Uptake Of Statins Research Articles

Gender disparities in utilization of statins for low density lipoprotein management across the spectrum of atherosclerotic cardiovascular disease: Insights from the houston methodist cardiovascular disease learning health system registry

IntroductionLower statin utilization is reported among women compared to men, however large-scale studies evaluating gender disparities in LDL-C management in individuals with ASCVD and its subtypes remain limited, particularly across age and racial/ethnic subgroups. In this study, we address this knowledge gap using data from a large US healthcare system. MethodsAll adult patients with established ASCVD in the Houston Methodist Learning Health System Registry during 2016–2022 were included. Statin use and dose were extracted from the database. The association between gender and statin utilization was evaluated using multivariate logistic regression analyses in patients with ASCVD overall, across ASCVD subtypes, and by age, racial/ethnic subgroups, and socioeconomic risk factors. ResultsA total of 97,819 patients with prevalent ASCVD were included. Women with ASCVD had lower utilization of any statin (64.3% vs 72.6 %; p < 0.001) and high-intensity statin (29.8% vs 42.5 % p < 0.001) compared with men. In fully adjusted models, women had 40 % lower odds of any (adjusted odds ratio [aOR]:0.58, 95 % CI 0.57–0.60) and high-intensity statin use (aOR:0.59, 0.57–0.61) relative to men. Women were also less likely to have guideline-recommended LDL-C < 70 mg/dL (30.2% vs 42.7 %; p < 0.01). These differences persisted across age, racial/ethnic and socioeconomic subgroups. ConclusionSignificant gender disparities exist in contemporary lipid management among patients with ASCVD, with women being less likely to receive any and high-intensity statin and achieving guideline defined LDL-C goal compared with men across age and racial/ethnic subgroups. These disparities underscore the need to further understand potential socioeconomic drivers of the observed lower statin uptake in women.

Statin use for cardiovascular disease prevention: perceptions among people living with HIV in the United States

BackgroundPeople living with HIV (PLWH) may be at heightened risk for cardiovascular disease (CVD). Statin use and lifestyle changes reduce the risk of CVD but remain under-prescribed among PLWH. The objective of this study was to characterize knowledge of CVD and statin use, current usage, barriers to taking statins, and information desired by PLWH to improve statin uptake among PLWH in Los Angeles, CA.MethodsBetween April 2019 and April 2020, we conducted four focus group discussions (n = 37) with patients across three public community health clinics that serve PLWH in Los Angeles County, California. All clinics participated in a larger study to improve statin prescribing for PLWH. We asked about knowledge of statins, willingness to take a statin, possible barriers to statin usage, preferred information sources for health information, and desired information about statins. We utilized standard qualitative content analysis methods to identify themes.ResultsWe found a range in the awareness of statins, with some participants reporting never having heard of statins while others had a history of statin use. There were concerns about the potential long-term effect of statin use, but participants expressed willingness to use CVD medications generally and statins specifically, especially if recommended by their healthcare provider. Participants also expressed interest in potential alternatives to statin usage such as exercising regularly and nutritious eating.ConclusionsMore interventions are needed to increase statin use among PLWH to improve CVD outcomes, which also has implications for HIV progression. Clinics should aim to increase patient and provider knowledge about CVD risk and statin use for PLWH and provide shared decision-making tools that are easy to use and culturally appropriate.

Construction and characterization of a humanized SLCO1B1 rat model with its application in evaluating the uptake of different statins

Organic anion-transporting polypeptides 1B1 (OATP1B1) plays a crucial role in the transport of statins. However, there are too few animal models related to OATP1B1, especially humanized animal models. In this study, the human SLCO1B1 cDNA was inserted into the second exon of the rat Slco1b2 gene using CRISPR/Cas9 technology. Pharmacokinetic characteristics of statins were conducted in wild-type (WT), humanized OATP1B1 (hOATP1B1), and OATP1B2 knockout (OATP1B2 KO) rats, respectively. The results showed that human OATP1B1 was successfully expressed in rat liver and exhibited transport function. Furthermore, the pharmacokinetic results revealed that OATP1B1 exhibited varying uptake levels of pivastatin, rosuvastatin, and fluvastatin, leading to different levels of exposure within the body. These results were consistent with those obtained from in vitro experiments using overexpressed cell lines. In conclusion, we established a novel humanized SLCO1B1 transgenic rat model to assess the role of human OATP1B1 in the uptake of different statins. The different uptake mediated by OATP1B1 may be an important reason for the different efficacy of statins. The hOATP1B1 rat is a promising model for improving the prediction of human drug transport.

Interpretation of Protein-Mediated Uptake of Statins by Hepatocytes Is Confounded by the Residual Statin-Protein Complex.

Inclusion of plasma (or plasma proteins) in human hepatocyte uptake studies narrows, but does not close, the gap in in vitro to in vivo extrapolation (IVIVE) of organic anion transporting polypeptide (OATP)-mediated hepatic clearance (CLh) of statins. We have previously shown that this "apparent" protein-mediated uptake effect (PMUE) of statins by OATP1B1-expressing cells, in the presence of 5% human serum albumin (HSA), is mostly an artifact caused by residual statin-HSA complex remaining in the uptake assay. We determined if the same was true with plated human hepatocytes (PHH) and if this artifact can be reduced using suspended human hepatocytes (SHH) and the oil-spin method. We quantified the uptake of a cocktail of five statins by PHH and SHH in the absence and presence of 5% HSA. After terminating the uptake assay, the amount of residual HSA was quantified by quantitative targeted proteomics. For both PHH and SHH, except for atorvastatin and cerivastatin, the increase in total, active, and passive uptake of the statins, in the presence of 5% HSA, was explained by the estimated residual stain-HSA complex. In addition, the increase in active statin uptake by SHH, where present, was marginal (<50%), much smaller than that observed with PHH. Such a marginal increase cannot bridge the gap in IVIVE of CLh of statins. These data disprove the prevailing hypotheses for the in vitro PMUE. A true PMUE should be evaluated using the uptake data corrected for the residual drug-protein complex. SIGNIFICANCE STATEMENT: We show that the apparent protein-mediated uptake (PMUE) of statins by human hepatocytes is largely confounded by residual statin when plated or suspended human hepatocytes are used. Therefore, mechanisms other than PMUE need to be explored to explain the underprediction of the in vivo human hepatic clearance of statins by human hepatocyte uptake assays.

Effect of SLCO1B1 c.521T>C polymorphism on the lipid response to statins in people living with HIV on a boosted protease inhibitor-containing regimen.

We previously observed that some individuals on HIV boosted protease inhibitor-containing regimen do not achieve their lipid targets despite elevated statin concentrations. This study evaluated whether the common single polymorphism c.521T>C in SLCO1B1, associated with reduced statin uptake in the liver, could explain this observation. People living with HIV in the Swiss HIV Cohort Study were eligible if they were on a boosted protease inhibitor concomitantly with a statin for at least 6 months and if their SLCO1B1 genotype was available. Furthermore, their lipids had to be documented before and after the introduction of the statin. The statin efficacy was defined as % change in total cholesterol, low-density lipoprotein-cholesterol, high-density lipoprotein-cholesterol and triglycerides levels after statin initiation compared to pretreatment levels. Lipid response was adjusted for differences in potency and dose between statins. In total, 88 people living with HIV were included, of whom 58, 28 and 2 carried the SLCO1B1 TT, TC and CC genotypes, respectively. The change in lipid levels after statin initiation tended to be lower in carriers of the polymorphism although the difference was not statistically significant (TT vs. TC/CC: total cholesterol: -11.7 vs. -4.8%; low-density lipoprotein- cholesterol: -20.6 vs. -7.4%; high-density lipoprotein-cholesterol: 1.6 vs. 0%; triglycerides: -11.5 vs. -7.9%). In the multiple linear regression, change in total cholesterol was inversely correlated with the total cholesterol level prestatin treatment (coefficient -6.60, 95% confidence interval: -9.63 to -3.56, P < .001). The lipid-lowering effect of statins tended to be attenuated by SLCO1B1 polymorphism and progressively declined as total cholesterol under the boosted protease inhibitor treatment decreased.

Evaluating Statin Knowledge-Perceptions and Receptivity Following a Comprehensive Lifestyle Modification Program

Background Though clinical guidelines for cholesterol-lowering therapies advocate for both a trial of lifestyle modification and the initiation of statin medication when appropriate, the extent to which lifestyle modification may alter a patient’s knowledge-perceptions and receptivity towards statins remains unclear. Methods Following completion of a 6-month comprehensive lifestyle modification program, perceived changes in knowledge and receptivity towards statins were examined across prespecified subgroups of age, sex, and statin eligibility using a mixed-methods questionnaire. Quantitative and qualitative analyses incorporated binomial tests, McNemar’s test, and thematic analyses. Results Among 192 patients who completed the program and exit questionnaire between December 15, 2020 and July 2, 2021, 88.4% of patients indicated a perceived improvement in cholesterol and/or statin knowledge (P &lt; . 0001). 48.2% of patients acknowledged that their receptivity towards taking statins increased (P = . 61). Changes in receptivity were attributed to several identified program themes including improvements in health knowledge and awareness, motivation and empowerment. Patients who noted improvements in their mental health also reported significantly increased receptivity towards statins (P &lt; . 001). Conclusions Patients’ perceived knowledge and receptivity towards statins may improve following participation in a comprehensive therapeutic lifestyle modification program. Future research must evaluate the impact of these programs on statin uptake, compliance and outcomes.

Abstract P3-03-14: Comparing risk of breast cancer and cardiovascular disease and uptake of chemoprevention and statins among racially/ethnically diverse women with atypical hyperplasia or lobular carcinoma in situ

Abstract Background: Chemoprevention with selective estrogen receptor modulators (SERMs) and aromatase inhibitors (AIs) has been shown in randomized controlled trials to decrease breast cancer incidence by 50-65% among women at high risk for breast cancer. However, chemoprevention uptake remains low among high-risk women. Women with atypical hyperplasia (AH) or lobular carcinoma in situ (LCIS) derive the greatest benefit from SERMs and AIs for breast cancer risk reduction. A potential barrier to chemoprevention uptake is competing comorbidities, including atherosclerotic cardiovascular disease (ASCVD). We calculated risk of breast cancer and ASCVD among women with AH or LCIS and assessed uptake of chemoprevention and statins among women who met high-risk criteria for both breast cancer and ASCVD. Methods: We conducted a retrospective cohort study among women, age 40-74 years, with AH or LCIS diagnosed in 2007-2015 at Columbia University Irving Medical Center (CUIMC) in New York City. Eligible women had sufficient data in the electronic health record (EHR) to calculate 5 and 10-year invasive breast cancer risk according to the Breast Cancer Surveillance Consortium (BCSC) risk calculator, including age, race/ethnicity, first-degree family history of breast cancer, breast biopsy results, and mammographic density. We calculated 10-year ASCVD risk using the 2013 American College of Cardiology (ACC)/American Heart Association (AHA) ASCVD risk calculator using additional EHR data, including systolic blood pressure, total and HDL cholesterol, history of diabetes, treatment for hypertension, and current smoking status. High-risk criteria to determine eligibility for SERMs/AIs and statins was defined as a 5-year invasive breast cancer risk 1.67% and 10-year ASCVD risk 7.5%, respectively. We compared mean 10-year risk of breast cancer vs. ASCVD using a paired t-test and uptake of SERMs/AIs vs. statins among women at high risk for breast cancer and ASCVD, respectively, using McNemar’s test. Results: Among 298 evaluable women, mean age was 58.2 years (standard deviation [SD], 8.34), with 33% non-Hispanic White, 41% Hispanic, 9% non-Hispanic Black, 6% Asian, and 11% other/unknown race/ethnicity. About 98% of women met high-risk criteria for breast cancer and 30% were high risk for ASCVD. Mean 10-year risk of breast cancer was higher than mean 10-year risk of ASCVD (9.14% vs. 6.69%, p&amp;lt; 0.001). Among women who met high-risk criteria for both breast cancer and ASCVD, uptake of statins was higher compared to SERMs/AIs (58% vs. 21%, p&amp;lt; 0.001). Comparing non-Hispanic Whites vs. racial/ethnic minorities, mean 10-year breast cancer risk was higher (12.12% vs. 7.71%, p&amp;lt; 0.001), but there were no statistically significant differences in ASCVD risk or uptake of chemoprevention or statins. Conclusions: Among women with AH or LCIS, mean absolute risk of breast cancer was higher compared to risk of ASCVD, however, uptake of statins was higher compared to chemoprevention with SERMs or AIs. To address under-utilization of chemoprevention among high-risk women, use of SERMs or AIs should be placed in the context of medications used for other chronic diseases, such as statins for ASCVD. Citation Format: Luisa Nilan, Jacquelyn N. Amenta, Julia E. McGuinness, Rita Kukafka, Katherine D. Crew, Kehinde Lawal. Comparing risk of breast cancer and cardiovascular disease and uptake of chemoprevention and statins among racially/ethnically diverse women with atypical hyperplasia or lobular carcinoma in situ [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-03-14.

Abstract P4-03-23: Comparison of Breast Cancer vs Cardiovascular Disease Risk and Uptake of Chemoprevention vs Statins in a Cohort of Predominantly Hispanic Women Undergoing Screening Mammography

Abstract Background: Atherosclerotic cardiovascular disease (ASCVD) and breast cancer are two of the most diagnosed chronic diseases among women in the U.S. Although prevention of ASCVD with statins is widely practiced, breast cancer chemoprevention with selective estrogen receptor modulators (SERMs) or aromatase inhibitors (AIs) is underutilized in the primary care setting, despite significant evidence in randomized controlled trials demonstrating its clinical benefits. We compared the risk of ASCVD and breast cancer among predominantly Hispanic women undergoing screening mammography, as well as uptake of statins and SERMs/AIs for ASCVD and breast cancer risk reduction, respectively, among high-risk women. Methods: We conducted a retrospective cohort study among 1,655 English or Spanish-speaking women, age 40-79 years, with no prior history of breast cancer, who underwent screening mammography from 2014 to 2016 at Columbia University Irving Medical Center in New York City. Participants completed a survey collecting data on sociodemographic and breast cancer risk factors and had available data in the electronic health record (EHR) for calculating ASCVD risk, including systolic blood pressure, total and HDL cholesterol, history of diabetes, treatment for hypertension, and current smoking status. The main outcomes included 5-year and lifetime invasive breast cancer risk according to the Gail model, and 10-year and lifetime ASCVD risk score according to the 2013 American College of Cardiology (ACC)/American Heart Association (AHA) ASCVD risk calculator. High-risk was defined as a 5-year invasive breast cancer risk 1.67% and 10-year ASCVD risk 7.5%. Secondary outcomes included uptake of chemoprevention with SERMs or AIs and statins among women at high-risk for breast cancer and ASCVD, respectively, based upon medication lists in the EHR. We compared mean lifetime risk of breast cancer vs ASCVD for the entire cohort using a paired t-test, and the proportion of high-risk women taking statins vs chemoprevention using McNemar’s test. Results: Among 1,655 evaluable women, mean age was 58 years (SD=10.1 years), with 76% Hispanic, 6% non-Hispanic White, 3% non-Hispanic Black, 2% Asian, and 13% other. About half (48%) of women met high-risk criteria for ASCVD compared to 15% who met high-risk criteria for breast cancer. Among all women, mean lifetime ASCVD risk was higher than mean lifetime breast cancer risk (10.71% vs. 5.46%, p&amp;lt; 0.001). Among women at high risk for ASCVD or breast cancer, respectively, statin uptake was higher compared to SERM/AI uptake for breast cancer chemoprevention (84% vs. 7%, p&amp;lt; 0.001). Overall, fewer Hispanic compared to non-Hispanic women met high-risk criteria for ASCVD (47% vs. 51%, respectively) and breast cancer (9% vs. 34%, respectively). Conclusions: In a population of predominantly Hispanic women undergoing screening mammography, we found that more women met high-risk criteria for ASCVD compared to breast cancer. Among women at high risk for ASCVD, statin uptake was about 12-fold higher compared to uptake of breast cancer chemoprevention among women at high risk for breast cancer. Given significant underutilization of breast cancer chemoprevention, placing this in the context of prevention of other chronic diseases, such as statins for ASCVD, may enhance uptake of SERMs or AIs in the primary care setting. Citation Format: Luisa Nilan, Mary M. McDermid, Jacquelyn N. Amenta, Julia E. McGuinness, Katherine D. Crew, Rita Kukafka. Comparison of Breast Cancer vs Cardiovascular Disease Risk and Uptake of Chemoprevention vs Statins in a Cohort of Predominantly Hispanic Women Undergoing Screening Mammography [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-03-23.

PharmVar GeneFocus: SLCO1B1.

The Pharmacogene Variation Consortium (PharmVar) is now providing star (*) allele nomenclature for the highly polymorphic human SLCO1B1 gene encoding the organic anion transporting polypeptide 1B1 (OATP1B1) drug transporter. Genetic variation within the SLCO1B1 gene locus impacts drug transport, which can lead to altered pharmacokinetic profiles of several commonly prescribed drugs. Variable OATP1B1 function is of particular importance regarding hepatic uptake of statins and the risk of statin-associated musculoskeletal symptoms. To introduce this important drug transporter gene into the PharmVar database and serve as a unified reference of haplotype variation moving forward, an international group of gene experts has performed an extensive review of all published SLCO1B1 star alleles. Previously published star alleles were self-assigned by authors and only loosely followed the star nomenclature system that was first developed for cytochrome P450 genes. This nomenclature system has been standardized by PharmVar and is now applied to other important pharmacogenes such as SLCO1B1. In addition, data from the 1000 Genomes Project and investigator-submitted data were utilized to confirm existing haplotypes, fill knowledge gaps, and/or define novel star alleles. The PharmVar-developed SLCO1B1 nomenclature has been incorporated by the Clinical Pharmacogenetics Implementation Consortium (CPIC) 2022 guideline on statin-associated musculoskeletal symptoms.

Unblinded and Blinded N-of-1 Trials Versus Usual Care: A Randomized Controlled Trial to Increase Statin Uptake in Primary Care.

The aim was to assess whether an intervention incorporating a practicable open-label n-of-1 trial would lead to greater uptake of statin than usual care and comparable uptake to a closed-label gold-standard n-of-1 trial. We enrolled patients who had stopped or declined statins into a 3-arm trial (usual care, unblinded, and blinded n-of-1 intervention arms). Physicians advised participants randomized to usual care to take statin therapy to prevent cardiovascular disease. In both intervention arms, physicians delivered a theoretically informed informed intervention endorsing the value of experimenting with medication in n-of-1 trials to assess whether it caused side-effects. In these trials, participants alternated between 4 weeks of medication and no medication (unblinded arm) or randomly sorted active and placebo (blinded arm) and recorded symptoms and symptom attributions for 6 months. Thereafter, physicians discussed participants' symptom reports during active/inactive treatment periods and asked participants to resume statins if appropriate. Seventy-three were randomized to the intervention arms and 20 to the control group. Fifty-six of 73 (77%) attempted the n-of-1 experiment; 28/36 (78%) in the unblinded arm; and 28/37 (76%) in the blinded arm. Forty-three of 56 (77%) completed the 6-month experiment and received feedback from the physician; 20/28 (71%) in the unblinded arm and 23/28 (82%) in the blinded arm. Thirty-three of 76 (45%) people restarted statins in the n-of-1 arms compared with 4/20 (20%) in the control arm, difference 24% (95% CI, 5%-43%; P=0.041). There was no evidence this differed between blinded and unblinded arms, difference 2% (95% CI, -20% to 24%; P=0.86). Adverse events occurred at a similar rate on and off statin. In patients refusing or intolerant of statin, supporting experimentation with n-of-1 trials increases medication uptake compared with usual care. Alternating on-off medication in unblinded n-of-1 experiments appears as effective as a blinded experiment. URL: https://doi.org/10.1186/ISRCTN11142694; Unique identifier: ISRCTN11142694.

Regulation of Blood-Brain Barrier Transporters by Transforming Growth Factor-β/Activin Receptor-Like Kinase 1 Signaling: Relevance to the Brain Disposition of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitors (i.e., Statins).

Our laboratory has shown that activation of transforming growth factor- β (TGF- β )/activin receptor-like kinase 1 (ALK1) signaling can increase protein expression and transport activity of organic anion transporting polypeptide 1a4 (Oatp1a4) at the blood-brain barrier (BBB). These results are relevant to treatment of ischemic stroke because Oatp transport substrates such as 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (i.e., statins) improve functional neurologic outcomes in patients. Advancement of our work requires determination if TGF- β /ALK1 signaling alters Oatp1a4 functional expression differently across brain regions and if such disparities affect central nervous system (CNS) statin disposition. Therefore, we studied regulation of Oatp1a4 by the TGF- β /ALK1 pathway, in vivo, in rat brain microvessels isolated from cerebral cortex, hippocampus, and cerebellum using the ALK1 agonist bone morphogenetic protein-9 (BMP-9) and the ALK1 inhibitor 4-[6-[4-(1-piperazinyl)phenyl]pyrazolo[1,5-a]pyrimidin-3-yl]quinoline dihydrochloride 193189. We showed that Oatp1a4 protein expression and brain distribution of three currently marketed statin drugs (i.e., atorvastatin, pravastatin, and rosuvastatin) were increased in cortex relative to hippocampus and cerebellum. Additionally, BMP-9 treatment enhanced Oatp-mediated statin transport in cortical tissue but not in hippocampus or cerebellum. Although brain drug delivery is also dependent upon efflux transporters, such as P-glycoprotein and/or Breast Cancer Resistance Protein, our data showed that administration of BMP-9 did not alter the relative contribution of these transporters to CNS disposition of statins. Overall, this study provides evidence for differential regulation of Oatp1a4 by TGF- β /ALK1 signaling across brain regions, knowledge that is critical for development of therapeutic strategies to target Oatps at the BBB for CNS drug delivery. SIGNIFICANCE STATEMENT: Organic anion transporting polypeptides (Oatps) represent transporter targets for brain drug delivery. We have shown that Oatp1a4 statin uptake is higher in cortex versus hippocampus and cerebellum. Additionally, we report that the transforming growth factor- β /activin receptor-like kinase 1 agonist bone morphogenetic protein-9 increases Oatp1a4 functional expression, but not efflux transporters P-glycoprotein and Breast Cancer Resistance Protein, in cortical brain microvessels. Overall, this study provides critical data that will advance treatment for neurological diseases where drug development has been challenging.

Atorvastatin-associated rhabdomyolysis in a patient with a novel variant of the SLCO1B1 gene: A case report

We report the case of an individual with severe hypercholesterolemia who experienced rhabdomyolysis with high dose atorvastatin. Genetic testing was undertaken to evaluate for suspected familial hypercholesterolemia (FH) and for the presence of gene variants associated with susceptibility to statin associated muscle disease. Genetic testing identified the presence of a potentially damaging variant of the hepatic xenobiotic transporter pump SLCO1B1, a single nucleotide variant (SNV) (rs77271279, c.481+1G>T) that disrupts the canonical donor splice motif. Although this variant has not previously been reported as associated with rhabdomyolysis and thus requires validation in population studies, it likely played a role in this patient's susceptibility to rhabdomyolysis based on functional assessment of the effect of this variant on SLCO1B1 protein function and given the known role of this transporter in statin uptake by the liver. The presence of this gene variant reinforced our decision to treat the patient's hypercholesterolemia with non-statin alternatives (PCSK9 inhibitor and ezetimibe). Genetic testing also identified the presence of a second SLCO1B1 gene variant, c.1200C>G (p.Phe400Leu, rs59113707) and homozygosity for an intron variant of the apolipoprotein(a) (LPA) gene (c.2604.138G>A intron variant, rs9457951) associated with increased Lp(a), a risk factor for atherosclerotic cardiovascular disease. Notably, all three variants are rare in persons of European descent but more frequent in African-Americans. These findings underscore the role of disabling mutations of the SLCO1B1 gene in statin myopathy and the need to validate these and other gene variants associated with statin myopathy in a population of patients with statin-associated muscle disease.

Factors affecting statin uptake among people living with HIV: primary care provider perspectives

BackgroundCardiovascular disease (CVD) is a major cause of morbidity and mortality among people living with HIV (PLWH), but statin therapy, safe and effective for PLWH, is under-prescribed. This study examined clinic leadership and provider perceptions of factors associated with statin prescribing for PLWH receiving care in eight community health clinics across Los Angeles, California.MethodsWe conducted semi-structured telephone interviews with clinic leadership and providers across community health clinics participating in a larger study (INSPIRE) aimed at improving statin prescribing through education and feedback. Clinics included federally qualified health centers (N = 5), community clinics (N = 1) and county-run ambulatory care clinics (N = 2). Leadership and providers enrolled in INSPIRE (N = 39) were invited to participate in an interview. We used the Consolidated Framework for Implementation Research (CFIR) to structure our interview guide and analysis. We used standard qualitative content analysis methods to identify themes within CFIR categories; we also assessed current CVD risk assessment and statin-prescribing practices.ResultsParticipants were clinic leaders (n = 6), primary care physicians with and without an HIV specialization (N = 6, N = 6, respectively), infectious diseases specialists (N = 12), nurse practitioners, physician assistants and registered nurses (N = 7). Ninety-five percent of providers from INSPIRE participated in an interview. We found that CVD risk assessment for PLWH is standard practice but that there is variation in risk assessment practices and that providers are unsure whether or how to adjust the risk threshold to account for HIV. Time, clinic and patient priorities impede ability to conduct CVD risk assessment with PLWH.ConclusionsProviders desire more data and standard practice guidance on prescribing statins for PLWH, including estimates of the effect of HIV on CVD, how to adjust the CVD risk threshold to account for HIV, which statins are best for people on antiretroviral therapy and on shared decision-making around prescribing statins to PLWH. While CVD risk assessment and statin prescribing fits within the mission and workflow of primary care, clinics may need to emphasize CVD risk assessment and statins as priorities in order to improve uptake.

Protective Effects of Statin Therapy in Cirrhosis Are Limited by a Common SLCO1B1 Transporter Variant.

Complications of cirrhosis and portal hypertension (PH) can be reduced by statin therapy. The common loss‐of‐function variant p.V174A in the solute carrier organic anion transporter gene 1B1 (SLCO1B1) gene encoding the organic anion transporting polypeptide 1B1 results in decreased hepatic uptake of statins. Our specific aim was to assess the impact of this variant in patients with cirrhosis and statin treatment while controlling for the stage of cirrhosis and other potential confounders with propensity score matching (PSM), availing of a large cohort of genotyped study patients. In total, from 1,088 patients with cirrhosis in two German academic medical centers, PSM yielded 154 patients taking statins and 154 matched controls. The effect on PH was assessed by the liver stiffness–spleen size–to–platelet score (LSPS), and complications of cirrhosis were retrospectively recorded applying consensus criteria. As hypothesized, patients on statin treatment presented less frequently with signs of PH: Esophageal varices (41% vs. 62%; P < 0.001) were less common, and LSPS (4.8 ± 11.5 vs. 5.6 ± 6.4; P = 0.01) was reduced. Correspondingly, decompensation events were also reduced in patients on statins (odds ratio [OR] = 0.54, 95% confidence interval [CI] 0.32‐0.90; P = 0.02). When the variant in SLCO1B1 was present in patients on statins, esophageal varices (OR = 2.68, 95% CI 1.24‐5.81; P = 0.01) and bacterial infections (OR = 2.50, 95% CI 1.14‐5.47; P = 0.02) were more common as compared with wild type carriers on statins.Conclusion: In this cohort, signs and complications of PH were reduced in patients with cirrhosis treated with statins. Notably, this effect was diminished by the common loss‐of‐function variant in SLCO1B1. Further prospective studies in independent cohorts are warranted to confirm these genotype‐specific observations.

Statins and risk of amyotrophic lateral sclerosis: a systematic review and meta-analysis.

Amyotrophic lateral sclerosis (ALS) is a paralytic, heterogeneous and progressive disease characterized by the degeneration of both upper and lower motor neurons. Several studies about the effects of statins drug on the risk of ALS showed contradictory results and evidence for this is inconclusive. So we aimed to perform a meta-analysis on previous studies to clarify the association between statin use and risk of ALS. The databases including PubMed, Scopus, and Web of science were searched in February 2021 for studies that reported the association between statin use and risk of ALS. The eligible studies had to provide a report on the effect of statin and the incidence of ALS while comparing it to the control group. Articles that had low statin exposure time, the absence of a control group and an unknown number of ALS patients were excluded. The rate ratio and 95% confidence interval (CI) were used for association measures in case-control and cohort studies. After full-text and abstract review, data from 8 studies with a total of 547,622 participants and 13,890 cases of ALS were entered in the present meta-analysis. We combined eight studies using a random-effect model and the RR for statin users among groups was 0.98 (95% CI 0.80-1.20) which indicates no association between statin and incidence of ALS. Also high heterogeneity was detected across the studies (Q value = 26.62, P = .00; I2 = 72.71%). In our meta-analysis study, we found no association between statin use and an increase in ALS incidence. This result is in line with some previous studies and provides strong evidence that denies the possible association between statin uptake and disease induction.

Patterns of drug use among type 2 diabetic patients with comorbidities attending a tertiary centre in Lagos Nigeria

Introduction – Diabetes care involves the use of drugs to control hyperglycaemia and treatment of comorbid disorders in order to prevent cardiovascular morbidity and other complications. This study investigated patterns of comorbidities and drug use among diabetic patients at a tertiary centre in Lagos, Nigeria. Method – This was a cross-sectional study carried out among 216 patients with type 2 DM attending Diabetes Clinic of a tertiary centre. Data was captured by using a questionnaire which documented biodata, number of comorbidities, number and combination of drugs for each participant and analysed using SPSS version 18. Results – Comorbidities were present among 215 out of 216 (99.54%) participants and hypertension and dyslipidaemia were the most common comorbid disorders. The number of pills consumed per patient ranged from 1 to10 with a mean of 4.78± 1.73 and 57.4% were on 5 pills or more. Fixed-dose combination was used in 37 (17.1%) of the patients. Majority of the patients were on metformin as monotherapy or in combination therapy. Antihypertensive most prescribed were renin-angiotensin system (RAS) blockers which was prescribed in 73% of participants. Antiplatelet drugs were used for both primary and secondary prevention of CVDs. Statin was used in less than 50% of the population. Double RAS blockade was also observed in 6% of participants. Conclusions – Comorbidities were common in the diabetic population. Pill load was high but appropriate in most patients. Statin uptake was suboptimal while there was increased uptake of antiplatelet drugs among participants.

Transport Properties of Statins by Organic Anion Transporting Polypeptide 1A2 and Regulation by Transforming Growth Factor-β Signaling in Human Endothelial Cells.

Our in vivo rodent studies have shown that organic anion transporting polypeptide (Oatp) 1a4 is critical for blood-to-brain transport of statins, drugs that are effective neuroprotectants. Additionally, transforming growth factor-β (TGF-β) signaling via the activin receptor-like kinase 1 (ALK1) receptor regulates Oatp1a4 functional expression. The human ortholog of Oatp1a4 is OATP1A2. Therefore, the translational significance of our work requires demonstration that OATP1A2 can transport statins and is regulated by TGF-β/ALK1 signaling. Cellular uptake and monolayer permeability of atorvastatin, pravastatin, and rosuvastatin were investigated in vitro using human umbilical vein endothelial cells (HUVECs). Regulation of OATP1A2 by the TGF-β/ALK1 pathway was evaluated using bone morphogenetic protein 9 (BMP-9), a selective ALK1 agonist, and LDN193189, an ALK1 antagonist. We showed that statin accumulation in HUVECs requires OATP1A2-mediated uptake but is also affected by efflux transporters (i.e., P-glycoprotein, breast cancer resistance protein). Absorptive flux (i.e., apical-to-basolateral) for all statins was higher than secretory flux (i.e., basolateral-to-apical) and was decreased by an OATP inhibitor (i.e., estrone-3-sulfate). OATP1A2 protein expression, statin uptake, and cellular monolayer permeability were increased by BMP-9 treatment. This effect was attenuated in the presence of LDN193189. Apical-to-basolateral statin transport across human endothelial cellular monolayers requires functional expression of OATP1A2, which can be controlled by therapeutically targeting TGF-β/ALK1 signaling. Taken together with our previous work, the present data show that OATP-mediated drug transport is a critical mechanism in facilitating neuroprotective drug disposition across endothelial barriers of the blood-brain barrier. SIGNIFICANCE STATEMENT: Transporter data derived from rodent models requires validation in human models. Using human umbilical vein endothelial cells, this study has shown that statin transport is mediated by OATP1A2. Additionally, we demonstrated that OATP1A2 is regulated by transforming growth factor-β/activin receptor-like kinase 1 signaling. This work emphasizes the need to consider endothelial transporter kinetics and regulation during preclinical drug development. Furthermore, our forward-thinking approach can identify effective therapeutics for diseases for which drug development has been challenging (i.e., neurological diseases).

Cell-to-Medium Concentration Ratio Overshoot in the Uptake of Statins by Human Hepatocytes in Suspension, but Not in Monolayer: Kinetic Analysis Suggesting a Partial Loss of Functional OATP1Bs

Suspended human hepatocytes (SHH) have long been used in assessing hepatic drug uptake, while plated human hepatocytes in short-term monolayer culture (PHH) have gained use in recent years. This study aimed to cross-evaluate SHH and PHH in measuring the hepatic uptake mediated by organic anion transporting polypeptide 1Bs (OATP1Bs). We compared the time courses of cell-to-medium (C/M) concentration ratios and initial uptake clearance values of the OATP1B substrates (pitavastatin, rosuvastatin, cerivastatin, pravastatin, dehydropravastatin, and SC-62807) between SHH and PHH. For all compounds except cerivastatin, the C/M ratios in SHH displayed an apparent overshoot (an initial increase followed by a decrease) during the 180-min uptake experiment, but not in PHH. Based on the literature evidence suggesting the possible internalization of OATP1Bs in primary hepatocytes, separate experiments measured the drug uptake after varying lengths of pre-incubation in the drug-free medium. The initial uptake clearances of pitavastatin and rosuvastatin declined in SHH beyond an apparent threshold time of 20-min drug-free pre-incubation, but not in PHH. Kinetic modeling quantitatively captured the decline in the active uptake clearance in SHH, and more than half of the active uptake clearances of pitavastatin and rosuvastatin were prone to loss during the 180-min uptake experiment. These results suggested a partial, time-delayed loss of the functional OATP1Bs in SHH upon prolonged incubation. Our results indicate that PHH is more appropriate for experiments where a prolonged incubation is required, such as estimation of unbound hepatocyte-to-medium concentration ratio (Kp,uu) at the steady-state.

Interplay Between Statins, Cav1 (Caveolin-1), and Aldosterone.

Statin use is associated with lower aldosterone levels. We hypothesized that caveolin-1 may be important for the uptake of statins into the adrenal gland and would affect statin’s aldosterone-lowering effects. The aim of this study was to test whether the caveolin-1 risk allele (rs926198) would affect aldosterone levels associated with statin use. The Hypertensive Pathotype database includes healthy and hypertensive individuals who have undergone assessment of adrenal hormones. Individuals were studied off antihypertensive medications but were maintained on statins if prescribed by their personal physician. Adrenal hormones were measured at baseline and after 1 hour of angiotensin II stimulation on both high- and low-sodium diets. A mixed-model repeated-measures analysis was employed with a priori selected covariates of age, sex, body mass index, and protocol (low versus high sodium, baseline versus angiotensin II stimulated aldosterone). A total of 250 individuals were included in the study; 31 individuals were taking statins (12.4%) and 219 were not. Among statin users, carrying a caveolin-1 risk allele resulted in a 25% (95% CI, 1–43.2) lower aldosterone level (P=0.04). However, among nonstatin users, carrying a caveolin-1 risk allele resulted in no significant effect on aldosterone levels (P=0.38). Additionally, the interaction between caveolin-1 risk allele and statin use on aldosterone levels was significant (P=0.03). These findings suggest caveolin-1 risk allele carrying individuals are likely to receive the most benefit from statin’s aldosterone-lowering properties; however, due to the observational nature of this study, these findings need further investigation.

584-P: Optimal Utilisation of Statins in Real-World Settings

Aim: The purpose of this retrospective data analysis is to assess prescription practices including appropriate use and dose of statins in patients with T2DM. Methods: This is an observational retrospective data analysis of T2DM patients with dyslipidemia and who were on statin treatment for at least 6 months. Data for this study was obtained from EMRs of diabetes and endocrinology specialty outpatient clinics (n=35), pan India between Jan 2018 and May 2019. Patients aged &amp;lt;40 and &amp;gt;75 years were excluded from the analysis. Patient’s record with demographics, medical history, prescriptions (antidiabetes and statin drugs) and lab investigations data were collected. Results: Of the total 45,205 diabetes patients, 15023(33%) were on statins. The mean age was 53.2 years, 64% were males and 36% were females. Final analysis included 4099 patients between ages 40 and 75 years on statin drugs along with antidiabetes drugs. Mean HbA1c, fasting and post-prandial blood glucose was 8.5%, 173mg/dL and 257 mg/dL, respectively. The lipid profile TC, TG, HDL, and LDL was 174mg/dL, 188 mg/dL, 41 mg/dL, and 107 mg/dL, respectively. Low-intensity statins (2539[62%]) were the most common prescriptions followed by moderate (1402[34%]) and high (158[4%]) intensity statins. Rosuvastatin (2615[64%]) was most commonly prescribed followed by atorvastatin (1302[32%]), and non-statin fenofibrate (182[4%]). 4% of the patients on low-intensity statins at the first visit moved to moderate or high dose intensity statins. In contrast, 2% of patients on moderate dose moved to low dose intensity. Conclusion: In endocrine clinic population with 45205 patients only 33% of patients were on statins. In the population between 40 and 75, a majority were on low-intensity statins with relatively very few progressing to moderate and high-intensity statin. The low uptake of statins and low dose use indicates the need to increase awareness of appropriate patient selection and correct dose of statin use in the clinic population including referral and tertiary care clinics. Disclosure S.G. Krishna: None. S. Das: None. N. Nk: None. S.P. Manohar: None. N. Bs: None. D. Mc: None. S. Shah: None. A. Ahmed: None. M. Chavan: None. S. Sathyakumar: None. V.K. Kolukula: None.