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Statin-induced LDL cholesterol response and type 2 diabetes: a bidirectional two-sample Mendelian randomization study.
Smit, RAJ, Trompet, S, Leong, A, Goodarzi, MO, Postmus, I, Warren, H, Theusch, E, Barnes, MR, Arsenault, BJ, Li, X, et al
The pharmacogenomics journal. 2020;(3):462-470
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Abstract
It remains unclear whether the increased risk of new-onset type 2 diabetes (T2D) seen in statin users is due to low LDL-C concentrations, or due to the statin-induced proportional change in LDL-C. In addition, genetic instruments have not been proposed before to examine whether liability to T2D might cause greater proportional statin-induced LDL-C lowering. Using summary-level statistics from the Genomic Investigation of Statin Therapy (GIST, nmax = 40,914) and DIAGRAM (nmax = 159,208) consortia, we found a positive genetic correlation between LDL-C statin response and T2D using LD score regression (rgenetic = 0.36, s.e. = 0.13). However, mendelian randomization analyses did not provide support for statin response having a causal effect on T2D risk (OR 1.00 (95% CI: 0.97, 1.03) per 10% increase in statin response), nor that liability to T2D has a causal effect on statin-induced LDL-C response (0.20% increase in response (95% CI: -0.40, 0.80) per doubling of odds of liability to T2D). Although we found no evidence to suggest that proportional statin response influences T2D risk, a definitive assessment should be made in populations comprised exclusively of statin users, as the presence of nonstatin users in the DIAGRAM dataset may have substantially diluted our effect estimate.
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High-Sensitivity C-Reactive Protein Combined with Low-Density Lipoprotein Cholesterol as the Targets of Statin Therapy in Patients with Acute Coronary Syndrome.
Fang, M, Qian, Q, Zhao, Z, Zhu, L, Su, J, Li, X
International heart journal. 2018;(2):300-306
Abstract
To investigate the combination of high-sensitivity C-reactive protein (hs-CRP) and Low-density lipoprotein (LDL)-C as the targets for statin treatment in patients with acute coronary syndrome (ACS). This single-center, prospective, randomized study was performed in 400 patients treated with atorvastatin 40 mg/day for 1 month and then with atorvastatin 20 mg/day as maintenance. The patients were randomized to the LDL group (LDL-C target of < 2.07 mmol/L according to the Chinese dyslipidemia guidelines) and to the LDL-CRP group (LDL-C target of < 2.07 mmol/L and hs-CRP target of < 3 mg/L). The patients were followed up for major adverse cardiac events (MACE) at 6, 12, and 18 months. The two groups had similar baseline characteristics and 391 patients completed the follow-up. No differences were found in LDL-C between the two groups, but a difference was found in hs-CRP at 12 and 18 months. There was a significant difference in revascularization (8.7% versus 3.6%, P = 0.04) and MACE (16.8% versus 9.7%; P = 0.04) between the LDL and LDL-CRP groups at 18 months. Compared to LDL-C as the single target, targeting both LDL-C and hs-CRP by statin therapy in patients with ACS could further reduce the incidence of MACE and the residual cardiovascular risk.
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Prescription of statins at discharge and 1-year risk of major clinical outcomes among acute coronary syndromes patients with extremely low LDL-cholesterol in clinical pathways for acute coronary syndromes studies.
Sun, Y, Xie, G, Patel, A, Li, S, Zhao, W, Yang, X, Wu, T, Li, M, Li, X, Du, X, et al
Clinical cardiology. 2018;(9):1192-1200
Abstract
OBJECTIVE The aim of this study was to investigate statin description on discharge and the benefit on the long-term outcomes in acute coronary syndromes (ACS) patients with very low baseline LDL-cholesterol (LDL-c). METHODS This is a post-hoc analysis of 3374 ACS patients who were discharged alive and had baseline LDL-c levels below 70 mg/dL (1.8 mmol/L). The propensity score of using statin was estimated with a multivariable Logistic model including patient's demography, social economic status, cardiovascular risk factors, subtype of the diagnosis, and treatments received during hospitalization and current LDL-c level. The risk of major adverse cardiovascular events (MACEs) was compared between patients received and not-received statin with Cox-regression models adjusting for the propensity score plus other factors. A sensitivity analysis was done in propensity score matched patients. RESULTS Compared with nonstatin group, the incidence of MACE at 12 months after discharge was lower in the statin group (11.1% vs 5.8%; P < 0.001). The propensity score plus other factors-adjusted hazard ratios for MACEs was significant (0.58; 95% CI: 0.39, 0.87). The effect showed a significant dose-response relationship (P for trend = 0.02). The results in analyses with propensity-score matched participants were in consistent with above findings. Analyses on total mortality in 12 months showed similar results. CONCLUSIONS Among ACS survivors with a very low baseline LDL-c, low to moderate intensity statin therapy was associated significantly with lower risk of MACEs and total mortality at 12 months. The results suggested that ACS survivors should take statin regardless of the baseline of LDL-c.
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Six-month adherence to Statin use and subsequent risk of major adverse cardiovascular events (MACE) in patients discharged with acute coronary syndromes.
Xie, G, Sun, Y, Myint, PK, Patel, A, Yang, X, Li, M, Li, X, Wu, T, Li, S, Gao, R, et al
Lipids in health and disease. 2017;(1):155
Abstract
BACKGROUND The evidence of adherence to statin decreasing risk of major adverse cardiovascular events (MACEs) is still lack among patients discharged with acute coronary syndrome (ACS). Our objective is to determine the relationship between six-month adherence to statins and subsequent risk of MACEs in patients discharged with ACS. METHODS Using two prospective registry cohorts (CPACS-1 and -2), we analyzed data from 12,516 consecutive patients with ACS who were prescribed statin at hospital discharge and survived beyond 6 months without recurrent myocardial infarction (MI) or stroke. Adherence to statin was defined as good (using statin at discharge and 6 months without declined dosage) and poor adherence groups (using statin at discharge but declining dosage or stopping at 6 months). We compared the hazard ratios of all-cause mortality and MACE in subsequent 6 months between groups, using Cox-regression models, adjusting for multiple potential confounders. RESULTS Seventy two percent of patients adhered to statin therapy at 6 months. The incident MACE in the poor adherence group was significantly higher than in good adherence group (2.7% vs. 1.8%, p = 0.002). Compared with poor adherence group, the good adherence group showed a 27% lower relative risk of MACE during the 6 month follow up (fully-adjusted hazard ratio (HR) = 0.73; 95%CI: 0.56-0.97). The protective effects of good adherence were similar in groups with different statin dose as well as groups by other baseline clinical characteristics and treatments (p > 0.05 for interaction). CONCLUSION Our study highlights the importance of adherence to statin therapy in prevention of MACE and clinicians should aim to achieve higher dosage if tolerable. CLINICAL TRIAL REGISTRATION CPACS2 was registered on URL: http://www.anzctr.org.au/default.aspx and unique identifier is ACTRN12609000491268 . CPACS1 was not a clinical trial and thus not registered.
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Meta-analysis of genome-wide association studies of HDL cholesterol response to statins.
Postmus, I, Warren, HR, Trompet, S, Arsenault, BJ, Avery, CL, Bis, JC, Chasman, DI, de Keyser, CE, Deshmukh, HA, Evans, DS, et al
Journal of medical genetics. 2016;(12):835-845
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Abstract
BACKGROUND In addition to lowering low density lipoprotein cholesterol (LDL-C), statin therapy also raises high density lipoprotein cholesterol (HDL-C) levels. Inter-individual variation in HDL-C response to statins may be partially explained by genetic variation. METHODS AND RESULTS We performed a meta-analysis of genome-wide association studies (GWAS) to identify variants with an effect on statin-induced high density lipoprotein cholesterol (HDL-C) changes. The 123 most promising signals with p<1×10-4 from the 16 769 statin-treated participants in the first analysis stage were followed up in an independent group of 10 951 statin-treated individuals, providing a total sample size of 27 720 individuals. The only associations of genome-wide significance (p<5×10-8) were between minor alleles at the CETP locus and greater HDL-C response to statin treatment. CONCLUSIONS Based on results from this study that included a relatively large sample size, we suggest that CETP may be the only detectable locus with common genetic variants that influence HDL-C response to statins substantially in individuals of European descent. Although CETP is known to be associated with HDL-C, we provide evidence that this pharmacogenetic effect is independent of its association with baseline HDL-C levels.
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Rooted in risk: genetic predisposition for low-density lipoprotein cholesterol level associates with diminished low-density lipoprotein cholesterol response to statin treatment.
Smit, RA, Postmus, I, Trompet, S, Barnes, MR, Warren, H, Arsenault, BJ, Chasman, DI, Cupples, LA, Hitman, GA, Krauss, RM, et al
Pharmacogenomics. 2016;(15):1621-1628
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Abstract
AIMS: To utilize previously reported lead SNPs for low-density lipoprotein cholesterol (LDL-c) levels to find additional loci of importance to statin response, and examine whether genetic predisposition to LDL-c levels associates with differential statin response. METHODS We investigated effects on statin response of 59 LDL-c SNPs, by combining summary level statistics from the Global Lipids Genetics and Genomic Investigation of Statin Therapy consortia. RESULTS Lead SNPs for APOE, SORT1 and NPC1L1 were associated with a decreased LDL-c response to statin treatment, as was overall genetic predisposition for increased LDL-c levels as quantified with 59 SNPs, with a 5.4% smaller statin response per standard deviation increase in genetically raised LDL-c levels. CONCLUSION Genetic predisposition for increased LDL-c level may decrease efficacy of statin therapy.
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Efficacy of high-dose rosuvastatin preloading in patients undergoing percutaneous coronary intervention: a meta-analysis of fourteen randomized controlled trials.
Pan, Y, Tan, Y, Li, B, Li, X
Lipids in health and disease. 2015;:97
Abstract
BACKGROUND Numerous studies have evidenced that statins can reduce the incidence of cardiovascular disease. However, the effects of high-dose rosuvastatin (RSV) preloading in patients undergoing percutaneous coronary intervention (PCI) are controversial. OBJECTIVE We attempted to identify and quantify the potential cardioprotective benefits of high-dose RSV preloading on final thrombolysis in myocardial infarction (TIMI) flow grade, major adverse cardiac events (MACE), and peri-procedural myocardial injury (PMI) in patients undergoing PCI. METHODS Pubmed, EMBASE, Cochrane Central Register of Controlled Trials and ISI Web of Science databases were systematically searched for randomized controlled trials (RCTs) up to June 2015. We assessed the incidence of MACE and PMI in all enrolled patients for subgroups stratified by clinical presentation and previous statin therapy during the follow-up period. RESULTS Fourteen trials with 3368 individuals were included in our meta-analysis. High-dose RSV preloading before PCI lead to a 58 % reduction in MACE (odds ratio [OR] = 0.42, 95 % confidence intervals [CI]: 0.29-0.61, P < 0.00001) and a 60 % reduction in PMI (OR = 0.40, 95 % CI: 0.25-0.63, P < 0.0001). This procedure also improved the final TIMI flow grade in patients undergoing PCI (OR = 1.61, 95 % CI: 1.09-2.38, P = 0.02). The benefits on MACE were significant for both stable angina patients (OR = 0.42, 95 % CI: 0.21-0.87, P = 0.02) and acute coronary syndrome (ACS) patients (OR = 0.42, 95 % CI: 0.27-0.65, P < 0.0001); and for both statin naïve patients (OR = 0.42, 95 % CI: 0.28-0.64, P < 0.0001) and previous statin therapy patients (OR = 0.28, 95 % CI: 0.10-0.73, P = 0.01). CONCLUSION High-dose RSV preloading can significantly improve myocardial perfusion and reduce both MACE and PMI in patients undergoing PCI. The cardioprotective benefits of RSV preloading were significant in not only stable angina and ACS patients but also statin naïve and previous statin therapy patients. The cardioprotective benefits of RSV preloading in the follow-up period mainly resulted from a reduction in spontaneous MI and TVR, especially for ACS and statin naïve patients.
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Pharmacogenetic meta-analysis of genome-wide association studies of LDL cholesterol response to statins.
Postmus, I, Trompet, S, Deshmukh, HA, Barnes, MR, Li, X, Warren, HR, Chasman, DI, Zhou, K, Arsenault, BJ, Donnelly, LA, et al
Nature communications. 2014;:5068
Abstract
Statins effectively lower LDL cholesterol levels in large studies and the observed interindividual response variability may be partially explained by genetic variation. Here we perform a pharmacogenetic meta-analysis of genome-wide association studies (GWAS) in studies addressing the LDL cholesterol response to statins, including up to 18,596 statin-treated subjects. We validate the most promising signals in a further 22,318 statin recipients and identify two loci, SORT1/CELSR2/PSRC1 and SLCO1B1, not previously identified in GWAS. Moreover, we confirm the previously described associations with APOE and LPA. Our findings advance the understanding of the pharmacogenetic architecture of statin response.
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Statin use and risk of depression: a Swedish national cohort study.
Redlich, C, Berk, M, Williams, LJ, Sundquist, J, Sundquist, K, Li, X
BMC psychiatry. 2014;:348
Abstract
BACKGROUND Statin medications, used to prevent heart disease by reducing cholesterol, also reduce inflammation and protect against oxidative damage. As inflammation and oxidative stress occur in depression, there is interest in their potential to reduce depression risk. We investigated whether use of statin medications was associated with a change in the risk of developing depression in a very large Swedish national cohort (n = 4,607,990). METHODS National register data for adults ≥40yr was analyzed to obtain information about depression diagnoses and prescriptions of statin medications between 2006 and 2008. Associations were tested using logistic regression. RESULTS Use of any statin was shown to reduce the odds of depression by 8% compared to individuals not using statin medications (OR = 0.92, 95% CI, 0.89-0.96; p < 0.001). Simvastatin had a protective effect (OR = 0.93, 95% CI, 0.89-0.97; p = 0.001), whereas atorvastatin was associated with increased risk of depression (OR = 1.11, 95% CI, 1.01-1.22; p = 0.032). There was a stepwise decrease in odds ratio with increasing age (OR ≥ 40 years = 0.95, OR ≥ 50 years = 0.91, OR ≥ 60 years = 0.85, OR ≥ 70 years = 0.81). CONCLUSIONS The use of any statin was associated with a reduction in risk of depression in individuals over the age of 40. Clarification of the strength of these protective effects, the clinical relevance of these effects and determination of which statins are most effective is needed.
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Genome-wide association of lipid-lowering response to statins in combined study populations.
Barber, MJ, Mangravite, LM, Hyde, CL, Chasman, DI, Smith, JD, McCarty, CA, Li, X, Wilke, RA, Rieder, MJ, Williams, PT, et al
PloS one. 2010;(3):e9763
Abstract
BACKGROUND Statins effectively lower total and plasma LDL-cholesterol, but the magnitude of decrease varies among individuals. To identify single nucleotide polymorphisms (SNPs) contributing to this variation, we performed a combined analysis of genome-wide association (GWA) results from three trials of statin efficacy. METHODS AND PRINCIPAL FINDINGS Bayesian and standard frequentist association analyses were performed on untreated and statin-mediated changes in LDL-cholesterol, total cholesterol, HDL-cholesterol, and triglyceride on a total of 3932 subjects using data from three studies: Cholesterol and Pharmacogenetics (40 mg/day simvastatin, 6 weeks), Pravastatin/Inflammation CRP Evaluation (40 mg/day pravastatin, 24 weeks), and Treating to New Targets (10 mg/day atorvastatin, 8 weeks). Genotype imputation was used to maximize genomic coverage and to combine information across studies. Phenotypes were normalized within each study to account for systematic differences among studies, and fixed-effects combined analysis of the combined sample were performed to detect consistent effects across studies. Two SNP associations were assessed as having posterior probability greater than 50%, indicating that they were more likely than not to be genuinely associated with statin-mediated lipid response. SNP rs8014194, located within the CLMN gene on chromosome 14, was strongly associated with statin-mediated change in total cholesterol with an 84% probability by Bayesian analysis, and a p-value exceeding conventional levels of genome-wide significance by frequentist analysis (P = 1.8 x 10(-8)). This SNP was less significantly associated with change in LDL-cholesterol (posterior probability = 0.16, P = 4.0 x 10(-6)). Bayesian analysis also assigned a 51% probability that rs4420638, located in APOC1 and near APOE, was associated with change in LDL-cholesterol. CONCLUSIONS AND SIGNIFICANCE Using combined GWA analysis from three clinical trials involving nearly 4,000 individuals treated with simvastatin, pravastatin, or atorvastatin, we have identified SNPs that may be associated with variation in the magnitude of statin-mediated reduction in total and LDL-cholesterol, including one in the CLMN gene for which statistical evidence for association exceeds conventional levels of genome-wide significance. TRIAL REGISTRATION PRINCE and TNT are not registered. CAP is registered at Clinicaltrials.gov NCT00451828.