Low-density Lipoprotein Cholesterol-lowering Drugs Research Articles

Drug intervention as an emerging concept for secondary prevention in patients with coronary disease.

Non-culprit lesion-related coronary events are a significant concern in patients with coronary artery disease (CAD) undergoing coronary intervention. Since several studies using intra-coronary imaging modalities have reported a high prevalence of vulnerable plaques in non-culprit lesions at the initial coronary event, the immediate stabilization of these plaques by intensive pharmacological regimens may contribute to the reduction in the adverse events. Although current treatment guidelines recommend the titration of statin and other drugs to attain the treatment goal of low-density lipoprotein cholesterol (LDL-C) level in patients with CAD, the early prescription of strong LDL-C lowering drugs with more intensive regimen may further reduce the incidence of recurrent cardiovascular events. In fact, several studies with intensive regimen have demonstrated a higher percentage of patients with the attainment of LDL-C treatment goal in the early phase following discharge. In addition to many imaging studies showing plaque stabilization by LDL-C lowering drugs, several recent reports have shown the efficacy of early statin and proprotein convertase subtilisin/kexin type 9 inhibitors on the immediate stabilization of non-culprit coronary plaques. To raise awareness regarding this important concept of immediate plaque stabilization and subsequent reduction in the incidence of recurrent coronary events, the term 'Drug Intervention' has been introduced and gradually applied in the clinical field, although a clear definition is lacking. The main target of this concept is patients with acute coronary syndrome as a higher prevalence of vulnerable plaques in non-culprit lesions in addition to the worse clinical outcomes has been reported in recent imaging studies. In this article, we discuss the backgrounds and the concept of drug intervention.

Low-Density Lipoprotein Cholesterol-Lowering Drugs: A Narrative Review.

The modern history of cholesterol-lowering drugs started in 1972 when Dr. Akira Endo identified an active compound (compactin) that inhibited cholesterol biosynthesis from the culture broth of blue-green mold (Penicillium citrinum Pen-51). Since 1987, statins have represented the milestone for the treatment of atherosclerotic cardiovascular disease. A new therapy for the treatment of hypercholesterolemia since the discovery of statins is ezetimibe, the first and only agent inhibiting intestinal cholesterol absorption. Ezetimibe was approved by the FDA in October 2002. A year later, the association between gain-of-function PCSK9 genetic mutations and hypercholesterolemia was reported, and this discovery opened a new era in lipid-lowering therapies. Monoclonal antibodies and small-interfering RNA approaches to reduce PCSK9 were developed and approved for clinical use in 2015 and 2022, respectively. Finally, the newly approved bempedoic acid, an oral adenosine triphosphate citrate lyase inhibitor that lowers LDL-C, is able to reduce major adverse cardiovascular events in both primary and secondary prevention. In the present narrative review, we summarize the pharmacological properties and the clinical efficacy of all these agents currently used for a tailored therapy of hypercholesterolemia in patients with atherosclerotic cardiovascular disease.

VXX-401, a novel anti-PCSK9 vaccine, reduces LDL-C in cynomolgus monkeys

Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of disease burden in the world and is highly correlated with chronic elevations of LDL-C. LDL-C-lowering drugs, such as statins or monoclonal antibodies against proprotein convertase subtilisin/kexin type 9 (PCSK9), are known to reduce the risk of cardiovascular diseases; however, statins are associated with limited efficacy and poor adherence to treatment, whereas PCSK9 inhibitors are only prescribed to a “high-risk” patient population or those who have failed other therapies. Based on the proven efficacy and safety profile of existing monoclonal antibodies, we have developed a peptide-based vaccine against PCSK9, VXX-401, as an alternative option to treat hypercholesterolemia and prevent ASCVD. VXX-401 is designed to trigger a safe humoral immune response against PCSK9, resulting in the production of endogenous antibodies and a subsequent 30–40% reduction in blood LDL-C. In this article, VXX-401 demonstrates robust immunogenicity and sustained serum LDL-C-lowering effects in nonhuman primates. In addition, antibodies induced by VXX-401 bind to human PCSK9 with high affinity and block the inhibitory effect of PCSK9 on LDL-C uptake in a hepatic cell model. A repeat-dose toxicity study conducted in nonhuman primates under good laboratory practices toxicity indicated a suitable safety and tolerability profile, with injection site reactions being the main findings. As a promising safe and effective LDL-C-lowering therapy, VXX-401 may represent a broadly accessible and convenient option to treat hypercholesterolemia and prevent ASCVD.

Clinical efficacy and safety outcomes of bempedoic acid for LDL-C lowering therapy in patients at high cardiovascular risk: a systematic review and meta-analysis

ObjectivesBempedoic acid (BA) is a novel oral low-density lipoprotein cholesterol lowering drug. This systematic review and meta-analysis aims to assess efficacy and safety for clinical outcomes in high cardiovascular (CV)...

Evinacumab Markedly Reduces Low-density Lipoprotein Cholesterol in Adolescent Patients With Homozygous Familial Hypercholesterolemia†

Lead Author's Financial Disclosures Nothing to disclose. Study Funding Regeneron Pharmaceuticals, Inc. Background/Synopsis Homozygous familial hypercholesterolemia (HoFH) is characterized by elevated low-density lipoprotein cholesterol (LDL-C) and premature cardiovascular disease, underscoring the need for early and aggressive treatment. Evinacumab, an angiopoietin-like protein 3 inhibitor, is an effective LDL-C lowering drug in adult HoFH patients. Objective/Purpose The primary objective of the study is to evaluate the safety and tolerability of intravenous evinacumab 15 mg/kg every 4 weeks in adolescent patients with HoFH. Methods This is an interim analysis of an evinacumab open-label phase 3 trial (NCT03409ba744) in adolescent patients (aged 12 to <18 years) with HoFH. Patients who participated in a previous study (NCT03399786) or who were evinacumab-naive received intravenous evinacumab 15 mg/kg every 4 weeks. All patients were genotyped. Results In total, 13 patients (8 male; mean [range] age 14 [12-17] years) were treated for a mean (range) duration of 34.5 (4-61) weeks. At baseline, mean (standard deviation [SD]) LDL-C was 310.3 [97.3] mg/dL; 8 patients (61.5%) received lipoprotein apheresis. Treatment-emergent adverse events (TEAEs) occurred in 6 (46.2%) patients; no TEAEs were reported in more than 1 patient. One patient reported 2 serious adverse events, both considered unrelated to study drug. LDL-C data were available for 9 patients at week 24. Overall, evinacumab reduced mean LDL-C by 52.4% (mean [SD], 183.4 [101.6] mg/dL; Figure) from baseline to week 24. In patients with null-null (n=4) and non-null (n=5) LDL-receptor variants, evinacumab reduced mean LDL-C levels by 67.2% and 40.6%, respectively. Conclusions In this small sample of adolescent patients with HoFH, evinacumab markedly reduced LDL-C irrespective of genotype or background treatment in patients with HoFH. Evinacumab was generally well-tolerated with few TEAEs. Nothing to disclose.

Comparison of Food and Nutrient Intakes between Japanese Dyslipidemic Patients with and without Low-Density Lipoprotein Cholesterol Lowering Drug Therapy: A Cross-Sectional Study.

Aim: We aimed to clarify actual food and nutrient intakes in Japanese patients with dyslipidemia. We also compared food and nutrient intakes between patients with and without low-density lipoprotein cholesterol (LDL-C) lowering drug therapy.Methods: Food and nutrient intakes were assessed employing 3-day weighted dietary records in this cross-sectional study of 104 Japanese outpatients with dyslipidemia, age 30–65 years, not given dietary counseling. Anthropometric and biochemical parameters were measured after an overnight fast. Food and nutrient intakes were compared between patients with versus without LDL-C lowering drug prescriptions. Stepwise multiple regression analysis was performed to identify relationships between the serum LDL-C concentrations and food intakes.Results: Of the 104 patients, 43.3% were prescribed LDL-C lowering drugs, primarily statins. Of the total patients, 83% had lipid intakes over 25% of total energy consumption (%E), exceeding the recommendation for dyslipidemia by the Japan Atherosclerosis Society. Similarly, 77% had saturated fatty acid intakes over 7%E, and 88% had cholesterol intakes over 200 mg per day. Dietary fiber consumption was low (< 25 g) in 97% of patients. Those taking LDL-C lowering drugs consumed less “meat, poultry and processed meat products” and “cereals”, and more “fish”, “fruits” and “nuts”, than patients not taking these drugs (p < 0.05). Food intakes correlating with LDL-C concentrations independently of drug therapy differed between patients taking versus not taking these medications.Conclusion: Our results support the necessity of diet therapy for patients with dyslipidemia regardless of whether LDL-C lowering drugs are prescribed.The clinical trial registration number: UMIN000022955

Evolocumab for Early Reduction of LDL Cholesterol Levels in Patients With Acute Coronary Syndromes (EVOPACS)

BackgroundAlthough guidelines recommend in-hospital initiation of high-intensity statin therapy in patients with acute coronary syndromes (ACS), low-density lipoprotein cholesterol (LDL-C) target levels are frequently not attained. Evolocumab, a rapidly acting, potent LDL-C–lowering drug, has not been studied in the acute phase of ACS. ObjectivesThe purpose of this study was to assess the feasibility, safety, and LDL-C–lowering efficacy of evolocumab initiated during the in-hospital phase of ACS. MethodsThe authors conducted an investigator-initiated, randomized, double-blind, placebo-controlled trial involving 308 patients hospitalized for ACS with elevated LDL-C levels (≥1.8 mmol/l on high-intensity statin for at least 4 weeks; ≥2.3 mmol/l on low- or moderate-intensity statin; or ≥3.2 mmol/l on no stable dose of statin). Patients were randomly assigned 1:1 to receive subcutaneous evolocumab 420 mg or matching placebo, administered in-hospital and after 4 weeks, on top of atorvastatin 40 mg. The primary endpoint was percentage change in calculated LDL-C from baseline to 8 weeks. ResultsMost patients (78.2%) had not been on previous statin treatment. Mean LDL-C levels decreased from 3.61 to 0.79 mmol/l at week 8 in the evolocumab group, and from 3.42 to 2.06 mmol/l in the placebo group; the difference in mean percentage change from baseline was −40.7% (95% confidence interval: −45.2 to −36.2; p < 0.001). LDL-C levels <1.8 mmol/l were achieved at week 8 by 95.7% of patients in the evolocumab group versus 37.6% in the placebo group. Adverse events and centrally adjudicated cardiovascular events were similar in both groups. ConclusionsIn this first randomized trial assessing a PCSK9 antibody in the very high-risk setting of ACS, evolocumab added to high-intensity statin therapy was well tolerated and resulted in substantial reduction in LDL-C levels, rendering >95% of patients within currently recommended target levels. (EVOlocumab for Early Reduction of LDL-cholesterol Levels in Patients With Acute Coronary Syndromes [EVOPACS]; NCT03287609)

Posttranslational modification of proprotein convertase subtilisin/kexin type 9 is differentially regulated in response to distinct cardiometabolic treatments as revealed by targeted proteomics

The proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secreted protein that interacts with the low-density lipoprotein (LDL) receptor at the surface of hepatocytes to regulate circulating LDL cholesterol levels. High circulating PCSK9 levels have been associated with elevated LDL cholesterol. Recently, the Food and Drug Administration of the United States approved new LDL cholesterol-lowering drugs that specifically target the inhibition of PCSK9. Similar to most human proteins, PCSK9 exists in multiple forms as it is the target of posttranslational modifications (PTMs) such as proteolytic cleavage, phosphorylation, and others, which can affect its biological activity. However, commercially available assays, such as enzyme-linked immunosorbent assays, do not discriminate between these forms. To investigate, in 2 patient cohorts, the relationships between circulating levels of multiple forms of PCSK9 and cardiometabolic interventions or treatments known to reduce LDL cholesterol levels. PCSK9 forms were measured in plasma: (1) in 20 patients before and 6months after bariatric surgery and (2) in 132 patients before and 12months after daily statin treatment. A series of specific peptides used as surrogates for various PCSK9 forms were quantified by a novel semiautomated proteomic assay termed protein affinity capture coupled to quantitative mass spectrometry. Bariatric surgery resulted in a decrease in the plasma level of PCSK9 prodomain (P<.05), but did not result in a significant change in other measured PCSK9 forms. Statin treatment resulted in an increase in all measured plasma PCSK9 peptides (P<.001), but a 25% decrease in the phosphorylated state of PCSK9 at S688 (P<.05). These unexpected findings indicate that measuring the circulating levels of the various domains and PTMs of PCSK9 provides more in depth information than total PCSK9 and that the prodomain and the phosphorylated state of S688 may represent novel biomarkers to explore in cardiometabolic diseases and response to treatment. In addition, our data generated new hypotheses on the function of PCSK9 PTMs in health and disease.

Diabetes Secondary to Treatment with Statins.

This review summarizes the recent population-based studies, clinical trials, clinical metabolic studies, and genetic studies reporting the effects of statin therapy on the risk of diabetes. Recent studies aiming to explain the mechanisms how statin treatment affects insulin sensitivity and insulin secretion are also reviewed. Statin therapy increases the risk of diabetes by 9%-12% in the two meta-analyses of statin trials and by 18%-99% in five population-based studies. Statin therapy impairs insulin sensitivity and insulin secretion based on clinical and epidemiologic studies. In vitro studies demonstrate that the most diabetogenic statins impair insulin sensitivity and insulin secretion by multiple mechanisms. Recent genetic studies suggest that the increased risk of type 2 diabetes may be partially explained by gene variants in the target genes for low-density lipoprotein cholesterol lowering drugs. Population-based studies report higher incidence rates for diabetes in individuals on statin treatment compared with clinical trials. Incident diabetes has not been a prespecified endpoint in statin trials and glucose and/or HbA1c have not been routinely measured. Therefore, it is possible that the risk of diabetes in individuals on statin treatment has been underestimated in previous statin trials. Accumulating evidence from several statin trials, population-based studies, clinical studies, and in vitro studies suggests that pravastatin is the least diabetogenic statin, and simvastatin, atorvastatin, and rosuvastatin the most diabetogenic statins. In vitro studies have reported new findings on mechanisms how statin treatment affects insulin sensitivity and insulin secretion. In spite of diabetogenicity of different statins, the consensus is that the benefits of statins in reducing cardiovascular events clearly outweigh the risk of diabetes.

The 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular disease risk: a new paradigm supported by more evidence.

The 2013 American College of Cardiology/American Heart Association cholesterol guideline was a major paradigm shift and heavily criticized by some experts. A better understanding of the methodology used to develop the guideline, the guideline recommendations, and the evidence supporting them addresses many of criticisms. An extensive body of evidence from randomized clinical trials supports the new risk-based approach. The emphasis is on the appropriate intensity of statin therapy in patients most likely to benefit. The National Institute for Health and Care Excellence guidelines have taken a similar approach. Recent studies have found the 2013 guideline outperforms earlier cholesterol guidelines recommending low-density lipoprotein cholesterol (LDL-C) treatment thresholds and targets. The 2013 cholesterol guideline better identifies high-risk patients with a greater burden of atherosclerosis and avoids treating those at lower risk with little atherosclerosis; its application would prevent up to 450 000 more atherosclerotic cardiovascular disease (ASCVD) events over 10 years. The 2013 cholesterol guideline also recommends regularly monitoring LDL-C levels to assess adherence to lifestyle and drug therapy, and adjusting treatment based on response to therapy and adverse events. Non-statins shown to reduce ASCVD events when added to statin therapy, and that have an acceptable margin of safety in randomized, controlled clinical trials, are preferred. Ezetimibe has now been shown to meet this standard. The concept of net benefit introduced in the 2013 ACC/AHA cholesterol guideline identifies patients most likely to benefit from statin therapy to reduce ASCVD risk. Net benefit, incorporating the absolute ASCVD risk of a patient and the relative reduction in ASCVD risk based on the magnitude of LDL-C reduction from the addition of a non-statin, can be used when considering whether to add ezetimibe or another LDL-C lowering drug.

Lipid-lowering therapy in older persons.

Numerous randomized, double-blind, placebo-controlled studies and observational studies have shown that statins reduce mortality and major cardiovascular events in older high-risk persons with hypercholesterolemia. The Heart Protection Study showed that statins reduced mortality and major cardiovascular events in high-risk persons regardless of the initial level of serum lipids, age, or gender. The updated National Cholesterol Education Program III guidelines state that in very high-risk persons, a serum low-density lipoprotein (LDL) cholesterol level of < 70 mg/dl (1.8 mmol/l) is a reasonable clinical strategy for moderately high-risk persons (2 or more risk factors and a 10-year risk for coronary artery disease of 10% to 20%), and the serum LDL cholesterol should be reduced to < 100 mg/dl (2.6 mmol/l). When LDL cholesterol-lowering drug therapy is used to treat high-risk persons or moderately high-risk persons, the serum LDL cholesterol should be reduced by at least 30% to 40%. The serum LDL cholesterol should be decreased to less than 160 mg/dl in persons at low risk for cardiovascular disease. Addition of other lipid-lowering drugs to statin therapy has not been demonstrated to further reduce cardiovascular events and mortality.

Abstract 9761: Novel Modulators of Low Density Lipoprotein Receptor Metabolism

Intervention with drugs to reduce Low Density Lipoprotein-cholesterol (LDL-C) has proven to decrease the risk of subsequent cardiovascular events, including mortality. Our goal is to develop novel, small molecule, LDL-C lowering drugs by targeting the Low Density Lipoprotein Receptor (LDLR) degradation pathway, which is modulated by the protease proprotein convertase subtilisin-like kexin type 9 (PCSK9). PCSK9 has been shown to bind to the epidermal growth factor-like repeat A (EGF-A) domain of the LDLR; it enhances the degradation of the LDLR by an unknown. We successfully integrated virtual screening methods and cell based assays into a simple, efficient procedure and identified compounds that interfere with the PCSK9-LDLR interaction. Using the atomic coordinates of the crystal structure of the PCSK9/LDLR-EGF-A complex, about a million drug-like compounds were docked in silico into the region of PCSK9 where LDLR-EGF-A binds. We selected 179 top scoring compounds that showed the best fit in the binding site as well as the greatest number of interactions with PCSK9. These compounds were tested in (a) our PCSK9/LDLR dependent HEK293 cell-based recombinant assay and (b) the endogenously expressed LDLR in HepG2/PCSK9 dependent cell based assay for their ability to upregulate the LDLR. From these screening campaigns, eleven compounds consistently exhibited concentration dependent increase in the LDLR as comparable to control, with IC 50 s in the low micromolar range. Three of the top picks were shown to exhibit a 5 to 10 fold up-regulation at 1.6 μM in two cell lines. In addition, these compounds also exhibited an increase in the fluorescently labeled DiI-LDL uptake in the nanomolar range in situ . Furthermore, in a two week animal study, subcutaneous injection of 4 mg/kg of one of these compounds resulted in a 32% reduction of the total cholesterol level in mice fed a high fat/high cholesterol diet as compared to 27% cholesterol reduction obtained with 40 mg/kg Atorvastatin. To our knowledge, no small molecule antagonist against PCSK9 has been reported, only mAbs. Thus, identifying such an oral small molecule PCSK9 inhibitor represents a tremendous advance and opportunity for drug development.

Treatment of Hypercholesterolemia

Numerous randomized, double blind, placebo-controlled studies and observational studies have shown that statins reduce mortality and major cardiovascular events in high-risk patients with hypercholesterolemia. The Heart Protection Study showed that statins reduced mortality and major cardiovascular events in high-risk patients regardless of the initial level of serum lipids, age, or gender. The updated National Cholesterol Education program III guidelines state that in very high-risk persons, a serum low-density lipoprotein (LDL) cholesterol level of <70 mg/L is a reasonable clinical strategy. For moderately high-risk persons ( 2 or more risk factors and a 10-year risk for coronary artery disease of 10% to 20%), the serum LDL cholesterol should be reduced to <100 mg/dL. When LDL cholesterol-lowering drug therapy is used to treat high-risk persons or moderately high-risk persons, the serum LDL cholesterol should be reduced at least 30% to 40%. The serum LDL cholesterol should be decreased to less than 160 mg/dl in persons at low risk for cardiovascular disease. Addition of other lipid-lowering drugs to statin therapy has not been found to further reduce cardiovascular events and mortality.

Dual Inhibition, Newer Paradigms for Cholesterol Lowering

Coronary heart disease (CHD) is the leading cause of death in United States. The National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III recommends new lower cholesterol levels, particularly for patients at moderate and high risk for coronary disease. Low-density lipoprotein (LDL) cholesterol is primarily the target of hypolipidemic drugs. The NCEP ATP III recommends an LDL cholesterol goal of <100 mg/dL in high-risk patients and an LDL cholesterol goal of <70 mg/dL as a therapeutic option, especially in patients with very high risk of CHD. Statins are potent LDL cholesterol-lowering drugs, but they are not as effective as fibrates and niacin in improving levels of triglycerides or high-density lipoprotein cholesterol. Ezetimibe represents a new class of hypolipidemic drugs that inhibit cholesterol absorption in the small intestine. The combination of ezetimibe with statins has been more effective than monotherapy alone in many randomized trials. LDL cholesterol reduction with statin occurs mainly with the initial dose, with relatively smaller reductions seen at higher doses. Ezetimibe was also shown to be useful in various population subgroups such as African-Americans, men and women, elderly and aged, and also those with kidney disease. We review various randomized clinical trials that used ezetimibe along with other hypolipidemic drugs like statins and fibrates. We also discuss the adverse effects of the various lipid-lowering drugs and their important drug interactions.

Management of Hypercholesterolemia in Older Persons for the Prevention of Cardiovascular Disease

Multiple randomized, double-blind, placebo-controlled studies and observational studies have demonstrated that statins decrease mortality and major cardiovascular events in high-risk persons with hypercholesterolemia. The Heart Protection Study showed that statins decreased mortality and major cardiovascular events in high-risk persons regardless of the initial level of serum lipids, age, or gender. The updated National Cholesterol Education Program III guidelines state that in very high-risk patients, a serum low-density lipoprotein (LDL) cholesterol level of <70 mg/dL is a reasonable clinical strategy, regardless of age. When a high-risk person has hypertriglyceridemia or low serum high-density lipoprotein cholesterol, consideration can be given to combining a fibrate or nicotinic acid with an LDL cholesterol-lowering drug. For moderately high-risk persons, the serum LDL cholesterol should be lowered to <100 mg/dL. When LDL cholesterol-lowering drug therapy is used to treat high-risk persons or moderately high-risk persons, the serum LDL cholesterol should be reduced at least 30% to 40%. High-risk older persons should be treated with lipid-lowering drug therapy according to National Cholesterol Education Program III updated guidelines to decrease cardiovascular morbidity and mortality. The LDL cholesterol should be decreased to <160 mg/dL in persons at low risk for cardiovascular disease.

Treatment of High-Risk Older Persons With Lipid-Lowering Drug Therapy

Randomized, double-blind, placebo-controlled studies and observational studies have demonstrated that statins reduce mortality and major cardiovascular events in high-risk persons with hypercholesterolemia. The aim of this study was to review the evidence for treating high-risk older persons with lipid-lowering drugs. A MEDLINE search of the English-language literature published from January 1, 1989, to June 2006 was conducted to review all studies in which lipid-lowering drug therapy was administered to high-risk older persons. The Heart Protection Study showed that statins reduced mortality and major cardiovascular events in high-risk persons, regardless of the initial level of serum lipids, age, or gender. The updated National Cholesterol Education Program (NCEP) III guidelines state that in very-high-risk patients, a serum low-density lipoprotein (LDL) cholesterol level of <70 mg/dL is a reasonable clinical strategy, regardless of age. When a high-risk person has hypertriglyceridemia or low serum high-density lipoprotein cholesterol, consideration can be given to combining a fibrate or nicotinic acid with an LDL cholesterol-lowering drug. For moderately-high-risk persons, the serum LDL cholesterol should be reduced to <100 mg/dL. When LDL cholesterol-lowering drug therapy is used for high-risk persons or moderately-high-risk persons, the serum LDL cholesterol should be reduced at least 30% to 40%. High-risk older persons should be treated with lipid-lowering drugs according to the NCEP III updated guidelines to reduce cardiovascular morbidity and mortality.

Management of hyperlipidemia with statins in the older patient

Numerous randomized, double-blind, placebo-controlled studies and observational studies have demonstrated that statins decrease mortality and major cardiovascular events in older high-risk persons with hypercholesterolemia. The Heart Protection Study found that statins decreased mortality and major cardiovascular events in high-risk persons regardless of the initial level of serum lipids, age, or gender. The updated National Cholesterol Education Program (NCEP) III guidelines state that in very high-risk patients, a serum low-density lipoprotein (LDL) cholesterol level of < 70 mg/dl is a reasonable clinical strategy, regardless of age. When a high-risk person has hypertriglyceridemia or low serum high-density lipoprotein cholesterol, consideration can be given to combining a fibrate or nicotinic acid with an LDL cholesterol-lowering drug. For moderately high-risk persons (2 or more risk factors and a 10-year risk for coronary heart disease of 10% to 20%), the serum LDL cholesterol should be decreased to < 100 mg/dl. When LDL cholesterol-lowering drug therapy is used to treat high-risk persons or moderately high-risk persons, the serum LDL cholesterol should be decreased at least 30% to 40%.

Recent National Cholesterol Education Program Adult Treatment Panel III Update: Adjustments and Options

In the summer of 2004, an evidence-based update of the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) guidelines for management of hypercholesterolemia was published. This detailed assessment of 5 major clinical trials, published since the ATP III report in 2001, was designed to provide guidance for physicians in decision making for patients at high risk and very high risk. We have tried to summarize this assessment by suggesting the following to clinicians: (1) Calculate global risk of coronary artery disease (CAD) to determine an overall strategy for cholesterol management. (2) Emphasize the benefits of diet, exercise, and weight control or therapeutic lifestyle change, especially in those with lifestyle risk factors. (3) Use 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors (statins) as first-line drugs to reduce risk of CAD and stroke in those at moderate to high risk. (4) If statins are prescribed, use moderate doses that reduce plasma levels of low-density lipoprotein (LDL) cholesterol by > or = 30% to 40%. (5) Strongly consider statin therapy in those with diabetes (with the exception of severe hypertriglyceridemia). (6) Consider LDL cholesterol-lowering drug therapy for lipids in older patients at risk. (7) Consider adding either a fibrate or nicotinic acid in high-risk patients with elevated plasma triglyceride values or low levels of plasma high-density lipoprotein cholesterol after statin therapy has achieved the LDL cholesterol goal. (8) Continue to treat those at low risk in similar fashion as before. This update is to inform current physician judgment in this area. Further clinical trial data that may modify or extend these recommendations are eagerly awaited.

P.4.020 Efficacy and tolerability of memantine in nursing home patients with moderate to severe dementia of the Alzheimer's type

The proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secreted protein that interacts with the low-density lipoprotein (LDL) receptor at the surface of hepatocytes to regulate circulating LDL cholesterol levels. High circulating PCSK9 levels have been associated with elevated LDL cholesterol. Recently, the Food and Drug Administration of the United States approved new LDL cholesterol–lowering drugs that specifically target the inhibition of PCSK9. Similar to most human proteins, PCSK9 exists in multiple forms as it is the target of posttranslational modifications (PTMs) such as proteolytic cleavage, phosphorylation, and others, which can affect its biological activity. However, commercially available assays, such as enzyme-linked immunosorbent assays, do not discriminate between these forms.To investigate, in 2 patient cohorts, the relationships between circulating levels of multiple forms of PCSK9 and cardiometabolic interventions or treatments known to reduce LDL cholesterol levels.PCSK9 forms were measured in plasma: (1) in 20 patients before and 6 months after bariatric surgery and (2) in 132 patients before and 12 months after daily statin treatment. A series of specific peptides used as surrogates for various PCSK9 forms were quantified by a novel semiautomated proteomic assay termed protein affinity capture coupled to quantitative mass spectrometry.Bariatric surgery resulted in a decrease in the plasma level of PCSK9 prodomain (P < .05), but did not result in a significant change in other measured PCSK9 forms. Statin treatment resulted in an increase in all measured plasma PCSK9 peptides (P < .001), but a 25% decrease in the phosphorylated state of PCSK9 at S688 (P < .05).These unexpected findings indicate that measuring the circulating levels of the various domains and PTMs of PCSK9 provides more in depth information than total PCSK9 and that the prodomain and the phosphorylated state of S688 may represent novel biomarkers to explore in cardiometabolic diseases and response to treatment. In addition, our data generated new hypotheses on the function of PCSK9 PTMs in health and disease.

Statins and the soul of medicine

Statins and the soul of medicine