A Man with Primary Hyperchylomicronemia with Triglyceride Levels Exceeding 11,000 mg/dL was Well Controlled by Pemafibrate Combined with Dietary Therapy: A Case Report.

A 50-year-old man with a triglyceride (TG) level of 11,397 mg/dL was admitted to our hospital. He consumed a high-fat and high-carbohydrate diet as well as more than 100 g of alcohol per day. He had type 2 diabetes and obesity and had previously suffered from severe acute pancreatitis twice. A genetic analysis revealed compound heterozygous mutations in APOA5 (c.56C>G and c.553G>T). In addition to low-fat meals and alcohol cessation, administration of pemafibrate lowered his triglyceride levels to <150 mg/dL.

Association between COVID-19 severity and relatively high serum adiponectin levels at the time of admission.

At the beginning of 2020, coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) led to epidemics worldwide. Obesity and visceral fat accumulation have been reported to be independent risk factors for severe COVID-19. Several reports have focused on the levels of adipocytokines/adipokines, including adiponectin (APN), which is exclusively secreted from adipocytes, although the importance of these factors in acute disease conditions remains unclear. Therefore, we investigated the relationship between serum adiponectin levels and COVID-19 severity. Patients with COVID-19 who were admitted to Sumitomo Hospital (Osaka, Japan) from May through October 2021 were included. A total of 107 patients were enrolled in this study. We obtained the anthropometric and clinical laboratory data of the patients at the time of admission and examined the associations between various parameters and COVID-19 severity. The mean period from onset to admission was 6.5 ± 2.8 days. We divided the patients into "non-severe" (mild, moderate-I and moderate-II) (n = 80) and "severe" (n = 27) groups. The "severe" patients were significantly older than "non-severe" patients. Additionally, no significant differences were observed in BMI, sex, or the period from onset to admission. The serum adiponectin levels of "severe" patients at the time of admission were significantly greater than those of "non-severe" patients even after adjusting for age, sex, and BMI. These results suggest that the serum APN levels at the time of admission can predict COVID-19 severity. However, further investigations on the changes in APN levels in acute diseases are needed.

Myocardial fat accumulation is associated with cardiac dysfunction in patients with type 2 diabetes, especially in elderly or female patients: a retrospective observational study.

BACKGROUND: Ectopic fat is fat that accumulates in or around specific organs or compartments of the body including myocardium. The clinical features of type 2 diabetes patients with high fat accumulation in the myocardium remain unknown. Moreover, little is known about the influence of myocardial fat accumulation in type 2 diabetes on coronary artery disease and cardiac dysfunction. We aimed to clarify the clinical features, including cardiac functions, of type 2 diabetes patients with myocardial fat accumulation. METHODS: We retrospectively enrolled type 2 diabetes patients who underwent ECG-gated coronary computed tomography angiography (CCTA) and abdominal computed tomography (CT) scan examinations within 1 year of CCTA from January 2000 to March 2021. High fat accumulation in the myocardium was defined as the low mean myocardial CT value of three regions of interest, and the associations between CT values and clinical characteristics or cardiac functions were assessed. RESULTS: In total, 124 patients were enrolled (72 males and 52 females). The mean age was 66.6 years, the mean BMI was 26.2 kg/m2, the mean ejection fraction (EF) was 67.6%, and the mean myocardial CT value was 47.7 Hounsfield unit. A significant positive correlation was found between myocardial CT value and EF (r = 0.3644, p = 0.0004). The multiple regression analyses also showed that myocardial CT value was independently associated with EF (estimate, 0.304; 95% confidence interval (CI) 0.092 to 0.517; p = 0.0056). Myocardial CT value showed significant negative correlations with BMI, visceral fat area and subcutaneous fat area (r = - 0.1923, - 0.2654, and -0.3569, respectively, p < 0.05). In patients who were ≥ 65 years or female, myocardial CT value showed significant positive correlations with not only EF (r = 0.3542 and 0.4085, respectively, p < 0.01) but also early lateral annular tissue Doppler velocity (Lat e') (r = 0.5148 and 0.5361, respectively, p < 0.05). The multiple regression analyses showed that myocardial CT value was independently associated with EF and Lat e' in these subgroups (p < 0.05). CONCLUSIONS: Patients with type 2 diabetes, especially in elderly or female patients, who had more myocardial fat had more severe left ventricular systolic and diastolic dysfunctions. Reducing myocardial fat accumulation may be a therapeutic target for type 2 diabetes patients.

Increase in glycemic set point, alongside a decrease in waist circumference, in the non-diabetic population during the Japanese National Intervention Program for metabolic syndrome: A single-center, large-scale, matched-pair analysis.

BACKGROUND: In 2008, the Japanese government implemented a National Intervention Program for metabolic syndrome. Low-risk individuals were not direct targets of this intervention. Nevertheless, they were indirectly enlightened by this massive campaign. Documentation of the metabolic shifts in low-risk individuals following the program launch may inform public health policy regarding approaches to metabolic risks in the general population. METHODS: We conducted a cross-sectional analysis of data from non-diabetic participants who underwent general health check-ups at the Physical Check-up Center of Sumitomo Hospital. Participants during 2007-2008 were pair-matched with those during 2015-2016 with respect to sex, age, smoking status, hemoglobin level, and red blood cell (RBC) count. Each participant was included only once in the study. RESULTS: Totals of 3,140 men and 2,048 women were pair-matched. The non-diabetic participants showed lower waist circumference, blood pressure, heart rate, and serum lipid concentrations during the second study period. In contrast, the entire distributions of fasting plasma glucose (FPG) concentration in both sexes and glycated hemoglobin (HbA1c) in women were shifted upwards. In men, Δ FPG was +1.6 mg/dL (P < 0.001) and Δ HbA1c was ±0% (P = 0.6). In women, Δ FPG was +3.0 mg/dL (P < 0.001), and Δ HbA1c was +0.1% (P < 0.001). Δ Homeostasis model assessment of ß-cell function was -6.6 in men (P < 0.001) and -10.3 in women (P < 0.001). The homeostasis model assessment of insulin resistance did not change significantly. CONCLUSIONS: The "glycemic set point" has increased in non-diabetic people in Japan during recent years. Lifestyle or environmental changes may have caused this metabolic shift through obesity-independent pathways, possibly through effects on pancreatic ß-cell function. The underlying mechanism awaits further investigation.

Integrated Analysis of Two Probucol Trials for the Secondary Prevention of Atherosclerotic Cardiovascular Events: PROSPECTIVE and IMPACT.

AIMS: In this study, we integrated two randomized control trials, PROSPECTIVE and IMPACT, to address the effect of probucol on cerebrocardiovascular events and carotid intima-media thickness (IMT) in Japanese, Korean, and Chinese patients with coronary artery disease (CAD). METHODS: A total of 1,025 patients from the PROSPECTIVE and IMPACT studies were enrolled. The time to the first major adverse cerebrocardiovascular event, in addition to carotid IMT and lipid levels, was compared between the control and probucol groups. RESULTS: In the integrated analysis, the adjusted hazard ratio (HR) and 95% confidence interval (CI) were 0.67 and 0.44-1.03, respectively, indicating a tendency to show the effect of probucol on cerebrocardiovascular events in secondary prevention. We also found no significant differences between the control and probucol groups in the mean IMT of the carotid arteries and its changes. However, we found a significant decrease in cerebrocardiovascular events in patients with reduced levels of HDL cholesterol (HDL-C) (≥ 6.25 mg/dL) compared with those with levels ＜6.25 mg/dL (p=0.024), without any increase in adverse events such as severe ventricular arrhythmias. CONCLUSION: We demonstrated a marginal effect of probucol on cerebrocardiovascular events in Asian patients with CAD, with reasonable safety profiles. A larger study may be needed to support the effect of probucol for cardiovascular prevention.

The Combination of High Levels of Adiponectin and Insulin Resistance Are Affected by Aging in Non-Obese Old Peoples.

Background: Adipokine dysregulation is a key feature of insulin resistance and a metabolic syndrome associated with obesity. Low adiponectin levels are associated with higher risks of cardiovascular diseases (CVD). However, high adiponectin levels have also been associated with increased all-cause and cardiovascular mortality in the elderly. This adiponectin paradox has yet to be clarified, which has hindered our understanding of the biological role of adiponectin. Adipokine dysregulation and insulin resistance are also associated with energy-deprivation conditions, such as frailty in old age. The objective of this study was to investigate the association between plasma adiponectin and insulin resistance using the homeostasis model assessment for insulin resistance (HOMA-IR) classified by age. In particular, we sought to determine the factors of the subjects associated with both high adiponectin levels and HOMA-IR (H-adiponectin/H-HOMA) and high adiponectin levels and low HOMA-IR (H-adiponectin/L-HOMA). Methods: The eligible subjects in this cross-sectional study were 33,216 individuals who had undergone health checkups at the Physical Checkup Center of Sumitomo Hospital between April 2008 and December 2018. After excluding 26,371 individuals who were under 60 years old, 529 who had been taking medications for diabetes mellitus, and 690 with missing data, the present study included 5,673 (3,467 males, 2,206 females) subjects with no missing data. The relationship between serum adiponectin levels and HOMA-IR was assessed using logistic regression models adjusted by clinically relevant factors. Results: In the multivariable logistic regression analysis, age and low BMI were shown to positively correlate with the characteristics of H-adiponectin/H-HOMA. In females, systolic blood pressure was also shown to be an associated factor. Conclusion: In conclusion, this study showed that aging or a low BMI may contribute to high adiponectin levels and insulin resistance.

Probucol Trial for Secondary Prevention of Atherosclerotic Events in Patients with Coronary Heart Disease (PROSPECTIVE).

AIMS: Although intensive statin therapy reduced cardiovascular risks, cardiovascular events have not been completely prevented. Probucol is a potent antioxidant and reduces tendon xanthomas in familial hypercholesterolemia patients despite reduction of high-density lipoprotein (HDL)-cholesterol (HDL-C). We investigated whether probucol can reduce cardiovascular events on top of conventional lipid-lowering therapy in patients with coronary heart disease (CHD). METHODS: PROSPECTIVE is a multicenter, randomized, prospective study that recruited 876 Japanese patients with CHD and dyslipidemia with a low-density lipoprotein (LDL)-cholesterol (LDL-C) level of ≥ 140 mg/dL without medication or those treated with lipid-lowering drugs. Lipid-lowering agents were administered during the study period in the control group (n=438), and probucol 500 mg/day was added to lipid-lowering therapy in the probucol group (n=438). Patients were randomly assigned to two treatment groups by adjusting the LDL-C level and presence of diabetes and hypertension and followed up for more than 3 years. The primary end point was a composite of cerebrovascular and cardiovascular events (cardiovascular disease death including sudden death, nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina, hospitalization for heart failure, or coronary revascularization). The secondary end point was carotid intima-media thickness in a subset of patients. RESULTS: The incidence of the primary end point showed a trend to be lower in the probucol group compared with that in the control group despite reduced HDL-C without serious adverse events. Anti-atherogenic effects of probucol may be attributed to its potent antioxidative function and enhancement of reverse cholesterol transport. CONCLUSION: Since there was no statistical significance between the probucol and control groups despite a marked reduction of HDL-C, further studies on the clinical outcomes of probucol on top of conventional therapy may be necessary in the future (UMIN000003307).

Effect of tasteless calorie-free gum chewing before meal on postprandial plasma glucose, insulin, glucagon, and gastrointestinal hormones in Japanese men without diagnosed glucose metabolism disorder: a pilot randomized crossover trial.

This pilot study aimed to examine the effect of pre-meal tasteless calorie-free gum chewing on post-meal blood levels of glucose, insulin, glucagon, and gastrointestinal hormones. This was an open-label, randomized, 2-sequence, 3-period, 2-treatment crossover trial with a 1:1 allocation. Sixteen Japanese adult male volunteers aged between 30 and 49 years without diagnosed glucose metabolism disorder were enrolled. Ingestion of 200-g cooked rice after 15-min tasteless calorie-free gum chewing (GUM+ treatment) was compared to that without preceding gum chewing (GUM- treatment). Cooked rice was divided into twelve equally sized portions and consumed by chewing each portion 30 times before swallowing. Treatment sessions were separated by an at least 1-week interval and attended after an overnight fast. Circulating levels of glucose, insulin, glucagon, active glucagon-like peptide (GLP)-1 and ghrelin were measured at baseline (before treatment) and 0, 15, 30, 60, and 120 min after completion of the meal ingestion, and the postprandial change from baseline was assessed. As a result, the change in glucose levels at 0 min was significantly lower in the GUM+ treatment than in the GUM- treatment (P = 0.004). Furthermore, the GUM+ treatment demonstrated higher incremental insulin levels at 15 min (P = 0.041) and higher incremental active GLP-1 levels at 30 and 60 min (P = 0.018 and 0.021, respectively); whereas, postprandial glucagon and ghrelin levels were not significantly different. In conclusion, the current pilot study demonstrated that tasteless calorie-free gum chewing before rice eating had a significant but limited impact on the increase of postprandial active GLP-1 levels in male individuals without diagnosed glucose metabolism disorder.

Gaps in beliefs and practice in dyslipidaemia management in Japan, Germany, Colombia and the Philippines: insights from a web-based physician survey.

BACKGROUND: Implementing evidence-based management of dyslipidaemia is a challenge worldwide. OBJECTIVES: To understand physician beliefs and behaviour and identify uncertainties in dyslipidaemia management across four world regions. METHODS: Web-based survey of 1758 physicians in Japan, Germany, Colombia and the Philippines who were selected randomly from existing databases. Key inclusion criteria were 1) for cardiologists and diabetes/endocrinology specialists: ≥50 dyslipidaemia patients examined in the last month; 2) for specialists in neurology/neurosurgery/stroke medicine: ≥50 dyslipidaemia patients and ≥ 20 patients with a history of ischaemic stroke examined in the last month; and 3) for specialists in nephrology and general medicine: based at centres with ≥20 beds and ≥ 50 dyslipidaemia patients examined in the last month. The self-report survey covered dyslipidaemia management, target low-density lipoprotein cholesterol (LDL-C) levels in different patient groups, and statin safety. All physicians gave voluntary consent and all data were anonymised. Analysis was solely descriptive. RESULTS: The survey highlighted key areas of uncertainty in dyslipidaemia management in the four countries. These related to LDL-C targets in different patient groups, the safety of low LDL-C levels, the safety of statins, especially for effects on cognitive, renal and hepatic function and for haemorrhagic stroke risk, and lipid management strategies in patients with chronic kidney disease, including those with concomitant hypertriglyceridaemia. CONCLUSIONS: This survey of physicians in Japan, Germany, Colombia and the Philippines has identified key gaps in knowledge about dyslipidaemia management. These relate to the safety of low LDL-C levels, the safety of statins, and lipid management of chronic kidney disease. The findings from this survey highlight the need for further education to improve the implementation of guideline recommendations for dyslipidaemia management.

Waist circumference as a vital sign in clinical practice: a Consensus Statement from the IAS and ICCR Working Group on Visceral Obesity.

Despite decades of unequivocal evidence that waist circumference provides both independent and additive information to BMI for predicting morbidity and risk of death, this measurement is not routinely obtained in clinical practice. This Consensus Statement proposes that measurements of waist circumference afford practitioners with an important opportunity to improve the management and health of patients. We argue that BMI alone is not sufficient to properly assess or manage the cardiometabolic risk associated with increased adiposity in adults and provide a thorough review of the evidence that will empower health practitioners and professional societies to routinely include waist circumference in the evaluation and management of patients with overweight or obesity. We recommend that decreases in waist circumference are a critically important treatment target for reducing adverse health risks for both men and women. Moreover, we describe evidence that clinically relevant reductions in waist circumference can be achieved by routine, moderate-intensity exercise and/or dietary interventions. We identify gaps in the knowledge, including the refinement of waist circumference threshold values for a given BMI category, to optimize obesity risk stratification across age, sex and ethnicity. We recommend that health professionals are trained to properly perform this simple measurement and consider it as an important 'vital sign' in clinical practice.

Pemafibrate, a New Selective PPARα Modulator: Drug Concept and Its Clinical Applications for Dyslipidemia and Metabolic Diseases.

PURPOSE OF REVIEW: Reduction of serum low-density lipoprotein cholesterol (LDL-C) levels by statins, ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors has been shown to significantly reduce cardiovascular events risk. However, fasting and postprandial hypertriglyceridemia as well as reduced high-density lipoprotein cholesterol (HDL-C) remain as residual risk factors of atherosclerotic cardiovascular diseases (ASCVD). To treat patients with hypertriglyceridemia and/or low HDL-C, drugs such as fibrates, nicotinic acids, and n-3 polyunsaturated fatty acids have been used. However, fibrates were demonstrated to cause side effects such as liver dysfunction and increase in creatinine levels, and thus large-scale clinical trials of fibrates have shown negative results for prevention of ASCVD. The failure could be attributed to their low selectivity and potency for binding to peroxisome proliferator-activated receptor (PPAR) α. To resolve these issues, the concept of selective PPARα modulator (SPPARMα) with a superior balance of efficacy and safety has been proposed and pemafibrate (K-877) has been developed. RECENT FINDINGS: Pemafibrate, one of SPPARMsα, was synthesized by Kowa Company, Ltd. for better efficiency and safety. Clinical trials in Japan have established the superiority of pemafibrate on effects on serum triglycerides (TG) reduction and HDL-C elevation as well safety. Although available fibrates showed worsening of liver and kidney function test values, pemafibrate indicated improved liver function test values and was less likely to increase serum creatinine or decrease estimated glomerular filtration rate (eGFR). Very few drug-drug interactions were observed even when used concomitantly with statins. Furthermore, pemafibrate is metabolized in the liver and excreted into the bile, while many of available fibrates are mainly excreted from the kidney. Therefore, pemafibrate can be used safely even in patients with impaired renal function since there is no significant increase in its blood concentration. A large-scale trial of pemafibrate, PROMINENT, for dyslipidemic patients with type 2 diabetes is ongoing. Pemafibrate is one of novel SPPARMsα and has superior benefit-risk balance compared to conventional fibrates and can be applicable for patients for whom the usage of existing fibrates is difficult such as those who are taking statins or patients with renal dysfunction. In the current review, all the recent data on pemafibrate will be summarized.

Adiponectin, a unique adipocyte-derived factor beyond hormones.

Visceral fat accumulation has a marked impact on atherosclerotic cardiovascular diseases and metabolic syndrome clustering diabetes, dyslipidemia, and hypertension. Adiponectin, an adipocyte-derived circulating protein, is a representative adipocytokine and uniquely possesses two major properties: 1) its circulating concentration is approximately 3-6 orders of magnitude greater than ordinary hormones and cytokines; 2) its concentration inversely correlates with body fat mass despite its adipocyte-specific production. Low serum levels of adiponectin correlate with cardiometabolic diseases. Extensive experimental evidence has demonstrated that adiponectin possesses multiple properties, such as anti-atherosclerotic, anti-diabetic, and anti-inflammatory activities. It has been shown to play a central role against the development of metabolic syndrome and its complications. However, even approximately 25 years after its discovery, the properties of adiponectin, including how and why it exerts multiple beneficial effects on various tissues and/or organs, remain unclear. Furthermore, the mechanisms responsible for the very high circulating concentrations of adiponectin in the bloodstream have not been elucidated. Several adiponectin-binding partners, such as AdipoR1/2, have been identified, but do not fully explain the multi-functional and beneficial properties of adiponectin. Recent advances in adiponectin research may resolve these issues. Adiponectin binds to and covers cell surfaces with T-cadherin, a unique glycosylphosphatidylinositol (GPI)-anchored cadherin. The adiponectin/T-cadherin complex enhances exosomal production and release, excreting cell-toxic products from cells, particularly in the vasculature. In this review, we discuss adiponectin and the role of the adiponectin/T-cadherin system in the maintenance of whole body homeostasis and cardiovascular protection.

Small-intestinal necrosis due to non-occlusive mesenteric ischemia with diabetic ketoacidosis after quetiapine treatment.

We report a 66-year-old male who developed diabetic ketoacidosis (DKA) and necrosis of the small intestine due to non-occlusive mesenteric ischemia (NOMI), 3 months after starting quetiapine treatment. He was transferred to our hospital and diagnosed as diabetic for the first time, associated with DKA. Despite improvement in DKA, abdominal pain worsened gradually 10 h after hospitalization. Computed tomography (CT) revealed bowel emphysema, and gas out of the gut wall, in the mesenteric veins and the intrahepatic portal vein, suggesting intestinal necrosis. He survived because of resection of necrotic small-intestinal tissue and he finally required no diabetes treatment. Mesenteric arteries were patent with good palpitation without occlusion or thrombosis, and pathological findings showed ischemic enteritis, which is consistent with NOMI. DKA is a rare but serious side effect of second-generation antipsychotic medications (SGAMs) such as quetiapine, which can result in NOMI: a life-threatening complication. We must keep in mind that the plasma glucose concentration may increase in patients taking SGAMs, or that NOMI may occur concurrently if DKA develops.

Visceral and ectopic fat, atherosclerosis, and cardiometabolic disease: a position statement.

Findings from epidemiological studies over the past 30 years have shown that visceral adipose tissue, accurately measured by CT or MRI, is an independent risk marker of cardiovascular and metabolic morbidity and mortality. Emerging evidence also suggests that ectopic fat deposition, including hepatic and epicardial fat, might contribute to increased atherosclerosis and cardiometabolic risk. This joint position statement from the International Atherosclerosis Society and the International Chair on Cardiometabolic Risk Working Group on Visceral Obesity summarises the evidence for visceral adiposity and ectopic fat as emerging risk factors for type 2 diabetes, atherosclerosis, and cardiovascular disease, with a focus on practical recommendations for health professionals and future directions for research and clinical practice. We discuss the measurement of visceral and ectopic fat, pathophysiology and contribution to adverse health outcomes, response to treatment, and lessons from a public health programme targeting visceral and ectopic fat. We identify knowledge gaps and note the need to develop simple, clinically applicable tools to be able to monitor changes in visceral and ectopic fat over time. Finally, we recognise the need for public health messaging to focus on visceral and ectopic fat in addition to excess bodyweight to better combat the growing epidemic of obesity worldwide.

Clinical Applications of a Novel Selective PPARα Modulator, Pemafibrate, in Dyslipidemia and Metabolic Diseases.

Fasting and postprandial hypertriglyceridemia is a risk factor for atherosclerotic cardiovascular diseases (ASCVD). Fibrates have been used to treat dyslipidemia, particularly hypertriglyceridemia, and low HDL-cholesterol (HDL-C). However, conventional fibrates have low selectivity for peroxisome proliferator-activated receptor (PPAR)α. Fibrates' clinical use causes side effects such as worsening liver function and elevating the creatinine level. Large-scale clinical trials of fibrates have shown negative results for prevention of ASCVD. To overcome these issues, the concept of the selective PPARα modulator (SPPARMα), with a superior balance of efficacy and safety, has been proposed. A SPPARMα, pemafibrate (K-877), was synthesized by Kowa Company, Ltd. for better efficacy and safety. Clinical trials conducted in Japan confirmed the superior effects of pemafibrate on triglyceride reduction and HDL-C elevation.Conventional fibrates showed elevated liver function test values and worsened kidney function test values, while pemafibrate demonstrated improved liver function test values and was less likely to increase serum creatinine or decrease the estimated glomerular filtration rate. There were extremely few drug interactions even when it was used concomitantly with various statins. Furthermore, unlike many of the conventional fibrates that are renal excretory-type drugs, pemafibrate is excreted into the bile, so it can be safely used even in patients with impaired renal function and there is no increase in its blood concentration.This novel SPPARMα, pemafibrate, has superior benefit-risk balance compared to conventional fibrates and can be used for patients for whom it was difficult to use existing fibrates, including those who are taking statins and those with renal dysfunction. A large-scale trial PROMINENT using pemafibrate for patients with type 2 diabetes is in progress. In the current review, the latest data on pemafibrate will be summarized.

Cultural Barriers in the Treatment of Dyslipidemia: A Survey of Japanese Physician Attitudes.

AIMS: To gain a more accurate understanding of the current real-world management of dyslipidemia in Japan, an online survey was conducted in a variety of physicians from five medical fields. METHODS: A web-based survey with online questionnaire was designed, and members of an on-line information service for physicians were invited to participate. The survey enrolled 500 physicians, 100 in each of five categories: cardiology; diabetes, metabolism and endocrinology; neurology/neurosurgery/stroke medicine; general internal medicine (hospitals ≥20 beds), and general internal medicine (self-employed practitioners at clinics or small hospitals ≤19 beds). RESULTS: Regardless of their specialties, most physicians recognized high low density lipoprotein cholesterol level as an important risk for atherosclerotic cardiovascular disease. Physicians with expertise in cardiology, diabetes, metabolism and endocrinology were most in favor of drug-based cholesterol lowering. Specialists in neurology/neurosurgery/stroke medicine and in general internal medicine were more concerned about statin safety and aggressive lipid-lowering therapy than those in cardiology and diabetes, metabolism and endocrinology, and tended to treat fewer patients with familial hypercholesterolemia (FH). Especially, those in general internal medicine (self-employed practitioners at clinics or small hospitals ≤19 beds) made less use of techniques for diagnosing FH. CONCLUSIONS: Awareness of target values for lipid management and of adverse reactions to drug therapy appears to vary somewhat depending on the participant's medical specialty. We also found that FH is probably underdiagnosed in Japan today. Further educations on proper diagnosis and management of dyslipidemia are required for physicians who are not specialized in cardiovascular health.

Cholesteryl ester transfer protein: An enigmatic pharmacology - Antagonists and agonists.

The cholesteryl ester transfer protein (CETP) system moves cholesteryl esters (CE) from high density lipoproteins (HDL) to lower density lipoproteins, i.e. very low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) in exchange for triglycerides (TGs). This shuttle process will ultimately form complexes facilitating a bidirectional exchange of CE and TGs, the end process being CE delivery to catabolic sites. The CETP system is generally characteristic of higher animal species; lower species, not provided with this system, have higher and enlarged HDL enriched with apo E, suitable for tissue receptor interaction. Discovery of the CETP system has led to the development of agents interfering with CETP, thus elevating HDL-C and potentially preventing cardiovascular (CV) disease. Activation of CETP leads instead to reduced HDL-C levels, but also to an enhanced removal of CE from tissues. CETP antagonists are mainly small molecules (torcetrapib, anacetrapib, evacetrapib, dalcetrapib) and have provided convincing evidence of a HDL-C raising activity, but disappointing results in trials of CV prevention. In contrast, the CETP agonist probucol leads to HDL-C lowering followed by an increment of tissue cholesterol removal (reduction of xanthomas, xanthelasmas) and positive findings in secondary prevention trials. The drug has an impressive anti-inflammatory profile (markedly reduced interleukin-1ß expression). Newer agents, some of natural origin, have additional valuable pharmacodynamic properties. The pharmacological approach to the CETP system remains enigmatic, although the failure of CETP antagonists has dampened enthusiasm. Studies on the system, a crossroad for any investigation on cholesterol metabolism, have however provided crucial contributions and will still be confronting any scientist working on CV prevention.