonly muscle pain, aching, or weakness, usually without significant elevations in levels of creatine kinase.2 All statins can cause myopathy, defined here and in the prescribing information for most statins as unexplained muscle pain or weakness accompanied by creatine kinase levels increased to more than 10 times the upper limit of normal. Prompt discontinuation of statins is mandatory in cases of suspected myopathy or its severe form, rhabdomyolysis. However, in large, longterm clinical trials, muscle adverse events of lesser clinical significance occur at similar rates, regardless of allocation to statin or placebo. This is shown in the Table, which includes placebo-controlled trials in the CTT meta-analysis1 that reported nonserious muscle adverse events, plus the SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol) trial,3 which was not available for the meta-analysis but is included because it used the maximal atorvastatin dose (80 mg). In recent years, concerns have been raised that the trials of cardiovascular outcomes with statins, which include more than 170 000 patients,1 do not reflect clinical practiceandthereforefailtoreliablyassessadverseeffects. Maningat and Breslow4 call for “pragmatic” clinical trials, in which the rigor of the double-blind placebo-controlled trial is sacrificed, for example by having no placebo, for the sake of generalizability. Some suggest that observational datamaybemorerepresentativeofreal-worldclinicalpractice, including clinicians who find that many patients discontinue statins because of adverse events, most commonly muscle adverse events, which reportedly occur in as many as 10% to 20% of patients.2,4,5 In this Viewpoint, we attempt to account for and explain the discrepancy between clinical trials and clinical practice. A frequent objection to reliance on the trials of outcomes with statins is that trials exclude many patients who would be prescribed a statin in clinical practice. These trials excluded patients unlikely to adhere to the demands of a long-term study and those taking known interacting drugs, but otherwise they include a broad array of patient types. The randomized patients included in the trials in the CTT meta-analysis include substantial numbers of women, elderly patients, and patients with coronary heart disease, stroke, diabetes, or endstage renal disease.1 This is not a patient population selected to minimize adverse events. Muscle symptoms (muscle aches, pain, or weakness) are subjective and have a high background prevalence in middle-aged or elderly patients. In the HPS (Heart Protection Study),6 participants were directly questioned at every visit about muscle adverse events; one-third reported these symptoms at least once, regardless of treatment group allocation. The risk of myopathy and rhabdomyolysis is prominent in patient information leaflets for statins, and clinicians warn patients to report muscle symptoms; furthermore, social media are replete with misinformation about statin adverse events, attributing causality without evidence. Therefore, it is likely that some patients will associate background muscle adverse events with their statin use. In a retrospective cohort study in eastern Massachusetts,7 18 778 of 107 835 statin-treated patients (17%) experienced a statin-related adverse event (40% musculoskeletal). Of these patients, 11 124 discontinued their statin and 6579 were rechallenged with a statin, with 92% success in restoring statin therapy, although not necessarily at the same dose or using the same statin. The high success rate is consistent with nonpharmacological mechanisms for the intolerance. Recently, preliminary but informative results were reported8 from a double-blind study enrolling 361 patients unable to tolerate at least 2 statins because of muscle symptoms (including 1 statin at its lowest dose). After a 4-week placebo run-in period, patients were randomly allocated to the proprotein convertase subtilisin/ kexin type 9 (PCSK9) monoclonal antibody alirocumab, the cholesterol absorption inhibitor ezetimibe, or atorvastatin (20 mg) for 24 weeks. Twenty-five patients (7%) withdrew because of muscle adverse events during the placebo run-in period, and after randomization 16% in the alirocumab group, 20% in the ezetimibe group, and 22% in the atorvastatin group withdrew due to muscle adverse events (P > .20); 82%, 75%, and 75% of study participants in these 3 groups, respectively, did not have an adverse event of any type causing discontinuation. Under the double-blind conditions of this study, patients deemed statin-intolerant because of muscle adverse events withdrew because of muscle adverse events at similar rates regardless of treatment group allocation, and most patients could tolerate atorvastatin when they did not know they were taking it. Together with the data in the Table and the observation that in clinical practice more than 90% of statin-intolerant patients can be successfully rechallenged,7 these findings suggest that statin intolerance is usually not of pharmacological origin. It is VIEWPOINT

The safety and tolerability of atorvastatin 10 mg in the Collaborative Atorvastatin Diabetes Study (CARDS)

The objective of this study was to evaluate the safety and tolerability of atorvastatin 10 mg compared with placebo in 2,838 patients with type 2 diabetes and no history of coronary heart disease who were enrolled in the Collaborative Atorvastatin Diabetes Study (CARDS) and followed for 3.9 years. The percentages of patients experiencing treatment-associated adverse events (AEs), serious AEs and discontinuations due to AEs in the atorvastatin (n=1,428) and placebo (n=1,410) groups were 23.0% vs. 25.4%, 1.1% vs. 1.1% and 2.9% vs. 3.4%, respectively. The most common treatment-associated AEs in the atorvastatin and placebo groups were digestive system-related (8.9% vs. 10.0%). All-cause and treatment-associated myalgia were reported in 4.0% and 1.0% of atorvastatin-treated patients, and 4.8% and 1.2% of placebo-treated patients. An analysis of selected AEs by tertiles of baseline low-density lipoprotein (LDL) cholesterol showed no relationship between LDL cholesterol levels and the incidence of myalgia, cancer or nervous system AEs in either treatment group. Overall, these data demonstrate that atorvastatin 10 mg was well tolerated in patients with type 2 diabetes during long-term treatment.

The nocebo effect in the context of statin intolerance

The nocebo effect, the inverse of the placebo effect, is a well-established phenomenon that is under-appreciated in cardiovascular medicine. It refers to adverse events, usually purely subjective, that result from expectations of harm from a drug, placebo, other therapeutic intervention or a nonmedical situation. These expectations can be driven by many factors including the informed consent form in a clinical trial, warnings about adverse effects communicated by clinicians when prescribing a drug, and information in the media about the dangers of certain treatments. The nocebo effect is the best explanation for the high rate of muscle and other symptoms attributed to statins in observational studies and clinical practice, but not in randomized controlled trials, where muscle symptoms, and rates of discontinuation due to any adverse event, are generally similar in the statin and placebo groups. Statin-intolerant patients usually tolerate statins under double-blind conditions, indicating that the intolerance has little if any pharmacological basis. Known techniques for minimizing the nocebo effect can be applied to the prevention and management of statin intolerance.

Statin tolerability: In defence of placebo-controlled trials

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.

Moderate Doses of hGH (0.64 mg/d) Improve Lipids But Not Cardiovascular Function in GH-Deficient Adults with Normal Baseline Cardiac Function

CONTEXT Data regarding effects of lower-dose GH on cardiopulmonary function in GH-deficient (GHD) adults are limited. OBJECTIVES The objective was to assess effects of lower-dose GH on exercise capacity and echocardiographic parameters in GHD adults. DESIGN The study was a 6-month double-blind, placebo-controlled randomized trial. SETTING The study was conducted at the General Clinical Research Center. PARTICIPANTS Thirty hypopituitary adults with GHD were studied. INTERVENTION Subjects were randomized to recombinant human GH or placebo for 6 months, followed by open-label recombinant human GH for 12 months. MAIN OUTCOME MEASURES Primary endpoints were exercise duration, maximal oxygen consumption, and left ventricular ejection fraction. Secondary endpoints were echocardiographic indices of systolic and diastolic function, left ventricular mass, lipids, and body composition. RESULTS In the 6-month double-blind phase, mean GH dose was 0.64 mg/d. Mean IGF-I sd score increased from -4.5 to -1.0. Exercise duration, maximal oxygen consumption, left ventricular ejection fraction, and other echocardiographic parameters were normal at baseline and did not change. GH decreased total and low-density lipoprotein cholesterol by 7.5% (P = 0.016) and 14.7% (P = 0.002) (P = 0.04 vs. placebo). Mean lean body mass increased by 2.2 kg (P = 0.004), fat mass decreased by 1.7 kg (P = 0.21), and percent body fat decreased by 2.5% (P = 0.018), although between-group changes were not significant. CONCLUSIONS Human GH did not improve exercise performance or echocardiographic parameters or decrease fat mass but significantly decreased total and low-density lipoprotein cholesterol, increased IGF-I, and increased lean body mass. These results indicate that responses to human GH are variable and should be assessed at baseline and during treatment.