Intensive lipid lowering therapy with titrated rosuvastatin yields greater atherosclerotic aortic plaque regression: Serial magnetic resonance imaging observations from RAPID study

Objective

Although previous randomized clinical trials established a basis for lipid guidelines worldwide, they employed fixed doses of statins throughout trials (fire-and-forget approach). In the real clinical setting, however, statin doses are titrated to achieve target low-density lipoprotein cholesterol (LDL-C) levels (treat-to-target approach). The major objective was to investigate whether intensive lipid-lowering therapy using the treat-to-target approach yielded greater regression of aortic plaques.

Methods

We therefore performed a prospective, randomized trial comparing the effects of standard (achieve LDL-C levels recommended by the Japanese guidelines) and intensive (achieve 30% lower LDL-C levels than standard) rosuvastatin therapy for 1 year in 60 hypercholesterolemic patients with a primary endpoint of aortic atherosclerotic plaques evaluated by non-invasive magnetic resonance imaging (MRI).

Results

Average doses were 2.9 ± 3.1 and 6.5 ± 5.1 mg/day for standard (n = 29) and intensive therapy group (n = 31), respectively. Although both therapies significantly reduced LDL-C and high-sensitivity C-reactive protein (hsCRP) levels, LDL-C reduction was significantly greater in the intensive group (−46 vs. −34%). MRI study showed that thoracic aortic plaques were significantly regressed in both groups, with greater regression of thoracic plaque in the intensive group (−9.1 vs. −3.2%, p = 0.01). Multivariate analyses revealed that thoracic plaque regression was significantly correlated with hsCRP reduction, but not with changes in serum lipids, endothelial function, or doses of rosuvastatin.

Conclusion

Intensive statin therapy with titration targeting lower LDL-C levels resulted in greater thoracic aortic plaque regression compared to standard therapy, which was correlated with hsCRP reduction, suggesting that intensive statin therapy could provide better clinical outcomes.     

Circulating PCSK9 levels in acute coronary syndrome: Results from the PC-SCA-9 prospective study

BackgroundSerum proprotein convertase subtilisin/kexin type 9 (PCSK9) concentrations have been shown to be positively associated with LDL cholesterol (LDL-C), but the relationship between PCSK9 and coronary atherosclerosis lesions remains unclear.ObjectiveThis study aims to investigate the correlation between serum PCSK9 levels and coronary damage severity in patients hospitalized for acute coronary syndrome (ACS).MethodsIn this prospective proof-of-concept study, coronary lesions were assessed using SYNTAX scores. Serum PCSK9 concentrations were measured on admission (Day 0) for ACS by Elisa, and on every day of hospitalization. Spearman's correlations were used to determine the association between PCSK9 levels, SYNTAX score and metabolic parameters.ResultsA total of 174 patients (mean age: 59 ± 14 years, 79% male) with ACS (on Day 0, 119 patients were not taking statins, but 55 were) were included. After initiation of high-intensity statin therapy, serum PCSK9 concentrations increased significantly, reaching maximum levels on Day 2 (+31% vs. Day 0), and remained stable up to Day 4 (P < 0.001, by mixed model). Serum PCSK9 on Day 0 was associated with LDL-C (rho = 0.226, P = 0.017) and apolipoprotein B (rho = 0.282, P = 0.005) in the statin-naïve group only, and with triglycerides and non-HDL-C in all groups. More important, PCSK9 levels on Day 0 were positively associated with SYNTAX scores in the statin-naïve group (rho = 0.239, P = 0.009), but not in the statin-treated group (P = NS). This association was maintained after adjusting for LDL-C (P = 0.014) and major CV risk factors (P = 0.008).ConclusionSerum PCSK9 levels are positively associated with severity of coronary artery lesions independently of LDL-C concentrations in patients hospitalized for ACS. This reinforces the potential importance of PCSK9 inhibition in the management of ACS.     

Very Low Levels of Atherogenic Lipoproteins and the Risk for Cardiovascular Events : A Meta-Analysis of Statin Trials

Background

Levels of atherogenic lipoproteins achieved with statin therapy are highly variable, but the consequence of this variability for cardiovascular disease risk is not well-documented.

Objectives

The aim of this meta-analysis was to evaluate: 1) the interindividual variability of reductions in low-density lipoprotein cholesterol (LDL-C), non–high-density lipoprotein cholesterol (non-HDL-C), or apolipoprotein B (apoB) levels achieved with statin therapy; 2) the proportion of patients not reaching guideline-recommended lipid levels on high-dose statin therapy; and 3) the association between very low levels of atherogenic lipoproteins achieved with statin therapy and cardiovascular disease risk.

Methods

This meta-analysis used individual patient data from 8 randomized controlled statin trials, in which conventional lipids and apolipoproteins were determined in all study participants at baseline and at 1-year follow-up.

Results

Among 38,153 patients allocated to statin therapy, a total of 6,286 major cardiovascular events occurred in 5,387 study participants during follow-up. There was large interindividual variability in the reductions of LDL-C, non-HDL-C, and apoB achieved with a fixed statin dose. More than 40% of trial participants assigned to high-dose statin therapy did not reach an LDL-C target <70 mg/dl. Compared with patients who achieved an LDL-C >175 mg/dl, those who reached an LDL-C 75 to <100 mg/dl, 50 to <75 mg/dl, and <50 mg/dl had adjusted hazard ratios for major cardiovascular events of 0.56 (95% confidence interval [CI]: 0.46 to 0.67), 0.51 (95% CI: 0.42 to 0.62), and 0.44 (95% CI: 0.35 to 0.55), respectively. Similar associations were observed for non-HDL-C and apoB.

Conclusions

The reductions of LDL-C, non-HDL-C, and apoB levels achieved with statin therapy displayed large interindividual variation. Among trial participants treated with high-dose statin therapy, >40% did not reach an LDL-C target <70 mg/dl. Patients who achieve very low LDL-C levels have a lower risk for major cardiovascular events than do those achieving moderately low levels.     

Improvement in LDL-cholesterol levels of patients with familial hypercholesterolemia: Can we do better? Analysis of results obtained during the past two decades in 1669 French subjects

Background

Heterozygous Familial Hypercholesterolemia (heFH) is an autosomal disease that affects about 1/500 people. It is characterized by markedly elevated plasma LDL-cholesterol (C) levels and an increased risk of cardiovascular disease (CVD). The aim of this study was to measure changes in LDL-C levels in heFH patients over two decades, and to evaluate if patients achieved LDL-C targets.

Methods

Data from 1669 heFH patients in five academic French centers were recorded between 1988 and 2011.

Results

The mean LDL-C concentrations under medical care improved between 1988 and 2011 (245 mg/dL before 1995, 164 mg/dL after 2009; p < 0.0001). However, mean LDL-C level and the number of patients treated with statins (79.3%) have not improved since 2005. In patients registered and treated after 2005 (n = 616), only 10.4% reached target LDL-C levels of <100 mg/dL. Indeed, 29.4% (n = 181) were treated with a maximal therapy (statins with a potency of >45% LDL-C reduction plus at least another lipid-lowering agent). Despite maximal treatment, only 18.8% of these heFH patients (n = 34/181) reached target LDL-C levels of <100 mg/dL. In addition, 75.3% of patients with CVD did not reach the LDL-C of <100 mg/dL.

Conclusion

This study demonstrates that after significant improvement over the past two decades, the mean LDL-C levels in heFH French patients has remained stable since 2005. We also show that most heFH patients are not achieving their recommended LDL-C goals: this highlights the need for improved treatment and for new therapeutics in this population.     

Can Group Medical Clinics Improve Lipid Management in Diabetes?

Background

Group medical clinics may improve diabetes and hypertension control, but data about dyslipidemia are limited. We examined the impact of group medical clinics on lipids among patients with uncontrolled diabetes and hypertension.

Methods

Prespecified secondary analysis of 239 veterans randomized to group medical clinics or usual care. Lipids were assessed at study baseline, midpoint, and end. We used linear mixed models to compare lipid levels between arms and generalized estimating equation models to compare low-density lipoprotein cholesterol (LDL-C) goal attainment. An additional post hoc analysis examined intensification of cholesterol-lowering medications in both arms.

Results

At baseline, mean total cholesterol was 169.7 mg/dL (SD 47.8), LDL-C 98.2 mg/dL (SD 41.7), and high-density lipoprotein cholesterol (HDL-C) 39.3 mg/dL (SD 13.0). Median baseline triglycerides were 131 mg/dL (interquartile range 122). By study end, mean total cholesterol and LDL-C in group medical clinics were 14.2 mg/dL (P = .01) and 9.2 mg/dL (P = .02) lower than usual care, respectively; 76% of group medical clinic patients met goals for LDL-C, versus 61% of usual care patients (P = .02). Triglycerides and HDL-C remained similar between study arms. Treatment intensification occurred in 52% of group medical clinic patients, versus 37% of usual care patients between study baseline and end (P = .04). The mean statin dose was higher in group medical clinic patients at study midpoint and end.

Conclusions

Group medical clinics appear to enhance lipid management among patients with diabetes and hypertension. This may be a result of greater intensification of cholesterol-lowering medications in group medical clinics relative to usual care.     

Inverse relationship between LDL cholesterol and PCSK9 plasma levels in dyslipidemic cynomolgus monkeys: Effects of LDL lowering by ezetimibe in the absence of statins

Objectives

To assess the lipid-lowering efficacy of ezetimibe in dyslipidemic cynomolgus monkeys comparing two dosing methods, and to evaluate PCSK9 plasma levels during dyslipidemia induction by feeding a high-fat/high-cholesterol diet (HFD), ezetimibe (Zetia^®, Ezetrol^®) treatment, ezetimibe washout, and HFD washout.

Methods and results

Twenty dyslipidemic cynomolgus monkeys on HFD for seven months (LDL cholesterol 100–400 mg/dL) were randomized into two groups and treated with ezetimibe for two weeks, either by oral gavage or by using food treats. The lipid-lowering effects of ezetimibe were identical between the two groups. After treatment, mean LDL cholesterol was decreased by 58% (174–72 mg/dL), total cholesterol by 42% (241–138 mg/dL), and PCSK9 levels were increased by 137% (147–314 ng/mL). PCSK9 levels on regular diet before and after HFD were also inversely correlated to LDL cholesterol.

Conclusions

In a cynomolgus dyslipidemia model, PCSK9 levels are inversely correlated with LDL cholesterol in the absence of statin treatment, regardless whether lipid changes are modulated by diet or ezetimibe treatment.     

PCSK9 inhibitors in clinical practice: Novel directions and new experiences

BackgroundIn randomized clinical trials, proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) effectively reduce low-density lipoprotein-cholesterol (LDL-C) with a favorable tolerability and safety profile. Our purpose is to provide real-world data regarding the indications, efficacy and safety of PCSK9i.MethodsThe cohort comprised 141 patients who attended the lipid clinic of 3 hospitals in Greece and started using PCSK9i. Patients were requested to attend the lipid clinic at 3 months and at 1 year.ResultsNinety percent of patients had heterozygous familial hypercholesterolaemia (heFH) and 75% had cardiovascular disease (CVD). A PCSK9i [evolocumab 140 mg/2 weeks (n = 82), alirocumab 75 mg/2 weeks (n = 46) and alirocumab 150 mg/2 weeks (n = 13)] was prescribed due to failure to achieve LDL-C targets despite maximum lipid-lowering therapy (LLT) in 75% of patients, while in the remaining cases, the indication was statin intolerance. The mean reduction of LDL-C at 3 months was 56.2% and remained constant at 12 months (55.8% reduction from baseline). LDL-C target was achieved by 68.1% of patients at 3 months. “Totally” intolerant to statins patients (unable to tolerate any statin dose, n = 23) showed the lowest LDL-C reduction (47.7%). Side effects attributed to treatment were reported by 14 patients (10%). The total number of patients who stopped PCSK9i at 1 year was 14 (10%) but only 2 (1.4%) discontinued treatment because of side effects (myalgias).ConclusionsOur real-world results of PCSK9i showed comparable efficacy and tolerability to those reported in clinical trials and highlighted the value of treatment with PCSK9i heFH patients not achieving LDL-C targets despite maximum LLT and high or very high risk statin intolerant patients.     

Effect of a hydrophilic and a hydrophobic statin on cardiac salvage after ST-elevated acute myocardial infarction – A pilot study

Objective

Early statin therapy after acute coronary syndrome reduces atherothrombotic vascular events. This study aimed to compare the effects of hydrophilic and hydrophobic statins on myocardial salvage and left ventricular (LV) function in patients with ST-elevated myocardial infarction (STEMI).

Methods

Seventy-five STEMI patients who had received emergency reperfusion therapy were enrolled and randomized into the hydrophilic statin group (rosuvastatin; 5 mg/day, n = 38) and hydrophobic statin group (atorvastatin; 10 mg/day, n = 37) for 6 months. LV ejection fraction (LVEF), and B-type natriuretic peptide (BNP) and co-enzyme Q10 (CoQ10) levels were measured at baseline and the end of treatment. The myocardial salvage index was assessed by single photon emission computed tomography with ¹²³⁻I-β-methyl-iodophenylpentadecanoic acid (ischemic area-at-risk at onset of STEMI: AAR) and ²⁰¹⁻thallium scintigraphy (area-at-infarction at 6 months: AAI) [myocardial salvage index = (AAR−AAI) × 100/AAR (%)].

Results

Onset-to-balloon time and maximum creatine phosphokinase levels were comparable between the groups. After 6 months, rosuvastatin (−37.6% ± 17.2%) and atorvastatin (−32.4% ± 22.4%) equally reduced low-density lipoprotein-cholesterol (LDL-C) levels (p = 0.28). However, rosuvastatin (+3.1% ± 5.9%, p < 0.05), but not atorvastatin (+1.6% ± 5.7%, p = 0.15), improved LVEF. Rosuvastatin reduced BNP levels compared with atorvastatin (−53.3% ± 48.8% versus −13.8% ± 82.9%, p < 0.05). The myocardial salvage index was significantly higher in the rosuvastatin group than the atorvastatin group (78.6% ± 29.1% versus 52.5% ± 38.0%, p < 0.05). CoQ10/LDL-C levels at 6 months were increased in the rosuvastatin group (+23.5%, p < 0.01) and percent changes in CoQ10/LDL-C were correlated with the myocardial salvage index (r = 0.56, p < 0.01).

Conclusion

Rosuvastatin shows better beneficial effects on myocardial salvage than atorvastatin in STEMI patients, including long-term cardiac function, associated with increasing CoQ10/LDL-C.Clinical trial registration: URL http://www.umin.ac.jp/ctr/index.htm Unique Identifier: UMIN000003893.     

Continuation of statin therapy and a decreased risk of atrial fibrillation/flutter in patients with and without chronic kidney disease

Background

To contain cost, Taiwan's previous National Health Insurance Reimbursement Policy requested that physicians discontinue their patients' statin therapy once the serum cholesterol had reached appropriate levels. This allowed us to evaluate the association between statin continuation and the occurrence of atrial fibrillation/flutter and whether it was modified by chronic kidney disease (CKD) status.

Methods

Patients who initiated statin therapy between January 1, 2001 and December 31, 2009 were identified from a random sample of one million subjects in the Taiwan National Health Insurance Research Database. The outcome was atrial fibrillation/flutter. A proportional hazard regression model with time-varying statin use was applied to estimate the hazard ratios (HR) and 95% confidence intervals (CIs) for atrial fibrillation/flutter according to current statin use versus treatment discontinuation, adjusted for baseline disease risk scores and time-varying covariates.

Results

A total of 6767 CKD and 63,678 non-CKD patients initiating statin therapy were included and followed for an average of 4.0 years. A total of 1118 participants experienced new-onset atrial fibrillation/flutter. The incidence of atrial fibrillation/flutter was approximately 2 fold higher in the CKD patients. Continuation of statin therapy was associated with a 22% (adjusted hazard ratio 0.78; 95% CI: 0.65–0.93) and 57% (adjusted HR 0.43; 95% CI: 0.27–0.68) decrease in atrial fibrillation/flutter hazard as compared with discontinuation in non-CKD and CKD patients, respectively.

Conclusions

Continuation of statin therapy was associated with a decreased risk of atrial fibrillation/flutter among CKD and non-CKD patients. However, further randomized studies are still needed to assess the association.     

Differential Effects of DPP-4 Inhibitors,Anagliptin and Sitagliptin,on PCSK9 Levels in Patients with Type 2 Diabetes Mellitus who are Receiving Statin Therapy

Aim: Proprotein convertase subtilisin/kexin type 9 (PCSK9) degrades the low-density lipoprotein (LDL) receptor, leading to hypercholesterolemia and cardiovascular risk. Treatment with a statin leads to a compensatory increase in circulating PCSK9 level. Anagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, was shown to decrease LDL cholesterol (LDL-C) levels to a greater extent than that by sitagliptin, another DPP-4 inhibitor, in the Randomized Evaluation of Anagliptin versus Sitagliptin On low-density lipoproteiN cholesterol in diabetes (REASON) trial. We investigated PCSK9 concentration in type 2 diabetes mellitus (T2DM) and the impact of treatment with anagliptin or sitagliptin on PCSK9 level as a sub-analysis of the REASON trial. Methods: PCSK9 concentration was measured at baseline and after 52 weeks of treatment with anagliptin ( n =122) or sitagliptin ( n =128) in patients with T2DM who were receiving statin therapy. All of the included patients had been treated with a DPP-4 inhibitor prior to randomization. Results: Baseline PCSK9 level was positively, but not significantly, correlated with LDL-C and was independently associated with platelet count and level of triglycerides. Concomitant with reduction of LDL-C, but not hemoglobin A1c (HbA1c), by anagliptin, PCSK9 level was significantly increased by treatment with sitagliptin (218±98 vs. 242±115 ng/mL, P =0.01), but not anagliptin (233±97 vs. 250±106 ng/mL, P =0.07). Conclusions: PCSK9 level is independently associated with platelet count and level of triglycerides, but not LDL-C, in patients with T2DM. Anagliptin reduces LDL-C level independent of HbA1c control in patients with T2DM who are on statin therapy possibly by suppressing excess statin-mediated PCSK9 induction and subsequent degradation of the LDL receptor.     

A systematic review of the time course of atherosclerotic plaque regression

Objective

We sought to determine the time required for lipid treatment to produce regression of atherosclerotic plaques.

Background

The cholesterol content of atherosclerotic plaques contributes to their instability, and most acute cardiac events including myocardial infarction and sudden death are produced by coronary plaque disruption. We systematically reviewed the literature on atherosclerosis regression to identify the time required for cholesterol egress, plaque regression, and possible plaque stabilization. Such information may help decide when patients with statin side effects or other reasons for statin discontinuation could consider a reduction in the intensity of treatment.

Methods

We performed a PubMed search to identify English language articles reporting atherosclerotic regression. Articles pertinent to the topic were reviewed in detail.

Results

We identified 189 articles, 50 of which provided sufficient information to establish a rate of regression and 31 of which demonstrated plaque regression with statin therapy in the carotid (n = 11), coronary (n = 16), and aortic (n = 4) vascular beds. Plaque regression occurred after an average of 19.7 months of treatment.

Conclusion

Regression of atherosclerotic plaque using statin therapy in those studies documenting regression occurred after an average time of 19.7 months. This suggests that patients should undergo approximately two years of aggressive lipid reduction before considering a reduction of statin therapy.     

Roux-en-Y gastric bypass,but not sleeve gastrectomy,decreases plasma PCSK9 levels in morbidly obese patients

AimProprotein convertase subtilisin/kexin type 9 (PCSK9) is a master regulator of low-density lipoprotein cholesterol (LDL-C) metabolism, acting as an endogenous inhibitor of the LDL receptor. While it has been shown that bariatric surgery differentially affects plasma LDL-C levels, little is known of its effects on plasma PCSK9 concentrations. Therefore, the present study aimed to: (i) investigate the effect of sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB) on plasma PCSK9 concentrations; and (ii) correlate baseline or postoperative plasma PCSK9 concentration variations with anthropometric and metabolic parameters.MethodsFasting plasma PCSK9 levels were measured by ELISA in morbidly obese patients before and 6 months after bariatric surgery. Patients were recruited from three prospective cohorts (in Nantes and Colombes in France, and Antwerp in Belgium).ResultsA total of 156 patients (34 SG, 122 RYGB) were included. Plasma PCSK9, LDL-C and non-high-density lipoprotein cholesterol (non-HDL-C) levels were significantly reduced after RYGB (−19.6%, −16.6% and −19.5%, respectively; P < 0.0001), but not after SG. In all patients, postoperative PCSK9 change was positively correlated with fasting plasma glucose (FPG; r = 0.22, P = 0.007), HOMA-IR (r = 0.24, P = 0.005), total cholesterol (r = 0.17, P = 0.037) and non-HDL-C (r = 0.17, P = 0.038) variations, but not LDL-C. In contrast to what was observed for glucose parameters (FPG, HOMA-IR), correlation between PCSK9 and non-HDL-C changes after RYGB was independent of total weight loss.ConclusionRYGB, but not SG, promotes a significant reduction in plasma PCSK9 levels, and such changes in circulating PCSK9 levels after RYGB appear to be more associated with glucose improvement than with lipid homoeostasis parameters.     

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.     

PCSK9 levels do not predict severity and recurrence of cardiovascular events in patients with acute myocardial infarction

Background and aimsIt remains unclear whether serum PCSK9 levels can predict the severity of the disease and the risk of future events in patients with coronary artery disease (CAD). We aimed to evaluate the association between PCSK9 levels, metabolic parameters, severity of CAD on coronary angiography (SYNTAX score), and the risk of in-hospital events and at one-year follow-up.Methods and resultsFrom September 2015 to December 2016, serum PCSK9 levels were measured on admission in patients not previously receiving statin therapy, and admitted for an acute myocardial infarction (MI), in an intensive care unit from a university hospital. In a total of 648 patients (mean age: 66 years, 67% male), median PCSK9 was 263 ng/ml, higher for females compared with males (270 vs 256 ng/ml, p = 0.009). Serum PCSK9 was associated with LDL cholesterol (r = 0.083, p = 0.036), total cholesterol (r = 0.136, p = 0.001) and triglycerides (r = 0.137, p = 0.001). A positive association was also observed in the subgroup of patients with CRP >10 mg/L (p < 0.001), but not with NT-proBNP, troponin and creatine kinase. PCSK9 levels were similar whatever the SYNTAX score or the number of significant coronary lesions. PCSK9 levels were not associated with in-hospital events (death, recurrent MI and stroke) and events (cardiovascular death, cardiovascular events, recurrent MI) at one-year follow-up.ConclusionsIn this large cohort of patients hospitalized for acute MI and not previously receiving statin therapy, PCSK9 levels was not associated with the severity or the recurrence of cardiovascular events. The clinical utility of measuring PCSK9 levels for this category of patients therefore appears limited.     

Peripheral microvascular dysfunction predicts residual risk in coronary artery disease patients on statin therapy

Objective

Although lowering of low-density lipoprotein cholesterol (LDL-C) by statins is essential in treatment of coronary artery disease (CAD) patients, there is considerable residual risk of secondary coronary artery events (CAE). We examined whether microvascular dysfunction (MiD), measured by peripheral artery tonometry (PAT), can predict prognosis of CAD patients previously treated with statins.

Methods

We measured log-transformed reactive hyperemia index (L_RHI) in 213 CAD patients who had already achieved LDL-C <100 by statin therapy. Patients were followed-up for secondary CAE for a median of 2.7 years. Patients were divided into two groups: L_RHI ≥ 0.54 (n = 99) and L_RHI < 0.54 (n = 114).

Results

During follow-up, CAE occurred in 4 (4.0%) patients in the L_RHI ≥ 0.54 group and 18 (15.8%) patients in the L_RHI < 0.54 group (P = 0.006). Cox regression analysis indicated that L_RHI was an independent predictor for CAE even after adjustment by Framingham traditional risk factors (FRF; age, T-C/HDL-C ratio, systolic blood pressure, diabetes, current smoker, and gender) and estimated glomerular filtration rate (eGFR) for secondary CAE (HR 0.79, 95% CI: 0.66–0.95). ROC analysis for CAE prediction showed that the AUC for models including FRF only, FRF + eGFR, and FRF + eGFR + L_RHI were 0.60, 0.71, and 0.77, respectively. Moreover, adding eGFR to FRF only (0.63, P = 0.003) and adding L_RHI to the FRF + eGFR model were associated with significant improvement of net reclassification improvement (0.79, P = 0.007).

Conclusion

MiD measured by non-invasive PAT adds incremental predictive ability to traditional risk factors for prognosis of CAD patients successfully treated with statins.     

Nonpharmacological Lipoprotein Apheresis Reduces Arterial Inflammation in Familial Hypercholesterolemia

Background

Patients with familial hypercholesterolemia (FH) are characterized by elevated atherogenic lipoprotein particles, predominantly low-density lipoprotein cholesterol (LDL-C), which is associated with accelerated atherogenesis and increased cardiovascular risk.

Objectives

This study used ¹⁸F-fluorodeoxyglucose positron emission tomography (¹⁸FDG-PET) to investigate whether arterial inflammation is higher in patients with FH and, moreover, whether lipoprotein apheresis attenuates arterial wall inflammation in FH patients.

Methods

In total, 38 subjects were recruited: 24 FH patients and 14 normolipidemic controls. All subjects underwent FDG-PET imaging at baseline. Twelve FH patients who met the criteria for lipoprotein apheresis underwent apheresis procedures followed by a second FDG-PET imaging 3 days (range 1 to 4 days) after apheresis. Subsequently, the target-to-background ratio (TBR) of FDG uptake within the arterial wall was assessed.

Results

In FH patients, the mean arterial TBR was higher compared with healthy controls (2.12 ± 0.27 vs. 1.92 ± 0.19; p = 0.03). A significant correlation was observed between baseline arterial TBR and LDL-C (R = 0.37; p = 0.03) that remained significant after adjusting for statin use (β = 0.001; p = 0.02) and atherosclerosis risk factors (β = 0.001; p = 0.03). LDL-C levels were significantly reduced after lipoprotein apheresis (284 ± 118 mg/dl vs. 127 ± 50 mg/dl; p < 0.001). There was a significant reduction of arterial inflammation after lipoprotein apheresis (TBR: 2.05 ± 0.31 vs. 1.91 ± 0.33; p < 0.02).

Conclusions

The arterial wall of FH patients is characterized by increased inflammation, which is markedly reduced after lipoprotein apheresis. This lends support to a causal role of apoprotein B–containing lipoproteins in arterial wall inflammation and supports the concept that lipoprotein-lowering therapies may impart anti-inflammatory effects by reducing atherogenic lipoproteins.     

Bergamot polyphenolic fraction enhances rosuvastatin-induced effect on LDL-cholesterol,LOX-1 expression and protein kinase B phosphorylation in patients with hyperlipidemia

Background

Statins are the most commonly prescribed drugs to reduce cardiometabolic risk. Besides the well-known efficacy of such compounds in both preventing and treating cardiometabolic disorders, some patients experience statin-induced side effects. We hypothesize that the use of natural bergamot-derived polyphenols may allow patients undergoing statin treatment to reduce effective doses while achieving target lipid values. The aim of the present study is to investigate the occurrence of an enhanced effect of bergamot-derived polyphenolic fraction (BPF) on rosuvastatin-induced hypolipidemic and vasoprotective response in patients with mixed hyperlipidemia.

Methods

A prospective, open-label, parallel group, placebo-controlled study on 77 patients with elevated serum LDL-C and triglycerides was designed. Patients were randomly assigned to a control group receiving placebo (n = 15), two groups receiving orally administered rosuvastatin (10 and 20 mg/daily for 30 days; n = 16 for each group), a group receiving BPF alone orally (1000 mg/daily for 30 days; n = 15) and a group receiving BPF (1000 mg/daily given orally) plus rosuvastatin (10 mg/daily for 30 days; n = 15).

Results

Both doses of rosuvastatin and BPF reduced total cholesterol, LDL-C, the LDL-C/HDL-C ratio and urinary mevalonate in hyperlipidemic patients, compared to control group. The cholesterol lowering effect was accompanied by reductions of malondialdehyde, oxyLDL receptor LOX-1 and phosphoPKB, which are all biomarkers of oxidative vascular damage, in peripheral polymorphonuclear cells.

Conclusions

Addition of BPF to rosuvastatin significantly enhanced rosuvastatin-induced effect on serum lipemic profile compared to rosuvastatin alone. This lipid-lowering effect was associated with significant reductions of biomarkers used for detecting oxidative vascular damage, suggesting a multi-action enhanced potential for BPF in patients on statin therapy.     

Safety and effectiveness of the association ezetimibe-statin (E-S) versus high dose rosuvastatin after acute coronary syndrome: The SAFE-ES study

Background

Statin therapy is a cornerstone therapy for secondary prevention after acute coronary syndrome (ACS). However, the use of these drugs can be limited by side effects, mainly muscular pain. Ezetimibe is a newer lipid-lowering agent, with fewer side effects.

Aims

The present study was designed to compare a commercially available association of ezetimibe and simvastatin (E-S) to high dose Rosuvastatin on cholesterol and muscular enzyme levels and occurrence of muscular pain.

Methods

All consecutive ACS statin-naïve patients with LDL cholesterol (LDL-C) > 100 mg/dL randomly received either high dose statin (Rosuvastatin 20 mg) or E-S 10/40-mg. All patients had one-month follow-up with biological testing and clinical examination. We compared the two groups on the biological efficiency and incidence of muscular pain.

Results

One hundred and twenty-eight patients were randomized; 64 received E-S and 64 Rosuvastatin. In the two groups, the lowering of LDL-C level (Δ = 51%) at one month was significant (P < 0.01) without any difference in the rate of lowering on LDL-C or HDL-C suggesting that E-S is as effective as high dose Rosuvastatin (P = 0.77 and P = 0.99). The rate of patients reaching the objective of LDL-C < 100 mg/dL (45%) and LDL-C < 70 mg/dL (51%) was not different in the two clusters (P = 0.65). Incidence of muscular pain was 15% higher in patients treated with Rosuvastatin (P = 0.01) without any difference on CPK level (P = 0.6).

Conclusion

Using an association of E-S in an effective alternative strategy to high dose Rosuvastatin with a lower incidence of muscular pain, which might impact adherence to medication after ACS.     

Statins and Their Effect on PCSK9—Impact and Clinical Relevance

Purpose of Review

To review the interactions between statins and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition.

Recent Findings

Statins are highly effective for reducing low-density lipoprotein cholesterol (LDL-C) and cardiovascular disease (CVD). However, statins also raise levels of PCSK9, a protein that increases circulating LDL-C levels by increasing LDL-C receptor degradation. Increases in PCSK9 levels also reduce the LDL-C response to statin therapy.

Summary

The interactions between statins, PCSK9, LDL-C, and cardiovascular risk are multifaceted and are influenced by genetic, lifestyle, and environmental factors as well as lipid-lowering therapies.