Diagnosis, Treatment and Long-Term Management of Vitamin B12 Deficiency in Adults: A Delphi Expert Consensus.

Background/Objectives: Vitamin B12 deficiency can cause variable symptoms, which may be irreversible if not diagnosed and treated in a timely manner. We aimed to develop a widely accepted expert consensus to guide the practice of diagnosing and treating B12 deficiency. Methods: We conducted a scoping review of the literature published in PubMed since January 2003. Data were used to design a two-round Delphi survey to study the level of consensus among 42 experts. Results: The panelists agreed on the need for educational and organizational changes in the current medical practices for diagnosing and treating B12 deficiency. Recognition of clinical symptoms should receive the highest priority in establishing the diagnosis. There is agreement that the serum B12 concentration is useful as a screening marker and methylmalonic acid or homocysteine can support the diagnosis. Patient lifestyle, disease history, and medications can provide clues to the cause of B12 deficiency. Regardless of the cause of the deficiency, initial treatment with parenteral B12 was regarded as the first choice for patients with acute and severe manifestations of B12 deficiency. The use of high-dose oral B12 at different frequencies may be considered for long-term treatment. Prophylactic B12 supplementation should be considered for specific high-risk groups. Conclusions: There is a consensus that clinical symptoms need to receive more attention in establishing the diagnosis of B12 deficiency. B12 laboratory markers can support the diagnosis. The severity of clinical symptoms, the causes of B12 deficiency, and the treatment goals govern decisions regarding the route and dose of B12 therapy.

Regional differences in physicians' behavior and factors influencing the intensity of PCSK9 inhibitor therapy with alirocumab: a subanalysis of the ODYSSEY APPRISE study.

Background: Despite better accessibility of the effective lipid-lowering therapies, only about 20% of patients at very high cardiovascular risk achieve the low-density lipoprotein cholesterol (LDL-C) goals. There is a large disparity between European countries with worse results observed for the Central and Eastern Europe (CEE) patients. One of the main reasons for this ineffectiveness is therapeutic inertia related to the limited access to appropriate therapy and suitable dosage intensity. Thus, we aimed to compare the differences in physicians' therapeutic decisions on alirocumab dose selection, and factors affecting these in CEE countries vs. other countries included in the ODYSSEY APPRISE study. Methods: ODYSSEY APPRISE was a prospective, single-arm, phase 3b open-label (≥12 weeks to ≤30 months) study with alirocumab. Patients received 75 or 150 mg of alirocumab every 2 weeks, with dose adjustment during the study based on physician's judgment. The CEE group in the study included Czechia, Greece, Hungary, Poland, Romania, Slovakia, and Slovenia, which we compared with the other nine European countries (Austria, Belgium, Denmark, Finland, France, Germany, Italy, Spain, and Switzerland) plus Canada. Results: A total of 921 patients on alirocumab were involved [modified intention-to-treat (mITT) analysis], including 114 (12.4%) subjects from CEE countries. Therapy in CEE vs. other countries was numerically more frequently started with lower alirocumab dose (75 mg) at the first visit (74.6 vs. 68%, p = 0.16). Since week 36, the higher dose was predominantly used in CEE patients (150 mg dose in 51.6% patients), which was maintained by the end of the study. Altogether, alirocumab dose was significantly more often increased by CEE physicians (54.1 vs. 39.9%, p = 0.013). Therefore, more patients achieved LDL-C goal at the end of the study (<55 mg/dl/1.4 mmol/L and 50% reduction of LDL-C: 32.5% vs. 28.8%). The only factor significantly influencing the decision on dose of alirocumab was LDL-C level for both countries' groups (CEE: 199.2 vs. 175.3 mg/dl; p = 0.019; other: 205.9 vs. 171.6 mg/dl; p < 0.001, for 150 and 75 mg of alirocumab, respectively) which was also confirmed in multivariable analysis (OR = 1.10; 95% CI: 1.07-1.13). Conclusions: Despite larger unmet needs and regional disparities in LDL-C targets achievement in CEE countries, more physicians in this region tend to use the higher dose of alirocumab, they are more prone to increase the dose, which is associated with a higher proportion of patients reaching LDL-C goals. The only factor that significantly influences decision whether to increase or decrease the dose of alirocumab is LDL-C level.

Expert opinion on the cooperation of diabetologists and internists with nephrologists in the care of patients with chronic kidney diseases.

Chronic kidney disease (CKD) affects 10% of the population of developed countries and significantly affects the population health. In addition to the well-known renoprotection tools slowing down the progression of CKD, SGLT2 inhibitors have been newly introduced into clinical practice based on the results of extensive studies, both in diabetics and non-diabetics. This expert opinion discusses the classification of CKD, current renoprotection options, and the recent role of SGLT2 inhibitors in the care of patients with CKD.

The time is now: Achieving FH paediatric screening across Europe - The Prague Declaration.

Familial hypercholesterolaemia (FH) is the most common inherited metabolic disorder characterized by high cholesterol and if left untreated leads to premature cardiovascular disease, such as heart attacks. Treatment that begins early in life, particularly in childhood, is highly efficacious in preventing cardiovascular disease and cost-effective, thus early detection of FH is crucial. However, in Europe, less than 10% of people living with FH are diagnosed and even less receive life-saving treatment. The Prague Declaration is a call to action for national and European Union policymakers and decision-makers and a result of the Czech EU Presidency meeting on FH Paediatric Screening (early detection of inherited high cholesterol) at the Czech Senate in Prague on 6th September 2022. It builds on a considerable body of evidence which was discussed at the Technical Meeting under the auspices of the Slovenian EU Presidency in October 2021. The Prague meeting addressed the outstanding barriers to the systematic implementation of FH paediatric screening across Europe. In this article, we present the key points from the Prague meeting and concrete actions needed to move forward.

Familial Hypercholesterolemia: Real-World Data of 1236 Patients Attending a Czech Lipid Clinic. A Retrospective Analysis of Experience in More than 50 years. Part II. Clinical Characteristics.

Introduction: Patients with familial hypercholesterolemia (FH) are at increased risk of premature atherosclerotic cardiovascular disease (ASCVD). Aim of study: To perform a retrospective analysis of data to assess the effects of individual lipoproteins and other risk factors (RFs) on the development of ASCVD and to compare these parameters in individuals with versus without ASCVD. Patients and methods: Our study group included a total of 1,236 patients with FH (395 men and 841 women with a mean age of 44.8 ± 16.7 years) attending a single lipid clinic. The diagnosis of FH was established using the Dutch Lipid Clinic Network score (DLCN). Among the 1236 FH patients, 1,008 of them [854 suspected with LDL receptor-mediated FH and 154 with familial defective apolipoprotein B-100 (FDB)] were genetically analysed. Their RFs were assessed based on the patients' clinical characteristics. Results: While patients with ASCVD had higher baseline LDL-C, TC, TG and Lp(a) compared with patients without this diagnosis, this ratio was just the opposite by the follow-up. The highest statistically significant differences were seen in the baseline levels of Lp(a) and, quite surprisingly, TG. Except for Lp(a), the levels of all lipid parameters declined significantly over time. While the incidence of diabetes and arterial hypertension was not higher in our group compared with the general population, these patients were at a more significant risk of ASCVD. Conclusion: Familial hypercholesterolemia is a major RF for the development of ASCVD. While our analysis confirmed the important role of LDL-C, it also corroborated a strong correlation between ASCVD and other lipid parameters, and Lp(a) and TG in particular. Familial hypercholesterolemia is not the only RF and, to reduce cardiovascular risk of their patients, physicians have to search for other potential RFs. Patients diagnosed to have FH benefit from attending a specialized lipid clinic perse.

PCSK9 Inhibitors in Real-world Practice: Analysis of Data from 314 Patients and 2 Years of Experience in a Center of Preventive Cardiology.

PURPOSE OF REVIEW: PCSK9 inhibitors have been shown to be the most effective class of drugs modifying the levels of LDL-cholesterol as the main risk factor for atherosclerotic cardiovascular disease. The aim of this paper is to assess the effect of monoclonal antibodies on lipid and lipoprotein metabolism in real-world practice. RECENT FINDINGS: The outcome trials showed effective reduction of LDL-C by 56-62%. Landmark studies enrolling over a total of 46,000 patients with CHD in their medical history demonstrated the beneficial effect of both agents on cardiovascular morbidity and mortality. The data from real everyday clinical practice are very limited or missing. Even in real-world practice, PCSK9 inhibitors have been shown to be an effective, safe, and well-tolerated class of drugs with effects comparable with those reported from large randomized controlled trials.

Familial Hypercholesterolemia: Real-World Data of 1236 Patients Attending a Czech Lipid Clinic. A Retrospective Analysis of Experience in More than 50 years. Part I: Genetics and Biochemical Parameters.

Introduction: The cause of familial hypercholesterolemia (FH) is defect in LDL receptor or familial defect of apolipoprotein B-100 (FDB) or, rarely, defect in proprotein convertase subtilisin/kexin type 9. Identification and treatment of patients with FH improves their prognosis. Our data represent retrospective analysis of 50 years of specialised care in our center. Patients and Methods: A group of 1236 FH patients (841 women, 395 men; 993 study subjects and 243 relatives; mean age 44.8 ± 16.7 years) included 154 FDB patients followed at the Lipid Clinic of the General University Hospital in Prague since the mid-1960s to the present. Clinical diagnosis was based on the Dutch Lipid Clinic Network Criteria. Genetic analysis was performed using PCR-RFLP to detect FDB and apolipoprotein E (APOE) polymorphism. Biochemical data were collected and statistically analysed. Results: At baseline, mean LDL-C and total cholesterol (TC) levels of all FH patients combined were 6.49 ± 1.92 mmol/L and 8.95 ± 1.95 mmol/L, respectively. Their LDL-C levels decreased to 3.26 ± 1.57 mmol/L and TC levels to 5.43 ± 1.69 mmol/L during follow-up. In the subgroup of LDL receptor-mediated FH (non-FDB) patients, baseline LDL-C and TC levels of 6.61 ± 1.95 mmol/L and 9.09 ± 1.97 mmol/L declined to 3.21 ± 1.60 mmol/L and 5.39 ± 1.72 mmol/L, respectively, during follow-up. In the FDB subgroup of patients, baseline levels of LDL-C and TC were 5.57 ± 1.46 mmol/L and 7.88 ± 1.58 mmol/L decreasing to 3.45 ± 0.24 mmol/L and 5.58 ± 1.37 mmol/L, respectively, during follow-up. Differences were also found in the effects of various APOE isoforms on lipid lowering. A significant decrease in lipid parameters was observed with the E2E2 isoform whereas a minimal decrease was seen with the E4E4 and E3E3 isoforms. Conclusion: Whereas, overall, non-FDB patients had higher baseline lipid levels, these levels declined more appreciably compared with FDB patients during follow-up. Our retrospective analysis also found different effects of APOE isoforms on the decrease in lipid levels.

Efficacy and Safety of K-877 (Pemafibrate), a Selective PPARα Modulator, in European Patients on Statin Therapy.

OBJECTIVE: High plasma triglyceride (TG) is an independent risk factor for cardiovascular disease. Fibrates lower TG levels through peroxisome proliferator-activated receptor α (PPARα) agonism. Currently available fibrates, however, have relatively low selectivity for PPARα. The aim of this trial was to assess the safety, tolerability, and efficacy of K-877 (pemafibrate), a selective PPARα modulator, in statin-treated European patients with hypertriglyceridemia. RESEARCH DESIGN AND METHODS: A total of 408 statin-treated adults were recruited from 68 European sites for this phase 2, randomized, double-blind, placebo-controlled trial. They had fasting TG between 175 and 500 mg/dL and HDL-cholesterol (HDL-C) ≤50 mg/dL for men and ≤55 mg/dL for women. Participants were randomly assigned to receive placebo or one of six pemafibrate regimens: 0.05 mg twice a day, 0.1 mg twice a day, 0.2 mg twice a day, 0.1 mg once daily, 0.2 mg once daily, or 0.4 mg once daily. The primary end points were TG and non-HDL-C level lowering at week 12. RESULTS: Pemafibrate reduced TG at all doses (adjusted P value <0.001), with the greatest placebo-corrected reduction from baseline to week 12 observed in the 0.2-mg twice a day treatment group (54.4%). Reductions in non-HDL-C did not reach statistical significance. Reductions in TG were associated with improvements in other markers for TG-rich lipoprotein metabolism, including reductions in apoB48, apoCIII, and remnant cholesterol and an increase in HDL-C levels. Pemafibrate increased LDL-cholesterol levels, whereas apoB100 was unchanged. Pemafibrate was safe and well-tolerated, with only minor increases in serum creatinine and homocysteine concentrations. CONCLUSIONS: Pemafibrate is effective, safe, and well-tolerated for the reduction of TG in European populations with hypertriglyceridemia despite statin treatment.

An Exploratory Analysis of Proprotein Convertase Subtilisin/Kexin Type 9 Inhibition and Aortic Stenosis in the FOURIER Trial.

Importance: Despite recent advances in treatment of severe aortic valve stenosis (AS), AS remains a life-threatening condition with no proven disease-modifying therapy. Low-density lipoprotein cholesterol (LDL-C) and lipoprotein(a) (Lp[a]) have been implicated in the pathobiology of AS. The proprotein convertase subtilisin/kexin type 9 inhibitor evolocumab reduces circulating LDL-C concentrations by 50% to 60% and Lp(a) by 20% to 30%. Objective: To determine whether evolocumab reduces the risk of AS events in patients with atherosclerotic cardiovascular disease. Interventions: Patients were randomized 1:1 to evolocumab or placebo. Design, Setting, and Participants: Exploratory analysis of the FOURIER trial, which enrolled 27 564 patients with stable atherosclerotic cardiovascular disease who were taking statin therapy at 1242 sites in 49 countries from February 2013 to November 2016. Patients were randomized to evolocumab or placebo and followed up for a median (interquartile range) of 2.2 (1.8-2.5) years. This post hoc analysis was performed from September 2019 to February 2020. Main Outcomes and Measures: Site-reported adverse events of new or worsening AS or aortic valve replacement (termed AS events). The adjusted risk of AS events was calculated with a multivariable model including concentrations of Lp(a) and LDL-C corrected for Lp(a) content, plus age, sex, diabetes, hypertension, current smoking, and estimated glomerular filtration rate. Evolocumab efficacy was tested using a Cox proportional hazards model. Results: Aortic stenosis events occurred in 63 patients (48 men [76%]; mean [SD] age, 69 [9] years) over a median of 2.2 years. Elevated Lp(a) concentration was associated with higher rates of AS events (adjusted hazard ratio [aHR], 1.55 [95% CI, 1.17-2.05] per SD; P = .002), including aortic valve replacement (aHR, 2.22 [95% CI, 1.38-3.58] per SD; P = .001), after multivariable adjustment. The corrected LDL-C concentration was not significantly associated with AS events (aHR, 1.23 [95% CI, 0.93-1.61] per SD; P = .14). The overall HR for AS events with evolocumab was 0.66 (95% CI, 0.40-1.09), with no apparent association in the first year (HR, 1.09 [95% CI, 0.48-2.47]) but an HR of 0.48 (95% CI, 0.25-0.93) after the first year of treatment. Conclusions and Relevance: In this exploratory analysis of the FOURIER trial, higher Lp(a) levels, but not Lp(a)-corrected LDL-C levels, were associated with a higher risk of subsequent AS events, including aortic valve replacement. Long-term therapy with evolocumab may reduce AS events, and this raises the possibility that specific pharmacologic lipid-lowering therapy could offer a means to prevent or slow the progression of AS. These exploratory findings merit further investigation with a dedicated randomized clinical trial. Trial Registration: ClinicalTrials.gov Identifier: NCT01764633.

Notes on the new “Recommendations for the treatment of dyslipidemia. Influencing of lipids to reduce cardiovascular risk”.

New guidelines on dyslipidemia (DLP) related problems appear earlier than planned. Primarily in view of the results of science and large clinical studies, but also with regard to the advent of biological therapy (PCSK9-i) in many Euro-pean countries. Also, the “conventional” hypolipidemic therapy is generified and therefore cheaper, more af-fordable. The recommendations are based, as the preceding ones, on the principle of estimating the overall cardiovascular risk. The innovated SCORE tables are used for this, but more emphasis is placed on non-invasive dia-gnostics using imaging methods, be it carotid ultrasound or, in particular, non-contrast CT coronarography. Perhaps the most significant outcome is the reduction of LDL-cholesterol (LDL-C) target values to 1.4 mmol/l and a 50% reduction of baseline LDL-C in patients belonging to the highest risk groups, and in secondary prevention. Moreover, in the case of “extreme” risk the goal is to reduce LDL-C below 1 mmol/l. Essential to DLP therapy is statin treatment. Especially in patients with acute coronary syndrome and those in the highest risk categories, the maximum tolerated doses of statin should be used, if necessary in combination with ezetimibe. Where this maximum “routine” treatment is insufficient to achieve the target values, PCSK9-i therapy is indicated. However the recommendations do not by any means omit non-pharmacological therapy, quite the opposite, it is always emphasized as the first step of DLP therapy. Worthy of notice is the introduction of the term “atherosclerotic cardiovascular disease” - ASCVD, which replaces the older and less accurate CVD.

Vascular age.

Age can be evaluated according to many criteria. Of course the objective measure is the calendar age which may differ from the biological age. The biological age more or less correlates with the vascular age. The concept of vascular age is based on the statement that “An individual is as old as his blood vessels”. The process of vascular aging already starts in childhood. Arterial aging may essentially be viewed from two standpoints. First, it involves stiffening of arteries and loss of their elasticity; second, degenerative changes and formation of atherosclerotic plaques occur, being the cause of ischemia, especially in case of the development of atherothrombosis. Both these processes can be monitored: The change of elasticity (arteriosclerosis) mainly by examination of pulse wave velocity (PWV), atherosclerosis then primarily with non-invasive methods, ultrasound or CT angiography examination. From the clinical point of view it is particularly important whether we can influence vascular age in some way. Evidence is available now that atherosclerosis can be affected by hypolipidemic treatment, arteriosclerosis then in particular by ACE inhibitors. The aforementioned possibility of influencing vascular age brings us to another problem, which is compliance of patients. With regard to that it is good that in a situation where we have two drugs affecting vascular age, we can use their fixed combination. It is available as a combination of atorvastatin and perindopril.

The Impact of the International Cooperation On Familial Hypercholesterolemia Screening and Treatment: Results from the ScreenPro FH Project.

PURPOSE OF REVIEW: Familial hypercholesterolemia (FH) is often perceived and described as underdiagnosed and undertreated, though effective treatment of FH is available. Owing to the mentioned facts, it is ever more imperative to screen and treat FH patients. Subsequent to the identification of patients, the project focuses on the improvement of their prognoses. The ScreenPro FH project was established as a functional international network for the diagnosis, screening, and treatment of FH. Individual countries were assigned goals, e.g., to define the actual situation and available treatment. With "central support," more centers and countries participated in the project. Subsequently, individual countries reported the results at the beginning and end of the project. Collected data were statistically evaluated. RECENT FINDINGS: The increasing number of patients in databases, from 7500 in 2014 to 25,347 in 2018, demonstrates the improvement in overall effectiveness, as well as an increase in the number of centers from 70 to 252. Before all, LDL-C decreased by 41.5% and total cholesterol by 32.3%. As data from all countries and patients were not available at the time of the analysis, only those results from 10 countries and 5585 patients at the beginning of the project and at the time of writing are included. Our data are quite positive. However, our results have only limited validity. Our patients are far from the target levels of LDL-C. The situation can be improved with the introduction of new therapy, PCSK9-i, evolocumab, and alirocumab. International cooperation improved the screening of FH and finally led to an improvement in cardiovascular risk.

The Gene Score for Predicting Hypertriglyceridemia: New Insights from a Czech Case-Control Study.

BACKGROUND: Plasma triglyceride (TG) values are significant predictors of cardiovascular and total mortality. The plasma levels of TGs have an important genetic background. We analyzed whether 32 single nucleotide polymorphisms (SNPs) identified in genome-wide association studies are discriminators of hypertriglyceridemia (HTG) in the Czech population. OBJECTIVES: The objective of this study was to replicate and test the original findings in an independent study and to re-analyze the gene score leading to HTG. METHODS: In total, we analyzed 32 SNPs in 209 patients with plasma TG levels over 10 mmol/L (HTG group) and compared them in a case-control design with 524 treatment-naïve controls (normotriglyceridemic [NTG] group) with plasma TG values below 1.8 mmol/L. RESULTS: Sixteen SNPs were significantly associated with an increased risk of HTG development, with odds ratios (ORs) (95% confidence interval [CI]) varying from 1.40 (1.01-1.95) to 4.69 (3.29-6.68) (rs964184 within the APOA5 gene). Both unweighted (sum of the risk alleles) and weighted gene scores (WGS) (log of the achieved ORs per individual genotype) were calculated, and both gene scores were significantly different between groups. The mean score of the risk alleles was significantly increased in the HTG group compared to the NTG group (18.5 ± 2.5 vs. 15.7 ± 2.3, respectively; P < 0.00001). Subjects with a WGS over 9 were significantly more common in the HTG group (44.5%) than in the NTG group, in which such a high score was observed in only 4.7% of subjects (OR 16.3, 95% CI 10.0-36.7; P < 0.0000001). CONCLUSIONS: An increased number of risk genetic variants, calculated both in a weighted or unweighted manner, significantly discriminates between the subjects with HTG and controls. Population-specific sets of SNPs included into the gene score seem to yield better discrimination power.

The selective peroxisome proliferator-activated receptor alpha modulator (SPPARMα) paradigm: conceptual framework and therapeutic potential : A consensus statement from the International Atherosclerosis Society (IAS) and the Residual Risk Reduction Initiative (R3i) Foundation.

In the era of precision medicine, treatments that target specific modifiable characteristics of high-risk patients have the potential to lower further the residual risk of atherosclerotic cardiovascular events. Correction of atherogenic dyslipidemia, however, remains a major unmet clinical need. Elevated plasma triglycerides, with or without low levels of high-density lipoprotein cholesterol (HDL-C), offer a key modifiable component of this common dyslipidemia, especially in insulin resistant conditions such as type 2 diabetes mellitus. The development of selective peroxisome proliferator-activated receptor alpha modulators (SPPARMα) offers an approach to address this treatment gap. This Joint Consensus Panel appraised evidence for the first SPPARMα agonist and concluded that this agent represents a novel therapeutic class, distinct from fibrates, based on pharmacological activity, and, importantly, a safe hepatic and renal profile. The ongoing PROMINENT cardiovascular outcomes trial is testing in 10,000 patients with type 2 diabetes mellitus, elevated triglycerides, and low levels of HDL-C whether treatment with this SPPARMα agonist safely reduces residual cardiovascular risk.

Effect of the PCSK9 Inhibitor Evolocumab on Total Cardiovascular Events in Patients With Cardiovascular Disease: A Prespecified Analysis From the FOURIER Trial.

Importance: The PCSK9 inhibitor evolocumab reduced low-density lipoprotein cholesterol and first cardiovascular events in the Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) trial, but patients remain at high risk of recurrent cardiovascular events. Objective: To evaluate the effect of evolocumab on total cardiovascular events, given the importance of total number of cardiovascular events to patients, clinicians, and health economists. Design, Setting, and Participants: Secondary analysis of a randomized, double-blind clinical trial. The FOURIER trial compared evolocumab or matching placebo and followed up patients for a median of 2.2 years. The study included 27 564 patients with stable atherosclerotic disease receiving statin therapy. Data were analyzed between May 2017 and February 2019. Main Outcomes and Measures: The primary end point (PEP) was time to first cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization; the key secondary end point was time to first cardiovascular death, myocardial infarction, or stroke. In a prespecified analysis, total cardiovascular events were evaluated between treatment arms. Results: The mean age of patients was 63 years, 69% of patients were taking high-intensity statin therapy, and the median LDL-C at baseline was 92 mg/dL (to convert to millimoles per liter, multiply by 0.0259). There were 2907 first PEP events and 4906 total PEP events during the trial. Evolocumab reduced total PEP events by 18% (incidence rate ratio [RR], 0.82; 95% CI, 0.75-0.90; P < .001) including both first events (hazard ratio, 0.85; 95% CI, 0.79-0.92; P < .001) and subsequent events (RR, 0.74; 95% CI, 0.65-0.85). There were 2192 total primary events in the evolocumab group and 2714 total events in the placebo group. For every 1000 patients treated for 3 years, evolocumab prevented 22 first PEP events and 52 total PEP events. Reductions in total events were driven by fewer total myocardial infarctions (RR, 0.74; 95% CI, 0.65-0.84; P < .001), strokes (RR, 0.77; 95% CI, 0.64-0.93; P = .007), and coronary revascularizations (RR, 0.78; 95% CI, 0.71-0.87; P < .001). Conclusions and Relevance: The addition of the PCSK9 inhibitor evolocumab to statin therapy improved clinical outcomes, with significant reductions in total PEP events, driven by decreases in myocardial infarction, stroke, and coronary revascularization. More than double the number of events were prevented with evolocumab vs placebo as compared with the analysis of only first events. These data provide further support for the benefit of continuing aggressive lipid-lowering therapy to prevent recurrent cardiovascular events. Trial Registration: ClinicalTrials.gov identifier: NCT01764633.

Consensus statement of professional associations on prescribing of PCSK9-inhibitors.

A new class of drugs known as PCSK9 inhibitors (PCSK9i) provide biological treatment for hypercholesterolemia. These drugs are administered using a subcutaneous injection once in two or four weeks. PCSK9i are not a replacement of the existing hypolipidemics, they just expand the therapeutic spectrum for the critically ill and those who cannot use the standard therapy and do not reach satisfactory target values. There are essentially two indications: (1) hypercholesterolemie and mixed dyslipidemia and (2) secondary prevention of cardiovascular diseases (CVD). Statin intolerance is not the only indication for treatment. However as its presence sometimes plays an essential role as to choosing the treatment, it will be also discussed in the paragraph on reimbursement conditions. Reimbursement conditions (very simplified): the treatment will be provided at selected centres. A list of the centres is included in an annexe to this article. You will find it also on www.interna-cz.eu, on www.kardio-cz.cz and www.athero.cz. The indicative concentration of LDL-cholesterol (LDL-C) from which on PCSK9i can be prescribed as covered from the public health insurance, is the following: (1) familial hypercholesterolemia 4.0 mmol/l, (2) for secondary prevention CVD 3.0 mmol/l - Please note: the presented LDL-C level is one reached under maximum (tolerated) high intensity hypo-lipidemic therapy. High intensity hypolipidemic therapy is defined as atorvastatin 40-80 mg or rosuvastatin 20-40 mg + ezetimibe. In the case of demonstrated intolerance of both the mentioned statins the patient has to be treated with a maximum tolerated dose of statins, in combination with another hypolipidemic drug (ezetimibe). Statin intolerance is defined as intolerance of at least two successive statins, which results in their discontinuation. Statin intolerance alone is not the indication for PCSK9i treatment! The payment criteria must always be complied with. A medical officer can of course be asked to approve such treatment in exceptional cases. Key words: alirocumab - PCSK9 inhibitors centers - center therapy - evolocumab - familial hypercholesterolemia - proprotein konvertase subtilisin kexin 9 inhibitors (PCSK9i) - secondary prevention - statins intolerance.

Comments on the most important and recent studies involving PCSK9i.

The paper provides a brief overview of the key studies focused on PCSK9 inhibitors. It mainly examines positive results of the FOURIER studies on evolocumab, the SPIRE study on boccocizumab and the ODYSSEY Outcomes study on alirocumab. All these studies have not only shown a significant decrease in LDL-cholesterol levels, but also the reduction of cardiovascular events just correlating with these levels. The treatment leading to a dramatic drop in LDL-cholesterol levels was safe and well tolerated by patients. All the studies provided with comments demonstrate a positive impact of biological treatment of hypercholesterolemia on cardiovascular disease and confirm validity of the hypothesis saying “the lower the better”, at least for LDL-cholesterol. In conclusion, Professor Braunwalds hypothesis is mentioned saying that this treatment might eventually lead to as much as eradication of atherothrombotic cardiovascular diseases. Key words: alirocumab - bococizumab - evolocumab - FOURIER - cardiovascular disease - LDL-cholesterol - ODYSSEY Outcomes - SPIRE.

Lipoprotein(a), PCSK9 Inhibition, and Cardiovascular Risk.

BACKGROUND: Lipoprotein(a) [Lp(a)] may play a causal role in atherosclerosis. PCSK9 (proprotein convertase subtilisin/kexin 9) inhibitors have been shown to significantly reduce plasma Lp(a) concentration. However, the relationship between Lp(a) levels, PCSK9 inhibition, and cardiovascular risk reduction remains undefined. METHODS: Lp(a) was measured in 25 096 patients in the FOURIER trial (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk), a randomized trial of evolocumab versus placebo in patients with established atherosclerotic cardiovascular disease (median follow-up, 2.2 years). Cox models were used to assess the independent prognostic value of Lp(a) and the efficacy of evolocumab for coronary risk reduction by baseline Lp(a) concentration. RESULTS: The median (interquartile range) baseline Lp(a) concentration was 37 (13-165) nmol/L. In the placebo arm, patients with baseline Lp(a) in the highest quartile had a higher risk of coronary heart disease death, myocardial infarction, or urgent revascularization (adjusted hazard ratio quartile 4: quartile 1, 1.22; 95% CI, 1.01-1.48) independent of low-density lipoprotein cholesterol. At 48 weeks, evolocumab significantly reduced Lp(a) by a median (interquartile range) of 26.9% (6.2%-46.7%). The percent change in Lp(a) and low-density lipoprotein cholesterol at 48 weeks in patients taking evolocumab was moderately positively correlated ( r=0.37; 95% CI, 0.36-0.39; P<0.001). Evolocumab reduced the risk of coronary heart disease death, myocardial infarction, or urgent revascularization by 23% (hazard ratio, 0.77; 95% CI, 0.67-0.88) in patients with a baseline Lp(a) >median, and by 7% (hazard ratio, 0.93; 95% CI, 0.80-1.08; P interaction=0.07) in those ≤median. Coupled with the higher baseline risk, the absolute risk reductions, and number needed to treat over 3 years were 2.49% and 40 versus 0.95% and 105, respectively. CONCLUSIONS: Higher levels of Lp(a) are associated with an increased risk of cardiovascular events in patients with established cardiovascular disease irrespective of low-density lipoprotein cholesterol. Evolocumab significantly reduced Lp(a) levels, and patients with higher baseline Lp(a) levels experienced greater absolute reductions in Lp(a) and tended to derive greater coronary benefit from PCSK9 inhibition. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01764633.

Body Adiposity Changes After Lifestyle Interventions in Children/Adolescents and the NYD-SP18 and TMEM18 Variants.

BACKGROUND This study was carried out to determine the relationship between the common TMEM-18 (rs4854344, G>T) and NYD-SP18 (rs6971091, G>A) gene variants and weight loss after lifestyle interventions (increased physical activity in conjunction with optimal dietary intake) in overweight/obese children/adolescents. MATERIAL AND METHODS We genotyped 684 unrelated, white, non-diabetic children (age 12.7±2.1 years, average BMI at baseline 30.66±4.80 kg/m²). Anthropometric and biochemical examinations were performed before and after 4 weeks of an intensive lifestyle intervention. RESULTS The mean weight loss achieved was 5.20±2.02 kg (P<0.001). NYDSP-18 AA homozygotes had significantly higher abdominal skinfold value before and after the intervention (both, P=0.001). No significant associations between BMI decrease and the NYD-SP18 and TMEM18 variants were found. Associations between all anthropometrical and biochemical changes and genes remained non-significant after data were adjusted for sex, age, and baseline values. CONCLUSIONS Decreased body weight in overweight/obese children is not significantly influenced by the NYD-SP18 rs6971091 or TMEM18 rs4854344 polymorphisms.

Comparison of Low-Density Lipoprotein Cholesterol Assessment by Martin/Hopkins Estimation, Friedewald Estimation, and Preparative Ultracentrifugation: Insights From the FOURIER Trial.

Importance: Recent studies have shown that Friedewald underestimates low-density lipoprotein cholesterol (LDL-C) at lower levels, which could result in undertreatment of high-risk patients. A novel method (Martin/Hopkins) using a patient-specific conversion factor provides more accurate LDL-C levels. However, this method has not been tested in proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor-treated patients. Objective: To investigate accuracy of 2 different methods for estimating LDL-C levels (Martin/Hopkins and Friedewald) compared with gold standard preparative ultracentrifugation (PUC) in patients with low LDL-C levels in the Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Patients With Elevated Risk (FOURIER) trial. Design, Setting, and Participants: The FOURIER trial was a randomized clinical trial of evolocumab vs placebo added to statin therapy in 27 564 patients with stable atherosclerotic cardiovascular disease. The patients' LDL-C levels were assessed at baseline, 4 weeks, 12 weeks, 24 weeks, and every 24 weeks thereafter, and measured directly by PUC when the level was less than 40 mg/dL per the Friedewald method (calculated as non-HDL-C level - triglycerides/5). In the Martin/Hopkins method, patient-specific ratios of triglycerides to very low-density lipoprotein cholesterol (VLDL-C) ratios were determined and used to estimate VLDL-C, which was subtracted from the non-HDL-C level to obtain the LDL-C level. Main Outcomes and Measures: Low-density lipoprotein cholesterol calculated by the Friedewald and Martin/Hopkins methods, with PUC as the reference method. Results: For this analysis, the mean (SD) age was 62.7 (9.0) years; 2885 of the 12 742 patients were women (22.6%). A total of 56 624 observations from 12 742 patients had Friedewald, Martin/Hopkins, and PUC LDL-C measurements. The median difference from PUC LDL-C levels for Martin/Hopkins LDL-C levels was -2 mg/dL (interquartile range [IQR], -4 to 1 mg/dL) and for Friedewald LDL-C levels was -4 mg/dL (IQR, -8 to -1 mg/dL; P < .001). Overall, 22.9% of Martin/Hopkins LDL-C values were more than 5 mg/dL different than PUC values, and 2.6% were more than 10 mg/dL different than PUC levels. These were significantly less than respective proportions with Friedewald estimation (40.1% and 13.3%; P < .001), mainly because of underestimation by the Friedewald method. The correlation with PUC LDL-C was significantly higher for Martin/Hopkins vs Friedewald (ρ, 0.918 [95% CI 0.916-0.919] vs ρ, 0.867 [0.865-0.869], P < .001). Conclusions and Relevance: In patients achieving low LDL-C with PCSK9 inhibition, the Martin/Hopkins method for LDL-C estimation more closely approximates gold standard PUC than Friedewald estimation does. The Martin/Hopkins method may prevent undertreatment because of LDL-C underestimation by the Friedewald method. Trial Registration: ClinicalTrials.gov Identifier: NCT01764633.