Effects of millet consumption on metabolic homeostasis (glycemic control and lipid profiles) in adults: A systematic review.

BackgroundThis study aimed to assess the associations of serum uric acid (SUA) levels and hyperuricemia with cardiometabolic risk factors in a Chinese community-dwelling population.MethodsA large cohort of 4706 residents was enrolled in this study. Physical examinations and laboratory tests were performed following a standardized protocol. Multiple linear and logistic regression analyses were conducted with adjustment of cardiometabolic risk factors including age, sex, body mass index (BMI), blood pressure (BP), triglyceride (TG), high-density lipoprotein-cholesterol (HDL-c), low-density lipoprotein-cholesterol (LDL-c) and fasting blood glucose (FBG) levels using SPSS version 17 software.ResultsThe prevalence of hyperuricemia was 7.6 %. There were significant differences in age, BMI, BP, TG, HDL-c, LDL-c and FBG levels and the proportion of men between participants with and without hyperuricemia. Multiple linear regression analysis showed that SUA levels were positively associated with age, sex, BMI, BP, TG and LDL-c levels, but negatively associated with HDL-c and FBG levels. Multiple logistic regression analysis showed that per unit increase in age was associated with a 1.014 times higher odds of the presence of hyperuricemia. Men had a 1.858 times higher odds of the presence of hyperuricemia compared with women. Per unit increases in BMI, BP, TG and LDL-c levels were associated with 1.103, 1.016, 1.173 and 1.200 times higher odds of the presence of hyperuricemia, respectively. Per unit increases in HDL-c and FBG levels were associated with 0.616 and 0.900 times lower odds of the presence of hyperuricemia, respectively.ConclusionsIn a Chinese community-dwelling population, age, sex, BMI, BP, TG, HDL-c, LDL-c and FBG levels are cardiometabolic risk factors that are significantly associated with SUA levels, as well as the presence of hyperuricemia.

Anti-Inflammatory Effects of Statins Beyond Cholesterol Lowering

The present study aims to assess the effects of zinc supplementation on metabolic parameters in patients with type 2 diabetes. A literature search was conducted in PubMedTM, Google ScholarTM, and ScopusTM up to March 2018. Twenty randomized controlled trials met the predefined inclusion criteria and were included in the meta-analysis. Weighted mean difference (WMD) with 95% confidence intervals (CIs) were calculated for net changes in glycemic indices including fasting blood glucose (FBG) and hemoglobin A1c (HbA1c), and in lipid markers including total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-c), and high density lipoprotein cholesterol (HDL-c). Subgroup analyses were performed based on intervention and study quality. Compared to controls, zinc supplementation significantly reduced the concentrations of both FBG and HbA1c (FBG WMD: −19.66 mg/dL, 95% CI: −33.71, −5.62; HbA1c WMD: −0.43 mg/dL, 95% CI: −0.80, −0.07). The pooled estimate showed a significant decrease in serum TC and LDL-c, and increase in serum HDL-c levels in treatment group compared with the control group (TC WMD: −18.51 mg/dL, 95% CI: −21.36, −15.66; LDL-c WMD: −4.80 mg/dL, 95% CI: −6.07, −3.53; HDL-c WMD: 1.45 mg/dL, 95% CI: 1.40, 1.51). Subgroup analysis of “no co-supplement” intervention demonstrated significant differences for mean changes in HDL-c and FBG levels, whereas subgroup analysis of high quality studies showed significant differences for mean changes of LDL-c, HDL-c, and FBG levels. Results suggested that zinc supplementation reduces FBG, HbA1c and LDL-c levels and increases HDL-C levels; however, these changes were related to intervention and quality of studies.

BackgroundCardiac rehabilitation (CR) programs provide an opportunity to measure low density lipoprotein cholesterol (LDL-C) levels and optimise lipid lowering therapy (LLT) accordingly. New ESC guidelines released in August 2019 recommend...

Objective: To explore the relationship between serum plasminogen activator inhibitor (PAI-1) level and Type 2 Diabetes Mellitus (T2DM) accompanied by overweight or obesity by observing not only the changes of PAI-1 level in T2DM patients with overweight or obesity, but also glucose and lipid metabolism related indicators, the changes of the inflammatory cytokines secreted by adipocytes, and then making an analysis on the correlation to PAI-1.Methods: 36 cases of healthy examinees were selected as normal control group (NC group), and the experimental group can be divided into T2DM group (54 cases), Overweight/Obesity group (35 cases) and T2DM + Overweight/Obesity group (48 cases). Glucose and lipid metabolism related indicators such as fasting blood glucose (FBG), triglyceride (TG), total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), glycated hemoglobin (HbA1c), fasting insulin (FINS), insulin resistance index (IR), body weight index (BMI) and inflammatory cytokines (interleukin-6 (IL-6), tumor necrosis factor (TNF-α) and PAI-1 were observed and compared between groups, and then made an analysis to explore the correlation of these factors to PAI-1.Results: (1) Compared with NC group, the levels of FBG, HbA1c, FINS and IR were increased in T2DM group, and the difference was of statistical significance. However, there was no statistically significant difference in TG, TC, LDL-C and BMI between NC group and T2DM group; the levels of FINS, IR, TG, LDL-C, TC and BMI were elevated in Overweight/Obesity group, and the difference was of statistical significance. However, there was no statistically significant difference in FBG and HbA1c; the levels of FBG, HbA1c, FINS, IR, TG, LDL-C, TC and BMI were up-regulated in T2DM + Overweight/Obesity group, and the difference was of statistical significance. Compared with T2DM group, the levels of TG, TC, LDL-C and BMI were increased in Overweight/Obesity group, and the difference was of statistical significance, however, the levels of FBG, HbA1c, FINS and IR were decreased, and the difference was statistically significant; The levels of FINS, IR, TG, TC, LDL-C and BMI were elevated in T2DM + Overweight/Obesity group, and the difference was of statistical significance, however, there was no statistically significant difference in FBG and HbA1c. Compared with Overweight/Obesity group, the levels of FBG, FINS, IR, HbA1c and LDL-C were increased in T2DM + Overweight/Obesity group, and the difference was of statistical significance. However, the difference in TG, TC and BMI was not statistically significant. (2) Compared with NC group, the levels of IL-6, TNF-α and PAI-1 were increased in T2DM group, Overweight/Obesity group and T2DM + Overweight/Obesity group, and the difference was statistically significant. Compared with T2DM group, the levels of IL-6 and TNF-α were elevated in Overweight/Obesity group, and the difference was of statistical significance, but there was no statistically significant difference in PAI-1; the levels of IL-6, TNF-α and PAI-1 were up-regulated in T2DM + Overweight/Obesity group, and the difference was statistically significant. Compared with Overweight/Obesity group, there was no statistically significant difference in IL-6 and TNF-α between T2DM + Overweight/Obesity group and Overweight/Obesity group, but the level of PAI-1 was increased in T2DM + Overweight/Obesity group, and the difference was of statistical significance. (3) Multivariate Logistic Regression Analysis showed that HbA1c, IR, TG, BMI, IL-6 and TNF-α were independently associated with the level of PAI-1 (all p < .05).Conclusions: (1) The level of PAI-1 is higher in type 2 diabetes mellitus patients with overweight or obesity than that in patients only with type 2 diabetes mellitus, and it is one of causes that result in vascular complications. (2) The increase in the level of PAI-1 is considered to be associated with IL-6 and TNF-α secreted by adipocytes.

BACKGROUNDType 2 diabetes mellitus (T2DM), a chronic metabolic disease with a high global incidence, has become a serious public health challenge. China has the largest number of T2DM patients worldwide, imposing a significant economic burden on the healthcare system. T2DM is closely associated with insulin resistance, impaired pancreatic B cell function, and disordered glucose and lipid metabolism, which can lead to various complications, reducing patients' quality of life and increasing the risk of disability and death. Thus, finding effective preventive and intervention measures is crucial. Exercise therapy, a key part of diabetes management, has gained attention in recent years, with many studies indicating its benefits for blood glucose control and other aspects in diabetic patients.AIMTo assess the effectiveness of combined resistance and aerobic exercise interventions on blood glucose control and metabolic indicators in patients with T2DM and to explore their application in diabetes management.METHODSSystematic searches were conducted using PubMed, EMBASE, Cochrane Library, and Chinese databases for relevant randomized controlled trials (RCTs). The inclusion criteria were participants aged ≥ 18 years with T2DM and the intervention involved combined resistance and aerobic exercise for ≥ 8 weeks. The primary outcome indicators were fasting blood glucose, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), glycated hemoglobin A1c (HbA1c), and total cholesterol (TC) levels. Data analysis was performed using RevMan software, and the interventional effects were assessed using weighted mean differences or standardized mean differences (SMD).RESULTSSix RCTs meeting the inclusion criteria were included, with a total sample size of 366 participants. The meta-analysis results showed that combined resistance and aerobic exercise significantly improved several metabolic indicators in patients with T2DM. Specific results were as follows: (1) For fasting blood glucose, combined exercise was more effective than aerobic exercise alone [SMD = 1.22; 95% confidence interval (95%CI): 0.70, 1.74; P < 0.00001]; (2) LDL-C levels were significantly reduced by the combined intervention (SMD = 1.45; 95%CI: 1.18-1.72; P < 0.00001); (3) The combined intervention significantly increased HDL-C levels (SMD = 1.42; 95%CI: 0.98-1.87; P < 0.00001); (4) The combined intervention significantly reduced TG levels (SMD = 1.12; 95%CI: 0.85-1.39; P < 0.00001; (5) No statistically significant difference was observed in HbA1c between the combined and the aerobic exercise group (SMD = −0.03; 95%CI: -1.09 to 1.04; P < 0.00001); and (6) The combined exercise intervention group significantly reduced TC levels (SMD = 2.66; 95%CI: 1.93-3.38; P < 0.00001). The subgroup analysis results suggest that the effect of exercise interventions may be influenced by various factors, including the patient's age, baseline blood glucose levels, and exercise intensity.CONCLUSIONCombined resistance and aerobic exercise intervention significantly improved fasting blood glucose, LDL-C, HDL-C, TG, and TC levels in patients with T2DM, especially in terms of blood glucose control and cardiovascular risk, demonstrating better outcomes than aerobic exercise alone.

Introduction An elevated level of low-density lipoprotein cholesterol (LDL-C) is associated with higher risk of atherosclerosis disease, and overwhelming evidence has demonstrated that lowering LDL-C reduces arteriosclerotic cardiovascular disease (ASCVD) events. However, many questions still remain regarding the use of LDL-C, such as “Are lower levels better?” and “How low is enough?” In this article, we discussed the optimal LDL-C level necessary to prevent atherosclerosis and cardiovascular events, reviewed the LDL-C level of newborns and adolescents, summarized the updated evidence of imaging and clinical benefits with lower LDL-C concentrations, and discussed the possible ways to reach lower levels of LDL-C and its safety. Atherosclerotic diseases were among the most important causes of death worldwide. Epidemiological, clinical, genetic, experimental, and pathological studies had clearly shown the role of lipoproteins in atherosclerosis. LD was the major atherogenic lipoprotein and many guidelines define it as the primary target of lipid-lowering treatment. Although the level of LDL, the primary target in the treatment of dyslipidemia, had been set to below 100 mg/dl in coronary heart diseases (CHDs) and CHD risk equivalents, it had been pulled down to below 70 mg/dl for the group defined as very high risk by guidelines following the new clinical studies. Was this target level low enough? Under intensive lipid-lowering therapy, even to the level as low as 55 mg/dL, the rate of cardiovascular events still remained at 0.77 and 1.36/100 person-years.[1] Hence, the optimal level of LDL-C may be lower than we had anticipated. As we already know, atherosclerosis begins in childhood as deposits of cholesterol and its esters, referred to as fatty streaks, in the intima of large muscular arteries. In adolescence, some fatty streaks accumulated more lipids and begin to develop a fibromuscular cap, forming the lesion termed a fibrous plaque. Further changes in fibrous plaques render them vulnerable to rupture, an event that precipitates occlusive thrombosis and clinically manifest diseases (sudden cardiac death, myocardial infarction, stroke, or peripheral arterial disease). In the neonatal stage, the progression of atherosclerosis was not yet initiated, so this suggests that the LDL levels should potentially be lowered to the levels at birth. Physical Low-density Lipoprotein Cholesterol Level in Newborn A sample of umbilical cord venous blood was obtained from 156 normal newborns (76 male) immediately after delivery: mean values of LDL-C in males, females, and in the total sample were 28.3, 32.4, and 30 mg/dl, respectively.[2] Cord blood mean (standard deviation [SD]) LDL-C values in 378 full-term Iranian newborns was 35.9 ± 22.4 in girls and 32.1 ± 16.3 in boys.[3] Another trial taken in Brazil showed that total cholesterol concentrations were 70.42 ± 1.63 mg/dl, and LDL-C level was 34.38 ± 1.29 mg/dl in the term group.[4] A study taken in china also determined the lipid profile in 242 healthy full-term newborn infants. The mean values of LDL-C in cord blood were 31.15 ± 8.08 mg/dL (mean ± SD).[5] A study was carried out in 137 healthy newborns (63 boys and 74 girls) coming from normal, physiological pregnancies, spontaneously born, and generally in good condition. The mean cholesterol LDL value was 34.12 ± 14.08 mg/dl. Recently, a cross-sectional study from Brazil tested the lipid profile of 435 parturient and their newborn babies. The mean LDL-C level in parturient and neonates were 112.7 mg/dL and 29.9 mg/dL, respectively. In addition, The LDL-C level in newborn is not influenced by change in the maternal lipid profile.[6] So according to the epidemiological studies, the natural cord blood and neonatal LDL level is about 30 mg/dL. Since atherosclerosis has not yet developed at birth, this may be the optimal physical cholesterol level for preventing atherosclerosis. Low-density Lipoprotein and Atherosclerosis in Children and Adolescent The LDL-C level and atherosclerosis both increase with aging. Many studies have investigated the LDL level in children ranging from 3 to 18 years old. The LDL level was 80-125 mg/dL.[7-14] It was normal according to the adult criteria in the practice guidelines, but much higher than in newborns. Meanwhile, studies showed that atherosclerosis also initiated at this period and progressed with age. A multicenter cooperative study,[15] Pathobiological Determinants of Atherosclerosis in Youth (PDAY) showed the extent of both fatty streaks and raised lesions (fibrous plaques and other advanced lesions) in the right coronary artery and in the abdominal aorta was associated positively with nonhigh-density lipoprotein -cholesterol (HDL-C) concentration. By 15-19 years of age, fatty streaks occupied ≈25% of the aortic intima in both the thoracic and abdominal aortas. By the age of 30-34 years, raised lesions occupied <0.5% of the thoracic aorta, but occupied ≈5% of the abdominal aortic surface. In the right coronary artery, fatty streaks increased in extent from ≈2% of the intimal surface at the age of 15-19 years to ≈8% at the age of 30-34 years and were equal in men and women. Raised lesions increased from ≈0.5% at the age of 15-19 years to >2% at the age of 30-34 years. The same phenomenon was observed in the Bogalusa Heart Study. Another study[10] related arterial distensibility, a marker of vascular function known to be altered early in atherosclerosis, to the lipid profile of a population-based sample of children aged 9-11 years. A noninvasive ultrasound technique was used to measure arterial distension during the cardiac cycle in the brachial arteries of 361 children from 4 towns in the United Kingdom. The mean LDL in the population was 110 [SD 25.4] mg/dL. There was a significant, inverse relation between LDL-C and distension of the artery across this range (linear regression P < 0.005). Hence LDL-C levels had an impact on arterial distensibility in the first decade of life. Although the LDL-C seems to be normal at in children and during the adolescent period, it still initiates damage to the vessel and progression of atherosclerosis. The fatty steak and small plaque develop with age. Low-density Lipoprotein Cholesterol Lowering and Atherosclerosis Progression and Regression Abundant data from many prospective trials revealed a strong and direct relationship between LDL levels and rates of atherosclerotic progression. Recently, trials showed that intensive lipid-lowering with statins or other drugs can halt or even reverse atherosclerosis. These randomized controlled trials showed that the atherosclerosis progression or regression was closely related to the on-treat LDL level. Intima-Media Thickness Evaluation Clinical sequelae, however, are preceded by silent changes. It has been now widely endorsed and standardized for measurement of intima-media thickness (IMT). Nowadays, carotid IMT changes over time have become an important surrogate endpoint in clinical intervention trials. Some studies demonstrated the relationship between LDL-C value and IMT. The effect of aggressive versus conventional lipid lowering on atherosclerosis progression in familial hypercholesterolemia was studied using a randomized, double-blind clinical trial in 325 patients.[16] After 2-year therapy, IMT decreased by 0.031 mm in the atorvastatin 80 mg group, whereas in the simvastatin 40 mg group, it increased by 0.036 mm. The LDL-C level was reduced from 307.69 mg/dl to 149.23 mg/dl and 320.38 mg/dl to 185 mg/dl, respectively. At the end of the ENHANCE[17] study, the mean (± SD) LDL-C level was 192.7 ± 60.3 mg/dl in the simvastatin group and 141.3 ± 52.6 mg/dl in the combined therapy group. The primary outcome, the mean (± SE) change in IMT, was 0.0058 ± 0.0037 mm in the simvastatin-only group and 0.0111 ± 0.0038 mm in the simvastatin plus ezetimibe group (P = 0.29). The Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER) trial[18] used 80 mg/d atorvastatin or 40 mg/d pravastatin in 161 patients with a mean baseline LDL of 150 mg/d. Atorvastatin reduced LDL to mean levels as well as to 76 mg/dl and 110 mg/dl in pravastatin. The IMT regressed 0.038 mm in atorvastatin compared with a mean progression of 0.026 mm in the pravastatin group. Another 984 patients were enrolled in Measuring Effects on Intima-Media Thickness: An Evaluation of Rosuvastatin (METEOR).[19] Among the patients who took rosuvastatin 40 mg, the LDL-C level of 155 mg/dl was reduced to 78 mg/dl. The change was −0.0014 mm/y and 0.0131 mm/y in rosuvastatin and in the placebo. Thus, rosuvastatin resulted in LDL-C levels as low to 78 mg/dl and induced statistically significant reductions in the rate of progression of maximum CIMT over 2 years versus placebo. Mean IMT measures (0.83 ± 0.13 mm vs. 0.87 ± 0.16 mm) were also significantly lower among those with Proprotein convertase subtilisin/kexin type 9 (PCSK9) gene variant when compared with the noncarriers with lower LDL-C level (95.5 ± 32.1 mg/dL vs. 109.6 ± 32.0 mg/dL) in a recent study.[20] These trials have further supported that decreasing LDL-C levels can delay thickening of IMT and intensive medication therapy can even stop or regress the progression of atherosclerosis, with LDL-C level around the 70-80 mg/dl. However, since the regression was very small, it seems that we should induce a greater reduction of LDL levels. Intravascular Ultrasound Evaluation Intravascular ultrasound (IVUS) imaging had emerged as the predominant approach for evaluating coronary atherosclerosis. IVUS provided a precise and reproducible method for determining the change in atheroma burden. The early trial used minimal lumen diameter change as endpoints. Recent trials measured atheroma volume, especially percent atheroma volume (PAV), the most rigorous IVUS parameter of disease progression and regression. The Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) study[21] was an 18-month trial comparing the effects of intensive versus moderate lipid-lowering therapy on plaque progression in patients. A total of 253 patients were randomized to atorvastatin 80 mg/d and 249 patients were randomized to pravastatin 40 mg/d. LDL-C levels decreased from a baseline mean of 150 mg/dL in both groups to 79 mg/dL in the atorvastatin group and 110 mg/dL in the pravastatin group. For the primary end-point of percent change in total atheroma volume, a significantly lower rate of progression from baseline was observed with atorvastatin (−0.4%) than with pravastatin (2.7%) (P = 0.02). More recently, prospective, open-label blinded trial (A Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound-Derived Coronary Atheroma Burden [ASTEROID]) enrolled 507 patients,[22] and 40 mg/d rosuvastatin were administered for 24 months. The LDL-C was reduced by 53.2%, from 130.4 mg/dL to 60.8 mg/dL (P < 0.01). The mean (SD) change in PAV was −0.98% (3.15%), with a median of −0.79% (97.5% confidence interval [CI] -1.21% to −0.53%) (both P < 0.01 vs. baseline). The investigator suggested that very high-intensive statin therapy with lower LDL-C level can regress atherosclerosis in CHD patients. The results of Multicenter Coronary Atherosclerosis Study Measuring Effects of Rosuvastatin Using Intravascular Ultrasound In Japanese Subjects (COSMOS) was published last year.[23] This 76-week open-label trial was performed in Japan. A total of 126 patients were given 2.5-20 mg/d rosuvastatin and had baseline and follow-up IVUS measurement. The mean (SD) LDL-C was reduced from 140.2 (31.5) mg/dl to 82.9 (18.7) mg/dl. The mean (SD) plaque volume was decreased from 72.1 (38.1) mm3 to 66.8 (34.0) mm3. Rosuvastatin also exerted significant regression of coronary plaque volume in Japanese patients with stable CAD. PRECISE-IVUS Trial[24] in Japanese patients who underwent percutaneous coronary intervention showed that the combination of atorvastatin/ezetimibe resulted in lower levels of LDL-C than atorvastatin monotherapy (63.2 vs. 73.3 mg/dl; P < 0.001). For the absolute change in PAV, the mean difference in ezetimibe combination group was noninferior compared with atorvastatin group. However, the absolute change in PAV did show superiority for the dual lipid-lowering strategy (−1.4%; 95% [CI]: −3.4% to −0.1% vs. −0.3%; 95% CI: −1.9% to 0.9% with atorvastatin alone; P < 0.001). For PAV, a significantly greater percentage of patients who received atorvastatin/ezetimibe showed coronary plaque regression (78% vs. 58%; P < 0.004). If the LDL-C level reduced to about 80 mg/dl, progression of atherosclerosis was halted in REVERSAL. When LDL level further decreased to 60-80 mg/dl, as low as 60.8 mg/dl in ASTEROID trial with intensive statin therapy and 63.2 mg/dl in PRECISE-IVUS trial with combination therapy, atherosclerosis was regressed [Figure 1]. Although the extent of regression was just about 0.2%-1.4%, it still supported the hypothesis that we should reduce LDL to newborn levels.Figure 1:: Relationship between low-density lipoprotein and change of atheroma (both percent atheroma volume and minimal lumen diameter change). Use Pearson correlation test. (PRECISE-IVUS study is not included)Low-density Lipoprotein and Clinical Events Many trials and meta-analyses had demonstrated the relationship between LDL level and coronary heart disease, including WOSCOPS, AFCAPS, ASCOT, and JUPITER in primary prevention and 4S, LIPID, CARE, HPS, IDEAL, TNT, and PROVIT-IT in secondary prevention. In a previous aggregated analysis, results indicated[25] that the LDL level at which the CHD rate predicated to approach 0 is 57 mg/dl for primary prevention and 30 mg/dl for secondary prevention. All these data support the theory “the lower the better.” In recent famous trial - Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER),[1] after rosuvastatin 20 mg/d treatment, LDL can be further reduced to 55 mg/dl, the lowest level in large clinical trial. The mean baseline LDL-C level was at 108 mg/dl. The combined primary end-point of myocardial infarction, stroke, arterial revascularization, hospitalization for unstable angina, or death from cardiovascular causes can also be reduced, 1.60% versus 2.82%. Recently, IMPROVE-IT study caught attention and discussion worldwide since its main results published not only because it is a mega trial in CV area but also because of its scientific significance. IMPROVE-IT study was an international, multicenter, randomized, double-blind active comparator trial of 18,144 patients with high-risk acute coronary syndromes (ACS).[26] At 7 years, 32.7% of patients taking ezetimibe plus simvastatin experienced a first primary end-point event (major cardiovascular event) compared to 34.7% of patients taking simvastatin alone, corresponding to a 6.4% relative risk reduction (absolute risk reduction 2%, hazard ratio of 0.936, 95% CI: 0.887-0.988, P = 0.016). The mean LDL-C in the study at 1 year was 53 mg/dL in the ezetimibe plus simvastatin arm and 70 mg/dL in the simvastatin arm. The conclusion from this study could be summarized as: Even lower is even better (achieved mean LDL-C 53 vs. 70 mg/dL at 1 year) to further reduce cardiovascular events in ACS patients. However, even with LDL levels at 53 mg/dL, cardiovascular risk still remained. Either in primary or secondary prevention, it seemed that we should reduce LDL even more. The results of IMPROVE-IT also supported that the extent of the benefit was consistent with that seen in previous trials, with a similar reduction in cardiovascular events according to the degree of LDL-C lowering in lower LDL-C levels. Thus, maybe we could have more clinical benefits by decreasing LDL-C to about 20-30 mg/dL as in newborns [Figures 2 and 3].Figure 2:: Relationship between low-density lipoprotein and coronary heart disease events (%) in primary prevention. Composite cardiovascular events for JUPITER trial. Use Pearson correlation testFigure 3:: Relationship between low-density lipoprotein and coronary heart disease events (%) in secondary prevention. Composite cardiovascular events for TNT trial. Use Pearson correlation testPCSK9 inhibitors are a new class of drugs that have shown to further decrease LDL-C by 50%-70% when administered as a monotherapy or in combination with statins.[27] The ongoing trials, such as ODYSSEY OUTCOMES, SPIRE-1, and SPIRE-2, will provide evidence for “the lower the better.” We will see whether the cardiovascular events can be further decreased with very-low LDL-C level by PCSK9 inhibitor. Too Low To Go? And How To Go There? The safety concerns stem from two different questions: A. Are very-low LDL-C levels safe? B. Are drugs leading to very-low LDL-C safe? First of all, cholesterol is an essential component of cell membranes and is a necessary precursor for bile acid, steroid hormone, and Vitamin D synthesis. The newborn LDL-C levels were enough for physical need. When human fibroblasts were grown in cell culture, they took up media LDL through the LDL receptor pathway until sufficient cholesterol was internalized to meet cellular needs, leading to the downregulation of LDL receptors. The amount of LDL-C that was needed in such cultures was only 2.5 mg/dl. Because there was a 10:1 gradient between plasma and interstitial fluid LDL levels, this implied that a plasma level of 25 mg/dl LDL-C would be sufficient to supply peripheral cholesterol needs.[28] People with heterozygous hypobetalipoproteinemia had LDL-C levels as low as 30 mg/dl. These patients were always free of atherosclerosis with longevity. There was also lack of other adverse effects that might have been caused by such a low LDL level.[29] In healthy persons with a nonsense mutation in each PCSK9 gene, LDL-C concentrations were reported as low as 14-16 mg/dl.[30,31] Thus, it seemed that a very-low level of LDL-C, as low as newborns, was safe. Second, clinical trials showed that the intensive statin therapy could decrease LDL-C value safely. The cumulative data with statin therapy showed impressive cardiovascular benefits without a corresponding increase in adverse events such as malignancy or noncardiovascular mortality. In the JUPITER trial[1] in which LDL-C levels were as low as 55 mg/dl, there was no difference between rosuvastatin (40 mg) and placebo in any serious adverse events, including muscular weakness/stiffness/pain, myopathy, rhabdomyolysis, newly diagnosis cancer, death from cancer, gastrointestinal disorder, renal disorder, and hepatic disorder. Hence, high-intensive statin therapy is recommended as first-line (Class I, A) for patients <75 years old with clinical ASCVD.[32] However, many meta-analysis also showed that the side effects of statins such as liver dysfunction, myopathy,[33] or newly diagnosed diabetes[34] were dose-dependent and more common in high intensive statins, where high dose of statins are usually needed for reaching lower LDL-C targets. Furthermore, it should be noticed that the safety of high doses of statins in the Chinese population is not yet confirmed. In 2013 American Heart Association and American Stroke Association guidelines,[32] evidence among Asian populations was not included, therefore, it is recommended that moderate intensive statins could be used in Asian ancestry, to avoid statin-associated side effects. The most common side effects of statin, liver, and muscle toxicity, was seen with high dose of statins, but not in relationship to the on-treatment LDL level. Therefore, combination therapy or a new potent drug might be an alternative to reach the much lower LDL-C level. IMPROVE-IT study[26] had confirmed the safety of intensive LDL-C lowering by combining ezetimibe with simvastatin. The mean LDL-C was 53 mg/dL in the combination group. There were no significant differences between the two study groups in any of the prespecified safety end-points or in the rate of discontinuation of study medication owing to adverse events including the incidence of rhabdomyolysis or myopathy, alanine aminotransferase and aspartate aminotransferase ≥3×, ULN, and cancer, etc. Add-on ezetimibe to statins did not show significant increase of adverse event. PCSK9 could reduce LDL-C dramatically as monotherapy and combination with statin, and the reduction is not affected by the dose of background statins. In published phase 3 trial, the rate of serious adverse events was 2%-6%. Adverse events causing discontinuation of the drug occurred in 2%-10%. Elevation of liver aminotransferase >3 times of upper normal limit was observed in >2% of the patients. Elevation of creatinine was similarly rare.[27] Summary Atherosclerosis develops progressively with age and is closely related to the LDL-C levels. It was not initiated in healthy newborns with LDL levels around 30 mg/Dl but had begun in children and adolescents with normal LDL-C values. Clinical trials had shown that reducing LDL could retard or even reverse atherosclerosis in much lower LDL levels (53-80 mg/dL) with intensive medication therapy, evaluated by IMT, IVUS, or clinical end-points. However, the extent of the regression was small and the risk of cardiovascular events remained. So maybe we should lower LDL to the safe levels that you are born with, which are around 30 mg/dL, to prevent the development of atherosclerosis or provide the best treatment effects. More well-designed trials (combination therapy or with new drugs) are needed to support this hypothesis and confirm its safety. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

Introduction Contradictory data have been reported about the association between testosterone levels and the levels of low-density lipoprotein cholesterol (LDL). Objective The aim of this study was to elucidate the association between testosterone and LDL levels. Methods A cross-sectional study was conducted that included 7,268 men who had participated in a health examination. Men who took agents that influence serum lipid profiles within the previous 6 months were excluded. A full metabolic work-up and serum testosterone level checks were performed. The main outcome measures included the testosterone level and testosterone deficiency (TD) prevalence of each decile of LDL and their polynomial trendlines and the odds ratio (OR) of TD according to the LDL level. Results The polynomial trendline suggests an inverted U-shaped curvilinear relationship between LDL and testosterone levels (figure 1) and a U-shaped curvilinear relationship between LDL levels and the prevalence of TD (figure 2). The adjusted ORs of TD in men in the lowest and highest deciles were significantly higher than those of men in the 10th – 90th deciles of LDL (90th LDL, OR for TD: 1.277, 95% CI: 1.006–1.621), which reinforces the U-shaped curvilinear relationship between LDL levels and the prevalence of TD. Conclusions There was a U-shaped curvilinear relationship between LDL levels and the prevalence of TD. Both low LDL and high LDL levels were significantly and independently associated with TD. Care should be taken to screen for TD in men with low LDL levels or high LDL levels. Further study to elucidate the effect of extremely lowering LDL levels on TD is needed. Disclosure No

Association of LDL Cholesterol and Inflammation With Cardiovascular Events and Mortality in Hemodialysis Patients With Type 2 Diabetes Mellitus

Resistance training is used as adjunctive therapy for type 2 diabetes (T2DM), and the aim of this study was to investigate the differences in the treatment effects of different intensities of resistance training in terms of glycemia, lipids, blood pressure, adaptations, and body measurements. A comprehensive search was conducted in the PubMed, EMBASE (Excerpta Medica dataBASE), EBSCO (Elton B. Stephens Company) host, Cochrane Library, WOS (Web of Science), and Scopus databases with a cut-off date of April 2022, and reference lists of relevant reviews were also consulted. The literature screening and data extraction were performed independently by two researchers. RoB2 (Risk of bias 2) tools were used for the literature quality assessment, the exercise intensity was categorized as medium-low intensity and high intensity, and the meta subgroup analysis was performed using R Version. A fixed or random effects model was selected for within-group analysis based on the heterogeneity test, and a random effects model was used for the analysis of differences between subgroups. A total of 36 randomized controlled trials were included, with a total of 1491 participants. It was found that resistance training significantly improved HbA1c (glycated hemoglobin), fasting blood glucose, TG (triglycerides), TC (total cholesterol), and LDL (low-density lipoprotein cholesterol) levels in patients with T2DM and caused a significant reduction in systolic blood pressure, percent of fat mass, and HOMA-IR (homeostatic model assessment for insulin resistance) indexes. The effects of high and medium-low intensity resistance training on T2DM patients were different in terms of HOMA-IR, maximal oxygen consumption, weight, waist-to-hip ratio, and body mass indexes. Only medium-low intensity resistance training resulted in a decrease in HOMA-IR. In addition to weight (MD = 4.25, 95% CI: [0.27, 8.22], I2 = 0%, p = 0.04; MD = -0.33, 95% CI: [-2.05, 1.39], I2 = 0%, p = 0.76; between groups p = 0.03) and HOMA-IR (MD = 0.11, 95% CI: [-0.40, -0.63], I2 = 0%, p = 0.85; MD = -1.09, 95% CI: [-1.83, -0.36], I2 = 87%, p = < 0.01; between groups p = 0.0085), other indicators did not reach statistical significance in the level of difference within the two subgroups of high intensity and medium-low intensity. The treatment effects (merger effect values) of high intensity resistance training were superior to those of medium-low intensity resistance training in terms of HbA1c, TG, TC, LDL levels and diastolic blood pressure, resting heart rate, waist circumference, fat mass, and percentage of fat mass. Therefore, high intensity resistance training can be considered to be a better option to assist in the treatment of T2DM and reduce the risk of diabetic complications compared to medium-low intensity resistance training. Only one study reported an adverse event (skeletal muscle injury) associated with resistance training. Although results reflecting the difference in treatment effect between intensity levels reached no statistical significance, the practical importance of the study cannot be ignored.

Influence of the Combination of Low-Density Lipoprotein Receptor and Interleukin 28B Genotypes on Lipid Plasma Levels in HIV/Hepatitis C-Coinfected Patients

Combination drug therapy has been shown to decrease cholesterol levels in hyperlipidemic patients. However, its efficacy has not been well studied in patients previously considered to be normolipidemic, many of whom are now candidates for this therapy. To determine the efficacy and tolerability of multidrug therapy designed to improve low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol levels in patients with coronary heart disease and average lipid levels. Randomized, placebo-controlled, 2.5-year trial comparing patients receiving usual care with patients receiving stepped-care drug therapy. Stepped-care therapy (pravastatin, nicotinic acid, cholestyramine, and gemfibrozil) to decrease total cholesterol levels to less than 4.1 mmol/L (160 mg/dL) and the ratio of LDL cholesterol to HDL cholesterol to less than 2.0. 2 academic, urban, tertiary care hospitals. 91 patients (80 men and 11 women) with coronary heart disease, a mean age of 60 years, total cholesterol levels less than 6.4 mmol/L (250 mg/dL) at baseline, and ratios of total cholesterol to HDL cholesterol greater than 4.0 at baseline. Fasting serum lipoprotein profile, fasting apolipoprotein levels, and frequency of adverse effects. Patients were assessed every 6 weeks during drug titration and every 3 months thereafter. Mean lipid levels at baseline were as follows: total cholesterol, 5.5 mmol/L (214 mg/dL); LDL cholesterol, 3.6 mmol/L (140 mg/dL); HDL cholesterol, 1.1 mmol/L (42 mg/dL); and triglycerides, 1.8 mmol/L (159 mg/dL). With pravastatin, changes in levels from baseline were -22% for total cholesterol, -32% for LDL cholesterol +8% for HDL cholesterol, and -15% for triglycerides (P < 0.001 for all comparisons). With the addition of 1.5 g of nicotinic acid, additional changes were -6% for total cholesterol (P < 0.002). -11% for LDL cholesterol, +8% for HDL cholesterol, and -10% for triglycerides (P < 0.001 for all comparisons). With 2.25 to 3 g of nicotinic acid, these changes were -7% for total cholesterol (P = 0.007), -14% for LDL cholesterol (P < 0.001), +6% for HDL cholesterol (P = 0.02), and -13% for triglycerides (P = 0.03). With cholestyramine, total cholesterol and LDL cholesterol levels were unchanged compared with the previous step; the change in HDL cholesterol level was -8% (P = 0.03); and the change in triglyceride level was +46% (P < 0.001). With gemfibrozil, total cholesterol level was unchanged; the additional change in LDL cholesterol level was +12% (P = 0.09); the change in HDL cholesterol level was +12% (P = 0.03); and the change in triglyceride level was -37% (P < 0.001). Apolipoprotein B levels decreased by 25% overall (P < 0.001); lipoprotein(a) levels did not change significantly. Adverse effects were primarily attributable to nicotinic acid or cholestyramine. In 18 of the 35 patients (50%) whose baseline LDL cholesterol levels were greater than 3.35 mmol/L (130 mg/dL), pravastatin decreased LDL cholesterol levels to 2.6 mmol/L (100 mg/dL) or less by 6 weeks; 70% of patients needed combination therapy to reach this National Cholesterol Education Program goal during the 2.5 years of the study. Adding nicotinic acid to pravastatin produced LDL cholesterol levels of 2.6 mmol/L or less in 15 more of these 35 patients, so that 94% (n = 33) of the patients receiving these two drugs reached this goal. To reach current goals for LDL cholesterol levels, most normolipidemic patients with coronary heart disease in this study needed combination therapy. Pravastatin with nicotinic acid and pravastatin with gemfibrozil are well-tolerated combinations that can maintain target LDL cholesterol levels, decrease triglyceride levels, and increase HDL cholesterol levels. Adding resin to these combinations produced no further benefit.

BackgroundGypenosides (Gyp) are the main ingredient of the Chinese medicine, Gynostemma pentaphyllum. They are widely used in Asia as a hepatoprotective agent. Here, we elucidated the mechanism of Gyp in non-alcoholic steatohepatitis (NASH) with a focus on farnesoid X receptor (FXR)-mediated bile acid and lipid metabolic pathways.MethodsNASH was induced in mice by high-fat diet (HFD) feeding, while mice in the control group were given a normal diet. At the end of week 10, HFD-fed mice were randomly divided into HFD, HFD plus Gyp, and HFD plus obeticholic acid (OCA, FXR agonist) groups and were given the corresponding treatments for 4 weeks. Next, we analyzed the histopathological changes as well as the liver triglyceride (TG) level and serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), fasting blood glucose (FBG), fasting insulin (FINS), TG, total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C) levels as well as the bile acid profile. We carried out RT-PCR and western blotting to detect HFD-induced alterations in gene/protein expression related to bile acid and lipid metabolism.ResultsThe HFD group had histopathological signs of hepatic steatosis and vacuolar degeneration. The liver TG and serum ALT, AST, FBG, FINS, TC, and LDL-C levels as well as the total bile acid level were significantly higher in the HFD group than in the control group (P < 0.01). In addition, we observed significant changes in the expression of proteins involved in bile acid or lipid metabolism (P < 0.05). Upon treatment with Gyp or OCA, signs of hepatic steatosis and alterations in different biochemical parameters were significantly improved (P < 0.05). Further, HFD-induced alterations in the expression genes involved in bile acid and lipid metabolism, such as CYP7A1, BSEP, SREBP1, and FASN, were significantly alleviated.ConclusionsGyp can improve liver lipid and bile acid metabolism in a mouse model of NASH, and these effects may be related to activation of the FXR signaling pathway.

BackgroundIn a previous study, a single injection of inclisiran, a chemically synthesized small interfering RNA designed to target PCSK9 messenger RNA, was found to produce sustained reductions in low-density lipoprotein (LDL) cholesterol levels over the course of 84 days in healthy volunteers.MethodsWe conducted a phase 2, multicenter, double-blind, placebo-controlled, multiple-ascending-dose trial of inclisiran administered as a subcutaneous injection in patients at high risk for cardiovascular disease who had elevated LDL cholesterol levels. Patients were randomly assigned to receive a single dose of placebo or 200, 300, or 500 mg of inclisiran or two doses (at days 1 and 90) of placebo or 100, 200, or 300 mg of inclisiran. The primary end point was the change from baseline in LDL cholesterol level at 180 days. Safety data were available through day 210, and data on LDL cholesterol and proprotein convertase subtilisin–kexin type 9 (PCSK9) levels were available through day 240.ResultsA total of 501 patients underwent randomization. Patients who received inclisiran had dose-dependent reductions in PCSK9 and LDL cholesterol levels. At day 180, the least-squares mean reductions in LDL cholesterol levels were 27.9 to 41.9% after a single dose of inclisiran and 35.5 to 52.6% after two doses (P<0.001 for all comparisons vs. placebo). The two-dose 300-mg inclisiran regimen produced the greatest reduction in LDL cholesterol levels: 48% of the patients who received the regimen had an LDL cholesterol level below 50 mg per deciliter (1.3 mmol per liter) at day 180. At day 240, PCSK9 and LDL cholesterol levels remained significantly lower than at baseline in association with all inclisiran regimens. Serious adverse events occurred in 11% of the patients who received inclisiran and in 8% of the patients who received placebo. Injection-site reactions occurred in 5% of the patients who received injections of inclisiran.ConclusionsIn our trial, inclisiran was found to lower PCSK9 and LDL cholesterol levels among patients at high cardiovascular risk who had elevated LDL cholesterol levels. (Funded by the Medicines Company; ORION-1 ClinicalTrials.gov number, NCT02597127.)

The clinical efficacy and tolerability of simvastatin and fluvastatin were compared in 432 patients with primary hypercholesterolaemia in a multinational, randomised, double-blind trial. Following at least 10 weeks on a lipid-lowering diet, patients continuing to have a total cholesterol level ≥ 6.5 mmol/L and elevated low density lipoprotein (LDL) cholesterol levels received 6 weeks of once-daily treatment with either simvastatin 5mg (n = 109), simvastatin 10mg (n =110), fluvastatin 20mg (n = 105), or fluvastatin 40mg (n = 108). The relative potency rates of simvastatin to fluvastatin in reducing LDL and total cholesterol levels were estimated to be 7.60 and 7.65, respectively. Significantly greater mean reductions in LDL cholesterol levels were found at week 6 with simvastatin 10mg (30%) compared with either fluvastatin 20mg (22%; p < 0.001) or fluvastatin 40mg (26%; p = 0.03). Similarly, LDL cholesterol was lowered more in the simvastatin 5mg group (26%) than in the fluvastatin 20mg group (22%; p = 0.03). No significant difference was seen between simvastatin 5mg and fluvastatin 40mg. Plasma total cholesterol levels were also significantly lower with simvastatin 10mg compared with fluvastatin 20mg (23 vs 16%; p < 0.001) and fluvastatin 40mg (23 vs 19%; p = 0.02), and with simvastatin 5mg compared with fluvastatin 20mg (19 vs 16%; p = 0.01). Simvastatin 5mg and fluvastatin 40mg both lowered total cholesterol levels by 19%. The percentage of patients reaching National Cholesterol Education Program Adult Treatment Panel II (NCEP ATP II) target LDL cholesterol levels after 6 weeks' treatment with simvastatin 5 or 10 mg/day or fluvastatin 20 or 40 mg/day was 24, 25, 12 and 21%, respectively. Tolerability profiles were generally similar, although significantly more gastrointestinal adverse events occurred in the fluvastatin-treated patients (23 vs 11%). In conclusion, simvastatin 10 mg/day is more effective in lowering total and LDL cholesterol levels than the maximum recommended dose of fluvastatin (40 mg/day), whereas simvastatin 5 mg/day and fluvastatin 40 mg/day showed similar efficacy.