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Statins Are Associated With Increased Insulin Resistance and Secretion.
Abbasi, F, Lamendola, C, Harris, CS, Harris, V, Tsai, MS, Tripathi, P, Abbas, F, Reaven, GM, Reaven, PD, Snyder, MP, et al
Arteriosclerosis, thrombosis, and vascular biology. 2021;(11):2786-2797
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Abstract
OBJECTIVE Statin treatment reduces the risk of atherosclerotic cardiovascular disease but is associated with a modest increased risk of type 2 diabetes, especially in those with insulin resistance or prediabetes. Our objective was to determine the physiological mechanism for the increased type 2 diabetes risk. APPROACH AND RESULTS We conducted an open-label clinical trial of atorvastatin 40 mg daily in adults without known atherosclerotic cardiovascular disease or type 2 diabetes at baseline. The co-primary outcomes were changes at 10 weeks versus baseline in insulin resistance as assessed by steady-state plasma glucose during the insulin suppression test and insulin secretion as assessed by insulin secretion rate area under the curve (ISRAUC) during the graded-glucose infusion test. Secondary outcomes included glucose and insulin, both fasting and during oral glucose tolerance test. Of 75 participants who enrolled, 71 completed the study (median age 61 years, 37% women, 65% non-Hispanic White, median body mass index, 27.8 kg/m2). Atorvastatin reduced LDL (low-density lipoprotein)-cholesterol (median decrease 53%, P<0.001) but did not change body weight. Compared with baseline, atorvastatin increased insulin resistance (steady-state plasma glucose) by a median of 8% (P=0.01) and insulin secretion (ISRAUC) by a median of 9% (P<0.001). There were small increases in oral glucose tolerance test glucoseAUC (median increase, 0.05%; P=0.03) and fasting insulin (median increase, 7%; P=0.01). CONCLUSIONS In individuals without type 2 diabetes, high-intensity atorvastatin for 10 weeks increases insulin resistance and insulin secretion. Over time, the risk of new-onset diabetes with statin use may increase in individuals who become more insulin resistant but are unable to maintain compensatory increases in insulin secretion.
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Prognostic effect of high-density lipoprotein cholesterol level in patients with atherosclerotic cardiovascular disease under statin treatment.
Li, YH, Tseng, WK, Yin, WH, Lin, FJ, Wu, YW, Hsieh, IC, Lin, TH, Sheu, WH, Yeh, HI, Chen, JW, et al
Scientific reports. 2020;(1):21835
Abstract
In patients with atherosclerotic cardiovascular disease (ASCVD) under statin treatment, the influence of on-treatment level of high-density lipoprotein cholesterol (HDL-C) on cardiovascular (CV) events is controversial. Statin-treated patients were selected from the Taiwanese Secondary Prevention for patients with AtheRosCLErotic disease (T-SPARCLE) Registry, a multicenter, observational study of adult patients with ASCVD in Taiwan. Low HDL-C was defined as < 40 mg/dL for men and < 50 mg/dL for women. The primary outcome was a composite CV events including CV death, myocardial infarction (MI), stroke or cardiac arrest with resuscitation. A total of 3731 patients (mean age 65.6 years, 75.6% men) were included. Patients with on-treatment low HDL-C (44%, mean HDL-C 34.9 ± 6.8 mg/dL) were younger and with more diabetes and higher body weight. The mean follow-up time was 2.7 years. We used restricted cubic spline curves to examine the potential non-linear association between HDL-C and adverse outcomes. Decreased HDL-C levels were associated with a significantly increased risk of CV events in women (< 49 mg/dL in women) but not in men (< 42 mg/dL in men). However, the protective effect of elevated HDL-C levels was more prominent in men than in women. In ASCVD patients with statin therapy, low on-treatment HDL-C was common in Taiwan and associated with an increased risk of CV events in women. Higher HDL-C levels provided more protective effect in men than in women.
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Efficacy and Safety of Omega-3 Fatty Acids in Patients Treated with Statins for Residual Hypertriglyceridemia: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial.
Jun, JE, Jeong, IK, Yu, JM, Kim, SR, Lee, IK, Han, KA, Choi, SH, Kim, SK, Park, HK, Mok, JO, et al
Diabetes & metabolism journal. 2020;(1):78-90
Abstract
BACKGROUND Cardiovascular risk remains increased despite optimal low density lipoprotein cholesterol (LDL-C) level induced by intensive statin therapy. Therefore, recent guidelines recommend non-high density lipoprotein cholesterol (non-HDL-C) as a secondary target for preventing cardiovascular events. The aim of this study was to assess the efficacy and tolerability of omega-3 fatty acids (OM3-FAs) in combination with atorvastatin compared to atorvastatin alone in patients with mixed dyslipidemia. METHODS This randomized, double-blind, placebo-controlled, parallel-group, and phase III multicenter study included adults with fasting triglyceride (TG) levels ≥200 and <500 mg/dL and LDL-C levels <110 mg/dL. Eligible subjects were randomized to ATOMEGA (OM3-FAs 4,000 mg plus atorvastatin calcium 20 mg) or atorvastatin 20 mg plus placebo groups. The primary efficacy endpoints were the percent changes in TG and non-HDL-C levels from baseline at the end of treatment. RESULTS After 8 weeks of treatment, the percent changes from baseline in TG (-29.8% vs. 3.6%, P<0.001) and non-HDL-C (-10.1% vs. 4.9%, P<0.001) levels were significantly greater in the ATOMEGA group (n=97) than in the atorvastatin group (n=103). Moreover, the proportion of total subjects reaching TG target of <200 mg/dL in the ATOMEGA group was significantly higher than that in the atorvastatin group (62.9% vs. 22.3%, P<0.001). The incidence of adverse events did not differ between the two groups. CONCLUSION The addition of OM3-FAs to atorvastatin improved TG and non-HDL-C levels to a significant extent compared to atorvastatin alone in subjects with residual hypertriglyceridemia.
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Safety and Efficacy of Pitavastatin in Patients With Impaired Fasting Glucose and Hyperlipidemia: A Randomized, Open-labeled, Multicentered, Phase IV Study.
Lee, HY, Han, KH, Chung, WB, Her, SH, Park, TH, Rha, SW, Choi, SY, Jung, KT, Park, JS, Kim, PJ, et al
Clinical therapeutics. 2020;(10):2036-2048
Abstract
PURPOSE Although the role of high-intensity lipid-lowering therapy in cardiovascular protection has broadened, concerns still exist about new-onset diabetes mellitus (NODM), especially in vulnerable patients. This study aimed to compare the effect of high-dose (4 mg/d) and usual dose (2 mg/d) pitavastatin on glucose metabolism in patients with hyperlipidemia and impaired fasting glucose (IFG). METHODS In this 12-month study, glucose tolerance and lipid-lowering efficacy of high-dose pitavastatin (4 mg [study group]) was compared with that of usual dose pitavastatin (2 mg [control group]) in patients with hyperlipidemia and IFG. The primary end point was the change of glycosylated hemoglobin (HbA1c) after 24 weeks of treatment. The secondary end points were as follows: (1) NODM within 1 year after treatment, (2) change of lipid parameters, (3) changes of adiponectin, and (4) change of blood glucose and insulin levels. FINDINGS Of the total 417 patients screened, 313 patients with hypercholesterolemia and IFG were randomly assigned into groups. The mean (SD) change in HbA1c was 0.06% (0.20%) in the study group and 0.03% (0.22%) in the control group (P = 0.27). Within 1 year, 27 patients (12.3%) developed NODM, including 12 (10.6%) of 113 patients in the study group and 15 (14.2%) of 106 in the control group (P = 0.43). The study group had a significantly higher reduction of total cholesterol and LDL-C levels and a higher increase in apolipoprotein A1/apolipoprotein B ratio (0.68 [0.40] vs 0.51 [0.35], P < 0.01). IMPLICATIONS The high-dose pitavastatin therapy did not aggravate glucose metabolism compared with the usual dose therapy. Moreover, it had a better effect on cholesterol-lowering and apolipoprotein distribution in the patients with hyperlipidemia and IFG.
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Expression of MMP-2, MMP-9, and NGAL in Tissue and Serum of Patients with Vascular Aneurysms and Their Modulation by Statin Treatment: A Pilot Study.
Cione, E, Piegari, E, Gallelli, G, Caroleo, MC, Lamirata, E, Curcio, F, Colosimo, F, Cannataro, R, Ielapi, N, Colosimo, M, et al
Biomolecules. 2020;(3)
Abstract
BACKGROUND Matrix metalloproteinases (MMPs) are involved in vascular wall degradation, and drugs able to modulate MMP activity can be used to prevent or treat aneurysmal disease. In this study, we evaluated the effects of statins on MMP-2, MMP-9, and neutrophil gelatinase-associated lipocalin (NGAL) in both plasma and tissue in patients with aneurysmal disease. METHODS We performed a prospective, single-blind, multicenter, control group clinical drug trial on 184 patients of both sexes >18 years old with a diagnosis of arterial aneurysmal disease. Enrolled patients were divided into two groups: Group I under statin treatment and Group II not taking statins. In addition, 122 patients without aneurysmal disease and under statin treatment were enrolled as a control group (Group III). The expression of MMPs and NGAL in plasma was evaluated using ELISA, while their expression in endothelial tissues was evaluated using Western blot. RESULTS The ELISA test revealed greater plasma levels (p < 0.01) of MMPs and NGAL in Groups I and II vs. Group III. Western blot analysis showed higher expression (p < 0.01) of MMPs and NGAL in Group II vs. Group I, and this increase was significantly higher (p < 0.01) in patients treated with low potency statins compared to high potency ones. CONCLUSIONS MMPs and NGAL seem to play a major role in the development of aneurysms, and their modulation by statins suggests that these drugs could be used to prevent arterial aneurysmal disease.
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Improvement of endothelial dysfunction is mediated through reduction of remnant lipoprotein after statin therapy in patients with coronary artery disease.
Nakamura, T, Uematsu, M, Yoshizaki, T, Kobayashi, T, Watanabe, Y, Kugiyama, K
Journal of cardiology. 2020;(3):270-274
Abstract
BACKGROUND Remnant lipoproteinemia with high levels of low-density lipoprotein cholesterol (LDL-C) is a high risk for endothelial dysfunction. Statins are the first-line lipid-lowering drugs for this combined hyperlipidemia. However, it remains undetermined whether reduction of remnant lipoprotein mediates the relationship between improvement in endothelial dysfunction and reduction of LDL-C level after statin treatment. METHODS A total of 122 coronary artery disease (CAD) patients with impaired flow-mediated dilation (FMD; <5.5%), high levels of LDL-C (≥100 mg/dL), and remnant-like lipoprotein particle cholesterol (RLP-C) (≥5 mg/dL) were examined in this study. The lipid profiles and FMD were measured before and after 6-9 months of statin treatment. The association between changes in LDL-C levels and its relationship with changes in FMD was investigated. Furthermore, mediation analysis was performed to assess the changes in RLP-C level as a mediator of the relationship between the reduction in LDL-C level and improvement of FMD. RESULTS Treatment with statins improved FMD in 69 (56.5%) patients. Patients with improved FMD showed lower percent changes of LDL-C, triglyceride (TG), RLP-C, RLP-C/TG, and C-reactive protein (CRP) levels, and higher percent change of HDL-C level, compared to patients who did not show improved FMD. The percent changes in FMD levels had a significant inverse correlation with the percent changes in LDL-C, (r = -0.18, p = 0.03), RLP-C (r = -0.39, p < 0.001), RLP-C/TG (r = -0.34, p < 0.001), and CRP (r = -0.27, p < 0.01). Mediation analysis showed that the relationship between reduction in LDL-C and improvement of FMD was mediated by reduction of RLP-C (34.5%), RLP-C/TG (24.4%), and CRP (24.9%) levels. CONCLUSION Improvement of remnant lipoproteinemia may be an important mediator for the relationship between improvement of endothelial dysfunction and LDL-lowering after statin treatment in patients with CAD.
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Comparison between Atorvastatin and Rosuvastatin on Secondary Percutaneous Coronary Intervention Rate and the Risk Factors in Patients with Coronary Heart Disease.
Zhang, J, Wang, J, Yu, H, Wang, G, Zhang, J, Zhu, R, Liu, X, Li, J
Current drug metabolism. 2020;(10):818-828
Abstract
OBJECTIVE The aim is to compare atorvastatin versus rosuvastatin on secondary percutaneous coronary intervention (PCI) rate and explore risk factors in coronary heart disease (CHD) patients. METHODS A cohort study with 283 CHD subjects was launched from 2011 to 2015. Cox proportional hazards regression model, Receiver Operating Characteristic (ROC) and nomogram were used to compare the effect of atorvastatin and rosuvastatin on secondary PCI rate and disease risk factors. Even why the two statins had different effects based on gene expression profile analysis has been explored. RESULTS Gene FFA (Freely fatty acid), AST (Aspartate Transaminase) and ALT (Alanine transaminase) showed the statistical difference between the four statin groups (P<0.05). In the AA group (Continuous Atorvastatin usage), albumin was a risk factor (Hazard Ratio (HR):1.076, 95%CI (1.001, 1.162), p<0.05). In the AR group (Start with Atorvastatin usage, then change to Rosuvastatin usage), ApoA was a protective factor (HR:0.004, 95%CI (0.001, 0.665), p<0.05). GLB (Galactosidase Beta) was a risk factor (HR:1.262, 95%CI (1.010, 1.576), p<0.05). In RR group (Continuous Rosuvastatin usage), ApoE was a protective factor (HR:0.943, 95%CI (0.890, 1.000), <0.05). ALT was a risk factor (HR:1.030, 95%CI (1.000, 1.060), p<0.05). CONCLUSION Patients in the RA group had the lowest secondary PCI rate. ALT was a risk factor in the RR group. Gene Gpt (Glutamic Pyruvic Transaminase) encoded for one subtype of ALT had a significantly different expression in different statin groups.
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Efficacy and Safety of Pemafibrate, a Novel Selective Peroxisome Proliferator-Activated Receptor α Modulator (SPPARMα): Pooled Analysis of Phase 2 and 3 Studies in Dyslipidemic Patients with or without Statin Combination.
Yamashita, S, Arai, H, Yokote, K, Araki, E, Matsushita, M, Nojima, T, Suganami, H, Ishibashi, S
International journal of molecular sciences. 2019;(22)
Abstract
Hypertriglyceridemia has emerged as an independent risk factor for cardiovascular events, despite low-density lipoprotein-cholesterol (LDL-C) well-controlled with statins. We pooled data from the first 12 weeks of six randomized double-blind placebo-controlled studies of pemafibrate in Japan and investigated its efficacy and safety with and without statins, particularly focusing on patients with renal dysfunction. Subjects were 1253 patients (677 in the "with-statin" group and 576 in the "without-statin" group). At Week 12 (last observation carried forward), triglyceride (TG) was significantly reduced at all pemafibrate doses (0.1, 0.2, and 0.4 mg/day), both with and without statin, compared to placebo (p < 0.001 vs. placebo for all groups). In the "with-statin" group, the estimated percent change from baseline was -2.0% for placebo and -45.1%, -48.5%, and -50.0%, respectively, for the pemafibrate groups. Findings for both groups showed significant decreases in TG-rich lipoproteins and atherogenic lipid parameters compared to placebo. The incidence of adverse events was similar between the pemafibrate and placebo groups and was also similar for patients with and without renal dysfunction in the "with-statin" group. Pemafibrate lowered TG and improved atherogenic dyslipidemia without a significant increase in adverse events in comparison to the placebo, even among "with-statin" patients who had renal dysfunction.
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Effects of Icosapent Ethyl (Eicosapentaenoic Acid Ethyl Ester) on Atherogenic Lipid/Lipoprotein, Apolipoprotein, and Inflammatory Parameters in Patients With Elevated High-Sensitivity C-Reactive Protein (from the ANCHOR Study).
Miller, M, Ballantyne, CM, Bays, HE, Granowitz, C, Doyle, RT, Juliano, RA, Philip, S
The American journal of cardiology. 2019;(5):696-701
Abstract
Icosapent ethyl is pure prescription eicosapentaenoic acid approved at 4 g/day as an adjunct to diet to reduce triglycerides (TG) in adults with TG ≥500 mg/dl. Elevated high-sensitivity C-reactive protein (hsCRP) is associated with increased cardiovascular risk. The 12-week ANCHOR study randomized 702 statin-treated patients at increased cardiovascular risk with TG 200 to 499 mg/dl despite low-density lipoprotein cholesterol (LDL-C) control (40 to 99 mg/dl). This post hoc analysis assessed 246 ANCHOR patients with baseline hsCRP ≥ 2.0 mg/L randomized to icosapent ethyl 4 g/day (n = 126; approved dose) or placebo (n = 120). Without increasing LDL-C, icosapent ethyl significantly reduced median TG (-20%; p < 0.0001), non-high-density lipoprotein cholesterol (-12.3%; p < 0.0001), total cholesterol (-11.1%; p < 0.0001), high-density lipoprotein cholesterol (-5.2%; p = 0.0042), very LDL-C (-21.0%; p < 0.0001), very low-density lipoprotein TG (-22.9%; p < 0.0001), remnant lipoprotein cholesterol (-23.0%; p = 0.0125), apolipoprotein B (-7.4%; p = 0.0021), apolipoprotein C-III (-16%; p < 0.0001), oxidized LDL (-13.7%; p = 0.0020), lipoprotein-associated phospholipase A2 (-19.6%; p < 0.0001), and hsCRP (-17.9%; p = 0.0213) versus placebo, while interleukin-6 and intercellular adhesion molecule-1 were not significantly changed. Eicosapentaenoic acid increased with icosapent ethyl 4 g/day +637% in plasma and +632% in red blood cells versus placebo (both p < 0.0001). Icosapent ethyl exhibited a safety profile similar to placebo. In conclusion, in statin-treated patients with hsCRP ≥ 2.0 mg/L and TG 200 to 499 mg/dl at baseline, icosapent ethyl 4 g/day significantly and safely reduced TG and other atherogenic and inflammatory parameters without increasing LDL-C versus placebo.
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Efficacy and Safety of Alirocumab 300 mg Every 4 Weeks in Individuals With Type 2 Diabetes on Maximally Tolerated Statin.
Müller-Wieland, D, Rader, DJ, Moriarty, PM, Bergeron, J, Langslet, G, Ray, KK, Manvelian, G, Thompson, D, Bujas-Bobanovic, M, Roth, EM
The Journal of clinical endocrinology and metabolism. 2019;(11):5253-5262
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Abstract
CONTEXT In the ODYSSEY CHOICE I trial, alirocumab 300 mg every 4 weeks (Q4W) was assessed in patients with hypercholesterolemia. Alirocumab efficacy and safety were evaluated in a patient subgroup with type 2 diabetes mellitus (T2DM) and who were receiving maximally tolerated statins with or without other lipid-lowering therapies. METHODS Participants received either alirocumab 300 mg Q4W (n = 458, including 96 with T2DM) or placebo (n = 230, including 50 with T2DM) for 48 weeks, with alirocumab dose adjustment to 150 mg every 2 weeks at Week (W) 12 if W8 low-density lipoprotein cholesterol (LDL-C) levels were ≥70 mg/dL or ≥ 100 mg/dL, depending on cardiovascular risk, or if LDL-C reduction was <30% from baseline. Efficacy end points included percentage change from baseline to W24 for lipids, and time-averaged LDL-C over W21 to W24. RESULTS In individuals with T2DM, LDL-C reductions from baseline to W24 and the average of W21 to W24 were significantly greater with alirocumab (-61.6% and -68.8%, respectively) vs placebo. At W24, alirocumab significantly reduced levels of non-high-density lipoprotein cholesterol (HDL-C) and other lipids. At W24, 85.9% and 12.5% of individuals in the alirocumab and placebo groups, respectively, reached both non-HDL-C <100 mg/dL and LDL-C <70 mg/dL. At W12, In total, 18% of alirocumab-treated participants received dose adjustment. The most common treatment-emergent adverse events were upper respiratory tract infection and injection-site reaction. No clinically significant changes in fasting plasma glucose and glycated hemoglobin were observed. CONCLUSION In individuals with T2DM, alirocumab 300 mg Q4W was generally well tolerated and efficacious in reducing atherogenic lipoproteins.