scholarly journals HMG-Coenzyme A Reductase as a Drug Target for the Prevention of Ankylosing Spondylitis

2021 ◽  
Vol 9 ◽  
Author(s):  
Zhenyu Zhong ◽  
Xiaojie Feng ◽  
Guannan Su ◽  
Liping Du ◽  
Weiting Liao ◽  
...  
Keyword(s):  
Ankylosing Spondylitis ◽  
Statin Therapy ◽  
Drug Targets ◽  
Ldl Cholesterol ◽  
Coenzyme A ◽  
Significant Heterogeneity ◽  
Genetic Score ◽  
Cholesterol Levels ◽  
Clinical Benefits ◽  
Coenzyme A Reductase

Statins are an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR). Growing evidence indicates that statins may have an anti-inflammatory effect. Whether genetically proxied HMGCR inhibition can reduce the risk of ankylosing spondylitis is unknown. We constructed an HMGCR genetic score comprising nearly randomly inherited variants significantly associated with LDL cholesterol levels within ± 100 kb from HMGCR to proxy for inhibition of HMGCR. We also constructed PCSK9 and NPC1L1 scores as well as the LDL polygenetic score to proxy for the inhibition of these drug targets as well as serum LDL cholesterol levels, respectively. We then compared the associations of these genetic scores with the risk of ankylosing spondylitis. Of 33,998 participants in the primary cohort, 12,596 individuals had been diagnosed with ankylosing spondylitis. Genetically proxied inhibition of HMGCR scaled to per mmol/L decrease in LDL cholesterol levels by the HMGCR score was associated with a lower risk of ankylosing spondylitis (OR, 0.57; 95% CI, 0.38–0.85; P value = 5.7 × 10–3). No significant association with ankylosing spondylitis was observed for the PCSK9 score (OR, 0.89; 95% CI, 0.68–1.16) and the NPC1L1 score (OR, 1.50; 95% CI, 0.39–5.77). For the LDL score, genetically determined per mmol/L decrease in LDL cholesterol levels led to a reduced risk of ankylosing spondylitis (OR, 0.64; 95% CI, 0.43–0.94), with significant heterogeneity and pleiotropy in the estimate. Exploratory analyses showed that genetically proxied inhibition of HMGCR appeared to have a similar effect to long-term statin therapy in modifying the risk of coronary artery disease and type 2 diabetes, suggesting that the HMGCR score might be a reliable model to assess the effect of statin. Genetically proxied inhibition of HMGCR was associated with a decreased risk of ankylosing spondylitis. This mechanism-based estimate was in line with existing observations suggesting the clinical benefits of statin therapy for ankylosing spondylitis.

Abstract 330: Ezetimibe Prevents Atherogenesis Through Increased Catabolism and Fecal Excretion of LDL-cholesterol and Reduced Atherosclerotic Plaque Inflammation in Apolipoprotein E Knock-out Mice Fed a Paigen Diet

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Francois Briand ◽  
Laurent Dumas ◽  
Alexis Broisat ◽  
Mitra Ahmadi ◽  
Sandrine Bacot ◽  
...  
Keyword(s):  
Statin Therapy ◽  
Ldl Cholesterol ◽  
Cholesteryl Oleate ◽  
Fecal Excretion ◽  
Atherosclerotic Plaques ◽  
Knock Out ◽  
Cholesterol Levels ◽  
Paigen Diet ◽  
Apoe Ko Mice ◽  
Fecal Cholesterol

Background: Intestinal cholesterol absorption inhibitor ezetimibe (EZE) added to a statin therapy has demonstrated benefits in the IMPROVE-IT trial by further reducing LDL-cholesterol levels than statin therapy alone. We investigated the mechanisms by which EZE could contribute to cardiovascular events reduction in apolipoprotein E knock-out (apoE ko) mice. Methods: ApoE ko mice were fed a Paigen diet without (control) or with EZE (7mg/kg/day) for 6 weeks. To evaluate the effects of EZE on LDL-cholesterol metabolism and excretion, a first set of mice was injected intravenously with 3 H-cholesteryl oleate labeled human LDL. A second set of mice was used for in vivo SPECT/CT imaging of 99m Tc-cAbVCAM1-5, a single domain antibody directed against the Vascular Cell Adhesion Molecule-1 (VCAM-1), which was used as a marker of inflamed atherosclerotic plaques. The same mice were sacrificed for autoradiography and histology of aortic atherosclerotic plaques. Results: Compared with control, EZE treatment for 6 weeks induced a significant 41% and 65% reduction in plasma total cholesterol levels and atherosclerotic plaque area, respectively. After injection of 3 H-cholesteryl oleate labeled human LDL, mice treated with EZE showed a 173% higher LDL-cholesteryl ester catabolism (p<0.001 vs. control). At time 96 hours after radiolabeled LDL injection, 3 H-tracer hepatic recovery was reduced by 61% with EZE (p<0.001). Meanwhile, LDL-derived 3 H-tracer excretion in the feces was increased by 107% in the fecal cholesterol fraction (p<0.001). Similar trends were observed for hepatic cholesterol levels and fecal cholesterol mass excretion, with a 75% reduction and 99% increase with EZE, respectively (both p<0.001). After intravenous injection of 99m Tc-cAbVCAM1-5, mice treated with EZE also showed a significant 52% reduction in aortic uptake, which was confirmed by significant reduction in tracer uptake in ex vivo biodistribution and autoradiography analysis. Conclusion: EZE promotes anti-atherosclerotic effects through increased LDL-cholesterol catabolism and LDL-derived cholesterol fecal excretion, and reduced inflamed atherosclerotic plaques. These mechanisms may contribute to the benefits of adding EZE to a statin therapy.

Abstract 15913: Statin And Ezetimibe in Silent Ambulatory Myocardial Ischemia (SESAMI Trial)

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Waleed Kadro ◽  
Maya Turkmani ◽  
Hussam Rahim ◽  
Oussama Beshir ◽  
Oussama Khatib ◽  
...  
Keyword(s):  
Myocardial Ischemia ◽  
Statin Therapy ◽  
Serum Cholesterol ◽  
Ldl Cholesterol ◽  
Ambulatory Monitoring ◽  
Cholesterol Lowering ◽  
Cholesterol Levels ◽  
St Segment ◽  
Cardiovascular Morbidity And Mortality

Introduction: Cholesterol lowering is associated with a reduction in cardiovascular morbidity and mortality. Statins are the main drugs for cholesterol lowering. Ezetimibe when added to statins gives further reduction in cholesterol but its long-term effect on cardiovascular morbidity and mortality and ischemic events is not known. This study sought to determine whether further cholesterol lowering with ezitimibe will also results in a reduction of myocardial ischemia during daily life. Hypothesis: Further cholestrol with ezetimibe lowering may reduce silent ischemia. Methods: We enrolled 50 patients with proven stable coronary artery disease (CAD) and at least one episode of ST-segment depression on ambulatory ECG monitoring. All of them were receiving optimal therapy for CAD including statin therapy for cholesterol reduction. 25 patients were randomized to continue their statin therapy (Statin only group) and 25 to recieve statin plus Ezitimibe 10mg/day (ezitimibe group). Serum cholesterol and LDL cholesterol levels and ambulatory monitoring were repeated after 4 to 6 months of therapy. The two groups were comparable with respect to baseline characteristics, number of episodes of ST-segment depression, and baseline serum cholesterol levels. Holters were read by a blinded cardiologist. Results: The ezitimibe group had lower mean total and LDL cholesterol levels at study end and experienced a significant reduction in the number of episodes of ST-segment depression compared with the statin only group. ST-segment depression was completely resolved in 13 of 25 patients (52%) in the ezitimibe group versus 3 of 25 (12%) in the statin only group. The ezitimibe group exhibited a highly significant reduction in ambulatory ischemia (P<.001). By logistic regression, treatment with ezitimibe was an independent predictor of ischemia resolution. Conclusions: Further cholesterol lowering with ezitimibe can result in reduction or resolution of myocardial ischemia recorded as episodes of ST-segment depression in ambulatory monitoring of the ECG. A larger study is required to confirm this results. This may be translated into long term mortality reduction for CAD by adding ezetimibe.

Patient adherence to statin therapy within 12 months after coronary stenting depending on regular or remote monitoring

2021 ◽  
Vol 28 (Supplement_1) ◽  
Author(s):  
A Osokina ◽  
A Filatova ◽  
A Potekhina ◽  
A Shchinova ◽  
S Provatorov
Keyword(s):  
Statin Therapy ◽  
Remote Monitoring ◽  
Ldl Cholesterol ◽  
Patient Adherence ◽  
Control Group ◽  
Cholesterol Levels ◽  
Outpatient Visits ◽  
Group 3 ◽  
Group 2 ◽  
Group 1

Abstract Funding Acknowledgements Type of funding sources: Other. Main funding source(s): Russian Ministry of Health Background. Low adherence to statins remains a challenge in the treatment of patients with cardiovascular diseases. Some patients who underwent coronary stenting (CS) are unavailable for regular follow-up with outpatient visits. The ability to remotely monitor patients after CS may facilitate adherence to treatment, achieve target low density lipoprotein (LDL) cholesterol levels and early detection of adverse events. We aimed to evaluate the adherence to statin therapy in patients after CS receiving remote monitoring or care with outpatient visits. Methods. We enrolled 279 consecutive stable CAD/silent myocardial ischemia patients (61.5 ± 9.5 years) who underwent CS. The patients were randomized into groups of regular outpatient visits (group 1, n = 96), remote monitoring (group 2, n = 95) and control group (group 3, n = 88). The visits (cardio exam and blood testing) and remote monitoring (videoconference, telephone care and blood tests interpretation) were performed at 1, 3, 6 and 12 months after CS for groups 1 and 2. Patients in the control group were cared by a physician at the residence place, the contact with the study coordinator was performed at baseline and 12 months after CS. Adherence to the prescribed medical therapy based on the four-item Morisky Green Levine Medication Adherence Scale was assessed at each contact with the study coordinator. Results. Patient adherence to statin therapy 12 months after CS was 53.6% for group 1, 55.8% for group 2 and 24.4% for group 3 (p &lt; 0.05 for group 3 versus groups 1 and 2). In group 1 26.9/36.5/31.7/37.4*/41.3*% of patients achieved target LDL level at baseline/1mo/3mo/6mo/12mo, respectively (р&lt;0.05 vs. baseline). In group 2 - 35.8/36.8/40.0/51.6*/57.9*% of patients (р&lt;0.05 vs. baseline). In group 3 25.5/28.2% of patients achieved target LDL level at baseline/12mo, respectively. The significant decrease in LDL cholesterol levels between baseline and 12mo values was observed in groups 1 and 2 (p &lt; 0.05). No differences were observed in group 3. Conclusion. The groups of patients receiving remote monitoring or care with outpatient visits demonstrate the same increase in the proportion of patients that achieved target LDL cholesterol levels within 12 months after CS. The remote monitoring is a safe strategy for improving and maintaining the adherence to statins in patients after CS.

scholarly journals Lipidek és az agyérbetegség – Új lehetőségek az LDL-koleszterin-szint csökkentésére

2016 ◽  
Vol 157 (52) ◽  
pp. 2059-2065 ◽  
Author(s):  
Emese Lovadi ◽  
Péter Csécsei ◽  
Csenge Lovig ◽  
Zsófia Karádi ◽  
László Szapáry
Keyword(s):  
Adverse Effects ◽  
Statin Therapy ◽  
Ldl Cholesterol ◽  
Statin Treatment ◽  
Cerebrovascular Diseases ◽  
High Dose ◽  
Cholesterol Levels ◽  
Cerebrovascular Events ◽  
Incidence And Mortality ◽  
Target Values

Abstract: Stroke is the third most common cause of death worldwide following myocardial infaction and malignancies, furthermore, its functional outcome is the worst of all conditions. Cholesterol, especially LDL-cholesterol plays a key role in the formation of atherosclerotic plaques. It has been verified recently that escalating incidence and mortality of cerebrovascular diseases are proportional to increased levels of LDL-cholesterol. Statin therapy undeniably reduces the risk of stroke, however other methods for decreasing lipid levels have not been proved significantly effective. Preventive effect of high-dose statin treatment is without doubt, although administration of such high dosage might require special precautions for patients with prior intracerebral hemorrhage and it also risks development of incident diabetes. The recently published IMPROVE-IT study is the first to prove that the addition of ezetimibe as a non-statin type drug, to statin treatment contributes to further reduction of LDL-cholesterol. The combination treatment results in additional decrease in the incidence and mortality of cerebrovascular events, without any expansion in the number or adverse effects. These results confirm the importance of any further reduction of LDL-cholesterol levels. Achieving target values with statin-ezetimibe combination allows administration of low to moderate dose of statin, which decreases risks of adverse effects related to high-dose statin therapy. Orv. Hetil., 2016, 157(52), 2059–2065.

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