Adverse effects of statin therapy: perception vs. the evidence - focus on glucose homeostasis, cognitive, renal and hepatic function, haemorrhagic stroke and cataract

Aims: To objectively appraise evidence for possible adverse effects of long-term statin therapy on glucose homeostasis, cognitive, renal and hepatic function, and risk for haemorrhagic stroke or cataract. Methods and results: A literature search covering 2000-2017 was performed. The Panel critically appraised the data and agreed by consensus on the categorization of reported adverse effects. Randomized controlled trials (RCTs) and genetic studies show that statin therapy is associated with a modest increase in the risk of new-onset diabetes mellitus (about one per thousand patient-years), generally defined by laboratory findings (glycated haemoglobin ≥6.5); this risk is significantly higher in the metabolic syndrome or prediabetes. Statin treatment does not adversely affect cognitive function, even at very low levels of low-density lipoprotein cholesterol and is not associated with clinically significant deterioration of renal function, or development of cataract. Transient increases in liver enzymes occur in 0.5-2% of patients taking statins but are not clinically relevant; idiosyncratic liver injury due to statins is very rare and causality difficult to prove. The evidence base does not support an increased risk of haemorrhagic stroke in individuals without cerebrovascular disease; a small increase in risk was suggested by the Stroke Prevention by Aggressive Reduction of Cholesterol Levels study in subjects with prior stroke but has not been confirmed in the substantive evidence base of RCTs, cohort studies and case-control studies. Conclusion: Long-term statin treatment is remarkably safe with a low risk of clinically relevant adverse effects as defined above; statin-associated muscle symptoms were discussed in a previous Consensus Statement. Importantly, the established cardiovascular benefits of statin therapy far outweigh the risk of adverse effects

A Differential Network Approach to Exploring Differences between Biological States: An Application to Prediabetes

Background: Variations in the pattern of molecular associations are observed during disease development. The comprehensive analysis of molecular association patterns and their changes in relation to different physiological conditions can yield insight into the biological basis of disease-specific phenotype variation. Methodology: Here, we introduce a formal statistical method for the differential analysis of molecular associations via network representation. We illustrate our approach with extensive data on lipoprotein subclasses measured by NMR spectroscopy in 4,406 individuals with normal fasting glucose, and 531 subjects with impaired fasting glucose (prediabetes). We estimate the pair-wise association between measures using shrinkage estimates of partial correlations and build the differential network based on this measure of association. We explore the topological properties of the inferred network to gain insight into important metabolic differences between individuals with normal fasting glucose and prediabetes. Conclusions/Significance: Differential networks provide new insights characterizing differences in biological states. Based on conventional statistical methods, few differences in concentration levels of lipoprotein subclasses were found between individuals with normal fasting glucose and individuals with prediabetes. By performing the differential analysis of networks, several characteristic changes in lipoprotein metabolism known to be related to diabetic dyslipidemias were identified. The results demonstrate the applicability of the new approach to identify key molecular changes inaccessible to standard approaches

A detailed Hapmap of the Sitosterolemia locus spanning 69 kb; differences between Caucasians and African-Americans

BACKGROUND: Sitosterolemia is an autosomal recessive disorder that maps to the sitosterolemia locus, STSL, on human chromosome 2p21. Two genes, ABCG5 and ABCG8, comprise the STSL and mutations in either cause sitosterolemia. ABCG5 and ABCG8 are thought to have evolved by gene duplication event and are arranged in a head-to-head configuration. We report here a detailed characterization of the STSL in Caucasian and African-American cohorts. METHODS: Caucasian and African-American DNA samples were genotypes for polymorphisms at the STSL locus and haplotype structures determined for this locus RESULTS: In the Caucasian population, 13 variant single nucleotide polymorphisms (SNPs) were identified and resulting in 24 different haplotypes, compared to 11 SNPs in African-Americans resulting in 40 haplotypes. Three polymorphisms in ABCG8 were unique to the Caucasian population (E238L, INT10-50 and G575R), whereas one variant (A259V) was unique to the African-American population. Allele frequencies of SNPs varied also between these populations. CONCLUSION: We confirmed that despite their close proximity to each other, significantly more variations are present in ABCG8 compared to ABCG5. Pairwise D' values showed wide ranges of variation, indicating some of the SNPs were in strong linkage disequilibrium (LD) and some were not. LD was more prevalent in Caucasians than in African-Americans, as would be expected. These data will be useful in analyzing the proposed role of STSL in processes ranging from responsiveness to cholesterol-lowering drugs to selective sterol absorption

Dynamics of Lamin-A Processing Following Precursor Accumulation

Lamin A (LaA) is a component of the nuclear lamina, an intermediate filament meshwork that underlies the inner nuclear membrane (INM) of the nuclear envelope (NE). Newly synthesized prelamin A (PreA) undergoes extensive processing involving C-terminal farnesylation followed by proteolysis yielding non-farnesylated mature lamin A. Different inhibitors of these processing events are currently used therapeutically. Hutchinson-Gilford Progeria Syndrome (HGPS) is most commonly caused by mutations leading to an accumulation of a farnesylated LaA isoform, prompting a clinical trial using farnesyltransferase inhibitors (FTI) to reduce this modification. At therapeutic levels, HIV protease inhibitors (PI) can unexpectedly inhibit the final processing step in PreA maturation. We have examined the dynamics of LaA processing and associated cellular effects during PI or FTI treatment and following inhibitor washout. While PI reversibility was rapid, with respect to both LaA maturation and associated cellular phenotype, recovery from FTI treatment was more gradual. FTI reversibility is influenced by both cell type and rate of proliferation. These results suggest a less static lamin network than has previously been observed

Familial hypercholesterolaemia in children and adolescents from 48 countries: a cross-sectional study

Background Approximately 450 000 children are born with familial hypercholesterolaemia worldwide every year, yet only 2·1% of adults with familial hypercholesterolaemia were diagnosed before age 18 years via current diagnostic approaches, which are derived from observations in adults. We aimed to characterise children and adolescents with heterozygous familial hypercholesterolaemia (HeFH) and understand current approaches to the identification and management of familial hypercholesterolaemia to inform future public health strategies. Methods For this cross-sectional study, we assessed children and adolescents younger than 18 years with a clinical or genetic diagnosis of HeFH at the time of entry into the Familial Hypercholesterolaemia Studies Collaboration (FHSC) registry between Oct 1, 2015, and Jan 31, 2021. Data in the registry were collected from 55 regional or national registries in 48 countries. Diagnoses relying on self-reported history of familial hypercholesterolaemia and suspected secondary hypercholesterolaemia were excluded from the registry; people with untreated LDL cholesterol (LDL-C) of at least 13·0 mmol/L were excluded from this study. Data were assessed overall and by WHO region, World Bank country income status, age, diagnostic criteria, and index-case status. The main outcome of this study was to assess current identification and management of children and adolescents with familial hypercholesterolaemia. Findings Of 63 093 individuals in the FHSC registry, 11 848 (18·8%) were children or adolescents younger than 18 years with HeFH and were included in this study; 5756 (50·2%) of 11 476 included individuals were female and 5720 (49·8%) were male. Sex data were missing for 372 (3·1%) of 11 848 individuals. Median age at registry entry was 9·6 years (IQR 5·8–13·2). 10 099 (89·9%) of 11 235 included individuals had a final genetically confirmed diagnosis of familial hypercholesterolaemia and 1136 (10·1%) had a clinical diagnosis. Genetically confirmed diagnosis data or clinical diagnosis data were missing for 613 (5·2%) of 11 848 individuals. Genetic diagnosis was more common in children and adolescents from high-income countries (9427 [92·4%] of 10 202) than in children and adolescents from non-high-income countries (199 [48·0%] of 415). 3414 (31·6%) of 10 804 children or adolescents were index cases. Familial-hypercholesterolaemia-related physical signs, cardiovascular risk factors, and cardiovascular disease were uncommon, but were more common in non-high-income countries. 7557 (72·4%) of 10 428 included children or adolescents were not taking lipid-lowering medication (LLM) and had a median LDL-C of 5·00 mmol/L (IQR 4·05–6·08). Compared with genetic diagnosis, the use of unadapted clinical criteria intended for use in adults and reliant on more extreme phenotypes could result in 50–75% of children and adolescents with familial hypercholesterolaemia not being identified. Interpretation Clinical characteristics observed in adults with familial hypercholesterolaemia are uncommon in children and adolescents with familial hypercholesterolaemia, hence detection in this age group relies on measurement of LDL-C and genetic confirmation. Where genetic testing is unavailable, increased availability and use of LDL-C measurements in the first few years of life could help reduce the current gap between prevalence and detection, enabling increased use of combination LLM to reach recommended LDL-C targets early in life. Funding Pfizer, Amgen, Merck Sharp & Dohme, Sanofi–Aventis, Daiichi Sankyo, and Regeneron

Cancer Biomarker Discovery: The Entropic Hallmark

Background: It is a commonly accepted belief that cancer cells modify their transcriptional state during the progression of the disease. We propose that the progression of cancer cells towards malignant phenotypes can be efficiently tracked using high-throughput technologies that follow the gradual changes observed in the gene expression profiles by employing Shannon's mathematical theory of communication. Methods based on Information Theory can then quantify the divergence of cancer cells' transcriptional profiles from those of normally appearing cells of the originating tissues. The relevance of the proposed methods can be evaluated using microarray datasets available in the public domain but the method is in principle applicable to other high-throughput methods. Methodology/Principal Findings: Using melanoma and prostate cancer datasets we illustrate how it is possible to employ Shannon Entropy and the Jensen-Shannon divergence to trace the transcriptional changes progression of the disease. We establish how the variations of these two measures correlate with established biomarkers of cancer progression. The Information Theory measures allow us to identify novel biomarkers for both progressive and relatively more sudden transcriptional changes leading to malignant phenotypes. At the same time, the methodology was able to validate a large number of genes and processes that seem to be implicated in the progression of melanoma and prostate cancer. Conclusions/Significance: We thus present a quantitative guiding rule, a new unifying hallmark of cancer: the cancer cell's transcriptome changes lead to measurable observed transitions of Normalized Shannon Entropy values (as measured by high-throughput technologies). At the same time, tumor cells increment their divergence from the normal tissue profile increasing their disorder via creation of states that we might not directly measure. This unifying hallmark allows, via the the Jensen-Shannon divergence, to identify the arrow of time of the processes from the gene expression profiles, and helps to map the phenotypical and molecular hallmarks of specific cancer subtypes. The deep mathematical basis of the approach allows us to suggest that this principle is, hopefully, of general applicability for other diseases

Gene-centric meta-analysis of lipid traits in African, East Asian and Hispanic populations.

Meta-analyses of European populations has successfully identified genetic variants in over 100 loci associated with lipid levels, but our knowledge in other ethnicities remains limited. To address this, we performed dense genotyping of ∼2,000 candidate genes in 7,657 African Americans, 1,315 Hispanics and 841 East Asians, using the IBC array, a custom ∼50,000 SNP genotyping array. Meta-analyses confirmed 16 lipid loci previously established in European populations at genome-wide significance level, and found multiple independent association signals within these lipid loci. Initial discovery and in silico follow-up in 7,000 additional African American samples, confirmed two novel loci: rs5030359 within ICAM1 is associated with total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) (p = 8.8×10(-7) and p = 1.5×10(-6) respectively) and a nonsense mutation rs3211938 within CD36 is associated with high-density lipoprotein cholesterol (HDL-C) levels (p = 13.5×10(-12)). The rs3211938-G allele, which is nearly absent in European and Asian populations, has been previously found to be associated with CD36 deficiency and shows a signature of selection in Africans and African Americans. Finally, we have evaluated the effect of SNPs established in European populations on lipid levels in multi-ethnic populations and show that most known lipid association signals span across ethnicities. However, differences between populations, especially differences in allele frequency, can be leveraged to identify novel signals, as shown by the discovery of ICAM1 and CD36 in the current report

Cost-Effectiveness of Icosapent Ethyl (IPE) for the Reduction of the Risk of Ischemic Cardiovascular Events in Canada

Jean Lachaine,1,2 Jean-Nicolas Charron,2 Jean C Gregoire,3 Robert A Hegele,4 Lawrence A Leiter5 1University of Montreal, Montreal, QC, Canada; 2PeriPharm Inc., Montreal, QC, Canada; 3Institut de cardiologie de Montréal, Montreal, QC, Canada; 4Robarts Research Institute, London, ON, Canada; 5Li Ka Shing Knowledge Institute, St. Michael’s Hospital, University of Toronto, Toronto, ON, CanadaCorrespondence: Jean Lachaine, Faculty of Pharmacy University of Montreal, 2900 Edouard-Montpetit Blvd, Montreal, Quebec, H3T 1J4, Canada, Email [email protected]: Despite the use of statins, many patients with cardiovascular disease (CVD) have persistent residual risk. In a large Phase III trial (REDUCE-IT), icosapent ethyl (IPE) was shown to reduce the first occurrence of the primary composite endpoint of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or hospitalization for unstable angina.Methods: We conducted a cost-utility analysis comparing IPE to placebo in statin-treated patients with elevated triglycerides, from a publicly funded, Canadian healthcare payer perspective, using a time-dependent Markov transition model over a 20-year time horizon. We obtained efficacy and safety data from REDUCE-IT, and costs and utilities from provincial formularies and databases, manufacturer sources, and Canadian literature sources.Results: In the probabilistic base-case analysis, IPE was associated with an incremental cost of $12,523 and an estimated 0.29 more quality-adjusted life years (QALYs), corresponding to an incremental cost-effectiveness ratio (ICER) of $42,797/QALY gained. At a willingness-to-pay of $50,000 and $100,000/QALY gained, there is a probability of 70.4% and 98.8%, respectively, that IPE is a cost-effective strategy over placebo. The deterministic model yielded similar results. In the deterministic sensitivity analyses, the ICER varied between $31,823-$70,427/QALY gained. Scenario analyses revealed that extending the timeframe of the model to a lifetime horizon resulted in an ICER of $32,925/QALY gained.Conclusion: IPE represents an important new treatment for the reduction of ischemic CV events in statin-treated patients with elevated triglycerides. Based on the clinical trial evidence, we found that IPE could be a cost-effective strategy for treating these patients in Canada.Keywords: cardiovascular diseases, icosapent ethyl, IPE, cost-effectiveness, cost per QAL