Diabetogenic Action of Statins: Mechanisms.

PURPOSE OF REVIEW: Observational studies and meta-analyses of randomized clinical trials data have revealed a 10-12% increased risk of new-onset diabetes (NOD) associated with statin therapy; the risk is increased with intensive treatment regimens and in people with features of the metabolic syndrome or prediabetes. The purpose of this review is to provide an updated summary of what is known about the potential mechanisms for the diabetogenic effect of statins. RECENT FINDINGS: Hydroxyl methyl glutaryl coenzyme A reductase (HMGCoAR) is the target of statin therapy and the activity of this key enzyme in cholesterol synthesis is reduced by statins in a partial and reversible way. Mendelian randomization studies suggest that the effect of statins on glucose homeostasis reflect reduced activity of HMGCoAR. In vitro and in vivo data indicate that statins reduce synthesis of mevalonate pathway products and increase cholesterol loading, leading to impaired ß-cell function and decreased insulin sensitivity and insulin release. While this effect has been thought to be a drug class effect, recent insights suggest that pravastatin and pitavastatin could exhibit neutral effects on glycaemic parameters in patients with and without diabetes mellitus. The mechanisms by which statins might lead to the development of NOD are unclear. The inhibition of HMGCoAR activity by statins appears to be a key mechanism. It is difficult to offer a comprehensive view regarding the diabetogenic effect of statins because our understanding of the most widely recognized potential mechanisms, i.e. underlying statin-induced reduction of insulin sensitivity and/or insulin secretion, is still far from complete. The existence of this dual mechanism is supported by the results of a study in a large group of non-diabetic men, showing that a 46% higher risk of NOD in statin users compared to non-users was accompanied by a significant 12% reduction in insulin secretion and a 24.3% increase in insulin resistance. Although statin therapy is associated with a modest increase in the risk of NOD (about one per thousand patient-years), patients should be reassured that the benefits of statins in preventing cardiovascular disease (CVD) events far outweigh the potential risk from elevation in plasma glucose.

Study on the 3-hydroxy-3-methyl-glutaryl CoA reductase inhibitory properties of Agaricus bisporus and extraction of bioactive fractions using pressurised solvent technologies.

BACKGROUND: Agaricus bisporus mushrooms were able to lower cholesterol levels in hypercholesterolaemic rats and it was suggested that dietary fibre might inhibit cholesterol absorption. However, A. bisporus extracts were also able to inhibit the 3-hydroxy-3-methyl-glutaryl CoA reductase (HMGCR, the key enzyme in the cholesterol biosynthetic pathway) and this might also contribute to the observed lowering of cholesterol levels in serum. RESULTS: The methanol-water extracts obtained from A. bisporus were able to inhibit up to 60% the HMGCR activity using an in vitro assay. The HMGCR inhibitory capacities depended on cultivation conditions, strains, etc. The potential inhibitors were not statins, they might be ß-glucans able to scavenge the substrate and impair the enzymatic reaction. They were present during all mushroom developmental stages and similarly distributed through all the tissues including the parts discarded as a by-product. Accelerated solvent extractions using 1:1 ethanol-water as pressurised solvent (10.7 MPa, 25°C, five cycles of 5 min) were more effective in the extraction of the HMGCiR inhibitor(s) than supercritical fluid extractions (9 MPa, 40°C) using CO2 with 10% ethanol. CONCLUSION: A mushroom cultivation and two extraction procedures were optimised to obtain fractions from A. bisporus with high HMGCR inhibitory activities to design novel ingredients for hypocholesterolaemic functional foodstuffs.

Spatial sterol metabolism unveiled by stimulated Raman imaging.

Spatiotemporal dynamics of small-molecule metabolites have gained increasing attention for their essential roles in deciphering the fundamental machinery of life. However, subcellular-level regulatory mechanisms remain less studied, particularly due to a lack of tools to track small-molecule metabolites. To address this challenge, we developed high-resolution stimulated Raman scattering (SRS) imaging of a genetically engineered model (GEM) to map metabolites in subcellular resolution. As a result, an unexpected regulatory mechanism of a critical metabolite, sterol, was discovered in yeast by amplifying the strength of vibrational imaging by genetic modulation. Specifically, isozymes of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) were evident to promote ergosterol distribution to distinct subcellular locations, where ergosterol was enriched by a local HMGR-directed synthesis. The heterogeneity of this expression pattern thus provides new insights into sterol metabolism and related disease treatment strategies. These findings demonstrate SRS-GEM as a promising platform for new possibilities in investigating metabolic regulation, disease mechanisms, and biopharmaceutical research.

Regulatory Effects of Statins on SIRT1 and Other Sirtuins in Cardiovascular Diseases.

Adverse cardiovascular disease (CVD) outcomes, such as sudden cardiac death, acute myocardial infarction, and stroke, are often catastrophic. Statins are frequently used to attenuate the risk of CVD-associated morbidity and mortality through their impact on lipids and they may also have anti-inflammatory and other plaque-stabilization effects via different signaling pathways. Different statins, including atorvastatin, rosuvastatin, pravastatin, pitavastatin, and simvastatin, are administered to manage circulatory lipid levels. In addition, statins are potent inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase via modulating sirtuins (SIRTs). During the last two decades, SIRTs have been investigated in mammals and categorized as a family of nicotinamide adenine dinucleotide (NAD)-dependent histone deacetylases (HDACs) with significant oxidative stress regulatory function in cells-a key factor in extending cell lifespan. Recent work has demonstrated that statins upregulate SIRT1 and SIRT2 and downregulate SIRT6 in both in vitro and in vivo experiments and clinical trials. As statins show modulatory properties, especially in CVDs, future investigations are needed to delineate the role of SIRT family members in disease and to expand knowledge about the effects of statins on SIRTs. Here, we review what is currently known about the impact of statins on SIRTs and how these changes correlate with disease, particularly CVDs.

Advances in ovarian cancer treatment using a combination of statins with other drugs.

New anti-cancer drugs are constantly being developed, especially targeted drugs. Although these drugs have achieved significant clinical efficacy, they do not play a significant role in ovarian cancer. Moreover, the research cycle and costs of such drugs are often huge. The repositioning of conventional drugs has gradually become a concern. Statins, as traditional lipid-lowering drugs, play a role mainly by inhibiting HMGCR. In recent years, epidemiological studies and in vitro experiments have confirmed its anti-cancer effect, especially the effect of anti-ovarian cancer. The mutation rate of TP53 in ovarian cancer is as high as 95%, while HMGCR is often highly expressed in TP53 mutant tumors. However, the effect of prospective clinical trials is not ideal. This result seems understandable considering that it seems unrealistic for a lipid-lowering drug to completely inhibit tumor growth. Therefore, statins play more synergistic roles in the treatment of ovarian cancer. Because ovarian cancer is a highly heterogeneous tumor, it may be a good choice to deeply understand the mechanism of statins in the treatment of ovarian cancer and achieve precise treatment by combining it with other drugs.

Combined inhibition of HMGCoA reductase and mitochondrial complex I induces tumor regression of BRAF inhibitor-resistant melanomas.

BACKGROUND: Primary and posttreatment resistance to BRAFV600 mutation-targeting inhibitors leads to disease relapse in a majority of melanoma patients. In many instances, this resistance is promoted by upregulation of mitochondrial oxidative phosphorylation (OxPhos) in melanoma cells. We recently showed that a novel electron transport chain (ETC) complex I inhibitor, IACS-010759 (IACS), abolished OxPhos and significantly inhibited tumor growth of high-OxPhos, BRAF inhibitor (BRAFi)-resistant human melanomas. However, the inhibition was not uniform across different high OxPhos melanomas, and combination with BRAFi did not improve efficacy. METHODS: We performed a high-throughput unbiased combinatorial drug screen of clinically relevant small molecules to identify the most potent combination agent with IACS for inhibiting the growth of high-OxPhos, BRAFi-resistant melanomas. We performed bioenergetics and carbon-13 metabolite tracing to delineate the metabolic basis of sensitization of melanomas to the combination treatment. We performed xenograft tumor growth studies and Reverse-Phase Protein Array (RPPA)-based functional proteomics analysis of tumors from mice fed with regular or high-fat diet to evaluate in vivo molecular basis of sensitization to the combination treatment. RESULTS: A combinatorial drug screen and subsequent validation studies identified Atorvastatin (STN), a hydroxymethylglutaryl-coenzyme A reductase inhibitor (HMGCRi), as the most potent treatment combination with IACS to inhibit in vitro cell growth and induce tumor regression or stasis of some BRAFi-resistant melanomas. Bioenergetics analysis revealed a dependence on fatty acid metabolism in melanomas that responded to the combination treatment. RPPA analysis and carbon-13 tracing analysis in these melanoma cells showed that IACS treatment decreased metabolic fuel utilization for fatty acid metabolism, but increased substrate availability for activation of the mevalonate pathway by HMGCR, creating a dependence on this pathway. Functional proteomic analysis showed that IACS treatment inhibited MAPK but activated AKT pathway. Combination treatment with STN counteracted AKT activation. CONCLUSIONS: STN and other clinically approved HMGCRi could be promising combinatorial agents for improving the efficacy of ETC inhibitors like IACS in BRAFi-resistant melanomas.

Self-reported Morisky Eight-item Medication Adherence Scale for Statins Concords with the Pill Count Method and Correlates with Serum Lipid Profile Parameters and Serum HMGCoA Reductase Levels.

Background It is imperative that non-compliance with statins be identified and addressed to maximize their clinical benefits. Patient self-reporting methods are convenient to apply in clinical practice but need to be validated. Objective We studied the concordance of a patient self-report method, Morisky eight-item medication adherence scale (MMAS)), with the pill count method in measuring adherence with statins and their correlation with extended lipid profile parameters and serum hydroxyl-methylglutaryl coenzyme A reductase (HMGCoA-R) enzyme levels. Methods MMAS and the pill count method were used to measure the adherence with statins in patients on statins for any duration. Patients were subjected to an estimation of extended lipid profile and serum HMGCoA-R levels at the end of three months follow-up. Results Out of a total of 200 patients included in the study, 117 patients had a low adherence (score less than 6 on MMAS) whereas 65 and 18 patients had medium (score 6 or 7) and high adherence (score of 8), respectively. The majority of patients who had low adherence to statins by MMAS were nonadherent by the pill count method yielding a concordance of 96.5%. Medium or high adherence to statins by the MMAS method had a concordance of 89.1% with the pill count method. The levels of total cholesterol, low-density lipoprotein-cholesterol, apolipoprotein B, and HMGCoA-R were negatively correlated with compliance measured by pill count and MMAS in a statistically significant way and with similar correlation coefficients. HMGCoA-R levels demonstrated a plateau phenomenon, with levels being 9-10 ng/ml when compliance with statin therapy was greater than 60% by pill count and greater than 6 on the Morisky scale. Conclusion In conclusion, MMAS and the pill count method showed concordance in measuring adherence to statins. These methods need to be explored further for their interchangeability as surrogates for biomarker levels.

Association of statin induced reduction in serum coenzyme Q10 level and conduction deficits in motor and sensory nerves: An observational cross-sectional study.

OBJECTIVE: The reduction of Coenzyme Q10 (CoQ10) levels following statin use has been linked to cause peripheral neuropathy. Hence, this study was planned to explore the effect of statin on the serum HMGCR (3-hydroxy-3-methyl-glutaryl-coenzyme A reductase), serum CoQ10 levels and nerve conduction and their correlation. PATIENTS AND METHODS: In an open labelled, cross-sectional, observational study, estimation of serum HMGCR and CoQ10 levels was performed in 50 atorvastatin/rosuvastatin users and 50 normal healthy volunteers (NHV). Statin users were also subjected to nerve conduction studies (NCS). RESULTS: Mean serum HMGCR level in NHV was higher (73.58 ± 7.64 ng/ml; p = 0.003) than that in statin users (49.11 ± 1.98 ng/ml). Similarly, mean serum CoQ10 levels was also lower (30.54 ± 2.03 ng/ml, p < 0.0001) in statin users than in NHV (49.43 ± 3.23 ng/ml). Amongst the 50 statin users, 29 had impaired NCS in sural, tibial and common peroneal nerve with lower mean serum CoQ10 levels (24.05 ± 1.96 ng/ml; p < 0.0001). Significant negative correlation was observed between onset time of action potential (AP) of the sural nerve and serum CoQ10 (r=-0.32) and HMGCR (r=-0.43) levels. There was significant positive correlation of conduction velocity of sural (r = 0.38) and tibial (r = 0.31) nerves with serum CoQ10 level. While conduction velocity in sural (r = 0.37) and common peroneal (r = 0.34) nerves positively correlated with serum HMGCR levels. The amplitude of the AP of the common peroneal nerve positively correlated with both serum CoQ10 (r = 0.52) and HMGCR (r = 0.46) levels. CONCLUSION: Statin users had lower serum CoQ10 and HMGCR levels associated with nerve conduction deficits suggesting a role of CoQ10 in the occurrence of the neurological adverse effects.

Pigments from Filamentous Ascomycetes for Combination Therapy.

Filamentous ascomycetes (Neurospora and Monascus) have been studied for a long time because of their production of secondary metabolites such as microbial pigments. The ascomycetes represent an interesting group of compounds with high potential for medicinal applications. Many recent studies have shown their efficacy in the treatment of serious pathological states such as oncological diseases, neurodegenerative diseases and hyperlipidaemia. Nevertheless, the clinical usability of ascomycetes is still limited. However, this problem can be solved by the use of these compounds with combinations of other therapeutic agents. This strategy can suppress their side effects and improve their therapeutic efficacy. Moreover, their co-application can significantly enhance conventional therapies that are used. This review summarizes and discusses the general principles of this approach, introduced and supported by numerous examples. In addition, the prediction of the future potential application of this methodology is included.

Advancement in nanotechnology-based approaches for the treatment and diagnosis of hypercholesterolemia.

Cardiovascular diseases have been the major cause of mortality and morbidity all over the world accounting for more than 80% of the deaths from heart attacks and strokes. Hypercholesterolemia, an autosomal disorder of lipoprotein metabolism is one of the foremost causes of CVDs. An increased level of low-density lipoprotein cholesterol (LDL-C) in the plasma results in the rise of incidence rates in disease patients. Several conventional and combinational therapies have been proposed for lowering the LDL-C levels in the blood. These therapeutic agents are designed to target some crucial molecules that participates in the lipid metabolism such as apolipoprotein B, HMGCoA reductase, proprotein convertase subtilisin/kexin 9, etc. Although these therapies are effective but are associated with certain side effects. This article presents an overview on different conventional and nanotechnology-based approaches for the treatment and diagnosis of hypercholesterolemia. Numerous nanomaterial-based therapies including polymeric nanoparticles, cationic lipids, liposomes, dendrimers and inorganic nanoparticles have been discussed in lowering the cholesterol level along with recent advancement in diagnosis and imaging.