Statins and their effect on cognition

Gauthier, Jeremie; Massicotte, Anne

doi:10.1177/1715163515578692

Cited by 18 publications

(13 citation statements)

References 11 publications

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“…There are case reports documenting mild and reversible impaired cognitive function in patients receiving statins . The results of several large meta‐analyses, however, seem to suggest no increase in risk, and a causal link with statin treatment has not been established . In 2014, the US Food and Drug Administration (FDA) requested that the feasibility of including analysis of neurocognitive AEs in late‐stage clinical trials of anti‐PCSK9 antibodies be assessed .…”

Section: Resultsmentioning

confidence: 99%

Anti-PCSK9 antibodies for hypercholesterolaemia: Overview of clinical data and implications for primary care

et al. 2017

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SummaryObjectivesTo put data from our recent systematic review of phase 3 studies of anti‐proprotein convertase subtilisin/kexin type 9 (PCSK9) antibodies into the context of clinical practice.MethodsData from studies previously identified by a systematic review of phase 3 studies of alirocumab and evolocumab and additional references from non‐systematic literature searches were used. We evaluated the hypothetical cardiovascular (CV) benefit in cases of typical patients in whom anti‐PCSK9 antibodies may be recommended, using preliminary major CV event (CVE) rates from long‐term clinical trials of anti‐PCSK9 antibodies and from extrapolations derived from correlation between low‐density lipoprotein cholesterol (LDL‐C) reduction and CV benefit with other lipid‐lowering therapies (LLTs).ResultsRapid (within 1‐2 weeks) and persistent (8‐74 weeks) reductions in LDL‐C levels were achieved with anti‐PCSK9 antibodies. When combined with statins (± ezetimibe), high rates of LDL‐C goal achievement were observed (41%‐87% with alirocumab and 63%‐100% with evolocumab). In long‐term alirocumab and evolocumab studies, reductions in major CVEs of 48% and 53%, respectively, were observed. For every 38.7 mg/dL (1 mmol/L) reduction in LDL‐C, a 22% reduction in relative CVE risk is predicted. Applying these assumptions to typical patients who have high–very high risk (15%‐60% absolute 10‐year CVE risk) and elevated LDL‐C despite maximally tolerated statins, the 10‐year number needed to treat with an anti‐PCSK9 antibody to prevent one additional CVE varies from 4 to 26, depending on baseline LDL‐C levels and residual absolute CVE risk.ConclusionsAnti‐PCSK9 antibodies effectively lower LDL‐C levels in a broad patient population. While awaiting comprehensive data from CV outcome trials, these agents should be considered in very high risk patients, such as those in secondary prevention and those with familial hypercholesterolaemia who are already receiving maximally tolerated LLTs, have not achieved their LDL‐C goal and require substantial reductions in LDL‐C.

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Section: Resultsmentioning

confidence: 99%

Anti-PCSK9 antibodies for hypercholesterolaemia: Overview of clinical data and implications for primary care

et al. 2017

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“…Adverse effects on energy levels and exertional fatigue [53] and reduced exercise capacity [54] have been reported, but not confirmed [55]. Similarly, there have been post-marketing case reports of statin-induced memory loss and confusion, although overall, statins are not currently thought to cause cognitive dysfunction [56,57].…”

Section: Introductionmentioning

confidence: 99%

Statin-Related Myotoxicity: A Comprehensive Review of Pharmacokinetic, Pharmacogenomic and Muscle Components

Turner

Pirmohamed

2019

JCM

146

126

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Statins are a cornerstone in the pharmacological prevention of cardiovascular disease. Although generally well tolerated, a small subset of patients experience statin-related myotoxicity (SRM). SRM is heterogeneous in presentation; phenotypes include the relatively more common myalgias, infrequent myopathies, and rare rhabdomyolysis. Very rarely, statins induce an anti-HMGCR positive immune-mediated necrotizing myopathy. Diagnosing SRM in clinical practice can be challenging, particularly for mild SRM that is frequently due to alternative aetiologies and the nocebo effect. Nevertheless, SRM can directly harm patients and lead to statin discontinuation/non-adherence, which increases the risk of cardiovascular events. Several factors increase systemic statin exposure and predispose to SRM, including advanced age, concomitant medications, and the nonsynonymous variant, rs4149056, in SLCO1B1, which encodes the hepatic sinusoidal transporter, OATP1B1. Increased exposure of skeletal muscle to statins increases the risk of mitochondrial dysfunction, calcium signalling disruption, reduced prenylation, atrogin-1 mediated atrophy and pro-apoptotic signalling. Rare variants in several metabolic myopathy genes including CACNA1S, CPT2, LPIN1, PYGM and RYR1 increase myopathy/rhabdomyolysis risk following statin exposure. The immune system is implicated in both conventional statin intolerance/myotoxicity via LILRB5 rs12975366, and a strong association exists between HLA-DRB1*11:01 and anti-HMGCR positive myopathy. Epigenetic factors (miR-499-5p, miR-145) have also been implicated in statin myotoxicity. SRM remains a challenge to the safe and effective use of statins, although consensus strategies to manage SRM have been proposed. Further research is required, including stringent phenotyping of mild SRM through N-of-1 trials coupled to systems pharmacology omics- approaches to identify novel risk factors and provide mechanistic insight.

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“…13 In contrast to the observational studies, meta-analyses of randomized trials have not demonstrated an adverse effect of statins on cognition. [14][15][16][17] We have previously reported the results of the Heart Outcomes Prevention Evaluation-3 (HOPE-3) trial, which examined the effects of BP lowering with candesartan plus hydrochlorothiazide and cholesterol lowering with rosuvastatin compared to placebo on major vascular events in patients at intermediate cardiovascular risk with no prior cardiovascular disease (CVD). This group represents a large proportion of middle-aged and older persons.…”

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confidence: 99%

Effects of blood pressure and lipid lowering on cognition

et al. 2019

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ObjectiveTo assess whether long-term treatment with candesartan/hydrochlorothiazide, rosuvastatin, or their combination can slow cognitive decline in older people at intermediate cardiovascular risk.MethodsThe Heart Outcomes Prevention Evaluation-3 (HOPE-3) study was a double-blind, randomized, placebo-controlled clinical trial using a 2 × 2 factorial design. Participants without known cardiovascular disease or need for treatment were randomized to candesartan (16 mg) plus hydrochlorothiazide (12.5 mg) or placebo and to rosuvastatin (10 mg) or placebo. Participants who were ≥70 years of age completed the Digit Symbol Substitution Test (DSST), the modified Montreal Cognitive Assessment, and the Trail Making Test Part B at baseline and study end.ResultsCognitive assessments were completed by 2,361 participants from 228 centers in 21 countries. Compared with placebo, candesartan/hydrochlorothiazide reduced systolic blood pressure by 6.0 mm Hg, and rosuvastatin reduced low-density lipoprotein cholesterol by 24.8 mg/dL. Participants were followed up for 5.7 years (median), and 1,626 completed both baseline and study-end assessments. Mean participant age was 74 years (SD ±3.5 years); 59% were women; 45% had hypertension; and 24% had ≥12 years of education. The mean difference in change in DSST scores was −0.91 (95% confidence interval [CI] −2.25 to 0.42) for candesartan/hydrochlorothiazide compared with placebo, −0.54 (95% CI −1.88 to 0.80) for rosuvastatin compared with placebo, and −1.43 (95% CI −3.37 to 0.50) for combination therapy vs double placebo. No significant differences were found for other measures.ConclusionsLong-term blood pressure lowering with candesartan plus hydrochlorothiazide, rosuvastatin, or their combination did not significantly affect cognitive decline in older people.ClinicalTrials.gov identifierNCT00468923.Classification of evidenceThis study provides Class II evidence that for older people, candesartan plus hydrochlorothiazide, rosuvastatin, or their combination does not significantly affect cognitive decline.

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Statins and their effect on cognition

Cited by 18 publications

References 11 publications

Anti-PCSK9 antibodies for hypercholesterolaemia: Overview of clinical data and implications for primary care

Anti-PCSK9 antibodies for hypercholesterolaemia: Overview of clinical data and implications for primary care

Statin-Related Myotoxicity: A Comprehensive Review of Pharmacokinetic, Pharmacogenomic and Muscle Components

Effects of blood pressure and lipid lowering on cognition

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