Association of lipid-lowering drugs with COVID-19 outcomes from a Mendelian randomization study

Background: Lipid metabolism plays an important role in viral infections. We aimed to assess the causal effect of lipid-lowering drugs (HMGCR inhibitiors, PCSK9 inhibitiors and NPC1L1 inhibitior) on COVID-19 outcomes using 2-sample Mendelian Randomization (MR) study. Methods: We used two kinds of genetic instruments to proxy the exposure of lipid-lowering drugs, including eQTLs of drugs target genes, and genetic variants within or nearby drugs target genes associated with LDL cholesterol from GWAS. Summary-data-based MR (SMR) and inverse-variance weighted MR (IVW-MR) were used to calculate the effect estimates. Results: SMR analysis found that a higher expression of HMGCR was associated with a higher risk of COVID-19 hospitalization (OR=1.38, 95%CI=1.06-1.81). Similarly, IVW-MR analysis observed a positive association between HMGCR-mediated LDL cholesterol and COVID-19 hospitalization (OR=1.32, 95%CI=1.00-1.74). No consistent evidence from both analyses was found for other associations. Conclusions: This 2-sample MR study suggested a potential causal relationship between HMGCR inhibition and the reduced risk of COVID-19 hospitalization. Funding: Fujian Province Major Science and Technology Program.

Genomics of Postprandial Lipidomics in the Genetics of Lipid-Lowering Drugs and Diet Network Study

Postprandial lipemia (PPL) is an important risk factor for cardiovascular disease. Inter-individual variation in the dietary response to a meal is known to be influenced by genetic factors, yet genes that dictate variation in postprandial lipids are not completely characterized. Genetic studies of the plasma lipidome can help to better understand postprandial metabolism by isolating lipid molecular species which are more closely related to the genome. We measured the plasma lipidome at fasting and 6 h after a standardized high-fat meal in 668 participants from the Genetics of Lipid-Lowering Drugs and Diet Network study (GOLDN) using ultra-performance liquid chromatography coupled to (quadrupole) time-of-flight mass spectrometry. A total of 413 unique lipids were identified. Heritable and responsive lipid species were examined for association with single-nucleotide polymorphisms (SNPs) genotyped on the Affymetrix 6.0 array. The most statistically significant SNP findings were replicated in the Amish Heredity and Phenotype Intervention (HAPI) Heart Study. We further followed up findings from GOLDN with a regional analysis of cytosine-phosphate-guanine (CpGs) sites measured on the Illumina HumanMethylation450 array. A total of 132 lipids were both responsive to the meal challenge and heritable in the GOLDN study. After correction for multiple testing of 132 lipids (α = 5 × 10−8/132 = 4 × 10−10), no SNP was statistically significantly associated with any lipid response. Four SNPs in the region of a known lipid locus (fatty acid desaturase 1 and 2/FADS1 and FADS2) on chromosome 11 had p < 8.0 × 10−7 for arachidonic acid FA(20:4). Those SNPs replicated in HAPI Heart with p < 3.3 × 10−3. CpGs around the FADS1/2 region were associated with arachidonic acid and the relationship of one SNP was partially mediated by a CpG (p = 0.005). Both SNPs and CpGs from the fatty acid desaturase region on chromosome 11 contribute jointly and independently to the diet response to a high-fat meal.

Use of electronic patient data overview with alerts in primary care increases prescribing of lipid-lowering medications in patients with type 2 diabetes

Aims/hypothesis We aimed to assess whether general practices (GPs) using an electronic disease management program (DMP) with population overviews, including alerts when patients failed to receive guideline-recommended prescription medications, increased prescriptions of lipid-lowering drugs for patients with type 2 diabetes with no history of lipid-lowering treatment. Methods This observational study included 165 GPs that reached a high level of use of the DMP in 2012 and a control group of 135 GPs who reached a high level of use in 2013 and, hence, who were less exposed to the DMP throughout 2012. A binary measure for having been prescribed and filled lipid-lowering drugs at any time within a 12-month exposure period was derived for all patients with type 2 diabetes who did not receive a prescription for lipid-lowering drugs in the baseline year prior to the study period (i.e. 2011). Results were derived using ORs from multivariate logistic regression analyses. Subgroup stratification based on age, sex, diabetes duration, deprivation status and Charlson Comorbidity Index (CCI) score was conducted and assessed. Placebo tests were carried out to assess bias from selection to treatment. Results Patients who did not receive a prescription of lipid-lowering drugs in the year prior to being listed with GPs that used the DMP had statistically significant greater odds of receiving a prescription of lipid-lowering medications when compared with individuals who attended control GPs (OR 1.23 [95% CI 1.09, 1.38]). When the analysis period was shifted back by 2 years, no significant differences in lipid-lowering drug prescription between the two groups were found to occur, which indicates that these results were not driven by selection bias. Subgroup analyses showed that the increase in lipid-lowering drug prescriptions was primarily driven by changes among male participants (OR 1.32 [95% CI 1.12, 1.54]), patients aged 60–70 years (OR 1.40 [95% CI 1.13, 1.74]), patients with a diabetes duration of ≤5 years (OR 1.33 [95% CI 1.13, 1.56]), non-deprived patients (OR 1.25 [95% CI 1.08, 1.45]) and patients without comorbidities (CCI score = 0; OR 1.27 [95% CI 1.11, 1.45]). Conclusions/interpretation Access to population overviews using a DMP with alerts of clinical performance measures with regard to adhering to guideline-recommended prescription of medications can increase GP prescriptions of lipid-lowering drugs. Graphical abstract

Anti-flavivirus Properties of Lipid-Lowering Drugs

Although Flaviviruses such as dengue (DENV) and zika (ZIKV) virus are important human pathogens, an effective vaccine or antiviral treatment against them is not available. Hence, the search for new strategies to control flavivirus infections is essential. Several studies have shown that the host lipid metabolism could be an antiviral target because cholesterol and other lipids are required during the replicative cycle of different Flaviviridae family members. FDA-approved drugs with hypolipidemic effects could be an alternative for treating flavivirus infections. However, a better understanding of the regulation between host lipid metabolism and signaling pathways triggered during these infections is required. The metabolic pathways related to lipid metabolism modified during DENV and ZIKV infection are analyzed in this review. Additionally, the role of lipid-lowering drugs as safe host-targeted antivirals is discussed.

Different perspectives of patients and physicians on LDL-C target achievement in the treatment of hypercholesterolemia: results on secondary prevention from the German PROCYON survey

Background Lowering low-density lipoprotein cholesterol (LDL-C) in hypercholesterolemia patients at very high cardiovascular (CV) risk is essential in preventing future CV events. However, LDL-C targets often remain unattained. Purpose The purpose of the present survey was to identify possible reasons for insufficient LDL-C target achievement despite the availability of efficacious lipid lowering drugs in the clinical setting of hypercholesterolemia management in secondary prevention patients in Germany. Methods PROCYON was an online survey with over 5,000 participants on disease perception, awareness, burden, and management of hypercholesterolemia consisting of a patient survey (PROCYON A) and a healthcare practitioner (HCP) survey (PROCYON B). To quantify patient self-activation, the PAM-13 Patient Activation Measure by Insignia Health was incorporated. Results on 1,696 patients in secondary prevention are presented. Results Most post-CV event patients do not achieve their LDL-C target. HCPs assume patients' poor adherence to medication and lifestyle adaptions to be the most important reason (Figure 1). However, this contradicts the patients' perception. Accordingly, 87% of the patients are on a lipid lowering therapy and 81% of them have stated to take their medication regularly. They rank their medication for LDL-C reduction as equally important as that for other diseases. In contrast, HCPs think that 46% of their patients do not take hypercholesterolemia seriously. However, HCPs also believe, that LDL target attainment is still “important” or “very important” to 81% of their patients. This is in line with the patients' perception: 84% of the patients consider reaching their target as “important” or “very important”. PAM-13 results underline these results: 60% of the patients are already activated and want to gain control over their disease (PAM-13 level 3 of 4) and 12% reach highest self-activation levels (level 4 of 4). The HCP remains the major source of information for 77% of the patients and only 42% reach out for online resources. The importance of educating patients on adherence is acknowledged by all HCPs. Therefore, 71% express their desire of educational material. With respect to LDL-C levels, 49% of the patients reported no improvement. Of the patients under treatment without LDL-C improvement, only 23% take more than one drug, and 47% reported a change of dose. Furthermore, collaboration between GPs and specialists (cardiologists, diabetologists, lipidologists) was not evident. Conclusion Although secondary prevention patients are motivated to pursue their LDL-C targets, HCPs consider patient adherence as major reason for failure. Instead, the survey indicated that therapeutic strategies are not fully exhausted and there is space for treatment improvement either by dose escalation or addition of further lipid lowering drugs. Furthermore, patient education and specialist collaboration could improve patient management. FUNDunding Acknowledgement Type of funding sources: Private company. Main funding source(s): Novartis Pharma GmbH Figure 1

An impact of lipid profile and lipid lowering drugs on ≥70 year olds of an upper socioeconomic class: a retrospective cohort study

Background Life expectancy has greatly increased, generating an improvement in screening programs for disease prevention, lifesaving drugs and medical devices. The impact of lowering low-density lipoprotein cholesterol (LDL-C) in the very elderly is not well-established. Our aim was to explore the association of LDL-C, high density lipoprotein cholesterol (HDL-C) and lipid lowering drugs (LLDs) on cognitive decline, malignancies and overall survival. Methods This was a retrospective cohort study. Our study comprised 1498 (72.7%) males and 561 (27.3%) females, aged ≥70 who had attended the Institute for Medical Screening (IMS), Sheba Medical Center, Israel at least twice during 2013–2019. Data were obtained from the computerized database of the IMS. A manual quality control to identify potential discrepancies was performed. Results Overall, 6.3% of the subjects treated with LLDs (95/1421) versus 4.2% not treated (28/638), cognitively declined during the study years. No statistically significant effects of LDL-C, HDL-C and LLDs on cognitive decline were observed after correcting for age, prior stroke and other vascular risk factors. With regard to cancer, after adjusting for confounders and multiple inferences, no definite relationships were found. Conclusions This analysis of an elderly, high socioeconomic status cohort suggests several relationships between the use of LLDs and health outcomes, some beneficial, especially, with regard to certain types of cancer, but with a higher risk of cognitive decline. Further studies are warranted to clarify the health effects of these medications in the elderly.

Association of lipid-lowering drugs with COVID-19 outcomes: A Mendelian Randomization study

Background: Lipid metabolism plays an important role in viral infections. Large cohort study suggested a protective potential of lipid-lowering drugs in COVID-19 outcomes, but the nature of observational study precludes it to draw a causal inference. Objectives: To assess the causal effect of lipid-lowering drugs (HMGCR inhibitors, PCSK9 inhibitors and NPC1L1 inhibitors) on COVID-19 outcomes using 2-sample Mendelian Randomization (MR) study. Methods: We used two kinds of genetic instruments to proxy the exposure of lipid-lowering drugs, including expression quantitative trait loci (eQTLs) of drugs target genes, and genetic variants within or nearby drugs target genes associated with low-density lipoprotein (LDL) cholesterol from genome-wide association study (GWAS). GWASs of COVID-19 outcomes (susceptibility, hospitalization and very severe disease) were obtained from the COVID-19 Host Genetics Initiative. Summary-data-based MR (SMR) and inverse-variance weighted MR (IVW-MR) were used to calculate the effect estimates. Results: SMR analysis found that a higher expression of HMGCR was associated with a higher risk of COVID-19 hospitalization (OR=1.38, 95%CI=1.06-1.81; P=0.019). Similarly, IVW-MR analysis observed a positive association between HMGCR-mediated LDL cholesterol and COVID-19 hospitalization (OR=1.32, 95%CI=1.00-1.74; P=0.049). No consistent evidence from both SMR and IVW-MR analyses was found for the association of HMGCR inhibitors with COVID-19 susceptibility or very severe disease, or for the association of PCSK9 inhibitors and NPC1L1 inhibitor with COVID-19 outcomes. Conclusions: In this 2-sample MR study, we found potential causal evidence that HMGCR inhibitors could reduce the risk of COVID-19 hospitalization. Further research is needed to explore the therapeutic role of statins for COVID-19.