Use of cholesterol-lowering medications in relation to risk of primary liver cancer in the Clinical Practice Research Datalink.

BACKGROUND: Although the relation between statin use and liver cancer risk has been extensively examined, few studies have examined other cholesterol-lowering medications in relation to liver cancer risk. The authors examined five classes of nonstatin medications and liver cancer risk. METHODS: A nested case-control including 3719 cases and 14,876 matched controls was conducted within the Clinical Practice Research Datalink. Additional matches on type 2 diabetes and chronic liver disease were also implemented. The medications examined included cholesterol absorption inhibitors, bile acid sequestrants, fibrates, niacin, and omega-3 fatty acids. Conditional logistic regression estimated odds ratios and 95% confidence intervals. RESULTS: Cholesterol absorption inhibitor use was associated with reduced liver cancer risk in the overall analysis (odds ratio, 0.69; 95% confidence interval, 0.50-0.96) and in analyses based on type 2 diabetes and chronic liver disease status. Although bile acid sequestrant use was associated with increased liver cancer risk in the overall analysis (odds ratio, 5.31; 95% confidence interval, 3.534-7.97), the results of the analyses based on type 2 diabetes and chronic liver disease status were inconsistent. No associations were observed for the other medications. CONCLUSIONS: Cholesterol absorption inhibitors may be associated with reduced liver cancer risk. Whether bile acid sequestrant use was associated with increased risk was only partially supported in the current study.

MicroRNA-206 as a potential cholesterol-lowering drug is superior to statins in mice.

Hypercholesterolemia is frequently intertwined with hepatosteatosis, hypertriglyceridemia, and hyperglycemia. This study is designed to assess the therapeutic efficacy of miR-206 in contrast to statins in the context of managing hypercholesterolemia in mice. We previously showed that miR-206 is a potent inhibitor of de novo lipogenesis (DNL), cholesterol synthesis, and gluconeogenesis in mice. Given that these processes occur within hepatocytes, we employed a mini-circle (MC) system to deliver miR-206 specifically to hepatocytes (designated as MC-miR-206). A single intravenous injection of MC-miR-206 maintained high levels of miR-206 in the liver for at least two weeks, thereby maintaining suppression of hepatic DNL, cholesterol synthesis, and gluconeogenesis. MC-miR-206 significantly reduced DNA damage, endoplasmic reticulum and oxidative stress, and hepatic toxicity. Therapeutically, both MC-miR-206 and statins significantly reduced total serum cholesterol and triglycerides as well as LDL cholesterol and VLDL cholesterol in mice maintained on the normal chow and high-fat high-cholesterol diet. MC-miR-206 reduced liver weight, hepatic triglycerides and cholesterol, and blood glucose, while statins slightly increased hepatic cholesterol and blood glucose and failed to affect levels of liver weight and hepatic triglycerides. Mechanistically, miR-206 alleviated hypercholesterolemia by inhibiting hepatic cholesterol synthesis, while statins increased HMGCR activity, hepatic cholesterol synthesis, and fecal-neutral steroid excretion. MiR-206 facilitates the regression of hypercholesterolemia, hypertriglyceridemia, hyperglycemia, and hepatosteatosis. MiR-206 outperforms statins by reducing hyperglycemia, hepatic cholesterol levels, and hepatic toxicity.

Role of Different Low-Density Lipoprotein-Lowering Medications on Secondary Prevention of Atherosclerotic Cardiovascular Disease in Patients With Diabetes Mellitus.

Purpose The objective of this study was to explore the optimal cholesterol-lowering therapy for diabetic patients categorized as having a very high risk for future atherosclerotic cardiovascular disease (ASCVD) events. The primary medications under investigation were statins, ezetimibe, and proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors (PCSK9-Is). The efficacy of different medication regimens helped to draw conclusions regarding the evolution of cholesterol management recommended under the American College of Cardiology's (ACC) 2013 and 2018 guidelines. Methods A retrospective chart review was conducted on a cohort of patients from a large, community-based cardiology practice. Inclusion criteria specified patients aged 30-82 with a past medical history of two or more ASCVD events or one ASCVD event and at least two high-risk comorbidities. Acquired data included demographics, all lipid panels, medications used, and ASCVD events between December 1, 2013, and December 31, 2019. The data were stored and encrypted on a REDCap account. Sub-group analysis was conducted on only diabetic patients, who were then categorized by medication regimen. The statistical analysis was completed using Fisher's exact test. A p-value <0.05 was considered significant. Results A total of 102 diabetic patients met the inclusion criteria. Our primary analysis determined the percentage of patients who achieved their goals on each medication regimen. The goal was defined as a low-density lipoprotein cholesterol (LDL-C) level of less than 70 mg/dL or at least a 50% reduction from baseline levels. The results are as follows: none (0%), statin (33.9%), ezetimibe (21.1%), statin + ezetimibe (73.5%), PCSK9-Is ± statin (83.3%), and PCSK9-Is and ezetimibe ± statin (100%). There proved to be a significant difference favoring all combination regimens over statins alone; however, there was no significant difference between these advanced regimens. A follow-up analysis determined if these patients were able to maintain their goals in the subsequent lipid panel after achieving their goals. The results are as follows: none (0%), statin (61.5%), ezetimibe (50%), statin + ezetimibe (77.8%), PCSK9-Is ± statin (100%), and PCSK9-Is and ezetimibe ± statin (66.6%). The only significant difference found was between PCSK9-Is ± statins and statins alone. Conclusions Our study revealed that regimens using PCSK9 inhibitors and ezetimibe, in addition to maximally tolerated statin therapy, were more effective than statin therapy alone in achieving the goal. On extended analysis, only PCSK9 inhibitors showed superior ability in terms of maintaining the goals for diabetic patients at very high risk for future ASCVD events. This implies that statins alone may be inadequate to properly treat this specific patient population. In the context of clinical practice, physicians could have heightened consideration for dual therapy consisting of maximally tolerated statins and a secondary agent in accordance with the 2018 ACC guidelines.

Perfluoroalkyl Substance Serum Concentrations and Cholesterol Absorption-Inhibiting Medication Ezetimibe.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) are human-made compounds with a widespread presence in human blood and other organs. PFAS have been associated with multiple health effects, including higher serum cholesterol and LDL cholesterol. OBJECTIVE: Potential population differences in serum PFAS attributable to ezetimibe, a medication that inhibits cholesterol absorption, are of interest for several reasons. The "C8" Health Project survey data from six contaminated water districts in the mid-Ohio Valley of the United States provide a wide enough range of serum PFAS and a sufficient number of ezetimibe takers to explore this topic. METHODS: A total of 44,126 adult participants of the C8 Health Survey were included in the community-based study. The status of taking (1075) or non-taking of ezetimibe, alone or in combination with another lipid-lowering agent, was acquired. The geometric mean serum concentrations of the four most commonly detected serum PFAS were compared based on the status of ezetimibe use. RESULTS: There is no significant difference in serum concentrations of perfluorohexanesulfonic acid (PFHxS), perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), and perfluorononanoic acid (PFNA) between ezetimibe users and non-users after adjustment for age, sex, body mass index, estimated glomerular filtration rate (eGFR), cigarette smoking, education, and average household income. CONCLUSION: The sterol absorption-inhibiting medication ezetimibe does not appear to affect serum PFAS concentrations. We sought but did not find direct evidence that ezetimibe could inhibit PFAS uptake nor inferential evidence that inter-individual differences in sterol absorption could provide a confounding factor explanation for the association of serum total- and LDL-cholesterol with serum PFAS.

Secondary Prevention Using Cholesterol-Lowering Medications in Patients with Prior Atherosclerotic Cardiovascular Disease Events: A Retrospective Cohort Analysis.

Background: Secondary prevention with lipid-lowering medications in patients with atherosclerotic cardiovascular disease (ASCVD) is known to reduce the risk of clinical events and death. Current guidelines codify recommendations for implementing secondary prevention in appropriate patients. However, in real-world practice, secondary prevention is frequently initiated only after the patient experiences a cardiovascular-related hospitalization. The impact of these delays is not well known. Objectives: To estimate the effects of delaying treatment on the risk of cardiovascular-related hospitalization and on costs for patients who meet the criteria for secondary prevention as specified in the 2013 American College of Cardiology/American Heart Association (ACC/AHA) Guidelines for Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults. Methods: This is a retrospective cohort analysis using Humana data. Eligible patients were categorized by treatment group: (1) patients who initiated treatment before an ASCVD-related hospitalization and (2) patients who either did not initiate treatment until after an ASCVD hospitalization or never initiated treatment. The associations between the timely initiation of cholesterol-lowering medications for secondary prevention and (1) the risk for an ASCVD hospitalization and (2) health-care costs over one year, were estimated using multivariate regressions. Results: A total of 272 899 secondary prevention patients were identified who met study selection criteria. Early treatment was associated with significant reductions in the risk of an ASCVD hospitalization at any time following the identification of the patient's eligibility for secondary prevention (by 33% compared to those treated late or never, P<.0001), but was significantly associated with higher total cost over the first post-index year (by US $509, P<.001). Patients whose low-density lipoprotein cholesterol (LDL-C) levels were >130 mg/dL experienced higher ASCVD hospitalization risks, and also larger risk reductions if treated before an ASCVD hospitalization compared to patients with lower LDL-C levels who were treated late or never treated. Conclusions: More widespread implementation of the treatment policies specified in the 2013 ACC/AHA Guidelines for secondary prevention should significantly reduce cardiovascular disease hospitalizations and reduce costs.

Low-fat dietary pattern and cardiovascular disease: results from the Women's Health Initiative randomized controlled trial.

Background: The influence of a low-fat dietary pattern on the cardiovascular health of postmenopausal women continues to be of public health interest.Objective: This report evaluates low-fat dietary pattern influences on cardiovascular disease (CVD) incidence and mortality during the intervention and postintervention phases of the Women's Health Initiative Dietary Modification Trial.Design: Participants comprised 48,835 postmenopausal women aged 50-79 y; 40% were randomly assigned to a low-fat dietary pattern intervention (target of 20% of energy from fat), and 60% were randomly assigned to a usual diet comparison group. The 8.3-y intervention period ended in March 2005, after which >80% of surviving participants consented to additional active follow-up through September 2010; all participants were followed for mortality through 2013. Breast and colorectal cancer were the primary trial outcomes, and coronary heart disease (CHD) and overall CVD were additional designated outcomes.Results: Incidence rates for CHD and total CVD did not differ between the intervention and comparison groups in either the intervention or postintervention period. However, CHD HRs comparing these groups varied strongly with baseline CVD and hypertension status. Participants without prior CVD had an intervention period CHD HR of 0.70 (95% CI: 0.56, 0.87) or 1.04 (95% CI: 0.90, 1.19) if they were normotensive or hypertensive, respectively (P-interaction = 0.003). The CHD benefit among healthy normotensive women was partially offset by an increase in ischemic stroke risk. Corresponding HRs in the postintervention period were close to null. Participants with CVD at baseline (3.4%) had CHD HRs of 1.47 (95% CI: 1.12, 1.93) and 1.61 (95% CI: 1.02, 2.55) in the intervention and postintervention periods, respectively. However, various lines of evidence suggest that results in women with CVD or hypertension at baseline are confounded by postrandomization use of cholesterol-lowering medications.Conclusions: CVD risk in postmenopausal women appears to be sensitive to a change to a low-fat dietary pattern and, among healthy women, includes both CHD benefit and stroke risk. This trial was registered at clinicaltrials.gov as NCT00000611.