Causal association between lipid-lowering drugs and cancers: A drug target Mendelian randomization study.

Accumulating evidences have indicated that lipid-lowering drugs have effect for the treatment of cancers. However, causal associations between lipid-lowering drugs and the risk of cancers are still unclear. In our study, we utilized single nucleotide polymorphisms of proprotein convertase subtilis kexin 9 (PCSK9) inhibitors and 3-hydroxy-3-methylglutaryl-assisted enzyme A reductase (HMGCR) inhibitors and performed a drug target Mendelian randomization to explore the causal association between lipid-lowering drugs and the risk of cancers. Five regression methods were carried out, including inverse variance weighted (IVW) method, MR Egger, weighted median, simple mode and weighted mode methods, of which IVW method was considered as the main analysis. Our outcome dataset contained the risk of breast cancer (BC), colorectal cancer, endometrial cancer, gastric cancer (GC), hepatocellular carcinoma (HCC), lung cancer, esophageal cancer, prostate cancer (PC), and skin cancer (SC). Our results demonstrated that PCSK9 inhibitors were significant associated with a decreased effect of GC [IVW: OR = 0.482, 95% CI: 0.264-0.879, P = .017]. Besides, genetic inhibitions of HMGCR were significant correlated with an increased effect of BC [IVW: OR = 1.421, 95% CI: 1.056-1.911, P = .020], PC [IVW: OR = 1.617, 95% CI: 1.234-2.120, P = .0005] and SC [IVW: OR = 1.266, 95% CI: 1.022-1.569, P = .031]. For GC [IVW: OR = 0.559, 95% CI: 0.382-0.820, P = .0029] and HCC [IVW: OR = 0.241, 95% CI: 0.085-0.686, P = .0077], HMGCR inhibitors had a protective risk. Our method suggested that PCSK9 inhibitors were significant associated with a protective effect of GC. Genetic inhibitions of HMGCR were significant correlated with an increased effect of BC, PC and SC. Meanwhile, HMGCR inhibitors had a protective risk of GC and HCC. Subsequent studies still needed to assess potential effects between lipid-lowering drugs and the risk of cancers with clinical trials.

Association between Statin Use and Chemotherapy-Induced Cardiotoxicity: A Meta-Analysis.

Background: Chemotherapy-induced cardiac dysfunction (CIC) is a significant and concerning complication observed among cancer patients. Despite the demonstrated cardioprotective benefits of statins in various cardiovascular diseases, their effectiveness in mitigating CIC remains uncertain. Objective: This meta-analysis aims to comprehensively evaluate the potential cardioprotective role of statins in patients with CIC. Methods: A systematic literature search was conducted using PubMed, Embase, and Scopus databases to identify relevant articles published from inception until 10th May 2023. The outcomes were assessed using pooled odds ratio (OR) for categorical data and mean difference (MD) for continuous data, with corresponding 95% confidence intervals (95% CIs). Results: This meta-analysis comprised nine studies involving a total of 5532 patients, with 1904 in the statin group and 3628 in the non-statin group. The pooled analysis of primary outcome shows that patients who did not receive statin suffer a greater decline in the LVEF after chemotherapy compared to those who receive statin (MD, 3.55 (95% CI: 1.04-6.05), p = 0.01). Likewise, we observed a significantly higher final mean LVEF among chemotherapy patients with statin compared to the non-statin group of patients (MD, 2.08 (95% CI: 0.86-3.30), p > 0.001). Additionally, there was a lower risk of incident heart failure in the statin group compared to the non-statin group of patients (OR, 0.41 (95% CI: 0.27-0.62), p < 0.001). Lastly, the change in the mean difference for LVEDV was not statistically significant between the statin and non-statin groups (MD, 1.55 (95% CI: -5.22-8.33), p = 0.65). Conclusion: Among patients of CIC, statin use has shown cardioprotective benefits by improving left ventricular function and reducing the risk of heart failure.

SLCO1B1 Exome Sequencing and Statin Treatment Response in 64,000 UK Biobank Patients.

The solute carrier organic anion transporter family member 1B1 (SLCO1B1) encodes the organic anion-transporting polypeptide 1B1 (OATP1B1 protein) that transports statins to liver cells. Common genetic variants in SLCO1B1, such as *5, cause altered systemic exposure to statins and therefore affect statin outcomes, with potential pharmacogenetic applications; yet, evidence is inconclusive. We studied common and rare SLCO1B1 variants in up to 64,000 patients from UK Biobank prescribed simvastatin or atorvastatin, combining whole-exome sequencing data with up to 25-year routine clinical records. We studied 51 predicted gain/loss-of-function variants affecting OATP1B1. Both SLCO1B1*5 alone and the SLCO1B1*15 haplotype increased LDL during treatment (beta*5 = 0.08 mmol/L, p = 6 × 10-8; beta*15 = 0.03 mmol/L, p = 3 × 10-4), as did the likelihood of discontinuing statin prescriptions (hazard ratio*5 = 1.12, p = 0.04; HR*15 = 1.05, p = 0.04). SLCO1B1*15 and SLCO1B1*20 increased the risk of General Practice (GP)-diagnosed muscle symptoms (HR*15 = 1.22, p = 0.003; HR*20 = 1.25, p = 0.01). We estimated that genotype-guided prescribing could potentially prevent 18% and 10% of GP-diagnosed muscle symptoms experienced by statin patients, with *15 and *20, respectively. The remaining common variants were not individually significant. Rare variants in SLCO1B1 increased LDL in statin users by up to 1.05 mmol/L, but replication is needed. We conclude that genotype-guided treatment could reduce GP-diagnosed muscle symptoms in statin patients; incorporating further SLCO1B1 variants into clinical prediction scores could improve LDL control and decrease adverse events, including discontinuation.

Low-dose colchicine for atherosclerosis: long-term safety.

Low-dose colchicine (0.5 mg daily) is now FDA-approved for secondary prevention in patients with coronary disease and will be increasingly prescribed in clinical practice. In this State-of-the-Art Review, data were collated from contemporary systemic reviews of case reports, drug registries, and placebo-controlled trials that assessed specific issues of safety related to the continuous use of colchicine in a range of clinical settings to inform physicians, pharmacists, and patients of the absolute risks of continuous use of low-dose colchicine, including among individuals taking statin therapy. Based upon these collective data, it is concluded that aside mild diarrhoea on initiation of colchicine that typically subsides in the vast majority of patients within a week of therapy, continuous use of low-dose colchicine is well tolerated and very safe. It does not affect renal, liver, or cognitive function, has no adverse effects on bleeding, wound healing, fertility, or pregnancy, and does not increase risks of cancer, serious infection, or cause-specific mortality. When appropriately prescribed to patients without significant renal or hepatic impairment, reports of myelosuppression, myotoxicity, and serious drug-drug interactions are rare and no more frequent than placebo, including in patients taking statin therapy. Physicians, pharmacists, and patients can be reassured that in the absence of significant renal or hepatic impairment continuous use of low-dose colchicine can be used safely in patients with atherosclerosis for the purpose of reducing cardiovascular risk.

Association between statin use and the risk for idiopathic pulmonary fibrosis and its prognosis: a nationwide, population-based study.

Given the pleiotropic effects of statins beyond their lipid-lowering effects, there have been attempts to evaluate the role of statin therapy in IPF, but they have shown inconclusive results. Data from the National Health Insurance Service (NHIS) database of South Korea were used to investigate the effects of statin therapy on IPF. The IPF cohort consisted of a total of 10,568 patients who were newly diagnosed with IPF between 2010 and 2017. These patients were then matched in a 1:3 ratio to 31,704 subjects from a control cohort without IPF, with matching based on age and sex. A case-control study was performed to evaluate the association between statin use and the risk for IPF, and the multivariable analysis revealed that statin use was associated with a lower risk for IPF (adjusted OR 0.847, 95% CI 0.800-0.898). Using the IPF cohort, we also evaluated whether statin use at the time of diagnosis was associated with future clinical outcomes. The statin use at the time of IPF diagnosis was associated with improved overall survival (adjusted HR 0.779, 95% CI 0.709-0.856). Further prospective studies are needed to clarify the role of statin therapy in IPF.

Predicted deleterious variants in ABCA1, LPL, LPA and KIF6 are associated with statin response and adverse events in patients with familial hypercholesterolemia and disturb protein structure and stability.

OBJECTIVES: This study explored the association of deleterious variants in pharmacodynamics (PD) genes with statin response and adverse effects in patients with familial hypercholesterolemia (FH) and analyzed their potential effects on protein structure and stability. METHODS: Clinical and laboratory data were obtained from 144 adult FH patients treated with statins. A panel of 32 PD genes was analyzed by exon-targeted gene sequencing. Deleterious variants were identified using prediction algorithms and their structural effects were analyzed by molecular modeling studies. RESULTS: A total of 102 variants were predicted as deleterious (83 missense, 8 stop-gain, 4 frameshift, 1 indel, 6 splicing). The variants ABCA1 rs769705621 (indel), LPA rs41267807 (p.Tyr2023Cys) and KIF6 rs20455 (p.Trp719Arg) were associated with reduced low-density lipoprotein cholesterol (LDLc) response to statins, and the LPL rs1801177 (p.Asp36Asn) with increased LDLc response (P < 0.05). LPA rs3124784 (p.Arg2016Cys) was predicted to increase statin response (P = 0.022), and ABCA1 rs769705621 to increase the risk of statin-related adverse events (SRAE) (P = 0.027). LPA p.Arg2016Cys and LPL p.Asn36Asp maintained interactions with solvent, LPA p.Tyr2023Cys reduced intramolecular interaction with Gln1987, and KIF6 p.Trp719Arg did not affect intramolecular interactions. DDMut analysis showed that LPA p.Arg2016Cys and p.Tyr2023Cys and LPL p.Asp36Asn caused energetically favorable changes, and KIF6 p.Trp719Arg resulted in unfavorable energetic changes, affecting protein stability. CONCLUSION: Deleterious variants in ABCA1, LPA, LPL and KIF6 are associated with variability in LDLc response to statins, and ABCA1 rs769705621 is associated with SRAE risk in FH patients. Molecular modeling studies suggest that LPA p.Tyr2023Cys and KIF6 p.Trp719Arg disturb protein conformational structure and stability.

Statin Therapy for Secondary Prevention in Ischemic Stroke Patients With Cerebral Microbleeds.

BACKGROUND AND OBJECTIVES: The association between statin use and the risk of intracranial hemorrhage (ICrH) following ischemic stroke (IS) or transient ischemic attack (TIA) in patients with cerebral microbleeds (CMBs) remains uncertain. This study investigated the risk of recurrent IS and ICrH in patients receiving statins based on the presence of CMBs. METHODS: We conducted a pooled analysis of individual patient data from the Microbleeds International Collaborative Network, comprising 32 hospital-based prospective studies fulfilling the following criteria: adult patients with IS or TIA, availability of appropriate baseline MRI for CMB quantification and distribution, registration of statin use after the index stroke, and collection of stroke event data during a follow-up period of ≥3 months. The primary endpoint was the occurrence of recurrent symptomatic stroke (IS or ICrH), while secondary endpoints included IS alone or ICrH alone. We calculated incidence rates and performed Cox regression analyses adjusting for age, sex, hypertension, atrial fibrillation, previous stroke, and use of antiplatelet or anticoagulant drugs to explore the association between statin use and stroke events during follow-up in patients with CMBs. RESULTS: In total, 16,373 patients were included (mean age 70.5 ± 12.8 years; 42.5% female). Among them, 10,812 received statins at discharge, and 4,668 had 1 or more CMBs. The median follow-up duration was 1.34 years (interquartile range: 0.32-2.44). In patients with CMBs, statin users were compared with nonusers. Compared with nonusers, statin therapy was associated with a reduced risk of any stroke (incidence rate [IR] 53 vs 79 per 1,000 patient-years, adjusted hazard ratio [aHR] 0.68 [95% CI 0.56-0.84]), a reduced risk of IS (IR 39 vs 65 per 1,000 patient-years, aHR 0.65 [95% CI 0.51-0.82]), and no association with the risk of ICrH (IR 11 vs 16 per 1,000 patient-years, aHR 0.73 [95% CI 0.46-1.15]). The results in aHR remained consistent when considering anatomical distribution and high burden (≥5) of CMBs. DISCUSSION: These observational data suggest that secondary stroke prevention with statins in patients with IS or TIA and CMBs is associated with a lower risk of any stroke or IS without an increased risk of ICrH. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that for patients with IS or TIA and CMBs, statins lower the risk of any stroke or IS without increasing the risk of ICrH.

Statin-induced immune-mediated necrotizing myopathy with concomitant increase of anti-HMGCR and anti-ACHR antibodies.

Statin-induced immune-mediated necrotizing myopathy (IMNM) is a rare systemic neuromuscular condition. We present a case of a patient with a severe phenotype of the disease that was found to have an increase in anti-HMGCR and anti-ACHR antibodies. A potential association between these antibodies have not been previously described. A 67-year-old male with hyperlipidemia, who was recently initiated on atorvastatin therapy, presented to the ED with progressive muscle weakness. Within a few days of admission, the patient developed complete flaccid paralysis and respiratory distress requiring intubation. The patient's CK was elevated to 24,000 and there was an increase of anti-HMGCR and anti-ACHR antibodies. Impressions from MRI and thigh biopsy solidified a diagnosis of statin-induced IMNM. The patient was treated with methylprednisolone, IVIG, and rituximab, which provided resolution of symptoms.

Angiotensin-converting enzyme inhibitors, statins and the polypill in cardiovascular diseases prevention: ignorance is bliss or not?

The polypill strategy, which combines several medicines that simultaneously control different risk factors/diseases in a single pill, is one of the approaches used in cardiovascular therapy. In different guidelines, this one-pill combination therapy is suggested as first-line step in disease management. Because the cardiovascular diseases (CVD) pandemia, prevention is essential. The approaches that could improve adherence are of great importance to achieve health, social and economical benefits. However, direct or indirect experience of adverse drug reaction is often the reason for discontinuation, with serious fatal and non-fatal consequences especially for a polypill. Angiotensin-converting enzyme inhibitors (ACEi) and statins are the most prescribed medications in CVD prevention. It is well known that both drugs may have adverse effects that induce discontinuation. Often, the personal awareness of these effects is a reason for self-discontinuation. In this study an analysis of the ACEi/statin awareness is reported. Is it potentially harmful for polypill?

Effect of statin treatment on the risk of cancer in patients with heart failure: A target trial emulation study.

PURPOSE: A recent observational study suggested statins could reduce cancer diagnosis in patients with heart failure (HF). The findings need to be validated using robust epidemiological methods. This study aimed to evaluate the effect of statin treatment on the risk of cancer in patients with HF. METHODS: We conducted two target trial emulations using primary care data from IQVIA Medical Research Database-UK (2000 to 2019) with a clone-censor-weight design. The first emulated trial addressed the treatment initiation effect: initiating within 1 year versus not initiating a statin after the HF diagnosis. The second emulated trial addressed the cumulative exposure effect: continuing a statin for ≤3 years, 3-6 years, and >6 years after initiation. The study outcomes were any incident cancer and site-specific cancer diagnoses. Weighted pooled logistic regression models were used to estimate 10-year risk ratios (RR). 95% confidence intervals (CIs) were estimated using non-parametric bootstrapping. RESULTS: The first emulated trial showed that, compared to no statin, statins did not reduce the cancer risk in patients with HF (RR, 1.05; 95% CI, 0.94-1.15). The second emulated trial showed that, compared to treatment ≤3 years, statins with longer durations did not reduce the cancer risk (3-6 years: RR, 0.94; 95% CI, 0.70-1.33. >6 years: RR, 0.97; 95% CI, 0.79-1.26). No significant risk difference was observed on any site-specific cancer diagnoses. CONCLUSIONS: The results from the target trial emulations suggest that statin treatment is not associated with cancer risk in patients with HF.

Evolocumab Treatment in Pediatric Patients With Homozygous Familial Hypercholesterolemia: Pooled Data From Three Open-Label Studies.

BACKGROUND: Pediatric patients with homozygous familial hypercholesterolemia (HoFH) have an increased risk of atherosclerotic cardiovascular disease and difficulty meeting low-density lipoprotein cholesterol (LDL-C) goals. In this post hoc analysis, we evaluated pooled safety and efficacy data from 3 studies in pediatric patients with HoFH treated with the PCSK9 (proprotein convertase subtilisin/kexin type 9) monoclonal antibody inhibitor evolocumab. METHODS: Patients with HoFH aged 10 to 17 years received treatment with open-label evolocumab 420 mg subcutaneously monthly or biweekly in the TAUSSIG, RAMAN, or HAUSER-OLE clinical studies. All patients received background statins with or without ezetimibe. Study duration ranged from 12 to 260 weeks. The primary end point was treatment-emergent adverse events per 100 patient-years. Efficacy end points were changes from baseline to week 12 in lipids and PCSK9. RESULTS: Of the 39 patients in the pooled analysis, 69.2% were males, median age was 13.0 years, and 79.5% (31/39) had genotyped HoFH with LDLR pathogenic variants. Overall, median exposure to evolocumab was 18.2 (Q1, Q3: 3.0, 18.5) months. Treatment-emergent adverse events with an exposure-adjusted patient incidence rate of ≥5% were upper respiratory tract infection (6.6%), influenza (5.2%), and acne (5.0%) per 100 patient-years. Exposure-adjusted patient incidence of serious treatment-emergent adverse events was 13.3% per 100 patient-years. Excluding 4 patients receiving lipoprotein apheresis, week 12 median percentage change from baseline in LDL-C was -2.9% (Q1, Q3: -21.7, 1.5); however, 42.9% (15/35) of patients achieved ≥15% reduction in LDL-C from baseline. Residual LDLR (LDL receptor) activity was not associated with a reduction in LDL-C. CONCLUSIONS: In this pooled data analysis from 3 studies in pediatric patients with HoFH, evolocumab was well tolerated, with no new safety signals reported. These safety findings are consistent with findings from previous studies of evolocumab. Patients showed marked variability in LDL-C reduction. Results from this pooled analysis support guidelines suggesting a trial of PCSK9 inhibitor therapy regardless of estimated residual LDLR function. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01624142, NCT03403374, and NCT02624869.

Association between Statin use and Incident Peripheral Artery Disease According to Race, Age, and Presence of Depression in the Multi-Ethnic Study of Atherosclerosis.

BACKGROUND: Peripheral artery disease (PAD) is associated with high morbidity and mortality and has been commonly described as a coronary heart disease equivalent. Statin medications are recommended for primary prevention of atherosclerotic cardiovascular disease (CVD) among other indications. Therefore, understanding the longitudinal relationship of incident PAD is necessary to inform future research on how to prevent the disease. Depression complicates CVD patients' ability to properly adhere to their medications, yet the effect of depression on the relationship between statin use and incident PAD is understudied. People with PAD have a higher incidence of depressive symptoms than people without PAD. Black American and Hispanic populations are disproportionately affected by both PAD and depression yet research on the modifying effect of either race or depression on the relationship between statin use and onset of PAD is minimal. While statin utilization is highest for ages 75-84 years, there is minimal evidence of favorable risk-benefit balance. Consequently, in this project, we examined the relationship between statin use and incident PAD and whether this relationship is modified by race/ethnicity, depressive symptoms, or age. METHODS: We used data on participants from the Multi-Ethnic Study of Atherosclerosis from visit 1 (2000) through study visit 6 (2020) who had three separate measurements of the ankle-brachial index (ABI) taken at visit 1, visit 3, and visit 5. Incident PAD was defined as 1) incident lower extremity amputation or revascularization or 2) ABI less than 0.90 coupled with ABI decrease greater than 0.15 over the follow-up period. Statin use was noted on the study visit prior to incident PAD diagnosis while depressive symptoms were measured at exam 1, visit 3, and visit 5. Propensity score matching was implemented to create balance between the participants in the two treatment groups, that is, statin-treated and statin-untreated groups, to reduce the problem of confounding by indication. Propensity scores were calculated using multivariate logistic regression model to estimate the probability of receiving statin treatment. We used Cox proportional hazards regression to investigate the relationship between time-dependent statin use as well as other risk factors with incident PAD, overall and stratified by 1) race, 2) depression status, and 3) age. RESULTS: A total of 4,210 participants were included in the final matched analytic cohort. There were 810 incident cases (19.3%) of PAD that occurred over an average (mean) of 11.3 years (SD = 5.7) of follow-up time. In the statin-treated group, and with an average follow-up time of 12.5 years (SD = 5.6), there were 281 cases (13.4%) of incident PAD with the average follow-up time of 10.1 years (SD = 5.5), whereas in the statin-untreated group, there were 531 cases (25.2%) (P < 0.001). Results demonstrate a lower risk of PAD event in the statin-treated group compared to the untreated group (hazard ratio [HR] = 0.45, 95% confidence interval [CI]: 0.33-0.62) over the span of 18.5 years. The interactions between 1) depression and 2) race with statin use for incident PAD were not significant. However, other risk factors which were significant included Black American race that had approximately 30% lower hazard of PAD compared to non-Hispanic White (HR = 0.70, 95% CI: 0.58-0.84); age-stratified models were also fitted, and stain use was still a significant treatment factor for ages 45-54 (HR = 0.45, 95% CI: 0.33-0.63), 55-64 (HR = 0.61, 95% CI: 0.46-0.79), and 65-74 years (HR = 0.61, 95% CI: 0.48-0.78) but not for ages 75-84 years. CONCLUSIONS: Statin use was associated with a decreased risk of incident PAD for those under the age of 75 years. Neither race nor depression significantly modified the relationship between statin use and incident PAD; however, the risk of incident PAD was lower among Black Americans. These findings highlight that the benefit of statin may wane for those over the age of 75 years. Findings also suggest that statin use may not be compromised in those living with depression.

First Report of Inclisiran Utilization for Hypercholesterolemia Treatment in Real-world Clinical Settings in a Middle East Population.

PURPOSE: Inclisiran is the first small interfering RNA-based treatment approved for reducing pro-atherogenic lipoproteins in patients with heterozygous familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease, who require additional lowering of low-density lipoprotein cholesterol (LDL-C). We report the first evaluation of the effects of inclisiran in a Middle East population. METHODS: We conducted a retrospective review of patients initiating inclisiran treatment at an outpatient diabetology, endocrinology, and cardiology center between May 2021 and December 2022. All patients followed up for 90 days or more, or with at least 1 lipid determination post initiation were included. Participants were categorized into primary prevention (n = 57) and secondary prevention (n = 89) groups according to previous atherosclerotic cardiovascular disease. FINDINGS: Inclisiran was initiated in 146 patients; mean (SD) age was 54.8 (12.12) years, 82 patients (56.2%) were male, 28 patients (19.2%) had received a diagnosis of familial hypercholesterolemia, 89 patients (61%) had received a diagnosis of diabetes mellitus, and 35 patients (23.9%) had a statin intolerance. Median (interquartile range) follow-up was 137 (90 to 193) days. At 90 days, median (interquartile range) reductions in serum LDL-C and triglycerides were -37.9% (-9.5% to -51.2%) and -12.0% (-9.8% to -40.5%), respectively, in primary prevention and -54.1% (-17.1% to -71.4%) and -15.3% (-14% to -38.8%), respectively, in secondary prevention (all, P < 0.001). LDL-C goals were attained in 110 patients (75.3%). Nonattainment of LDL-C goal was attributed to system effect in 26 patients (72.2%), biological effect in 5 patients (13.9%), and discontinuation of treatment in 5 patients (13.9%). Therapy was well tolerated. IMPLICATIONS: This study is the first from the Middle East and North Africa region that reported the real-world efficacy and safety profile of inclisiran in a mixed-risk population of patients with heterozygous familial hypercholesterolemia and other non-familial hypercholesterolemia indications. Clinically meaningful and sustained reductions in pro-atherogenic lipids with good tolerability were observed after inclisiran initiation. Fewer AEs were reported in this predominantly Arabic population, consistent with previous safety reports for inclisiran. It is important to note that no patient stopped inclisiran treatment due to AEs. Strengths of our study included an optimal cohort, patient heterogeneity, and high retention. In addition, we were able to report mean robust effects of inclisiran and good medication tolerability, quite like randomized studies and open-label extension periods. Despite this, our study had some limitations, including selection bias due to the retrospective design and the absence of a comparative group.

Rhabdomyolysis and acute kidney injury potentiated by a drug-drug interaction between cyclosporine, leflunomide, and rosuvastatin in a kidney transplant recipient: A missed opportunity for pharmacist involvement.

BACKGROUND: This study aimed to describe a case of rhabdomyolysis and acute kidney injury potentiated by a drug-drug interaction (DDI) between cyclosporine, leflunomide, and rosuvastatin in a kidney transplant recipient. CASE SUMMARY: A 74-year-old male with end-stage kidney disease secondary to type 2 diabetes mellitus and hypertension received a deceased by cardiac death kidney transplant. The patient's medical history included coronary artery disease and hyperlipidemia for which he was receiving rosuvastatin 40 mg daily. Five months after transplant, the patient developed BK viremia, which required multiple changes in immunosuppression and resulted in the initiation of leflunomide and cyclosporine modified. The patient used multiple pharmacies and coupon cards that delayed the identification of the DDIs between leflunomide, cyclosporine, and rosuvastatin. Approximately, 13 months after transplant, the biopsy report of the patient's allograft kidney showed acute cellular rejection Banff IB, hypertensive changes, and transplant glomerulopathy. This prompted the patient to receive a 3-day course of methylprednisolone 250 mg intravenous at the outpatient infusion center. Two weeks later, the patient presented to the transplant clinic with lightheadedness, dizziness, weakness, fatigue, bilateral eye drainage, and a decrease in appetite and was admitted to the hospital for further workup. On admission, creatine kinase was 2080 IU/L with myoglobin of 7601 ng/mL. The patient's diagnosis was statin myopathy with possible rhabdomyolysis acute kidney injury. Likely contributing factors included cyclosporine, leflunomide, and rosuvastatin DDI and administration of high-dose methylprednisolone. PRACTICE IMPLICATIONS: This case demonstrates the importance of pharmacist involvement throughout all phases of care in a kidney transplant recipient.

Atorvastatin-associated myotoxicity: A toxicokinetic review of pharmacogenetic associations to evaluate the feasibility of precision pharmacotherapy.

Atorvastatin (ATV) and other statins are highly effective in reducing cholesterol levels. However, in some patients, the development of drug-associated muscle side effects remains an issue as it compromises the adherence to treatment. Since the toxicity is dose-dependent, exploring factors modulating pharmacokinetics (PK) appears fundamental. The purpose of this review aims at reporting the current state of knowledge about the singular genetic susceptibilities influencing the risk of developing ATV muscle adverse events through PK modulations. Multiple single nucleotide polymorphisms (SNP) in efflux (ABCB1, ABCC1, ABCC2, ABCC4 and ABCG2) and influx (SLCO1B1, SLCO1B3 and SLCO2B1) transporters have been explored for their association with ATV PK modulation or with statin-related myotoxicities (SRM) development. The most convincing pharmacogenetic association with ATV remains the influence of the rs4149056 (c.521 T > C) in SLCO1B1 on ATV PK and pharmacodynamics. This SNP has been robustly associated with increased ATV systemic exposure and consequently, an increased risk of SRM. Additionally, the SNP rs2231142 (c.421C > A) in ABCG2 has also been associated with increased drug exposure and higher risk of SRM occurrence. SLCO1B1 and ABCG2 pharmacogenetic associations highlight that modulation of ATV systemic exposure is important to explain the risk of developing SRM. However, some novel observations credit the hypothesis that additional genes (e.g. SLCO2B1 or ABCC1) might be important for explaining local PK modulations within the muscle tissue, indicating that studying the local PK directly at the skeletal muscle level might pave the way for additional understanding.

Update About the Management of Low-Density Lipoprotein Cholesterol and Hypertriglyceridemia in Lower Extremity Peripheral Artery Disease Patients: Consensus of the French Society of Vascular Medicine and the French Society for Vascular and Endovascular Surgery.

BACKGROUND: A French intersociety consensus on behalf the Société Française de Médecine Vasculaire and the Société de Chirurgie Vasculaire et Endovasculaire was proposed in 2021 for the management of patients with lower extremity peripheral artery disease (LEAD). Recent studies have been published and an update of this consensus about the management of low-density lipoprotein cholesterol (LDLc) and hypertriglyceridemia was required. METHODS: A steering committee of 12 vascular physicians and surgeons defined questions of interest about LDLc and hypertriglyceridemia management. A French expert panel voted the proposals. Consensus was considered to have been achieved if more than 80% of the responses corresponded to either "Agreement" or "Disagreement". RESULTS: Among the 56 experts who were asked to participate, 46 (82%) accepted. After the first round of the Delphi procedure, the 4 proposals reached consensus. The following suggestions and recommendations were approved: 1. For LEAD patients treated by the highest tolerated statin dose ± ezetimibe and who have an LDLc ≥0.70 g/L, we recommend adding a proprotein convertase subtilisin/kexin type 9 inhibitor. 2. For LEAD patients treated by statin and who have elevated triglyceride level between ≥150 mg/dL and ≤500 mg/dL, we suggest adding Icosapent Ethyl. 3. Before adding Icosapent Ethyl in LEAD patients treated with statin, we suggest looking for symptoms that may suggest atrial fibrillation. 4. For LEAD patients treated by Icosapent Ethyl and who have symptoms that suggest atrial fibrillation, we recommend performing an electrocardiogram. CONCLUSIONS: This update will help clinicians to improve LEAD patient management.

Patients with Prior Exposure to a Combination of Statins & Angiotensin-Converting Enzyme Inhibitors (ACE-Is)/Angiotensin Receptor Blockers (ARBs) Have Better Outcomes after Carotid Revascularization than Patients with Prior Exposure to Statins Alone: A MultiCenter Analysis.

BACKGROUND: Statin use has been studied and confirmed to have a beneficial impact on perioperative carotid endarterectomy (CEA) and carotid artery stenting (CAS) outcomes. The benefits of Angiotensin-converting enzyme inhibitors (ACE-I) in hypertension, ischemic heart disease, heart failure, diabetes mellitus, and renal disease are well-known; however, the impact of continuing or withholding ACE-Is/angiotensin receptor blockers (ARBs) on CEA and CAS outcomes is not addressed well in the literature. This study aimed to evaluate the impact of preoperative statin use combined with ACE-Is/ARBs in patients undergoing CEA or CAS on mortality and morbidity using a multi-institutional database. METHODS: Using the data of all patients who underwent carotid artery revascularization, including CEA, transcarotid artery revascularization, and transfemoral carotid artery stenting from 2016 to 2021 in the Vascular Quality Initiative data, we determined as our primary outcome 30-day mortality/stroke after carotid revascularization based on periop exposure to statins alone, or the combination of statins and ACE-Is/ARBs. Secondary outcomes were postop myocardial infarction and postop congestive heart failure. Poisson regression with robust variance was used to determine postop outcomes comparing the combination of statin and ACE-Is/ARBs group with statins alone group. RESULTS: A total of 131,285 patients were included in the study, with 59,860 (46%) patients receiving statin only, and 71,425 (54%) receiving both statin and ACE-Is/ARBs preoperatively. Both patient groups differed significantly in preop clinical and demographic characteristics. After adjusting for potential confounders, the statins plus ACE-I/ARB group had a 12% lower risk of postop mortality/stroke (Incident Rate Ratio comparing Statin/ACE group to Statins Only group [IRR] 0.88, 95% confidence interval 0.81-0.95, P = 0.001), 18% lower risk of postop congestive heart failure (IRR 0.82, 95% CI 0.68-0.98, P = 0.029), and similar risk of postop myocardial infarction (IRR 1.05 95% confidence interval 0.91-1.20, P = 0.54) compared to the statin-only group. CONCLUSION: Statins combined with ACE-Is/ARBs perioperatively offer better protection compared to statins alone in patients undergoing carotid revascularization surgery. We recommend the continuation of ACE-Is/ARBs use in patients undergoing carotid revascularization, especially if they have concurrent hypertension. Further prospective studies are needed to evaluate the benefit of adding ACE-Is/ARBs.