2019 ESC/EAS guidelines for the management of dyslipidaemias: Lipid modification to reduce cardiovascular risk

In the paper

“Ultimately, more women die from CVD than men.”

In the paper

“the multiplier is higher in women and lower in older people.”

In the paper

“In general, people who stop smoking halve their cumulative risk over a relatively short period of time.”

In the paper

“Risk estimates are lower in women than in men.”

In the paper

“The SCORE data indicate that the total CVD event risk is about three times higher than the risk of fatal CVD for men, so a SCORE risk of 5% translates into a CVD risk of ∼15% of total (fatal + non-fatal) CVD endpoints”

In the paper

“Overall, the available evidence on functional foods so far identified in this field is incomplete; the major gap is an absence of diet-based intervention trials of enough duration to be relevant for the natural history of dyslipidaemia and CVD.”

In the paper

“In addition, studies of the clinical safety of these very low achieved LDL-C values have proved reassuring, albeit monitoring for longer periods is required.”

In the paper

“Furthermore, these clinical trials have clearly indicated that the lower the achieved LDL-C values, the lower the risk of future cardiovascular (CV) events, with no lower limit for LDL-C values, or 'J'-curve effect.”

In the paper

“Several recent placebo-controlled clinical studies have shown that the addition of either ezetimibe or antiproprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies (mAbs) to statin therapy provides a further reduction in atherosclerotic cardiovascular disease (ASCVD) risk, which is directly and positively correlated with the incrementally achieved absolute LDL-C reduction.”

In the paper

“The previous ESC/EAS lipid Guidelines were published in August 2016 [1].”

What the sources say

• Not checked yetcites [1] source

In the paper

“While no threshold is universally applicable, the intensity of advice should increase with increasing risk.”

In the paper

“Other risk estimation systems-using both fatal and non-fatal events-can also be recalibrated, but the process is easier and scientifically more robust for mortality than for total events.”

In the paper

“Persons with documented ASCVD, type 1 or type 2 DM (T1DM and T2DM, respectively), very high levels of individual risk factors, or chronic kidney disease (CKD) are generally at very-high or high total CV risk. No risk estimation models are needed for such persons; they all need active management of all risk factors.”

In the paper

“Non-invasive imaging techniques can detect the presence, estimate the extent, and evaluate the clinical consequences of atherosclerotic vascular damage.”

In the paper

“Social deprivation: the origin of many of the causes of CVD. Obesity and central obesity as measured by the body mass index and waist circumference, respectively. Physical inactivity. Psychosocial stress including vital exhaustion.”

In the paper

“All risk estimation systems are relatively crude and require attention to qualifying statements.”

In the paper

“The Guidelines were developed after careful consideration of the scientific and medical knowledge and the evidence available at the time of their dating.”

In the paper

“The longer the treatment and the more effective it is, the greater the reduction in risk, but in general it will not be more than about one-third of the baseline risk.”

In the paper

“in these Guidelines, the cut-off point for calling a country 'low CVD risk' is based on WHO data derived from the Global Burden of Disease Study.”

What the sources say

• Not checked yetcites WHO
• Not checked yetcites Global Burden of Disease Study

In the paper

“age has been extended from age 65 to 70; (ii) the interaction between age and each of the other risk factors has been incorporated, thus reducing the overestimation of risk in older persons in the original Systematic Coronary Risk Estimation charts; and (iii) the cholesterol band of 8 mmoL/L has been removed”

In the paper

“To convert the risk of fatal cardiovascular disease to risk of total (fatal + non-fatal) cardiovascular disease, multiply by 3 in men and by 4 in women, and slightly less in older people.”

In the paper

“Social deprivation and psychosocial stress set the scene for increased risk [13].”

What the sources say

• Not checked yetcites [13] source

In the paper

“A critical evaluation of diagnostic and therapeutic procedures was performed, including assessment of the risk-benefit ratio.”

In the paper

“After appropriate revisions the Guidelines are approved by all the experts involved in the Task Force.”

In the paper

“Relative risks may be unexpectedly high in young persons, even if absolute risk levels are low.”

In the paper

“Detection of coronary artery calcification with noncontrast computed tomography (CT) gives a good estimate of the atherosclerotic burden and is strongly associated with CV events [18].”

What the sources say

• Not checked yetcites [18] source

In the paper

“Additional factors affecting risk can be accommodated in electronic risk estimation systems such as HeartScore (www.heartscore.org).”

In the paper

“The Task Force received its entire financial support from the ESC and EAS without any involvement from the healthcare industry.”

In the paper

“In apparently healthy persons, CVD risk is most frequently the result of multiple, interacting risk factors.”

In the paper

“Some factors such as a high HDL-C up to 2.3 mmoL/L (90mg/dL) [17] or a family history of longevity can also be associated with lower risk.”

What the sources say

• Not checked yetcites [17] source

In the paper

“Risk age has been shown to be independent of the CV endpoint used [6,8], can be used in any population regardless of baseline risk or secular changes in mortality, and therefore avoids the need for recalibration.”

What the sources say

• Not checked yetcites [6] source
• Not checked yetcites [8] source

In the paper

“Use of the low- or the high-risk SCORE charts will depend on the CVD mortality experience in each country.”

In the paper

“A particular problem relates to young people with high levels of risk factors; a low absolute risk may conceal a very high relative risk requiring at least intensive lifestyle advice.”

In the paper

“Selected experts in the field from both societies undertook a comprehensive review of the published evidence for management of a given condition according to ESC Committee for Practice Guidelines (CPG) policy.”

In the paper

“The Members of this Task Force were selected by the ESC and EAS, including representation from relevant ESC sub-specialty groups, in order to represent professionals involved with the medical care of patients with this pathology.”

In the paper

“However, risk is only deferred in women; the risk of a 60-year-old woman is similar to that of a 50-year-old man.”

In the paper

“Calibrated country-specific versions are available for many European countries and can be found at http:// www.heartscore.org.”

In the paper

“the Systematic Coronary Risk Estimation chart is for use in people without overt cardiovascular disease, diabetes (type 1 and 2), chronic kidney disease, familial hypercholesterolaemia, or very high levels of individual risk factors”

In the paper

“The ESC Guidelines undergo extensive review by the CPG and external experts.”

In the paper

“The ESC CPG supervises and coordinates the preparation of new Guidelines. The Committee is also responsible for the endorsement process of these Guidelines.”

In the paper

“Risk will be overestimated in countries with decreasing CVD mortality, and underestimated in countries in which mortality is increasing. This is dealt with by recalibration”

In the paper

“The European Guidelines on CVD prevention in clinical practice (both the 2012 [9] and 2016 [10] versions) recommend the use of the SCORE system because it is based on large, representative European cohort data sets and because it is relatively straightforward to recalibrate for individual countries.”

What the sources say

• Not checked yetcites [9] source
• Not checked yetcites [10] source

In the paper

“The greater the burden of risk factors, the higher the lifetime risk.”

In the paper

“The level of evidence and the strength of the recommendation of particular management options were weighed and graded according to predefined ESC scales, as outlined in the tables below.”

In the paper

“For other, apparently healthy people, the use of a risk estimation system such as SCORE, which estimates the 10 year cumulative risk of a first fatal atherosclerotic event, is recommended to estimate total CV risk, since many people have several risk factors that, in combination, may result in high levels of total CV risk.”

In the paper

“A risk estimation system such as SCORE can assist in making logical management decisions, and may help to avoid both under- and overtreatment.”

In the paper

“While older people benefit from smoking cessation, and control of hypertension and hyperlipidaemia (see section 9.3)”

What the sources say

• Not checked yetcites section 9.3

In the paper

“A recent meta-analysis from the US Preventive Services Task Force summarized the available evidence on the value of non-traditional risk factors for risk prediction, and found that, although there are no randomized trials showing that the use of CAC reduces health outcomes, nevertheless it improves both discrimination and reclassification [19].”

What the sources say

• Not checked yetcites [19] source

In the paper

“The cut-off points that are used to define high-risk are, in part, both arbitrary and based on the risk levels at which benefit is evident in clinical trials.”

In the paper

“The total risk approach allows flexibility; if optimal control cannot be achieved with one risk factor, trying harder with the other factors can still reduce risk.”

In the paper

“The experts of the writing and reviewing panels provided declaration of interest forms for all relationships that might be perceived as real or potential sources of conflicts of interest.”

In the paper

“Risk estimates have been produced as charts for high- and low-risk regions in Europe (Fig. 1 and 2) [11].”

What the sources say

• Not checked yetcites [11] source

In the paper

“The reasons for retaining a system that estimates fatal as opposed to total fatal + non-fatal events are that nonfatal events are dependent on definition, developments in diagnostic tests, and methods of ascertainment, all of which can vary, resulting in very variable multipliers to convert fatal to total events.”

In the paper

“Assessment of carotid or femoral plaque burden with ultrasound has also been demonstrated to be predictive of CV events, comparable to CAC [20-23]”

What the sources say

• Not checked yetcites [20] source
• Not checked yetcites [21] source
• Not checked yetcites [22] source
• Not checked yetcites [23] source

In the paper

“the use of a risk estimation system such as SCORE, which estimates the 10 year cumulative risk of a first fatal atherosclerotic event, is recommended to estimate total CV risk”

In the paper

“Therefore, the clinical benefit of therapies that lower LDL-C by reducing LDL particle mass will be proportional to the absolute reduction in LDLC, because-on average-the reduction in LDL-C and LDL particles will be concordant [34,50,54,55].”

What the sources say

• Not checked yetcites [34] source
• Not checked yetcites [50] source
• Not checked yetcites [54] source
• Not checked yetcites [55] source

In the paper

“However, this evidence must be interpreted with caution because most genetic variants associated with HDL-C are also associated with directionally opposite changes in TGs, LDL-C, or both, thus making estimates of the effect of HDL-C on the risk of ASCVD very difficult using the Mendelian randomization study design.”

In the paper

“These data are consistent in showing that, since the relative risk reduction is proportional to the absolute reduction in LDL-C and the absolute reduction in LDL-C resulting from a particular drug regimen depends only on baseline LDL-C, at any given level of baseline risk the higher the initial LDL-C level the greater the absolute reduction in risk.”

In the paper

“Similarly, lowering TG with fibrates reduces the risk of CV events by the same amount as LDL-C-lowering therapies when measured per unit change of non-HDL-C [50], suggesting that the effect of plasma TGs on ASCVD is mediated by changes in the concentration of TG-rich lipoproteins as estimated by non-HDL-C.”

What the sources say

• Not checked yetcites [50] source

In the paper

“Eventually, the increase of the atherosclerotic plaque burden along with changes in the composition of the plaque reaches a critical point at which disruption of a plaque can result, with the formation of an overlying thrombus that acutely obstructs blood flow resulting in unstable angina, myocardial infarction (MI), or death.”

In the paper

“A recent Mendelian randomization study demonstrated that TG-lowering lipoprotein lipase (LPL) variants and LDL-C-lowering LDL receptor variants had the same effect on the risk of ASCVD per unit change of ApoB, suggesting that all ApoB-containing lipoproteins have the same effect on the risk of CHD [53].”

What the sources say

• Not checked yetcites [53] source

In the paper

“Mendelian randomization studies also suggest that the association between plasma TGs and the risk of CHD may be causal; however, this evidence must be interpreted with caution because nearly all variants associated with TGs are also associated with HDL-C, LDL-C, or Lp(a) [56-59].”

What the sources say

• Not checked yetcites [56] source
• Not checked yetcites [57] source
• Not checked yetcites [58] source
• Not checked yetcites [59] source

In the paper

“These data provide strong support for the concept that LDL particles have both a causal and cumulative effect on the risk of ASCVD.”

In the paper

“Data from the Multi-Ethnic Study of Atherosclerosis (MESA) showed that 41-57% of individuals who would be eligible for statin therapy had a CAC score of zero and the rate of atherosclerotic CVD events in the 10 year follow-up period was low (1.5-4.9%) [26].”

What the sources say

• Not checked yetcites [26] source

In the paper

“Continued exposure to ApoB-containing lipoproteins leads to additional particles being retained over time in the artery wall, and to the growth and progression of atherosclerotic plaques.”

In the paper

“While randomized trials evaluating therapies that lower Lp(a) by 20-30% (including niacin and CETP inhibitors) have not provided evidence that lowering Lp(a) reduces the risk of ASCVD beyond that which would be expected from the observed reduction in ApoB-containing lipoproteins, recent data with PCSK9 inhibitors have suggested a possible role for Lp(a) lowering in reducing CV risk [76].”

What the sources say

• Not checked yetcites [76] source

In the paper

“Furthermore, the concentration of Lp(a) is reported as either a molar concentration (nmol/L) or as a mass (mg/dL) by the various assays, and conversion between molar and mass concentrations has been found to be both size- and concentration-dependent [91-93].”

What the sources say

• Not checked yetcites [91] source
• Not checked yetcites [92] source
• Not checked yetcites [93] source

In the paper

“Furthermore, several randomized trials have shown that directly infused HDL mimetics increase plasma HDL-C concentrations, but do not reduce the progression of atherosclerosis as measured by intravascular ultrasound [68,69].”

What the sources say

• Not checked yetcites [68] source
• Not checked yetcites [69] source

In the paper

“Pro-atherogenic effects of Lp(a) have also been attributed to pro-coagulant effects as Lp(a) has a similar structure to plasminogen, and it has pro-inflammatory effects most likely related to the oxidized phospholipid load carried by Lp(a) [71].”

What the sources say

• Not checked yetcites [71] source

In the paper

“Measurement of plasma TC is needed to calculate risk using SCORE, while the inclusion of plasma HDL-C level can improve risk estimation using the online SCORE calculator.”

In the paper

“Because about 90% of a person's Lp(a) level is inherited, extremely elevated Lp(a) may represent a new inherited lipid disorder that is associated with extremely high lifetime risk of ASCVD and is two-fold more prevalent than HeFH [77].”

What the sources say

• Not checked yetcites [77] source

In the paper

“Higher plasma Lp(a) concentrations are associated with an increased risk of ASCVD, but it appears to be a much weaker risk factor for most people than LDL-C [72,73].”

What the sources say

• Not checked yetcites [72] source
• Not checked yetcites [73] source

In the paper

“Similarly, in the Assessment of Clinical Effects of Cholesteryl Ester Transfer Protein Inhibition with Evacetrapib in Patients at a High-Risk for Vascular Outcomes (ACCELERATE) and Randomized Evaluation of the Effects of Anacetrapib Through Lipid Modification (REVEAL) trials, treatment with CETP inhibitors more than doubled HDL-C levels, but did not appear to reduce the risk of ASCVD events beyond”

What the sources say

• Not checked yetcites [2] source
• Not checked yetcites [63] source
• Not checked yetcites [64] source

In the paper

“In the Effects of Dalcetrapib in Patients with a Recent Acute Coronary Syndrome (dal-OUTCOMES) trial, treatment with the cholesteryl ester transfer protein (CETP) inhibitor dalcetrapib increased HDL-C without any effect on LDL-C or ApoB, but did not reduce the risk of major CV events [65].”

What the sources say

• Not checked yetcites [65] source

In the paper

“low intakes of fats and oils increase the risk of inadequate intakes of vitamin E and of essential fatty acids, and may contribute to a reduction of HDL-C [164].”

What the sources say

• Not checked yetcites [164] source

In the paper

“The trans fatty acids produced in the partial hydrogenation of vegetable oils account for 80% of total intake.”

In the paper

“the intake of trans fatty acids has decreased substantially over the past 10-15 years.”

In the paper

“this approach also leads to the greatest improvement in physical performance and quality of life, and mitigates reductions in muscle and bone mass, particularly in older people [176].”

What the sources say

• Not checked yetcites [176] source

In the paper

“The lack of concordance between studies is due both to methodological problems (particularly inadequate sample sizes or short study durations) and the difficulties of evaluating the impact of a single dietary factor independently of any other changes in the diet [130].”

What the sources say

• Not checked yetcites [130] source

In the paper

“Weight reduction increases HDL-C levels; a 0.01 mmoL/L (0.4 mg/ dL) increase is observed for every kilogram decrease in body weight when weight reduction has stabilized.”

In the paper

“Dietary carbohydrate has a 'neutral' effect on LDL-C, although excessive consumption is represented by untoward effects on plasma TGs and HDL-C levels [164].”

What the sources say

• Not checked yetcites [164] source

In the paper

“These effects are dose-dependent; with a habitual fructose consumption between 15 and 20% of total energy intake, plasma TG increases by as much as 30-40%.”

What the sources say

• Not checked yetcites [159] source
• Not checked yetcites [173] source
• Not checked yetcites [174] source

In the paper

“Dietary fibre (particularly of the soluble type)-which is present in legumes, fruits, vegetables, and wholegrain cereals (e.g. oats and barley)-has a hypocholesterolaemic effect and represents a good dietary substitute for saturated fat to maximize the effects of the diet on LDL-C levels, and to minimize the untoward effects of a high-carbohydrate diet on other lipoproteins [140,179].”

What the sources say

• Not checked yetcites [140] source
• Not checked yetcites [179] source

In the paper

“Weight reduction improves insulin sensitivity and decreases TG levels.”

In the paper

“The detrimental effects of a high-carbohydrate diet on TGs occur mainly when refined carbohydrate-rich foods are consumed, while they are much less prominent if the diet is based largely on fibrerich, low-glycaemic index foods. This applies particularly to people with DM or MetS [171,172].”

What the sources say

• Not checked yetcites [171] source
• Not checked yetcites [172] source

In the paper

“In a meta-analysis [201], elevations in HDL-C levels varied with dose among the respective statins; such elevations ranged from 1 to 10%.”

What the sources say

• Not checked yetcites [201] source

In the paper

“More potent statins (atorvastatin, rosuvastatin, and pitavastatin) demonstrate robust lowering of TG levels, especially at high doses and in patients with elevated TGs (HTG), in whom the absolute risk, and therefore the absolute risk reduction, is larger.”

What the sources say

• Not checked yetcites [199] source

In the paper

“Statins only marginally affect Lp(a) plasma levels. Previous studies have reported either no effect on or an increase of Lp(a) levels after statin treatment [202,203].”

What the sources say

• Not checked yetcites [202] source
• Not checked yetcites [203] source

In the paper

“Moreover, the long-term safety of the regular consumption of these products has not been fully documented and safety issues due to the possible presence of contaminants in some preparations have been raised.”

What the sources say

• Not checked yetcites [144]
• Not checked yetcites [185] source

In the paper

“The cholesterol-lowering effect of soy is generally attributed to its isoflavone and phytoestrogen content, which decreases progressively with the increasing degree of soybean processing.”

What the sources say

• Not checked yetcites [187] source
• Not checked yetcites [188] source

In the paper

“Total fat and types of fat were not associated with CVD, MI, or CVD mortality, whereas saturated fat had an inverse association with stroke [181].”

What the sources say

• Not checked yetcites [181] source

In the paper

“Soy protein has also been indicated as being able to induce a modest LDL-C-lowering effect when replacing animal protein foods. However, this was not confirmed when changes in other dietary components were taken into account [187,188].”

What the sources say

• Not checked yetcites [187] source
• Not checked yetcites [188] source

In the paper

“Observational evidence indicates that consumption of fish (at least twice a week) and vegetable foods rich in n-3 fatty acids (α-linoleic acid is present in walnuts, some vegetables, and some seed oils) is associated with lower risk of CV death and stroke, but has no major effects on plasma lipoprotein metabolism [178,192].”

What the sources say

• Not checked yetcites [178] source
• Not checked yetcites [192] source

In the paper

“Different commercial preparations of RYR have different concentrations of monacolins, and lower TC and LDL-C levels to variable extents, but the consumer is not able to make that distinction [144,185].”

What the sources say

• Not checked yetcites [144]
• Not checked yetcites [185] source

In the paper

“The degree of LDL-C reduction is dose-dependent and varies between the different statins.”

What the sources say

• Not checked yetcites [31] source

In the paper

“Daily consumption of 2 g of phytosterols can effectively lower TC and LDL-C levels by 7-10% in humans (with a certain degree of heterogeneity among individuals), while it has little or no effect on HDL-C and TG levels [143].”

What the sources say

• Not checked yetcites [143] source

In the paper

“However, due to the lack of highquality randomized clinical trials, the efficacy of berberine for treating dyslipidaemia needs to be further validated.”

What the sources say

• Not checked yetcites [187] source

In the paper

“The mechanism of the TG-lowering effect has not been fully elucidated, but it seems to be partly independent of the LDLR pathway. It may involve the upregulation of VLDL uptake by hepatocytes, as well as a reduction of the production rate of VLDLs; these effects seem to be dependent on pre-treatment VLDL concentrations [200].”

What the sources say

• Not checked yetcites [200] source

In the paper

“A fat-modified diet that provides 25-40 g per day of total dietary fibre, including ≥7-13 g of soluble fibre, is well tolerated, effective, and recommended for plasma lipid control”

What the sources say

• Not checked yetcites [182] source

In the paper

“Foods enriched with these fibres or supplements are well tolerated, effective, and recommended for LDL-C lowering [186].”

What the sources say

• Not checked yetcites [186] source

In the paper

“The proportional effects (per mmol/L reduction in LDL-C) on major vascular events were similar in all subgroups examined, so the absolute risk reduction was proportional to the absolute baseline risk.”

What the sources say

• Not checked yetcites [34] source

In the paper

“Smoking cessation has clear benefits regarding overall CV risk, and specifically on HDL-C levels [163].”

What the sources say

• Not checked yetcites [163] source

In the paper

“These effects have been shown in vitro and in experimental systems, but their clinical relevance remains unproven [18,206].”

What the sources say

• Not checked yetcites [18] source
• Not checked yetcites [206] source

In the paper

“Pharmacological doses of long-chain n-3 fatty acids (2-3 g/day) reduce TG levels by about 30% and also reduce the post-prandial lipaemic response, but a higher dosage may increase LDL-C levels.”

What the sources say

• Not checked yetcites [156] source
• Not checked yetcites [193] source

In the paper

“for each 1 mmoL/L reduction in LDL-C, statin/more statin reduced major vascular events (MI, CAD death, or any stroke or coronary revascularization) by ∼22%, major coronary events by 23%, CAD death by 20%, total stroke by 17%, and total mortality by 10% over 5 years.”

What the sources say

• Not checked yetcites [34] source

In the paper

“Poor responses to statin treatment in clinical studies are to some extent caused by poor compliance, but may also be explained by genetic backgrounds [195,196].”

What the sources say

• Not checked yetcites [195] source
• Not checked yetcites [196] source

In the paper

“Mild elevation of ALT has not been shown to be associated with true hepatotoxicity or changes in liver function.”

What the sources say

• Not checked yetcites [243] source

In the paper

“Mild elevation of ALT occurs in 0.5-2.0% of patients on statin treatment, more commonly with potent statins or high doses.”

What the sources say

• Not checked yetcites [243] source

In the paper

“Other conditions, such as dementia [224], hepatic steatosis [225], venous thromboembolism [226], atrial fibrillation [227,228], and polycystic ovary syndrome [229] have also been studied, and no effect of statins on these conditions has been reliably demonstrated.”

What the sources say

• Not checked yetcites [224] source
• Not checked yetcites [225] source
• Not checked yetcites [226] source
• Not checked yetcites [227] source
• Not checked yetcites [228] source
• Not checked yetcites [229] source

In the paper

“They concluded that a nocebo effect (i.e. one caused by negative expectations) may partly explain the higher frequency of SAMS in observational studies compared with in trials.”

What the sources say

• Not checked yetcites [238] source

In the paper

“Current available evidence from meta-analyses suggests that the clinical benefit of statin treatment is largely a class effect, driven by the absolute LDL-C reduction; therefore, the type of statin used should reflect the treatment goals for a given patient.”

In the paper

“Patients on statin treatment have been shown to exhibit an increased risk of dysglycaemia and development of type 2 diabetes mellitus (T2DM). Several studies have shown that this is a consistent, dose-related effect [232].”

What the sources say

• Not checked yetcites [232] source

In the paper

“Although statins are generally very well tolerated, they do have some specific adverse effects on muscle, glucose haemostasis, and haemorrhagic stroke. However, there is also widespread misinformation about potential adverse effects, as reviewed recently [232,233].”

What the sources say

• Not checked yetcites [232] source
• Not checked yetcites [233] source

In the paper

“The suggested effect on Alzheimer's disease was recently reviewed in a Cochrane analysis reporting no conclusive effect from statins [230].”

What the sources say

• Not checked yetcites [230] source

In the paper

“In rhabdomyolysis, creatine kinase (CK) levels are elevated by ≥ 10 times, and often ≥40 times, the upper limit of normal (ULN) [234].”

What the sources say

• Not checked yetcites [234] source

In the paper

“The proteinuria induced by statins is of tubular origin, usually transitory, and is believed to be due to reduced tubular reabsorption and not to glomerular dysfunction [254,255].”

What the sources say

• Not checked yetcites [254] source
• Not checked yetcites [255] source

In the paper

“This effect is probably related to the mechanism of action of statins, as Mendelian randomization studies have confirmed the increased risk of DM in individuals with HMG-CoA reductase polymorphisms that reduce cholesterol synthesis [250].”

What the sources say

• Not checked yetcites [250] source

In the paper

“The frequency of rhabdomyolysis has been estimated to represent 1-3 cases/100 000 patient-years [235].”

What the sources say

• Not checked yetcites [235] source

In the paper

“However, the risk is higher with the more potent statins at high doses [248], and is also higher in the elderly, and in the presence of other risk factors for diabetes such as overweight or insulin resistance [249].”

What the sources say

• Not checked yetcites [248] source
• Not checked yetcites [249] source

In the paper

“Myopathy is the most clinically relevant adverse effect of statins. Among the risk factors for myopathy, it is particularly important that interaction with concomitant drug therapy is considered (see below).”

What the sources say

• Not checked yetcites [234] source

In the paper

“Statin treatment increases circulating PCSK9 serum levels [282], and thus the best effect of these mAbs has been demonstrated in combination with statins.”

What the sources say

• Not checked yetcites [282] source

In the paper

“Given the mechanism of action, these drugs are effective at reducing LDL-C in all patients capable of expressing LDLR in the liver. Therefore, this pharmacological approach is effective in the vast majority of patients, including those with HeFH and, albeit to a lower level, those with HoFH with residual LDLR expression. Receptor-deficient HoFH responds poorly to the therapy [285].”

What the sources say

• Not checked yetcites [285] source

In the paper

“There was no evidence of harm caused by ezetimibe or the further LDL-C reduction.”

What the sources say

• Not checked yetcites [33] source

In the paper

“Colesevelam is better tolerated and has fewer interactions with other drugs, and can be taken together with statins and several other drugs [279].”

What the sources say

• Not checked yetcites [279] source

In the paper

“A meta-analysis of RCTs that included over 2700 people showed an 18.5% reduction in LDL-C as compared with placebo [262]. In addition, there was a significant 3% increase in HDL-C, a significant 8% reduction in TGs, and a 13% reduction in TC with ezetimibe as compared with placebo.”

What the sources say

• Not checked yetcites [262] source

In the paper

“Bile acid sequestrants have major drug interactions with several commonly prescribed drugs, and must therefore be administered either 4 h before or 1 h after other drugs.”

What the sources say

• Not checked yetcites [279] source

In the paper

“There are no clinically significant effects of age, sex, or race on ezetimibe pharmacokinetics, and no dosage adjustment is necessary in patients with mild hepatic impairment or mild-to-severe renal insufficiency.”

What the sources say

• Not checked yetcites [261] source

In the paper

“Both alirocumab and evolocumab have also been shown to effectively lower LDL-C levels in patients who are at high CV risk, including those with DM [284].”

What the sources say

• Not checked yetcites [284] source

In the paper

“In clinical trials, the frequency of proteinuria is generally low and, in most cases, is not higher than for placebo [256].”

What the sources say

• Not checked yetcites [256] source

In the paper

“Therefore, the study supports the proposition that LDL-C lowering by means other than statins is beneficial and safe.”

In the paper

“A total of 18 144 patients were randomized to statin or statin plus ezetimibe, and 5314 patients over 7 years experienced a CV event; 170 fewer events (32.7 vs. 34.7%) were recorded in the group taking simvastatin plus ezetimibe ( P =0.016).”

What the sources say

• Not checked yetcites [33] source

In the paper

“Combination of statins with gemfibrozil enhances the risk of myopathy, and its association with statins must be avoided.”

What the sources say

• Not checked yetcites [259] source
• Not checked yetcites [260] source

In the paper

“Reduced absorption of fat-soluble vitamins has been reported. Furthermore, these drugs may increase circulating TG levels in certain patients.”

What the sources say

• Not checked yetcites [279] source

In the paper

“In combination with high-intensity or maximally tolerated statins, alirocumab and evolocumab reduced LDL-C by 46-73% more than placebo, and by 30% more than ezetimibe.”

What the sources say

• Not checked yetcites [283] source

In the paper

“Elevated concentration or function of this protein in plasma reduces LDLR expression by promoting, upon binding, LDLR lysosomal catabolism and a subsequent increase in plasma LDL concentrations, while lower concentration or function of PCSK9 is related to lower plasma LDL-C levels [281].”

What the sources say

• Not checked yetcites [281] source

In the paper

“No major effect on HDL-C has been reported, while TGs may increase in some predisposed patients [274].”

What the sources say

• Not checked yetcites [274] source

In the paper

“Since this interaction triggers the intracellular degradation of the LDLR, lower levels of circulating PCSK9 will result in increased expression of LDLRs at the cell surface and therefore in a reduction of circulating LDL-C levels [281].”

What the sources say

• Not checked yetcites [281] source

In the paper

“In other studies, this combination has also significantly improved reductions in LDL-C levels when compared with doubling of the statin dose (13-20%), and after switching from statin monotherapy to ezetimibe and statin combination therapy (11-15%) [263].”

What the sources say

• Not checked yetcites [263] source

In the paper

“Ezetimibe is rapidly absorbed and extensively metabolized to pharmacologically active ezetimibe glucuronide.”

What the sources say

• Not checked yetcites [261] source

In the paper

“In clinical studies, ezetimibe in monotherapy at 10 mg/day reduces LDL-C in hypercholesterolaemic patients by 15-22% with relatively high interindividual variation [261].”

What the sources say

• Not checked yetcites [261] source

In the paper

“Fibrates are agonists of peroxisome proliferator-activated receptorα (PPAR-α), acting via transcription factors regulating, among other things, various steps in lipid and lipoprotein metabolism.”

In the paper

“Indeed, the development programme for a third PCSK9 inhibitor, bococizumab, a humanized antibody, was discontinued because of an increase of neutralizing antibodies, which resulted in the attenuation of the LDL-C-lowering effect over time, as well as a higher rate of injection site reactions [300].”

What the sources say

• Not checked yetcites [300] source

In the paper

“In the FOURIER trial, allocation to evolocumab did not reduce the risk of CV mortality (HR 1.05, 95% CI 0.88-1.25) or allcause mortality.”

What the sources say

• Not checked yetcites [119] source

In the paper

“In contrast to statins, inhibiting PCSK9 with mAbs also reduces Lp(a) plasma levels. Pooled results of phase II trials have shown that treatment leads to an Lp(a) reduction of about 30-40% [288,289].”

What the sources say

• Not checked yetcites [288] source
• Not checked yetcites [289] source

In the paper

“As a consequence of its mechanism of action, lomitapide has been shown to be associated with increased aminotransferase levels, which most likely reflects the increased fat in the liver, as well as poor GI tolerability [301,302].”

What the sources say

• Not checked yetcites [301] source
• Not checked yetcites [302] source

In the paper

“As a consequence, fibrates have good efficacy in lowering fasting TG levels, as well as post-prandial TGs and TG-rich lipoprotein (TRL) remnant particles.”

In the paper

“After subcutaneous injection, the oligonucleotide is preferentially transported to the liver, where it binds to a specific mRNA preventing the translation of ApoB protein and, consequently, reducing the production of atherogenic lipids and lipoproteins, including LDL and Lp(a) [303].”

What the sources say

• Not checked yetcites [303] source

In the paper

“While recent investigations have attempted to unravel the mechanism, it remains unclear. However, it appears to be distinct from that of statins, which also enhance LDLR function but do not lower circulating Lp(a) levels in humans.”

What the sources say

• Not checked yetcites [288] source
• Not checked yetcites [289] source

In the paper

“An analysis of the time to benefit also showed that there was a lower benefit in the first year than in subsequent years, consistent with the effects of statins observed within the CTT metaanalysis [268].”

What the sources say

• Not checked yetcites [268]

In the paper

“Both studies had relatively short follow-up periods and the evidence from statin trials indicates that the clinical benefits of LDL-lowering may only emerge after about 1 year [51], so these trials may have underestimated the potential impact of longer-term treatment [120,290].”

What the sources say

• Not checked yetcites [51] source
• Not checked yetcites [120] source
• Not checked yetcites [290] source

In the paper

“However, the EBBINGHAUS trial [231], which was specifically designed to detect neurocognitive function changes, was reassuring, as were the safety reports in both the FOURIER and ODYSSEY trials.”

What the sources say

• Not checked yetcites [231] source

In the paper

“Although the HHS reported a significant reduction in CVD outcomes with gemfibrozil, neither the FIELD nor the ACCORD studies involving fenofibrate showed a reduction in total CVD outcomes.”

What the sources say

• Not checked yetcites [306] source
• Not checked yetcites [307] source
• Not checked yetcites [308] source
• Not checked yetcites [309] source
• Not checked yetcites [310] source
• Not checked yetcites [311] source

In the paper

“In phase II trials, evolocumab lowered TG levels by 26%, and raised HDL-C and ApoA-I by 9 and 4%, respectively; similar findings have been reported for alirocumab [286,287].”

What the sources say

• Not checked yetcites [286] source
• Not checked yetcites [287] source

In the paper

“The designs of the trials were similar with regard to the settings of secondary prevention and background therapy; however, the populations enrolled had either stable CHD, peripheral arterial disease (PAD), or stroke; or a recent (median 2.6 months) ACS, respectively.”

What the sources say

• Not checked yetcites [119] source
• Not checked yetcites [120] source

In the paper

“Results from other meta-analyses suggest reduced major CVD events in patients with high TGs and low HDL-C in fibrate-treated patients, but no decrease in CVD or total mortality [314-316].”

What the sources say

• Not checked yetcites [314] source
• Not checked yetcites [315] source
• Not checked yetcites [316] source

In the paper

“However, a fibrate-induced increase in homocysteine may blunt elevation of both HDL-C and ApoA1 levels, and this effect may contribute to the smaller than estimated benefits of fenofibrate in CV outcome parameters [322].”

What the sources say

• Not checked yetcites [322] source

In the paper

“The risk of myopathy has been reported to be 5.5-fold greater with fibrate monotherapy (mainly with gemfibrozil) compared with a statin, and it varies with different fibrates and statins used in combination.”

What the sources say

• Not checked yetcites [319] source

In the paper

“The data remain inconclusive and the clinical efficacy of omega-3 fatty acids appears to be related to non-lipid effects [330,331].”

What the sources say

• Not checked yetcites [330] source
• Not checked yetcites [331] source

In the paper

“A Cochrane meta-analysis, including 112 059 people from 79 trials, reported no overall effect of omega-3 PUFAs on total mortality (relative risk 0.98, 95% CI 0.90-1.03) or CV events (relative risk 0.99, 95% Cl 0.94-1.04), with only a suggestion that omega-3 fatty acids reduced CHD events (relative risk 0.93, 95% Cl 0.88-0.97) [328].”

What the sources say

• Not checked yetcites [328] source

In the paper

“In general, myopathy, liver enzyme elevations, and cholelithiasis represent the most well-known adverse effects associated with fibrate therapy [319].”

What the sources say

• Not checked yetcites [319] source