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Statins redux: A re-assessment of how statins lower plasma cholesterol.

ABSTRACT: Obesity associated dyslipidemia and its negative effects on the heart and blood vessels have emerged as a major healthcare challenge around the globe. The use of statins, potent inhibitors of hydroxyl-methyl glutaryl (HMG) Co-A reductase, a rate-limiting enzyme in cholesterol biosynthesis, has significantly reduced the rates of cardiovascular and general mortality in patients with coronary artery disease. How statins lower plasma cholesterol levels presents a mechanistic conundrum since persistent exposure to these drugs in vitro or in vivo is known to induce overexpression of the HMG Co-A reductase gene and protein. In an attempt to solve this mechanistic puzzle, Schonewille et al, studied detailed metabolic parameters of cholesterol synthesis, inter-organ flux and excretion in mice treated with 3 common statins, rosuvastatin, atorvastatin or lovastatin, each with its unique pharmacokinetics. From the measurements of the rates of heavy water (D2O) and [13C]-acetate incorporation into lipids, the authors calculated the rates of whole body and organ-specific cholesterol synthesis in control and statin-treated mice. These analyses revealed dramatic enhancement in the rates of hepatic cholesterol biosynthesis in statin-treated mice that concomitantly elicited lower levels of cholesterol in their plasma. The authors have provided strong evidence to indicate that statin treatment in mice led to induction of compensatory metabolic pathways that apparently mitigated an excessive accumulation of cholesterol in the body. It was noted however that changes in cholesterol metabolism induced by 3 statins were not identical. While sustained delivery of all 3 statins led to enhanced rates of biliary excretion of cholesterol and its fecal elimination, only atorvastatin treated mice elicited enhanced trans-intestinal cholesterol excretion. Thus, blockade of HMGCR by statins in mice was associated with profound metabolic adaptations that reset their cholesterol homeostasis. The findings of Schonewille et al, deserve to be corroborated and extended in patients in order to more effectively utilize these important cholesterol-lowering drugs in the clinic.

SUBMITTER: Raghow R

PROVIDER: S-EPMC5483422 | biostudies-other | 2017 Jun

REPOSITORIES: biostudies-other

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Project description:BackgroundPhenylketonuria (PKU; OMIM#261600) is a rare metabolic disorder caused by mutations in the phenylalanine hydroxylase (PAH) gene resulting in high phenylalanine (Phe) in blood and brain. If not treated early this results in intellectual disability, behavioral and psychiatric problems, microcephaly, motor deficits, eczematous rash, autism, seizures, and developmental problems. There is a controversial discussion of whether patients with PKU have an additional risk for atherosclerosis due to interference of Phe with cholesterol synthesis and LDL-cholesterol regulation. Since cholesterol also plays a role in membrane structure and myelination, better insight into the clinical significance of the impact of Phe on lipoprotein metabolism is desirable. In 22 treated PKU patients (mean age 38.7 years) and 14 healthy controls (mean age 35.2 years), we investigated plasma with NMR spectroscopy and quantified 105 lipoprotein parameters (including lipoprotein subclasses) and 24 low molecular weight parameters. Analysis was performed on a 600 MHz Bruker AVANCE IVDr spectrometer as previously described.ResultsConcurrent plasma Phe in PKU patients showed a wide range with a mean of 899 μmol/L (50-1318 μmol/L). Total cholesterol and LDL-cholesterol were significantly lower in PKU patients versus controls: 179.4 versus 200.9 mg/dL (p < 0.02) and 79.5 versus 104.1 mg/dL (p < 0.0038), respectively. PKU patients also had lower levels of 22 LDL subclasses with the greatest differences in LDL2 Apo-B, LDL2 Particle Number, LDL2-phospholipids, and LDL2-cholesterol (p < 0.0001). There was a slight negative correlation of total cholesterol and LDL-cholesterol with concurrent Phe level. VLDL5-free cholesterol, VLDL5-cholesterol, VLDL5-phospholipids, and VLDL4-free cholesterol showed a significant (p < 0.05) negative correlation with concurrent Phe level. There was no difference in HDL and their subclasses between PKU patients and controls. Tyrosine, glutamine, and creatinine were significantly lower in PKU patients compared to controls, while citric and glutamic acids were significantly higher.ConclusionsUsing NMR spectroscopy, a unique lipoprotein profile in PKU patients can be demonstrated which mimics a non-atherogenic profile as seen in patients treated by statins.

Project description:ImportanceThe use of statins in patients with symptomatic peripheral artery disease remains suboptimal despite strong clinical practice guideline recommendations; however, it is unknown whether rates are associated with substantial improvements after lower extremity revascularization.ObjectiveTo report longitudinal trends of statin use in patients with peripheral artery disease undergoing lower extremity revascularization and to identify the clinical and procedural characteristics associated with prescriptions for new statin therapy at discharge.Design, setting, and participantsThis was a retrospective cross-sectional study using data from the Vascular Quality Initiative registry of patients who underwent lower extremity peripheral artery disease revascularization from January 1, 2014, through December 31, 2019. The Vascular Quality Initiative is a multicenter registry database including academic and community-based hospitals throughout the US. Patients aged 18 years or older undergoing lower extremity revascularization with available statin data (preprocedure and postprocedure) were included. Those not receiving statin therapy for medical reasons were excluded from final analyses.ExposuresPatients undergoing lower extremity revascularization for whom statin therapy is indicated.Main outcomes and measuresMultivariate logistic regression was used to determine the clinical and procedural characteristics associated with new statin prescription for patients not already taking a statin preprocedure. The overall rates of statin prescription as well as rates of new statin prescription at discharge were determined. In addition, the clinical, demographic, and procedural characteristics associated with new statin prescription were analyzed.ResultsThere were 172 025 procedures corresponding to 125 791 patients (mean [SD] age, 67.7 [11.0] years; 107 800 men [62.7%]; and 135 405 White [78.7%]) included in the analysis. Overall rates of statin prescription at discharge improved from 17 299 of 23 093 (75%) in 2014 to 29 804 of 34 231 (87%) in 2019. However, only 12 790 of 42 020 patients (30%) not already taking a statin at the time of revascularization during the study period were newly discharged with a statin medication. New statin prescription rates were substantially lower after endovascular intervention (7745 of 29 581 [26%]) than after lower extremity bypass (5045 of 12 439 [41%]). Body mass index of 30 or greater (odds ratio [OR], 1.13; 95% CI, 1.04-1.24; P < .001), diabetes (diet-controlled vs no diabetes, OR, 1.22; 95% CI, 1.05-1.41; P = .01), smoking (current vs never, OR, 1.32; 95% CI, 1.21-1.45; P < .001), hypertension (OR, 1.19; 95% CI, 1.09-1.29; P < .001), and coronary heart disease (OR, 1.26; 95% CI, 1.17-1.35; P < .001) were associated with an increased likelihood of new statin prescription after endovascular intervention, whereas female sex, older age, antiplatelet use, and prior peripheral revascularization were associated with a decreased likelihood.Conclusions and relevanceIn this cross-sectional study, although statin use was associated with a substantial improvement after lower extremity revascularization, more than two-thirds of patients not already taking a statin preprocedure remained not taking a statin at discharge. Further investigations to understand the clinical implications of these findings and develop clinician- and system-based interventions are needed.

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Statins redux: A re-assessment of how statins lower plasma cholesterol.

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