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1.
Bempedoic Acid: A New Tool in the Battle Against Hyperlipidemia.
Powell, J, Piszczatoski, C
Clinical therapeutics. 2021;(2):410-420
Abstract
PURPOSE This article discusses the pharmacology of bempedoic acid, the trials that led to United States Food and Drug Administration (FDA) approval of its use, and the overall safety and efficacy of this therapy in heterozygous familial hypercholesterolemia, established atherosclerotic cardiovascular disease (ASCVD), and hyperlipidemia. METHODS A database search of PubMed and ClinicalTrials.gov was conducted for articles published between January 2012 to September 2020 and containing the key words bempedoic acid, ezetimibe, Nexletol and Nexlizet. Trials from the CLEAR series were selected, as they played a pivotal role in the establishment of FDA approval, along with additional trials published after FDA approval, which provided novel evidence on the use of bempedoic acid in the treatment of hypercholesterolemia. Publications that were not randomized, controlled trials were not included in this review. Only randomized controlled trials in which ezetimibe was used in conjunction with bempedoic acid were included in this review as they were relevant to the new FDA approval of bempedoic acid. FINDINGS The findings of the present review show that bempedoic acid is both an effective and well-tolerated option for the treatment of hypercholesterolemia when used without ezetimibe in addition to standard therapy. It also appears that the combination with ezetimibe increases the cholesterol-lowering effect more than either agent alone when added to standard therapy. IMPLICATIONS Hypercholesteremia continues to be a major contributing factor leading to ASCVD. Bempedoic acid is an additional treatment option, along with both statins and diet and exercise, for reducing cholesterol levels and ASCVD events. With the new FDA approval, bempedoic acid may offer an effective therapy for reducing low-density lipoprotein cholesterol in patients at high risk for cardiovascular events due to established ASCVD or heterozygous familial hypercholesterolemia.
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2.
Residual Cardiovascular Risk at Low LDL: Remnants, Lipoprotein(a), and Inflammation.
Hoogeveen, RC, Ballantyne, CM
Clinical chemistry. 2021;(1):143-153
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Abstract
BACKGROUND Current guidelines target low-density lipoprotein cholesterol (LDL-C) concentrations to reduce atherosclerotic cardiovascular disease (ASCVD) risk, and yet clinical trials demonstrate persistent residual ASCVD risk despite aggressive LDL-C lowering. CONTENT Non-LDL-C lipid parameters, most notably triglycerides, triglyceride-rich lipoproteins (TGRLs), and lipoprotein(a), and C-reactive protein as a measure of inflammation are increasingly recognized as associated with residual risk after LDL-C lowering. Eicosapentaenoic acid in statin-treated patients with high triglycerides reduced both triglycerides and ASCVD events. Reducing TGRLs is believed to have beneficial effects on inflammation and atherosclerosis. High lipoprotein(a) concentrations increase ASCVD risk even in individuals with LDL-C < 70 mg/dL. Although statins do not generally lower lipoprotein(a), proprotein convertase subtilisin/kexin type 9 inhibitors reduce lipoprotein(a) and cardiovascular outcomes, and newer approaches are in development. Persistent increases in C-reactive protein after intensive lipid therapy have been consistently associated with increased risk for ASCVD events. SUMMARY We review the evidence that biochemical assays to measure TGRLs, lipoprotein(a), and C-reactive protein are associated with residual risk in patients treated to low concentrations of LDL-C. Growing evidence supports a causal role for TGRLs, lipoprotein(a), and inflammation in ASCVD; novel therapies that target TGRLs, lipoprotein(a), and inflammation are in development to reduce residual ASCVD risk.
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Evaluation of Medical Care for Diabetic and Hypertensive Patients in Primary Care in Mexico: Observational Retrospective Study.
Lara-Esqueda, A, Zaizar-Fregoso, SA, Madrigal-Perez, VM, Ramirez-Flores, M, Montes-Galindo, DA, Martinez-Fierro, ML, Rodriguez-Sanchez, IP, Guzman-Esquivel, J, Meza-Robles, C, Ceja-Espiritu, G, et al
Journal of diabetes research. 2021;:7365075
Abstract
INTRODUCTION The present study evaluated the quality of medical care for patients diagnosed with diabetes mellitus (DM), hypertension (HBP), and both pathologies (DM+HBP) within a public health system in Mexico. METHODS 45,498 patients were included from 2012 to 2015. All information was taken from the electronic medical record database. Each patient record was compared against the standard to test the quality of medical care. RESULTS Glycemia with hypertension goals reached 29.6% in DM+HBP, 48.6% in DM, and 53.2% in HBP. The goals of serum lipids were reached by 3% in DM+HBP, 5% in DM, and 0.2% in HBP. Glycemia, hypertension, and LDL cholesterol reached 0.04%. 15% of patients had an undiagnosed disease. Clinical follow-up examinations reached 20% for foot examination and clinical eye examination. Specialty referrals reached 1% in angiology or cardiology. CONCLUSION Goals for glycemic and hypertension reached 50% in the overall population, while serum lipids, clinical follow-up examinations, and referral to a specialist were deficient. Patients who had both diseases had more consultations, better control for hypertension and lipids, but inferior glycemic control. Overall, quality care for DM and/or HBP has not been met according to the standards.
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Targeting the Cholesterol Paradigm in the Risk Reduction for Atherosclerotic Cardiovascular Disease: Does the Mechanism of Action of Pharmacotherapy Matter for Clinical Outcomes?
Zhou, R, Stouffer, GA, Smith, SC
Journal of cardiovascular pharmacology and therapeutics. 2021;(6):533-549
Abstract
Hypercholesterolemia is a well-established risk factor for atherosclerotic cardiovascular disease (ASCVD). Low-density lipoprotein cholesterol (LDL-C) has been labeled as "bad" cholesterol and high-density lipoprotein cholesterol (HDL-C) as "good" cholesterol. The prevailing hypothesis is that lowering blood cholesterol levels, especially LDL-C, reduces vascular deposition and retention of cholesterol or apolipoprotein B (apoB)-containing lipoproteins which are atherogenic. We review herein the clinical trial data on different pharmacological approaches to lowering blood cholesterol and propose that the mechanism of action of cholesterol lowering, as well as the amplitude of cholesterol reduction, are critically important in leading to improved clinical outcomes in ASCVD. The effects of bile acid sequestrants, fibrates, niacin, cholesteryl ester transfer protein (CETP) inhibitors, apolipoprotein A-I and HDL mimetics, apoB regulators, acyl coenzyme A: cholesterol acyltransferase (ACAT) inhibitors, cholesterol absorption inhibitors, statins, and proprotein convertase subtilisin kexin 9 (PCSK9) inhibitors, among other strategies are reviewed. Clinical evidence supports that different classes of cholesterol lowering or lipoprotein regulating approaches yielded variable effects on ASCVD outcomes, especially in cardiovascular and all-cause mortality. Statins are the most widely used cholesterol lowering agents and have the best proven cardiovascular event and survival benefits. Manipulating cholesterol levels by specific targeting of apoproteins or lipoproteins has not yielded clinical benefit. Understanding why lowering LDL-C by different approaches varies in clinical outcomes of ASCVD, especially in survival benefit, may shed further light on our evolving understanding of how cholesterol and its carrier lipoproteins are involved in ASCVD and aid in developing effective pharmacological strategies to improve the clinical outcomes of ASCVD.
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Asymptomatic peripheral artery disease: Silent but deadly.
Behroozian, AA, Beckman, JA
Progress in cardiovascular diseases. 2021;:2-8
Abstract
Peripheral Artery Disease (PAD) is a manifestation of atherosclerosis characterized by diminished perfusion of the limb and a state of dysmetabolism. The asymptomatic PAD phenotype is a relatively recent classification. It is unknown how many people currently live with asymptomatic PAD because there are no universal screening recommendations for patients at risk for PAD. Patients with asymptomatic PAD suffer from a similar risk profile of morbidity and mortality as their counterparts with claudication. Despite this increased risk, there is a dearth of clinical investigations into therapies that specifically benefit the asymptomatic PAD population. At present, current pharmacotherapies that have been studied in PAD patient populations do not stratify by symptom status. We believe that further investigation of the impact of existing therapies in this unique population presents an opportunity to reduce morbidity and mortality due to PAD. This can only be achieved in combination with wide-spread adoption of screening for asymptomatic PAD.
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Umbrella Review on Non-Statin Lipid-Lowering Therapy.
Beshir, SA, Hussain, N, Elnor, AA, Said, ASA
Journal of cardiovascular pharmacology and therapeutics. 2021;(5):437-452
Abstract
OBJECTIVES The main aim of this review was to summarize current evidence on approved and emerging non-statin lipid-lowering therapies. METHODS AND MATERIALS Recent literature on U.S. FDA approved non-statin lipid-lowering therapies and evolving lipid-lowering drugs currently under development was reviewed. RESULTS AND DISCUSSION In the past 20 years, the emergence of non-statin cholesterol-lowering drugs has changed the landscape of dyslipidemia management. Food and Drug Administration approval of non-statin lipid-lowering therapies such as ezetimibe, proprotein convertase subtilisin/Kexin type 9 (PCSK9) inhibitors (evolocumab, alirocumab), bempedoic acid and combination of bempedoic acid and ezetimibe, evinacumab and other triglyceride-lowering agents (eg, icosapent ethyl) has emerged. The European Commission has also recently approved inclisiran for treatment of hypercholesterolemia and mixed hypercholesterolemia even though FDA has put the approval of this drug on hold. Recent guidelines have incorporated PCSK9 inhibitors to treat patients with primary hyperlipidemia and patients with very high-risk ASCVD, who could not achieve adequate lipid-lowering with combination therapy of maximally tolerated statin and ezetimibe. Icosapent ethyl use as an adjunct therapy to statins is also recommended to reduce the risk of ASCVD in patients with hypertriglyceridemia. CONCLUSION Despite cost limitations, the uptake of PCSK9 inhibitors is increasing. Approval of bempedoic acid alone or in combination with ezetimibe has provided additional oral lipid-lowering drug alternatives to ezetimibe. Various lipid-lowering drug targets are under investigation.
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Effect of Bempedoic Acid on atherogenic lipids and inflammation: A meta-analysis.
Masson, W, Lobo, M, Lavalle-Cobo, A, Molinero, G
Clinica e investigacion en arteriosclerosis : publicacion oficial de la Sociedad Espanola de Arteriosclerosis. 2021;(3):117-126
Abstract
BACKGROUND Bempedoic acid is a novel non-statin drug that was developed to treat hyperlipidemia in combination with other lipid-lowering drugs in those patients who need additional lipid lowering. OBJECTIVES (1) To investigate the lipid efficacy of bempedoic acid; (2) to analyze the anti-inflammatory effects of bempedoic acid estimated through high sensitivity C-reactive protein (hsCRP). METHODS We performed a meta-analysis including randomized trials of bempedoic acid therapy, reporting low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B and hsCRP with a minimum of 4 weeks of follow-up. The primary endpoint was defined as the percentage change in lipids and hsCRP levels measured from baseline to follow-up, comparing groups of subjects on bempedoic acid versus placebo. RESULTS Seven eligible trials of bempedoic acid (3892 patients) were included. The bempedoic acid therapy was associated with a significant reduction in LDL-C levels [-20.3% (CI 95% -23.5 to -17.1)]; I2=43%]. Similarly, a significant percentage reduction in the apolipoprotein B levels [-14.3% (CI 95% -16.4 to -12.1)]; p<0.05; I2=46%], non-HDL-C levels [-15.5% (CI 95% -18.1 to -13.0)]; p<0.05; I2=53%] and hsCRP [-23.4% (CI 95% -32.6 to -14.2)]; p<0.05; I2=69%] was demonstrated with the bempedoic acid use. The sensitivity analysis showed that the results were robust. CONCLUSION Our data suggests that the use of bempedoic acid significantly reduces the levels of all atherogenic lipid markers, including LDL-C, non-HDL-C and apolipoprotein B. Furthermore, considering hsCRP levels, the drug produces an anti-inflammatory effect.
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Protective lipid-lowering variants in healthy older individuals without coronary heart disease.
Lacaze, P, Riaz, M, Sebra, R, Hooper, AJ, Pang, J, Tiller, J, Polekhina, G, Tonkin, A, Reid, C, Zoungas, S, et al
Open heart. 2021;(2)
Abstract
OBJECTIVE Genetic variants that disrupt the function of the PCSK9 (proprotein convertase subtilisin kexin type 9) and APOB (apolipoprotein B)genes result in lower serum low-density lipoprotein cholesterol (LDL-C) levels and subsequently confer protection against coronary heart disease (CHD). The objective of this study was to measure the prevalence and selective advantage of such variants among healthy older individuals without a history of CHD. METHODS We performed targeted sequencing of the PCSK9 and APOB genes in 13 131 healthy individuals without CHD aged 70 years or older enrolled into the ASPirin in Reducing Events in the Elderly trial. We detected variants in the PCSK9 and APOB genes with predicted loss-of-function. We associated variant carrier status with serum LDL-C and total cholesterol (TC) levels at the time of study enrolment, adjusting for statin use. RESULTS We detected 22 different rare PCSK9/APOB candidate variants with putative lipid-lowering effect, carried by 104 participants (carrier rate 1 in 126). Serum LDL-C and TC concentrations for rare PCSK9/APOB variant carriers were consistently lower than non-carriers. Rare variant carrier status was associated with 19.4 mg/dL (14.6%) lower LDL-C, compared with non-carriers (p≤0.001, adjusted for statin use). Statin prescriptions were less prevalent in rare variant carriers (16%) than non-carriers (35%). The more common PCSK9 R46L variant (rs11591147-T) was associated with 15.5 mg/dL (11.8%) lower LDL-C in heterozygotes, and 25.2 mg/dL (19.2%) lower LDL-C in homozygotes (both p≤0.001). CONCLUSIONS Lipid-lowering genetic variants are carried by healthy older individuals and contribute to CHD-free survival. TRIAL REGISTRATION NUMBER NCT01038583.
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Fenofibrate increases circulating haematopoietic stem cells in people with diabetic retinopathy: a randomised, placebo-controlled trial.
Bonora, BM, Albiero, M, Morieri, ML, Cappellari, R, Amendolagine, FI, Mazzucato, M, Zambon, A, Iori, E, Avogaro, A, Fadini, GP
Diabetologia. 2021;(10):2334-2344
Abstract
AIM/HYPOTHESIS In two large RCTs, fenofibrate reduced the progression of diabetic retinopathy. We investigated whether fenofibrate increases circulating haematopoietic stem/progenitor cells (HSPCs), which have vascular properties and have been shown to protect from retinopathy. METHODS We conducted a 12 week parallel-group RCT comparing fenofibrate vs placebo. Patients with diabetic retinopathy and without other conditions that would affect HSPCs were enrolled at a tertiary diabetes outpatient clinic and randomised to receive fenofibrate or placebo based on a computer-generated sequence. Patients and study staff assessing the outcomes were blinded to group assignment. The primary endpoint was the change in the levels of circulating HSPCs, defined by expression of the stem cell markers CD34 and/or CD133. Secondary endpoints were the changes in endothelial progenitor cells, lipids, soluble mediators and gene expression. We used historical data on the association between HSPCs and retinopathy outcomes to estimate the effect of fenofibrate on retinopathy progression. RESULTS Forty-two participants with diabetic retinopathy were randomised and 41 completed treatment and were analysed (20 in the placebo group and 21 in the fenofibrate group). Mean age was 57.4 years, diabetes duration was 18.2 years and baseline HbA1c was 60 mmol/mol (7.6%). When compared with placebo, fenofibrate significantly increased levels of HSPCs expressing CD34 and/or CD133. CD34+ HSPCs non-significantly declined in the placebo group (mean ± SD -44.2 ± 31.6 cells/106) and significantly increased in the fenofibrate group (53.8 ± 31.1 cells/106). The placebo-subtracted increase in CD34+ HSPCs from baseline was 30% (99.3 ± 43.3 cells/106; p = 0.027) which, projected onto the relationship between HSPC levels and retinopathy outcomes, yielded an OR of retinopathy progression of 0.67 for fenofibrate vs placebo. Endothelial differentiation of CD34+ cells, estimated by the %KDR (kinase insert domain receptor) expression, was significantly reduced by fenofibrate. Fenofibrate decreased serum triacylglycerols, but the change in triacylglycerols was unrelated to the change in HSPCs. No effect was observed for endothelial progenitor cells, cytokines/chemokines (stromal-cell derived factor-1, vascular endothelial growth factor, monocyte chemoattractant protein-1) and gene expression in peripheral blood mononuclear cells. CONCLUSIONS/INTERPRETATION Fenofibrate increased HSPC levels in participants with diabetic retinopathy and this mechanism may explain why fenofibrate reduced retinopathy progression in previous studies. TRIAL REGISTRATION ClinicalTrials.gov NCT01927315.
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Hypolipaemic nutraceutics: red yeast rice and Armolipid, berberine and bergamot.
Kłosiewicz-Latoszek, L, Cybulska, B, Stoś, K, Tyszko, P
Annals of agricultural and environmental medicine : AAEM. 2021;(1):81-88
Abstract
INTRODUCTION Increased serum cholesterol levels constitute one of the main risk factors for cardiovascular diseases. Statins are a major method for reducing the levels which also lower the risk of cardiovascular events. However, these valuable drugs cannot be used in all patients who need them due to contraindications and intolerance. In such cases, help can be sought from nutraceutics that reduce the serum cholesterol concentration. Since there are numerous products of this type available at drugstores, registered as supplements, there seems to be a need to demonstrate their effectiveness in preventing cardiovascular diseases induced by atherosclerosis. In literature, increasingly more attention is drawn to red yeast rice, Armolipid, berberine and bergamot. BRIEF DESCRIPTION This article presents knowledge about these nutraceutics based on clinical studies and expert statements relating to their use. The results of clinical studies and metaanalyses have shown that nutraceutics with cholesterol lowering properties, red yeast rice and Armolipid are the most favourable for reducing cardiovascular events. However, the evidence of benefits of berberine and bergamot is not so conclusive. CONCLUSIONS Red yeast rice products and Armolipid may be used as an alternative treatment in statin intolerant patients, especially in combination with ezetimibe. These nutraceutics can be also considered, as an adjunct to diet therapy in primary prevention of cardiovascular diseases in patients with mild and moderate hypercholesterolaemia. The opinion of experts on berberine and bergamot is ambiguous.