Cardiology Plus

: 2017  |  Volume : 2  |  Issue : 4  |  Page : 18--25

Treatment of Hyperlipidemia: Consensus and Controversies

Christoph H Saely1, Reinhard R Saely2, Heinz Drexel3,  
1 Department of Medicine I, Academic Teaching Hospital Feldkirch; Vorarlberg Institute for Vascular Investigation and Treatment, Feldkirch, Austria; Private University of the Principality of Liechtenstein, Triesen, Liechtenstein; Division of Angiology, Swiss Cardiovascular Center, University Hospital Berne, Berne, Switzerland
2 Private University of the Principality of , Triesen, Liechtenstein
3 Department of Medicine I, Academic Teaching Hospital Feldkirch; Vorarlberg Institute for Vascular Investigation and Treatment, Feldkirch, Austria; Private University of the Principality of Liechtenstein, Triesen, Liechtenstein; Division of Angiology, Swiss Cardiovascular Center, University Hospital Berne, Berne, Switzerland; Drexel University College of Medicine, Philadelphia, PA, USA

Correspondence Address:
Dr. Christoph H Saely
Vorarlberg Institute for Vascular Investigation and Treatment, Feldkirch


Based on epidemiological, genetic, and clinical trial data, there is a consensus now that low-density lipoproteins (LDL) cholesterol causes atherosclerosis and that lowering LDL cholesterol reduces the risk of atherosclerotic cardiovascular disease. Current guidelines on lipid management, therefore, focus on LDL cholesterol. The absolute benefit derived from lowering LDL cholesterol is greatest with the highest baseline risk; the most intensive treatment, therefore, is appropriate in the patients at the highest risk. Regarding the choice of drugs, statins are the basis of lipid management; if treatment goals are not met with statins alone, ezetimibe and proprotein convertase subtilisin/kexin type 9 inhibitors can be added to further reduce cardiovascular risk. Several questions remain open to debate. For example, the long-term net benefit of statin treatment in young patients with a low 10-year, but a high lifetime risk of cardiovascular events has not been demonstrated; in the absence of robust data, also lipid management in very old patients remains a question of clinical judgment. Further, given the evidence from clinical trials for further risk reduction with lowering LDL cholesterol below currently recommended targets, there is no universal consent on how low to go with LDL cholesterol. Also, with the availability of potent but expensive treatment options, the cost-effectiveness of lipid management remains a field of controversy. Finally, new lipid drugs are under development that yet has to prove their role in lipid management.

How to cite this article:
Saely CH, Saely RR, Drexel H. Treatment of Hyperlipidemia: Consensus and Controversies.Cardiol Plus 2017;2:18-25

How to cite this URL:
Saely CH, Saely RR, Drexel H. Treatment of Hyperlipidemia: Consensus and Controversies. Cardiol Plus [serial online] 2017 [cited 2021 Dec 9 ];2:18-25
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 A Brief History of Lipids and Atherosclerosis Research

In the 19th century, atherosclerosis was generally considered as a degenerative disease, as an eventually inevitable consequence of aging. However, already at the beginning of the 20th century, the Russian pathologist Anitschkow demonstrated an association between cholesterol and atherosclerosis.[1] Feeding rabbits with cholesterol led to the development of atherosclerosis in these animals. Given that being fed on cholesterol is not physiological for herbivore rabbits, many did not regard these findings relevant for human pathophysiology.

In the 1950s, John Gofman investigated how hydrophobic cholesterol is transported in blood; he found that the transport of cholesterol takes place in lipoproteins of varying composition and density, described low-density lipoproteins (LDL) and high-density lipoproteins (HDL) and found that atherosclerosis is associated with high LDL cholesterol and low HDL cholesterol.[2]

As the first prospective cohort study, the Framingham study in 1961 found an association between high blood cholesterol and a high risk of cardiovascular events.[3] Association, however, does not necessarily imply causality. An important criterion for the causality of a risk factor in the development of the disease is reversibility, i.e., the reduction of disease with a reduction of the risk factor.

Already in the early 1950s reduced blood cholesterol with a dietary exchange of saturated by unsaturated fatty acids was observed. Three controlled trials - the Oslo Heart Study,[4] the Veterans Administration Hospital Study[5] and the Finnish Mental Hospitals Study[6] subsequently reported a reduction of cardiovascular risk by cholesterol reducing dietary interventions. However, diets to efficiently reduce cholesterol are difficult to implement and even more difficult to maintain, and the pathophysiology of lipid metabolism was only vaguely understood in the mid-20th century. Lipid interventions, therefore, did not play a very important role in preventive medicine then.

Fredrickson based on the work of Gofman classified disorders of lipid metabolism descriptively and investigated the association between the patterns of dyslipidemia and atherosclerosis.[7] However, pathophysiological mechanisms and importantly, the genetic basis of lipid disorders remained unknown. The regulation of cholesterol metabolism was not elucidated until the work of Goldstein and Brown;[8] for their pioneering work, these scientists were awarded the Nobel prize for medicine and physiology in 1985. The seminal discovery of Golstein and Brown was that the number and function of LDL receptors on the cell membrane of hepatocytes is the major determinant for the blood cholesterol level. Plenty of functionally intact LDL receptors provide for rapid uptake of LDL particles into hepatocytes; LDL particles are thus removed from the blood, LDL cholesterol decreases.

A proof that pharmacological LDL cholesterol lowering lowers cardiovascular risk was lacking until in the early 1980s the Coronary Primary Prevention Trial reported that cholestyramine, which lowers blood cholesterol by inhibition of the resorption of cholesterol in the intestine significantly lowers cardiovascular events.[9] The cholesterol hypothesis by then had at least become extremely plausible. However, the cholesterol-lowering potency of cholestyramine is not very strong, and correspondingly, cardiovascular risk reduction in the Coronary Primary Prevention Trial although significant was not strong either.

LDL receptors are upregulated when intracellular cholesterol is low. Inhibiting intracellular cholesterol synthesis, therefore, leads to a reduction in LDL cholesterol. The rate-limiting step in cholesterol biosynthesis is catalyzed using the enzyme 3-hydroxy-3-methylglutaryl-coenzym-A - reductase (HMG-CoA-reductase). Akira Endo in 1975 discovered that this enzyme can be effectively inhibited by natural fungal compounds.[10] Starting from this observation, potent HMGCoA inhibitors were developed, the statins. In 1994, the Scandinavian Simvastatin Survival Study showed that simvastatin 40 mg/d significantly reduces LDL cholesterol by 35%, severe cardiovascular events by 34%, and even total mortality by 30% in hypercholesterolemic secondary prevention patients.[11] Statins became a cornerstone of cardiovascular prevention.

 Statins Lower Low-Density Lipoproteins Cholesterol and Reduce Cardiovascular Risk

Subsequently, cardiovascular event reductions were demonstrated with statin treatment in various patient populations in secondary as well as in primary prevention. The following important observations were made:

The more LDL cholesterol is reduced with statins, the more cardiovascular risk is reduced. Lowering LDL cholesterol by 1 mmol/L (i.e., about 40 mg/dl) reduces cardiovascular risk by about 20%.[12]Highly potent statins reduce cardiovascular risk stronger than moderately potent statins. Statins are referred to as highly potent when they on an average reduce LDL cholesterol by >50%; this is the case for atorvastatin 40 mg/day and 80 mg/day as well as for rosuvastatin 20 mg/day and 40 mg/day. More reduction of LDL cholesterol translates into more reduction of cardiovascular risk[13]The relative reduction of cardiovascular risk per absolute amount of LDL cholesterol lowering is independent from various patient characteristics, in particular from age, sex, the presence of established cardiovascular disease, or diabetes status[12],[13],[14]Statins, also highly potent statins are safe.[13] At least, the benefit of statin treatment outweighs potential adverse treatment effects in patients at high and generally also in those at moderate cardiovascular risk. An increased risk of incident diabetes with statin treatment has raised concern in the past several years. Whereas this effect is real, it should be seen in context: the absolute number of additional diabetes cases with statin treatment is much lower than the absolute number of cardiovascular events prevented by statins, and a cardiovascular event is much more severe than an increase in glucose that moves a patient from the category of prediabetes to that of diabetes[15]The absolute amount of cardiovascular risk reduction strongly depends on baseline risk. When baseline risk is high (e.g., in patients with established coronary artery disease), a 20% event reduction translates into a greater absolute benefit and leads to a lower number to treat than when baseline risk is low. High-risk patients, therefore, benefit more from the aggressive lowering of LDL cholesterol than lower risk patients.[12],[13],[14]

 Also Reduction of Low-Density Lipoproteins Cholesterol With Ezetimibe Reduces Cardiovascular Risk

As the above findings were derived from statin trials, it was hypothesized that not the reduction of cholesterol per se reduces cardiovascular risk but other, so-called pleiotropic effect of statins. However, in 2015, the IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT)[16] showed that also LDL cholesterol reduction with the cholesterol resorption inhibitor ezetimibe significantly reduces cardiovascular risk; indeed, it reduced cardiovascular risk to the same amount that is to be anticipated when the same amount of LDL cholesterol reduction would have been achieved by statin treatment. In brief, in IMPROVE-IT 18.144 acute coronary syndrome patients with low baseline LDL cholesterol on the basis of simvastatin 40–80 mg/day were randomized to receive ezetimibe 10 mg/day or placebo. On-treatment LDL cholesterol was 54 mg/dl in the ezetimibe arm and 70 mg/dl in the placebo arm. This 16 mg/dl difference in LDL cholesterol translated in a 6.4% reduction of major cardiovascular events over a median follow-up period of 6 years.

 Lowering Low-Density Lipoproteins Cholesterol With Proprotein Convertase Subtilisin/kexin Type 9 Inhibition Is Another Option to Reduce Cardiovascular Risk

Very potent lowering of LDL cholesterol is possible with the more recent drug class of proprotein convertase subtilisin/kexin type 9 (PCSK9)-inhibitors.[17] PCSK9 attaches to LDL receptors and prevents them from being recycled to the cell surface after having been internalized together with an LDL particle. Thus, PCSK9 reduces the number of available LDL receptors, fewer LDL particles are cleared from the circulation, and LDL cholesterol rises. The currently approved PCSK9 inhibitors alirocumab and evolocumab are monoclonal antibodies directed against PCSK9 and are subcutaneously injected every 2–4 weeks.

Reducing PCSK9 with these monoclonal antibodies reduces LDL cholesterol by more than 50% over and above what can be achieved with highly potent statins alone. The very large further cardiovascular outcomes research with PCSK9 inhibition in patients with elevated risk (FOURIER) trial[18] showed in over 27.000 statin-treated patients with established cardiovascular disease a significant reduction of cardiovascular risk with the PCSK9 inhibitor evolocumab. LDL cholesterol was reduced from 92 mg/dl in the placebo arm to 30 mg/dl in the evolocumab arm; the cardiovascular event risk over a trial duration of only about 2 years was significantly reduced by 15%. Like in the statin trials risk reduction increased with increasing treatment duration; the treatment effects within the first as well within the 2nd year of treatment with evolocumab were the same that could have been expected when the same amount of LDL cholesterol reduction would have been achieved by statin treatment.

In the FOURIER trial, 42% of the patients treated with evolocumab had an LDL cholesterol <25 mg/dl. A recent secondary analysis showed that cardiovascular risk decreased with decreasing LDL cholesterol down to lowest categories of LDL cholesterol.[19] Even with extremely low LDL cholesterol levels of 10 mg/dl the treatment was excellently tolerated. In particular, no unfavorable effect on cognition with aggressively lowering LDL cholesterol down to extremely low levels was observed in the EBBINGHAUS study that was imbedded in the FOURIER trial.[20] Separately published subgroup analysis demonstrated the efficacy of evolocumab to reduce cardiovascular events in particular for patients with diabetes.[21] The cardiovascular outcome trial for alirocumab, ODYSSEY OUTCOMES, is expected to report at the American College of Cardiology (ACC) conference in early 2018.

 Current Consensus: Low-Density Lipoproteins Cholesterol Causes Atherosclerosis and Lowering Low-Density Lipoproteins Cholesterol Reduces Cardiovascular Risk

The available evidence leaves hardly any room for doubt that LDL cholesterol causes atherosclerosis. Statins, ezetimibe, and PCSK9 inhibitors all lower LDL cholesterol and cardiovascular risk, epidemiological studies show clear associations between high LDL cholesterol and increased cardiovascular risk, and genetic polymorphisms predisposing to high LDL cholesterol are strongly associated with increased cardiovascular risk; mendelian randomization studies clearly imply a causal impact of LDL cholesterol on the development of atherosclerotic cardiovascular disease.[22]

Therefore, and because pharmacologic interventions to reduce LDL cholesterol have been proven to be excellently safe, lowering LDL cholesterol is the mainstay in the current lipid management. Given that individuals at the highest risk derive the greatest absolute benefit from statin treatment, the intensity of LDL cholesterol lowering is tailored to the level of risk.

Current European Society of Cardiology (ESC) guidelines define four categories of risk: very high, high, moderate, and low.[23] A patient is considered to be at very high risk in the presence of any of the following criteria:

Documented atherosclerotic cardiovascular disease; either clinically evident cardiovascular disease such as a history of myocardial infarction, acute coronary syndrome, ischemic stroke, or coronary or other arterial revascularization; or atherosclerotic disease that is unequivocally present at visualization such as a carotid plaque in carotid sonography; a merely increased intima-media thickness does not qualify a patient for the very high-risk stratumBesides patients with the documented cardiovascular disease, those with diabetes are considered to be at very high risk when target organ damage (such as for example proteinuria) is present or when an additional major risk factor for cardiovascular disease is present. Most of the patients with type 2 diabetes fall into the very high-risk categoryFurthermore, patients with severe chronic kidney disease (glomerular filtration rate [GFR] <30 ml/min/1.73 m2) are considered to be at very high riskPatients with a 10-year-risk of cardiovascular death of ≥10%; this risk according to ESC guidelines is estimated with SCORE-charts that depending on age, sex, smoking, total cholesterol, and systolic blood pressure estimate cardiovascular risk. SCORE chart risk estimation is recommended for patients who do not fulfil the above criteria that also otherwise would allocate them into the very high-risk group.

Patients with strong individual risk factors are considered to be at high cardiovascular risk, such as primary prevention patients with familial hypercholesterolemia, or patients with blood pressure ≥180/110 mmHg. Most diabetes patients who do not fall into the category of very high risk are in this high-risk category. Further, patients with moderate chronic kidney disease (GFR 30–59 ml/min/1.73 m2) and patients with 10-year cardiovascular mortality ≥5 but ≤10% are attributed to this risk category. Cardiovascular risk is considered moderate when the 10-year risk of cardiovascular mortality is ≥1 but <5%; if cardiovascular mortality risk is <1% patients are attributed to the low-risk category.

The ESC goal for LDL cholesterol in patients at very high cardiovascular risk is <70 mg/dl, or when untreated baseline LDL cholesterol is between 70 and 135 mg/dl an at least 50% reduction of cardiovascular risk. If for example a patient with an untreated LDL cholesterol of 100 mg/dl suffers myocardial infarction, the current LDL cholesterol goal is <50 mg/dl, not <70 mg/dl. This new recommendation in the ESC 2016 guidelines takes into account the fact that also with low baseline LDL cholesterol, reducing LDL cholesterol by 50% is associated with a significant reduction of cardiovascular events.[24]

For patients at high cardiovascular risk, the LDL cholesterol goal is <100 mg/dl; if untreated baseline LDL cholesterol is between 100 and 200 mg/dl, a reduction of LDL cholesterol by at least 50% should be achieved. For patients at moderate or low cardiovascular risk, an LDL cholesterol goal <115 mg/dl should be considered.

Regarding the different options to pharmacologically reduce LDL cholesterol, statins are the first choice. Statins are efficient and excellently tolerated; extensive evidence shows the safety of statin therapy.[25] The ESC guidelines, therefore, advise to prescribe statins up to the highest recommended dose to reach the LDL cholesterol goal. In the case of statin intolerance ezetimibe is a possible alternative.

If the LDL cholesterol target cannot be achieved with statin monotherapy, the combination of a statin with ezetimibe is the next step. If also this combination does not suffice, adding a PCSK9 inhibitor should be considered.

In 2013, the ACC together with the American Heart Association (AHA) issued guidelines that markedly differed from the European recommendations in that no lipid goals were set.[26] Indeed, a no clinical trial data are available that explicitly demonstrated a benefit with a treat-to-target approach; rather, in the existing trials, patients were randomized to receive one of two treatment modalities such as statin versus placebo or highly intensive statin versus moderately intensive statin.

Four major statin benefit groups were identified in the ACC/AHA guidelines for whom the authors concluded that the reduction of the risk of atherosclerotic cardiovascular disease clearly outweighs the risk of adverse events. These included the following: (1) individuals with clinical atherosclerotic cardiovascular disease; clinical atherosclerotic cardiovascular disease was defined by the inclusion criteria for the secondary prevention statin trials, i.e., acute coronary syndromes, a history of myocardial infarction, stable or unstable angina, coronary or other arterial revascularization, stroke, transient ischemic attacks, or peripheral arterial disease presumed to be of atherosclerotic origin, (2) individuals with primary elevations of LDL cholesterol >190 mg/dl, (3) patients with diabetes aged 40–75 years with LDL cholesterol 70–189 mg/dl and without clinical atherosclerotic cardiovascular disease, and (4) individuals without clinical atherosclerotic cardiovascular disease or diabetes with LDL cholesterol 70–189 mg/dl and an estimated 10-year risk of clinical atherosclerotic cardiovascular disease > 7.5%. For the primary prevention of atherosclerotic cardiovascular disease in individuals without clinical atherosclerotic cardiovascular disease and LDL cholesterol 70–189 mg/dl, the estimated absolute 10-year risk of atherosclerotic cardiovascular disease was recommended to be used to guide the initiation of statin therapy. A novel 10-year atherosclerotic cardiovascular disease risk calculator, the Pooled Cohort Equations calculator was recommended for the estimation of atherosclerotic cardiovascular disease risk,[27] which was defined as nonfatal myocardial infarction, coronary heart disease death, and nonfatal and fatal stroke.

For patients ≤75 years of age with established clinical atherosclerotic cardiovascular disease, for individuals with an LDL cholesterol >190 mg/dl, and for diabetes patients with an estimated 10-year risk of atherosclerotic cardiovascular disease ≥7.5% high-intensity statin therapy was recommended, for atherosclerotic cardiovascular disease patients >75 years and for diabetes patients with an estimated 10-year risk <7.5% a moderate-intensity statin, and for individuals aged 40–75 years who did not fall into the above categories but had a 10-year risk ≥7.5% a moderate-to-high intensity statin.

Other interventions to reduce LDL cholesterol were not recommended in the ACC/AHA guidelines because at the time of their publication the IMPROVE-IT[16] and FOURIER[18] trials had not been published yet and the guidelines focused on then available evidence from randomized controlled trials rather than on lowering LDL cholesterol per se. Furthermore, it was not generally recommended to modify treatment according to the response to statin treatment. A weak recommendation was made that clinicians treating high-risk patients who have a less-than-anticipated response to statins, who are unable to tolerate a less-than-recommended intensity of a statin, or who are completely statin intolerant may consider the addition of nonstatin cholesterol-lowering therapy.

In 2016, the ACC published an expert statement that maintained the statin benefit groups postulated in the 2013 ACC/AHA recommendations but took the response to LDL cholesterol lowering therapy into account;[28] it now was recommended to take into account for further management decisions whether the patient responded to initial statin therapy with an at least 50% LDL cholesterol reduction and to also consider goal achievement defined as LDL cholesterol <70 mg/dl in those with clinical atherosclerotic cardiovascular disease, with comorbities or untreated LDL cholesterol ≥190 mg/dl and LDL cholesterol <100 mg/dl in the other statin benefit groups. It now is also recommended to consider the nonstatin LDL cholesterol-lowering medications ezetimibe, bile acid sequestrants, and PCSK9 inhibitors.

In 2017, the American Association of Clinical Endocrinologists (AACE) issued another set of guidelines that is interesting in that a separate extremely high risk group was defined above the very high risk group that includes patients with progressive atherosclerotic cardiovascular disease in patients having achieved an LDL cholesterol <70 mg/dl, patients with established clinical cardiovascular disease who also have diabetes, chronic kidney disease stages 3 or 4 or heterozygous familial hypercholesterolemia, and patients with a history of premature atherosclerotic cardiovascular disease. For these patients, an LDL-cholesterol target of <55 mg/dl is recommended.

 Lipid Treatment Beyond Low-Density Lipoproteins Cholesterol

Hypertriglyceridemia is associated with an increased cardiovascular event risk. Statins are not as potent in the reduction of triglycerides as they are in the reduction of LDL cholesterol. However, statins are the first choice to reduce cardiovascular risk also in patients with hypertriglyceridemia; the decision on whether to start statin treatment in a patient with hypertriglyceridemia depends on LDL cholesterol levels as well as on the risk category the patient is attributed to.

Fibrates potently reduce triglycerides; evidence for further cardiovascular risk reduction with fibrates in statin-treated patients, however, is very limited. Only subgroup analyses from fibrate trials suggest a benefit of fibrate therapy added to statin therapy in patients who concomitantly have high triglycerides and low HDL cholesterol.[29]

According to ESC guidelines, it may be considered to add fenofibrate to statin treatment in statin-treated patients with triglycerides >200 mg/dl. Due to the risk of myopathy, gemfibrozil should not be combined with statins. When triglycerides are not adequately controlled despite statins and fibrates, Ω-3-fatty acids are a further option to reduce triglycerides.[23]

It is not recommended to pharmaceutically aim at increasing HDL cholesterol.[23] The results of HDL cholesterol increasing cholesteryl ester transfer protein (CETP)-inhibitor trials[30],[31],[32],[33] were disappointing, at least with regard to the impact of the HDL increase on cardiovascular event risk, and also adding HDL cholesterol increasing niacin to statin therapy did not further reduce cardiovascular events in two trials.[34],[35]

 Lifestyle Interventions to Improve the Lipid Profile

Lifestyle interventions should accompany every pharmacological lipid therapy.[23] To reduce LDL cholesterol a reduction of trans fatty acids and of saturated fatty acids is recommended; a reduction of cholesterol intake on average has a comparably weak effect on blood cholesterol. Triglycerides are reduced mainly by weight control and by a reduction of alcohol intake. Further, increasing physical activity, reducing the intake of carbohydrates, in particular of mono- and disaccharides, and supplementation with Ω-3-unsaturated fatty acids reduces triglycerides. On average, lifestyle measures to reduce triglycerides are much more effective than those to reduce LDL cholesterol.

 Lipid Management in Important Patient Groups


Cardiovascular risk reduction by lowering LDL cholesterol is the same in women as in men.[36] Like in men, statins are the first choice to pharmacologically reduce LDL cholesterol in women. However, statins are contraindicated in pregnancy.

Elderly Patients

The relative risk reduction of cardiovascular risk with LDL cholesterol lowering is the same in elderly as in younger patients.[12],[13],[14] Due to the higher absolute risk of elderly patients the absolute benefit of statin treatment in them is particularly high. Therefore, treatment recommendations are not generally different in the elderly.[37] However, given the frequent comorbidities and potentially altered pharmacokinetics in the elderly treatment in these patients should be initiated at a lower dose than in younger patients. Of course, in geriatric patients physicians should take into account severe comorbidities, quality of life or limited life expectancy in the decisions regarding lipid management.

Patients with Diabetes

Cardiovascular events are the most common cause of death in patients with diabetes,[38] and lowering LDL cholesterol is equally effective to reduce cardiovascular risk in patients with diabetes as in patients who do not have diabetes.[14] Similar as in the elderly, the absolute benefit of patients with diabetes is particularly high, given their high absolute risk.

This holds true even though high LDL cholesterol is not characteristic for patients with diabetes. Generally, patients with type 2 diabetes as a consequence of insulin resistance display dyslipidemia with high triglycerides, low HDL cholesterol and small LDL particles.[39] As a consequence of the small LDL particles in patients with diabetes these patients at a given level of LDL cholesterol have more LDL particles than insulin-sensitive nondiabetic patients. The number of LDL particles, however, is a paramount determinant for the atherogenic impact of LDL cholesterol. The same level of LDL cholesterol, therefore, is more noxious in patients with diabetes than in nondiabetic patients.

Patients with Chronic Kidney Disease

Cardiovascular risk in patients with chronic kidney disease stage III is at least high, in stages IV and V it is very high.[37] These patients should receive appropriate LDL cholesterol lowering therapy. The beneficial effect of statin treatment on cardiovascular events in patients with chronic kidney disease Stages III and IV is beyond doubt. In dialysis patients, individual trials did not demonstrate a benefit of statin treatment with regard to the primary cardiovascular endpoint; a meta-analysis, however, showed a significant albeit attenuated beneficial effect of statin treatment on cardiovascular events also in dialysis patients. Given the extremely high absolute risk of dialysis patients, their absolute benefit from statin treatment was similar to that of other chronic kidney disease patients.[40]

Familial Hypercholesterolemia

Heterozygous familial hypercholesterolemia is not at all a rare disease; its prevalence is estimated between 1:200 and 1:500.[41] Untreated, these patients are at very high risk of premature cardiovascular disease. Heterozygous familial hypercholesterolemia should be considered in patients with premature cardiovascular disease (in men before age 55; in women before age 60), in patients with relatives with premature cardiovascular disease, in patients with tendon xanthomas or in those whose relatives have tendon xanthomas, and in patients with an LDL cholesterol >190 mg/dl. In children, already an LDL cholesterol above 150 mg/dl should rise suspicion. The diagnosis of familial hypercholesterolemia is made using the Dutch Lipid Clinic Network Criteria.

According to these criteria, patients receive score points according to clinical history, family history, presence of tendon xanthomas, premature arcus cornealis (which is frequently observed in elderly individuals; in patients <45 years an arcus cornealis by no means is normal but a sign of severe hypercholesterolemia), LDL cholesterol values, and the results of optional genetic testing. Depending on the summed up score points the Dutch Lipid Clinic Network Criteria discern definite, probable, and possible familial hypercholesterolemia.

Patients with familial hypercholesterolemia should receive potent statin therapy, if necessary in combination with ezetimibe. Their target LDL cholesterol is at least <100 mg/dl; if the atherosclerotic disease has already become manifest or when another very high-risk stigma is present, LDL cholesterol should be at least <70 mg/dl. A PCSK9 inhibitor should be considered when these goals are not met on oral therapy alone.

 Current Developments in Lipid Management

New options of lipid therapy are currently being developed. Inclisiran, a small inhibiting RNA molecule, inhibits messenger RNA for PCSK9 and thus inhibits PCSK9.[42] The efficacy of this drug to reduce LDL cholesterol has already been shown; in contrast to monoclonal antibodies for PCSK9 inhibition, which should be injected every 2–4 weeks, for inclisiran an injection every 3 months is sufficient. Whether this substance regarding the efficacy to reduce cardiovascular events and regarding safety is better, equal, or worse than the monoclonal antibodies has to be shown in randomized controlled outcome trials.

After several very disappointing trials with the HDL cholesterol increasing CETP inhibitors that did not show a cardiovascular benefit,[31],[32] and in the case of torcetrapib[30] even an increased mortality risk, the randomized evaluation of the Effects of Anacetrapib through Lipid-modification (REVEAL) trial[33] reported a cardiovascular event reduction with the CETP inhibitor anacetrapib, that besides increasing HDL cholesterol strongly reduces LDL cholesterol. Anacetrapib had a favorable tolerability profile in the trial but accumulated in fatty tissue. The manufacturer of anacetrapib after weighing risks and benefits has decided not to market the drug.

Novel therapy options are developed also beyond LDL cholesterol lowering.[43] The potent new fibrate pemafibrate[44] currently is tested with regard to its impact on cardiovascular event risk in patients with dyslipidemia. Further, antisense oligonucleotides to lower the highly atherogenic lipoprotein(a) have been developed;[45] also they are going to be tested in a cardiovascular endpoint trial.

The primary focus of lipid therapy however currently remains lowering LDL cholesterol. Since LDL cholesterol is causally responsible for the development of atherosclerosis, it is to be expected that LDL cholesterol will remain at the center of cardiovascular risk management.

 Gaps in Evidence and Ongoing Controversies

Overall, there is much more consensus than controversy in current lipid management. It now is beyond doubt that lowering LDL cholesterol reduces cardiovascular events and that this benefit in patients at high risk of cardiovascular events exceeds potential harm from lipid-lowering therapy. Furthermore, the safety of statin treatment has been convincingly shown both in clinical trials and long-term observations.

However, no data are available over very long time periods >20 years. The long-term net benefit of statin treatment in young individuals who have risk factors but due to their young age are at a low 10-year cardiovascular risk is not known. The lifetime risk of cardiovascular events for these individuals is high, but whether they will benefit from the early initiation of statin therapy has not been demonstrated yet.

At the other end of the age spectrum, it has not been explicitly shown that elderly individuals ≥75 years without established clinical atherosclerotic cardiovascular disease benefit from statin treatment. However, large meta-analyses[12],[13] did not show any impact of age on cardiovascular risk reduction with lowering LDL cholesterol. A meta-analysis explicitly addressing individuals ≥65 years of age found that myocardial infarction and stroke but not cardiovascular or total mortality was reduced in these patients.[46] Evidence for treatment in the very old, particularly for those above 80–85 years of age, is limited, and current ESC guidelines state that clinical judgment should guide decisions in the very old.[37]

Regarding LDL cholesterol goals <70 mg/dl currently is most widely recommended for very high-risk patients.[28],[37] However, the AACE[47] recommends an LDL cholesterol target <55 mg/dl for extremely high risk patients. Indeed, the clinical trial evidence is available that lowering LDL cholesterol <70 mg/dl further reduces cardiovascular risk.

While statins and ezetimibe now are cheap or only moderately expensive, the cost of the new and potent PCSK9 inhibitors is higher.[48] PCSK9 inhibition reduces cardiovascular events. However, considering the limited resources of health-care systems, it is a question of debate in which patient populations treatment with PCSK9 inhibitors is cost-efficient.

Current lipid management is focused on LDL cholesterol, and interventions addressing HDL overall have been disappointing. Mendelian randomization does not support a causal role of HDL cholesterol in the development of the atherosclerotic cardiovascular disease;[49] HDL cholesterol is a risk marker rather than a risk factor. However, HDL cholesterol levels are an imperfect surrogate for HDL functionality, and it cannot be excluded that in the future therapies addressing HDL functionality will eventually emerge.[43]

For now, LDL cholesterol remains the major target of lipid intervention. The benefits of this approach are clear. However, it remains a major problem to translate what we know into clinical reality. Still, the majority even of patients with the established cardiovascular disease do not reach their lipid goals.[50] It is an important challenge to improve both physician adherence to evidence-based guidelines and patient adherence to prescribed LDL cholesterol-lowering medications.[51]

Financial support and sponsorship


Conficts of interest

Christoph H. Saely: Received lecture and consultant honoraria from Amgen, Astra Zeneca, Merck Sharp & Dohme, Merck, Pfizer and Sanofi-Aventis.

Reinhard R. Saely: None.

Heinz Drexel: Received lecture and consultant honoraria from Amgen, Astra Zeneca, Merck Sharp & Dohme, Merck, Pfizer and Sanofi-Aventis.


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