Non-traditional Dosing of Statins in Statin-Intolerant Patients—Is It Worth a Try?

Cornier, Marc‐Andre; Eckel, Robert H.

doi:10.1007/s11883-014-0475-4

Cited by 14 publications

(12 citation statements)

References 56 publications

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“…Thus, inhibition of PCSK9 leads to increased LDL receptor expression, increased clearance of lipoproteins, and decreased plasma LDL cholesterol levels (10 -12). Because both statins and PCSK9 antibodies reduce plasma cholesterol by modulating LDL receptor expression, they are ineffective in homozygous familial hypercholesterolemia subjects with Ͻ2% of the LDL receptor activity (11,13,14). In addition, a significant percentage of the general population experiences significant side effects with statins and PCSK9 inhibitors (13-15).…”

mentioning

confidence: 99%

MicroRNA-30c Mimic Mitigates Hypercholesterolemia and Atherosclerosis in Mice

Irani

Pan

Peck

et al. 2016

Journal of Biological Chemistry

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High plasma cholesterol levels are a major risk factor for atherosclerosis. Plasma cholesterol can be reduced by inhibiting lipoprotein production; however, this is associated with steatosis. Previously we showed that lentivirally mediated hepatic expression of microRNA-30c (miR-30c) reduced hyperlipidemia and atherosclerosis in mice without causing hepatosteatosis. Because viral therapy would be formidable, we examined whether a miR-30c mimic can be used to mitigate hyperlipidemia and atherosclerosis without inducing steatosis. Delivery of a miR-30c mimic to the liver diminished diet-induced hypercholesterolemia in C57BL/6J mice. Reductions in plasma cholesterol levels were significantly correlated with increases in hepatic miR-30c levels. Long term dose escalation studies showed that miR-30c mimic caused sustained reductions in plasma cholesterol with no obvious side effects. Furthermore, miR-30c mimic significantly reduced hypercholesterolemia and atherosclerosis in Apoe ؊/؊ mice. Mechanistic studies showed that miR-30c mimic had no effect on LDL clearance but reduced lipoprotein production by down-regulating microsomal triglyceride transfer protein expression. MiR-30c had no effect on fatty acid oxidation but reduced lipid synthesis. Additionally, whole transcriptome analysis revealed that miR-30c mimic significantly down-regulated hepatic lipid synthesis pathways. Therefore, miR-30c lowers plasma cholesterol and mitigates atherosclerosis by reducing microsomal triglyceride transfer protein expression and lipoprotein production and avoids steatosis by diminishing lipid syntheses. It mitigates atherosclerosis most likely by reducing lipoprotein production and plasma cholesterol. These findings establish that increasing hepatic miR-30c levels is a viable treatment option for reducing hypercholesterolemia and atherosclerosis.Atherosclerosis, hardening of the arteries secondary to lipid deposition, is the major cause of morbidity and mortality in the United States (1-3). High plasma cholesterol levels are a major risk factor for cardiovascular diseases, and their reduction is a national goal (2, 4). Currently, statins are the standard of care. They lower plasma cholesterol by reducing cholesterol synthesis and enhancing the rate of removal of lipoproteins from the plasma. Statins lower plasma cholesterol by 20 -30% and cardiovascular disease mortality by 30 -40% (5-8). Recently, proprotein convertase subtilisin/kexin type 9 (PCSK9) 2 inhibitors have emerged as potential new drugs for the treatment of hyperlipidemia (9). PCSK9 binds to LDL receptor and targets it for lysosomal degradation. Thus, inhibition of PCSK9 leads to increased LDL receptor expression, increased clearance of lipoproteins, and decreased plasma LDL cholesterol levels (10 -12). Because both statins and PCSK9 antibodies reduce plasma cholesterol by modulating LDL receptor expression, they are ineffective in homozygous familial hypercholesterolemia subjects with Ͻ2% of the LDL receptor activity (11,13,14). In addition, a significant percentage o...

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mentioning

confidence: 99%

MicroRNA-30c Mimic Mitigates Hypercholesterolemia and Atherosclerosis in Mice

Irani

Pan

Peck

et al. 2016

Journal of Biological Chemistry

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“…Recognising the true cases of statin intolerance is essential to avoid unnecessary cessation. In true statin intolerance, low doses can still be used and if tolerated, should be gradually increased to achieve the highest tolerable dose – as even low doses do provide a reasonable degree of lipid‐lowering effect …”

Section: What Is New In Lipid‐lowering Therapies In Diabetes?mentioning

confidence: 99%

“…In true statin intolerance, low doses can still be used and if tolerated, should be gradually increased to achieve the highest tolerable doseas even low doses do provide a reasonable degree of lipid-lowering effect. 12 A current RCT 13 aims to determine if treatment with 180 mg of bempedoic acid versus placebo decreases the risk of CV events in patients who are statin intolerant. Bempedoic acid inhibits adenosine triphosphate-citratelyase, an enzyme involved in fatty acid and cholesterol synthesis.…”

Section: Statin Intolerancementioning

confidence: 99%

What is new in lipid‐lowering therapies in diabetes?

Cheung

O’Brien

Ekinci

2019

Internal Medicine Journal

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Diabetes can lead to a myriad of microvascular and macrovascular complications – with the leading cause of mortality in diabetes being cardiovascular disease. Low‐density lipoprotein cholesterol, along with non‐high‐density lipoprotein cholesterol and triglycerides are proven, modifiable risk factors for cardiovascular disease. This article will focus on lipid‐lowering agents in individuals with diabetes. It will summarise relevant changes in the latest guidelines for dyslipidaemia and will also review the mechanisms of action of lipid‐lowering agents along with the latest cardiovascular outcomes data specific to individuals with diabetes. Older agents such as statins, ezetimibe, fibrates and nicotinic acid will be reviewed with a focus on new diabetes‐specific evidence. Similarly, a relatively novel agent proprotein‐convertase subtilisin‐kexin type 9 will be reviewed and details around the Pharmaceutical Benefits Scheme criteria governing its usage in Australia will be reported. Finally, this review will touch on agents still on the horizon such as icosapent ethyl, high‐density lipoprotein mimetics, bempedoic acid, omega‐3 free fatty acids, bromodomain and extra‐terminal protein inhibitors and inclisiran – a long‐acting ribonucleic acid interference agent. In the appropriately selected population of individuals with diabetes, these agents can assist to improve further lipid profile and reduce cardiovascular events.

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“…There is significant uncertainty regarding the actual incidence, and there is insufficient knowledge concerning the best therapeutic approaches to the problem. Most cases of statin intolerance are related to muscle complaints, [5][6][7] with increased liver or muscle enzymes. 8 Various neurological symptoms 9 and other problems being much less frequent.…”

Section: Introductionmentioning

confidence: 99%