Effects of PCSK9 Inhibitor on Favorable Limb Outcomes in Patients with Chronic Limb-Threatening Ischemia

Aim: The aim of this study was to examine the effects of evolocumab on favorable limb events in patients with chronic limb-threatening ischemia (CLTI). Methods: A single-center, prospective observational study was performed on 30 patients with CLTI. The subjects were divided into 2 groups based on evolocumab administration: evolocumab-treated (E) group ( n =14) and evolocumab non-treated (non-E) group ( n =16). The primary outcome was 12-month freedom from major amputation. The secondary outcomes were 12-month amputation-free survival (AFS), overall survival (OS), and wound-free limb salvage. The mean follow-up period was 18±11 months. Results: No significant difference was detected between the two groups for the 12-month freedom from major amputation (log-rank p =0.15), while the 12-month AFS rate was significantly higher in the E group than that in the non-E group (log-rank p =0.02). The 12-month OS rate in the E group was shown a tendency for improvement, as compared with that in the non-E group (log-rank p =0.056). Evolocumab administration was not associated with a significant change in freedom from major amputation (HR, 0.23, 95% CI, 0.03-2.07, p =0.19). However, evolocumab administration was related to a tendency for improvement of AFS and OS (HR, 0.13, 95% CI, 0.02-1.06, p =0.056; HR, 0.16, 95% CI, 0.02-1.37, p =0.09, respectively). Moreover, The E group had a higher proportion of wound-free limb salvage at 12 months (92% vs. 42%, p =0.03). Conclusion: Evolocumab administration was associated with a better AFS outcome in patients with CLTI. Long-term administration of evolocumab over 12 months contributed to improving proportion of wound-free limb salvage.     

Serum Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) is Independently Associated with Insulin Resistance,Triglycerides, Lipoprotein(a) Levels but not Low-Density Lipoprotein Cholesterol Levels in a General Population

Aim: Proprotein convertase subtilisin/kexin type 9 (PCSK9) has been identified as an important regulator of low-density lipoprotein (LDL) receptor processing. Evolocumab and alirocumab are PCSK9 inhibitors; however, little is known about the association between PCSK9 levels and lipid profiles in a general population. Because PCSK9 inhibitors have LDL-C lowering effects, we investigated whether there is a positive correlation between serum PCSK9 levels and LDL-C or lipoprotein(a) [Lp(a)].Methods: In Uku town, 674 residents (mean age; 69.2 ± 8.3 years) received health check-ups. The participants underwent a physical examination and blood tests, including PCSK9 and Lp(a). Serum PCSK9 and Lp(a) were measured by ELISA and Latex methods, respectively. HOMA-IR was calculated by fasting plasma glucose × insulin levels/405.Results: The mean (range) of PCSK9 and Lp(a) were 211.2 (49–601) ng/mL and 60 (1–107) mg/dL, respectively. Because of a skewed distribution, the log-transformed values were used. With univariate linear regression analysis, PCSK9 levels were associated with Lp(a) (p = 0.028), triglycerides (p < 0.001), and HOMA-IR (p < 0.001), but not with LDL-C (p = 0.138) levels. Multiple stepwise regression analysis revealed that serum PCSK9 levels were independently associated with triglycerides (p < 0.001), Lp(a) (p = 0.033) and HOMA-IR (p = 0.041).Conclusions: PCSK-9 is independently associated with triglycerides, Lp(a) levels, and HOMA-IR, but not LDL-C, in a relatively large general population sample.     

Circulating PCSK7 Level is Independently Associated with Obesity,Triglycerides Level and Fatty Liver Index in a General Population without Medication

Aim: Dyslipidemia and altered iron metabolism are typical features of non-alcoholic fatty liver disease (NAFLD). Proprotein convertase subtilisin/kexin type 7 (PCSK7), a transmembrane-anchored endonuclease, is associated with triglycerides level and processing of transferrin receptor 1. However, the significance of circulating PCSK7 has not been fully addressed, though prosegment PCSK7 is secreted from cells. We investigated the associations of plasma PCSK7 level with several parameters. Methods: Plasma PCSK7 concentration was measured in 282 subjects (male/female: 126/156) without medication of the Tanno-Sobetsu Study, a population-based cohort study. Results: There was no significant sex difference in PCSK7 level. Current smoking habit, but not alcohol drinking habit, was associated with increased PCSK7 level. PCSK7 concentration was negatively correlated with age and blood urea nitrogen and was positively correlated with body mass index (BMI) and levels of γ-glutamyl transpeptidase (γGTP), triglycerides and fatty liver index (FLI), which is calculated by BMI, waist circumference and levels of γGTP and triglycerides, as a noninvasive and simple predictor of NAFLD. There were no significant correlations of PCSK7 level with levels of iron and plasma PCSK9, a secreted PCSK family member and a regulator of low-density lipoprotein cholesterol level. Multivariable regression analyses after adjustment of age, sex and current smoking habit showed that PCSK7 concentration was independently associated with BMI (β=0.130,P=0.035), triglycerides (β=0.141,P=0.027) or FLI (β=0.139,P=0.030). Conclusions: Plasma PCSK7 concentration is independently associated with chronic liver disease including obesity and elevated triglycerides level in a general population of individuals who had not regularly taken any medications.     

NMR‐based lipoprotein analysis for patients with severe hypercholesterolemia undergoing lipoprotein apheresis or PCSK9‐inhibitor therapy (NAPALI‐Study)

Taking into account the discordance between low‐density lipoprotein cholesterol (LDL‐C) and LDL particle (LDL‐P) number, cardiovascular risk more closely correlates with LDL‐P in patients. The aim of our study was to evaluate the number of lipid particles in patients with severe hypercholesterolemia treated with different lipid‐lowering regimens. Four groups of patients differing with respect to lipid‐lowering therapy were recruited from hypercholesterolemic outpatients and lipoprotein apheresis (LA) facilities, and were treated with statins alone (group A), with statins and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors (PCSK9i) (group B), with statins and LA (group C), or with statins, PCSK9i, and LA (group D). Cholesterol, triglycerides, LDL‐C, high‐density lipoprotein cholesterol (HDL‐C), LDL‐P number and size, HDL‐P number and size were determined using nuclear magnetic resonance spectroscopy. The lowest LDL‐P number was achieved at the end of LA sessions in combination with statins or in combination with statins and a monoclonal PCSK9i (median; 25th and 75th percentile) (group C: 244 nmoL/L: 237, 244, P < 0.05; group D: 244 nmoL/L: 99, 307, P < 0.05). Comparing LDL‐P number at the start of LA (group C: 978 nmoL/L: 728, 1404; group D: 954 nmoL/L: 677, 1521) to the other patient groups (groups A and B), the lowest LDL‐P number was measured in patients treated with PCSK9i and a statin (group B): LDL‐P (762 nmoL/L: 604, 1043, P < 0.05), large LDL‐P (472 nmoL/L: 296, 574, P < 0.05), and small LDL‐P (342 nmoL/L: 152, 494, P < 0.05). Very low‐density lipoprotein and HDL particle sizes remained approximately the same in all groups. LA in combination with statins or in combination with statins and PCSK9i most reduced LDL‐P numbers in hypercholesterolemic patients.     

Association between causative mutations and response to PCSK9 inhibitor therapy in subjects with familial hypercholesterolemia: A single center real-world study

Background and aimsFamilial hypercholesterolemia (FH) is an autosomal dominant disease that leads to cardiovascular (CV) disease. Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9-I) demonstrated efficacy in low-density lipoprotein cholesterol (LDL-C) reduction and in prevention of CV events. The aim of our study is to evaluate the relationship between LDL receptor (LDLR) mutations and response to PCSK9-I therapy.Methods and resultsWe evaluated total cholesterol (TC), LDL-C, high-density lipoprotein cholesterol (HDL-C) and triglycerides (TG) in consecutive patients with FH before PCSK9-I treatment and after 12 (T12w) and 36 (T36w) weeks of treatment. We evaluated LDL-C target achievement according to different mutations in LDLR. Eighty FH subjects (mean age:54 ± 13.3 years), 39 heterozygous (He) with defective LDLR gene mutations, 30 He with null mutations and 11 compound-He or homozygous (Ho) were recruited. At baseline, 69 subjects were under maximal lipid lowering therapy (MLLT) and 11 subjects had statin-intolerance. From baseline to T36w we observed an overall 51% reduction in LDL-C. We found no difference in LDL-C changes between subjects with He-defective mutation and He-null mutations both at T12w (p = 1.00) and T36w (p = 0.538). At T36w, LDL-C target was achieved in 59% of He-defective mutations subjects and in 36% of He-null mutations subgroup (p = 0.069), whereas none of compound-He/Ho-FH achieved LDL-C target.ConclusionsAfter 36 weeks there were no differences in response to PCSK9-I therapy between different groups of He-FH subjects. Response to PCSK9-I was significantly lower in carriers of compound-He/Ho mutations.Registration number for clinical trials: NCT04313270 extension.     

An Update on the Clinical Development of Proprotein Convertase Subtilisin Kexin 9 Inhibitors,Novel Therapeutic Agents for Lowering Low‐Density Lipoprotein Cholesterol

Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays an essential role in the degradation of low‐density lipoprotein C (LDL‐C) receptors, and PCSK9 inhibitors have recently emerged as a potential treatment option to reduce LDL‐C. Our paper reviewed the current available Phase II clinical trials of PCSK9 inhibitors for the treatment of dyslipidemia. A second objective of this review was to evaluate the potential clinical role of PCSK9 inhibitors in the management of dyslipidemia. Studies evaluating the efficacy and safety of any PCSK9 inhibitors in patients with dyslipidemia were included. The monoclonal antibodies REGN727/SAR236553 and AMG145 have the most published clinical data. Seven phase II trials were retrieved that evaluated the efficacy and safety of REGN727/SAR236553 or AMG145 in patients with either hypercholesterolemia or heterozygous familial hypercholesterolemia (HeFH). These two agents significantly decreased LDL‐C levels either as monotherapy or in combination with other lipid‐lowering agents. REGN727/SAR236553 and AMG145 have been well tolerated. The ongoing phase III trials of these two agents are summarized. REGN727/SAR236553 and AMG145 have demonstrated the potential to further decrease LDL‐C levels when added to conventional lipid‐lowering therapy. Morbidity and mortality data are required to define their roles in clinical practice.     

Effects of proprotein convertase subtilisin/kexin type-9 inhibitors on fatty liver

BACKGROUNDMany studies have investigated the progression of nonalcoholic fatty liver disease (NAFLD) and its predisposing risk factors, but the conclusions from these studies have been conflicting. More challenging is the fact that no effective treatment is currently available for NAFLD.AIMTo determine the effects of proprotein convertase subtilisin/kexin type-9 (PCSK9) inhibitors on fatty infiltration of the liver.METHODSThis retrospective, chart review-based study was conducted on patients, 18-year-old and above, who were currently on PCSK9 inhibitor drug therapy. Patients were excluded from the study according to missing pre- or post-treatment imaging or laboratory values, presence of cirrhosis or rhabdomyolysis, or development of acute liver injury during the PCSK9 inhibitor treatment period; the latter being due to false elevation of liver function markers, alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Radiographic improvement was assessed by a single radiologist, who read both the pre- and post-treatment images to minimize reading bias. Fatty infiltration of the liver was also assessed by changes in ALT and AST, with pre- and post-treatment levels compared by paired t-test (alpha criterion: 0.05).RESULTSOf the 29 patients included in the study, 8 were male (27.6%) and 21 were female (72.4%). Essential hypertension was present in 25 (86.2%) of the patients, diabetes mellitus in 18 (62.1%) and obesity in 15 (51.7%). In all, patients were on PCSK9 inhibitors for a mean duration of 23.69 ± 11.18 mo until the most recent ALT and AST measures were obtained. Of the 11 patients who received the radiologic diagnosis of hepatic steatosis, 8 (72.73%) achieved complete radiologic resolution upon use of PCSK9 inhibitors (mean duration of 17.6 mo). On average, the ALT level (IU/L) decreased from 21.83 ± 11.89 at pretreatment to 17.69 ± 8.00 at post-treatment (2-tailed P = 0.042) and AST level (IU/L) decreased from 22.48 ± 9.00 pretreatment to 20.59 ± 5.47 post-treatment (2-tailed P = 0.201).CONCLUSIONPCSK9 inhibitors can slow down or even completely resolve NAFLD.     

冠心病患者血清前蛋白转化酶枯草溶菌素9与小而密低密度脂蛋白胆固醇的相关性研究

目的探讨冠心病患者血清前蛋白转化酶枯草溶菌素9(PCSK9)与小而密低密度脂蛋白胆固醇(sd LDLC)的关系。方法收集2014年3月至2014年12月在山西医科大学第一医院住院且行冠状动脉造影术确诊为冠心病的患者100例作为冠心病组,同期健康体检者67例作为对照组。Lipoprint脂蛋白分析仪检测LDLC颗粒大小、sd LDLC颗粒数及sd LDLC所占LDLC的百分比(简称sd LDLC百分比);酶联免疫吸附法测定血清PCSK9。结果冠心病组LDLC颗粒大小低于对照组(264.07±6.78比267.37±5.15,P0.01),sd LDLC颗粒数多于对照组(5.0±9.5比4.0±5.0,P0.05),sd LDLC百分比大于对照组(5.95%±10.50%比3.70%±5.85%,P0.01)。冠心病组血清PCSK9显著高于对照组(15.48μg/L比14.95μg/L,U=-2.74,P=0.006)。冠心病组血清PCSK9与sd LDLC百分比、LDLC呈正相关(r=0.212,P=0.034;r=0.202,P=0.032)。结论冠心病患者血清PCSK9与sd LDLC百分比呈正相关,抑制PCSK9可以预防冠心病。     

二肽基肽酶4抑制剂治疗多囊卵巢综合征合并糖代谢异常患者的初步临床研究

目的 比较二肽基肽酶4（DPP-4）抑制剂与二甲双胍对多囊卵巢综合征（PCOS）合并糖代谢异常患者代谢和内分泌参数的影响. 方法 将24例PCOS合并糖代谢异常患者分为二甲双胍组和DPP-4抑制剂组,各12例.分别服用二甲双胍500mg,3次/d和DPP-4抑制剂100mg,1次/d,治疗12周.评估治疗前后各项代谢指标和性激素水平的变化. 结果 与治疗前比较,两组HbA1c水平和胰岛素抵抗指数（HOMA-IR）均降低[HbA1 c：（5.8±0.7）％ vs （6.9±1.7）％,（5.8±0.3）％vs（6.5±1.1）％;HOMA-IR：4.0（3.0,5.2） vs2.3（1.1,4.2）,7.1（5.4,8.6）vs 5.7（3.9,6.7）,P＜0.05].二甲双胍组血清睾酮（T）水平降低[1.8（1.2,2.8） vs 1.1（0.7,1.7） nmol/L,P＜0.05],DPP-4抑制剂组血清T水平也有降低的趋势,但差异无统计学意义. 结论 DPP-4抑制剂可改善PCOS合并糖代谢异常患者的高血糖和IR,并可能有助于改善高雄激素血症.     

早期应用PCSK9抑制剂对非ST段抬高型急性冠状动脉综合征患者PCI后炎症水平和微循环功能的影响

[目的]探讨早期应用前蛋白转化酶枯草溶菌素9(PCSK9)抑制剂对非ST段抬高型急性冠状动脉综合征(NSTE-ACS)患者PCI后炎症水平和微循环功能的影响。[方法]选取2019年12月—2021年12月河南中医药大学人民医院收治行PCI的NSTE-ACS患者110例,按照随机数字表法随机分为对照组(55例)与PCSK9抑制剂组(55例),对照组予阿托伐他汀钙片,PCSK9抑制剂组在对照组治疗的基础上联合依洛尤单抗,治疗6个月后对比两组在血脂、炎症水平、冠状动脉微循环阻力指数(IMR)及冠状动脉TIMI心肌灌注分级(TMPG)方面的差异。[结果]与对照组相比,治疗后PCSK9抑制剂组甘油三酯(TG)、总胆固醇(TC)、低密度脂蛋白胆固醇(LDLC)及脂蛋白(a)水平均明显降低,差异有统计学意义(P<0.05);治疗后高敏C反应蛋白(hs-CRP)、肿瘤坏死因子α(TNF-α)及白细胞介素6(IL-6)水平均明显降低,差异有统计学意义(P<0.05);治疗后PCSK9抑制剂组IMR低于对照组,差异有统计学意义(P<0.05)。术后6个月时PCSK9抑制剂组TMPG 3级...     

Dipeptidyl Peptidase-4 Inhibitors,Peripheral Arterial Disease,and Lower Extremity Amputation Risk in Diabetic Patients

Background

Recent studies have elucidated the vascular protective effects of dipeptidyl peptidase-4 (DPP-4) inhibitors. However, to date, no large-scale studies have been carried out to determine the impact of DPP-4 inhibitors on the occurrence of peripheral arterial disease, and lower extremity amputation risk in patients with type 2 diabetes mellitus.

DPP-4 Inhibitors and Combined Treatment in Type 2 Diabetes: Re-evaluation of Clinical Success and Safety

The incretin system has proven to be a new source of glucose-lowering drugs. Glucon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) are the incretins which are degraded by dipeptidyl peptidase-4 (DPP-4). GLP-1 is the major relevant incretin in type 2 diabetes, GIP has little stimulatory capacity. Oral inhibitors of DPP-4 increase GLP-1 levels and this leads to lower glucose levels caused by increased insulin secretion and decreased glucagon levels. There are currently two oral drugs registered with the European Medicinal Evaluation Agency: sitagliptin and vidagliptin. Both compounds have shown similar effects to date. A main issue is to establish the value of this new class of drugs in the treatment of patients with type 2 diabetes. In this article, results from randomized studies on the efficacy of the new drugs are discussed: 1. comparison with placebo to establish long-term efficacy, 2. comparison with placebo when added to the regimen in patients failing on another oral glucose-lowering drug and 3. comparison in a head-to-head trial with other conventional drugs. Also, the combination with insulin is a promising new avenue. Both efficacy and safety (regarding hypoglycemia, body weight changes and changes in lipid levels) are major components in the decision of the optimal pharmacological treatment, which is discussed in this article. Finally, the advantages, disadvantages and risks of the new anti-diabetic compounds are highlighted, which are applicable to other classes of diabetes drugs.     

Targeting Incretins in Type 2 Diabetes: Role of GLP-1 Receptor Agonists and DPP-4 Inhibitors

Until recently, the pathogenesis of type 2 diabetes mellitus (T2DM) has been conceptualized in terms of the predominant defects in insulin secretion and insulin action. It is now recognized that abnormalities in other hormones also contribute to the development of hyperglycemia. For example, the incretin effect, mediated by glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), is attenuated in T2DM. Intravenous administration of GLP-1 ameliorates hyperglycemia in patients with T2DM, but an extremely short half-life limits its utility as a therapeutic agent. Strategies to leverage the beneficial effects of GLP-1 include GLP-1 receptor agonists or analogs or dipeptidyl peptidase-4 (DPP-4) inhibitors-agents that act by slowing the inactivation of endogenous GLP-1 and GIP. The GLP-1 agonist exenatide has been shown to improve HbA1c and decrease body weight. However, exenatide is limited by its relatively short pharmacologic half-life, various gastrointestinal (GI) side effects, and the development of antibodies. Studies of a long-acting exenatide formulation suggest that it has improved efficacy and also promotes weight loss. Another prospect is liraglutide, a once-daily human GLP-1 analog. In phase 2 studies, liraglutide lowered HbA1c by up to 1.7% and weight by approximately 3 kg, with apparently fewer GI side effects than exenatide. DPP-4 inhibitors such as sitagliptin and vildagliptin result in clinically significant reductions in HbA1c, and are weight neutral with few GI side effects. This review will provide an overview of current and emerging agents that augment the incretin system with a focus on the role of GLP-1 receptor agonists and DPP-4 inhibitors.     

2型糖尿病患者RBP4水平与颈动脉粥样硬化的关系

目的探讨2型糖尿病(T2DM)患者血清视黄醇结合蛋白4(RBP4)水平与颈动脉粥样硬化(AS)的关系。方法 T2DM患者148例,按超声诊断仪测量的颈动脉内膜中层厚度(IMT)结果和粥样斑块将其分三组:非IMT增厚组46例I、MT增厚组53例和斑块形成组49例,并选择健康体检者50例作为对照组,分别检测身高、体重、血脂、血糖、空腹胰岛素、RBP4,并计算BMI及IR,分析其相关性。结果 T2DM患者组血清RBP4水平均高于对照组(P<0.05),非IMT增厚组I、MT增厚组和斑块形成组组间比较差异有统计学意义(P<0.05);T2DM患者各组的RBP4水平与BMI、TG、HOMA-IR呈正相关,IMT增厚组和斑块形成组的RBP4水平与IMT呈正相关;Logistic回归分析显示血清RBP4水平是IMT值的独立相关因素。结论血清RBP4水平升高是T2DM患者颈动脉内膜增厚的主要危险因素,与颈动脉粥样硬化发病关系密切。     

罗格列酮对2型糖尿病肥胖病人颈动脉内膜中层厚度及斑块的影响

目的应用超声评价2型糖尿病病人经罗格列酮长期治疗后颈动脉内膜中层厚度(IMT)及斑块的变化.方法选择59例2型糖尿病伴肥胖病人,随机分成对照组(29例)与治疗组(30例),治疗组加用罗格列酮治疗24个月,治疗前后应用高频超声检测IMT及斑块变化,同时测定血清一氧化氮(NO)、C反应蛋白(CRP)、肿瘤坏死因子-α(TNF-α).结果与对照组比较,治疗组IMT及斑块检出率降低(P＜0.01或P＜0.05),血清NO增加,CRP、TNF-α降低(P＜0.01).与治疗前比较,对照组IMT增加(P＜0.01),斑块检出率及血清NO、CRP、TNF-α无明显变化(P＞0.05).结论罗格列酮长期治疗能延缓2型糖尿病病人颈动脉粥样硬化进展,稳定斑块.