Effect of intensive LDL cholesterol lowering with PCSK9 monoclonal antibodies on tendon xanthoma regression in familial hypercholesterolemia

Background and aims: The effect of LDLc lowering with PCSK9 antibodies on tendon xanthomas (TX) is unknown. Methods: TX was measured in 24 heterozygous familial hypercholesterolemia (HeFH) cases and in 24 HeFH controls with or without PCSK9 inhibitors for at least one year. Results: Exposure to PCSK9 inhibitors in cases was 2.96 ± 1.33 years. LDLc decreased 80.8 ± 7.66% in cases and 56.9 ± 11.1% in controls. There was a decrease in maximum (-5.03%) and mean (-5.32%) TX in cases but not in controls (+3.97%, +3.16, respectively, p = 0.01). PCSK9 inhibitor treatment was independently associated with TX reduction. Conclusion: Addition of a PCSK9 inhibitor to statin and ezetimibe resulted in a greater decrease in LDLc and TX after 3 years of treatment

Lipid phenotype and heritage pattern in families with genetic hypercholesterolemia not related to LDLR, APOB, PCSK9, or APOE

Background: A substantial proportion of individuals clinically diagnosed as familial hypercholesterolemia (FH) do not carry pathogenic mutations in candidate genes. Whether in them the high cholesterol trait is transmitted monogenically has not been studied. Objectives: We assessed the inheritance pattern, penetrance, and expression of high low-density lipoprotein (LDL)-cholesterol (LDLc) in families with genetic hypercholesterolemia (GH) without known causative mutations (non-FH-GH). Methods: The study included probands with a clinical diagnosis of FH and their families attending 2 lipid clinics in Spain. Inclusion criteria for probands were LDLc >95th percentile, triglycerides 90th percentile, >5 points in the Dutch Lipid Clinic Network criteria score, and absence of mutations in LDLR, APOB, PCSK9 or APOE. Eleven FH families with a LDLR mutation were also examined for comparison. Results: We analyzed 49 non-FH-GH probands and 277 first-and second-degree relatives. LDLc was >90th percentile in 37.8% of blood relatives, at concentrations similar to those of probands. LDLc had a normal distribution in non-FH-GH families, in contrast with a bimodal distribution in FH families. When a dominant model was tested, family-based association tests gave much lower heritability values for total cholesterol and LDLc in non-FH-GH (0.39 and 0.32, respectively) than in FH (0.78 and 0.61, respectively). Conclusions: Non-FH-GH families have a milder lipid phenotype than genetically defined FH. The heritage pattern of LDLc in non-FH-GH does not fit with a monogenic disorder. Our findings support the concept that most non-FH-GHs are polygenic hypercholesterolemias

Bile acid synthesis precursors in subjects with genetic hypercholesterolemia negative for LDLR/APOB/PCSK9/APOE mutations. Association with lipids and carotid atherosclerosis

Some oxysterols are precursors of bile acid synthesis and play an important role in cholesterol homeostasis. However, if they are involved in the pathogeny of genetic hypercholesterolemia has not been previously explored. We have studied non-cholesterol sterol markers of cholesterol synthesis (lanosterol and desmosterol) and oxysterols (7a-hydroxy-4-cholesten-3-one, 24S-hydroxycholesterol and 27-hydroxycholesterol) in 200 affected subjects with primary hypercholesterolemia of genetic origin, negative for mutations in LDLR, APOB, PCSK9 and APOE genes (non-FH GH) and 100 normolipemic controls. All studied oxysterols and cholesterol synthesis markers were significantly higher in affected subjects than controls (P < 0.001). Ratios of oxysterols to total cholesterol were higher in non-FH GH than in controls, although only 24S-hydroxycholesterol showed statistical significance (P < 0.001). Cholesterol synthesis markers had a positive correlation with BMI, triglycerides, cholesterol and apoB in control population. However, these correlations disappeared in non-FH GH with the exception of a weak positive correlation for non-HDL cholesterol and apoB. The same pattern was observed for oxysterols with high positive correlation in controls and absence of correlation for non-FH GH, except non-HDL cholesterol for 24S-hydroxycholesterol and 27-hydroxycholesterol and apoB for 27-hydroxycholesterol. All non-cholesterol sterols had positive correlation among them in patients and in controls. A total of 65 (32.5%) and 35 (17.5%) affected subjects presented values of oxysterols ratios to total cholesterol above the 95th percentile of the normal distribution (24S-hydroxycholesterol and 27-hydroxycholesterol, respectively). Those patients with the highest levels of 24S-hydroxycholesterol associated an increase in the carotid intima media thickness. These results suggest that bile acid metabolism is affected in some patients with primary hypercholesterolemia of genetic origin, negative for mutations in the candidate genes, and may confer a higher cardiovascular risk. Our results confirm that cholesterol synthesis overproduction is a primary defect in non-HF GH and suggest that subjects with non-FH GH show high levels of oxysterols in response to hepatic overproduction of cholesterol

The additive effect of adherence to multiple healthy lifestyles on subclinical atherosclerosis: Insights from the AWHS

Background: Public health strategies targeting multiple healthy behaviors, rather than individual factors, have been proposed as more efficient strategies to promote cardiovascular health. However, the additive effect of multiple targets on primary prevention has not been fully characterized. Objective: To examine how adherence to multiple healthy behaviors is associated with the presence of subclinical atherosclerosis, a measure of early cardiovascular disease. Methods: Analysis of a baseline data from 1798 middle-aged men from the Aragon Workers Health Study conducted between 2009 and 2010. Healthy behaviors were defined according to American Heart Association recommendations, aligned with Spanish Nutritional recommendations and included moderate alcohol consumption, smoking abstinence, no abdominal adiposity, decreased sedentarism, and adherence to Alternate Mediterranean Dietary Index. Presence of coronary artery calcium and plaques in femoral and carotid was quantified by a 16-slice computed tomography scanner and 2D ultrasound. Results: Moderate alcohol consumption, as well as adherence to Mediterranean diet is independently associated with a 6% lower risk of having subclinical atherosclerosis. Smoking abstinence is associated with a 11% lower risk of subclinical atherosclerosis. Those who follow 3 lifestyle behaviors (Mediterranean diet, nonsmoking, and moderate alcohol intake) have 18% lower odds of presenting subclinical atherosclerosis compared with those who do not follow these protective lifestyle habits. Conclusion: Adoption of multiple healthy lifestyle behaviors early in life could be a key strategy to tackle the onset of atherosclerosis and reduce cardiovascular disease burden

Lipid-lowering response in subjects with the p.(Leu167del) mutation in the APOE gene

Background and aims: The aim of this work was to compared the effect of lipid lowering drugs among familial hypercholesterolemia (FH) subjects with a functional mutation in LDLR (LDLR FH) and FH with the p.(Leu167del) mutation in APOE. Methods: We retrospectively selected all adults with the p.(Leu167del) mutation on lipid-lowering treatment (n = 22) attending the Lipid Unit at the Hospital Miguel Servet. Age and sex matched LDLR FH from the same Unit were randomly selected as a control group (n = 44). Results: The mean percentage reduction in LDLc was significantly higher in the p.(Leu167del) carriers (-52.1%) than in the LDLR FH (-39.7%) (p = 0.040) when on high intensity statins. Similar differences between groups were observed in non-HDLc -49.4% and -36.4%, respectively (p = 0.030). Conclusions: Subjects with p.(Leu167del) mutation have a higher lipid-lowering response to statins with or without ezetimibe than LDLR FH. This supports the use of genetics for a more efficient management of FH

Effect of Lifestyle Intervention in the Concentration of Adipoquines and Branched Chain Amino Acids in Subjects with High Risk of Developing Type 2 Diabetes: Feel4Diabetes Study

Introduction: The global prevalence of type 2 diabetes (T2D) is increasing rapidly, especially in low- and middle-income countries and has a high number of associated comorbidities. Plasmatic concentrations of branched chain amino acids (BCAA) and retinol-binding protein 4 (RBP4) have been shown to be elevated in T2D subjects in cross-sectional studies. However, the effect of lifestyle community-based interventions on BCAA and RBP4 concentrations has not yet been analyzed. Material and methods: The Feel4Diabetes study is a school and community-based intervention that identified 360 European families with a high risk of developing T2D according to the FINDRISC questionnaire. Families were randomized in control and intervention groups were followed-up from 2016 to 2018. In the Spanish families, the concentration of BCAA and RBP4 was determined in 266 subjects (115 control and 151 intervention group) that attended the three time-point assessments by colorimetric and ELISA reaction, respectively. Results: Baseline BCAA levels showed positive correlations with the FINDRISC score and glucose impairment (baseline glucose, insulin, and glycated hemoglobin), body mass index, and body weight. The participants receiving the community-based intervention showed a significant decrease in glycated hemoglobin and BCAA levels compared to the control group (p = 0.011 and p < 0.001, respectively). However, baseline RBP4 did not show significant correlations with anthropometric and glycemic parameters, and no significant change was observed in anthropometric parameters and RBP4 concentrations throughout the follow-up. Conclusion: A community-based intervention on lifestyle led to a significant reduction in BCAA levels regardless of weight loss. These findings suggest that this interventional approach could be promising in T2D prevention

Different protein composition of low-calorie diet differently impacts adipokine profile irrespective of weight loss in overweight and obese women

Background and aims: High-protein (HP) diets have shown benefits in cardiometabolic markers such as insulin or triglycerides but the responsible mechanisms are not known. We aimed to assess the effect of three energy-restricted diets with different protein contents (20%, 27%, and 35%; similar to 80% coming from animal source) on plasma adipokine concentration and its association with changes in cardiometabolic markers. Methods: Seventy-six women (BMI 32.8 +/- 2.93) were randomized to one of three calorie-reduced diets, with protein, 20%, 27%, or 35%; carbohydrates, 50%, 43%, or 35%; and fat, 30%, for 3 months. Plasma adipokine (leptin, resistin, adiponectin, and retinol-binding protein 4; RBP4) levels were assessed. Results: After 3 months, leptin concentration decreased in all groups without differences among them, while resistin levels remained unchanged. Adiponectin concentration heterogeneously changed in all groups (P for trend = 0.165) and resistin concentration did not significantly change. RPB4 significantly decreased by -17.5% (-31.7, -3.22) in 35%-protein diet (P for trend = 0.024 among diets). Triglycerides improved in women following the 35%-protein diet regardless of weight loss; RBP4 variation significantly influenced triglyceride concentration change by 24.9% and 25.9% when comparing 27%- and 35%- with 20%-protein diet, respectively. Conclusions: A 35%-protein diet induced a decrease in RBP4 regardless of weight loss, which was directly associated with triglyceride concentration improvement. These findings suggest that HP diets improve the cardiometabolic profile, at least in part, through changes in adipokine secretion. Whether this beneficial effect of HP diet is due to improvements in hepatic or adipose tissue functionality should be elucidated

Effect of an alcohol-free beer enriched with isomaltulose and a resistant dextrin on insulin resistance in diabetic patients with overweight or obesity

Background & aims: The quality of carbohydrates has an essential role in nutritional management of type 2 diabetes mellitus (T2DM) because of its substantial impact on glucose homeostasis. Alcohol-free beer has beneficial bioactive components but it has a relatively high glycemic-index so its consumption is restricted in diabetic subjects. We aimed to explore the effect of an alcohol-free beer with modified carbohydrate composition almost completely eliminating maltose and adding isomaltulose (16.5 g/day) and a resistant maltodextrin (5.28 g/day) in comparison to a regular alcohol-free beer on glycemic control of diabetic subjects with overweight or obesity. Design: We randomized 41 subjects into two groups: a) consumption of 66 cL/day of; regular alcohol-free beer for the first 10 weeks and 66 cL/day of alcohol-free beer with modified carbohydrate composition for the next 10 weeks; b) the same described intervention in opposite order. There was a washout period for 6–8 weeks between the two interventions. Participants were counseled to adhere to a healthy diet for cardiovascular health and to increase physical activity. Clinical, biochemical, anthropometric, lifestyle and satiety assessments were performed at the beginning and at the end of each period. Results: Subjects showed significantly weight loss after the two ten weeks periods (-1.69 ± 3.21% and -1.77 ± 3.70% after experimental and regular alcohol-free beers, respectively, P = 0.881). Glucose and glycated hemoglobin did not significantly change after any period. Insulin concentrations and HOMA-IR significantly decreased (-11.1 [–21.3-4.64]% and -1.92 ± 32.8% respectively) after the intake of experimental alcohol-free beer but not after regular alcohol-free beer. Reductions remained statistically significant after adjusting for weight loss, energy intake, physical activity and intervention order. Subjects reported higher satiety scores after consuming experimental alcohol-free beer. Conclusions: An alcohol-free beer including the substitution of regular carbohydrates for low doses of isomaltulose and the addition of a resistant maltodextrin within meals led to an improvement in insulin resistance in subjects with T2DM and overweight or obesity. Clinical trial registration: The clinical trial has been registered in ClinicalTrials.gov (Identifier: NCT03337828)

Frequency of rare mutations and common genetic variations in severe hypertriglyceridemia in the general population of Spain

Background: Hypertriglyceridemia (HTG) is a common complex metabolic trait that results of the accumulation of relatively common genetic variants in combination with other modifier genes and environmental factors resulting in increased plasma triglyceride (TG) levels. The majority of severe primary hypertriglyceridemias is diagnosed in adulthood and their molecular bases have not been fully defined yet. The prevalence of HTG is highly variable among populations, possibly caused by differences in environmental factors and genetic background. However, the prevalence of very high TG and the frequency of rare mutations causing HTG in a whole non-selected population have not been previously studied. Methods: The total of 23, 310 subjects over 18 years from a primary care-district in a middle-class area of Zaragoza (Spain) with TG >500 mg/dL were selected to establish HTG prevalence. Those affected of primary HTG were considered for further genetic analisys. The promoters, coding regions and exon-intron boundaries of LPL, LMF1, APOC2, APOA5, APOE and GPIHBP1 genes were sequenced. The frequency of rare variants identified was studied in 90 controls. Results: One hundred ninety-four subjects (1.04 %) had HTG and 90 subjects (46.4 %) met the inclusion criteria for primary HTG. In this subgroup, nine patients (12.3 %) were carriers of 7 rare variants in LPL, LMF1, APOA5, GPIHBP1 or APOE genes. Three of these mutations are described for the first time in this work. The presence of a rare pathogenic mutation did not confer a differential phenotype or a higher family history of HTG. Conclusion: The prevalence of rare mutations in candidate genes in subjects with primary HTG is low. The low frequency of rare mutations, the absence of a more severe phenotype or the dominant transmission of the HTG would not suggest the use of genetic analysis in the clinical practice in this population

Glycerol kinase deficiency in adults: Description of 4 novel cases, systematic review and development of a clinical diagnostic score

Background and aims: Glycerol kinase deficiency (GKD) is a rare genetic disorder characterized by hyperglycerolemia and glyceroluria, which could be misdiagnosed as a moderate to severe hypertriglyceridemia (HTG). We aimed to describe four novel cases of GKD, to complete a systematic review of all cases of isolated GKD published so far, and to develop a suspicion clinical diagnostic score for GKD. Methods: We reported four cases with suspicion of GKD and compared their phenotype with 584 males with triglycerides (TG) > 300 mg/dL, selected as control group (HTG non-GKD). The GK gene was sequenced in all cases. Lipoprotein particle concentrations were measured in all cases with GKD. The systematic review involved a PubMed, Cochrane and Scopus databases search to identify anthropometric and biochemical characteristics of all described cases with GKD. Results: The systematic review retrieved a total of 15 articles involving 39 subjects with GKD. GKD cases reported a history of high TG levels resistant to lipid-lowering therapy. Compared to GKD subjects (n = 43), HTG non-GKD subjects (n = 584) showed significantly higher BMI, total cholesterol, non-HDL cholesterol and gamma-glutamyltransferase, significantly lower HDL cholesterol and TG, and higher prevalence of diabetes. The proposed diagnostic score was significantly higher in GKD than in HTG non-GKD subjects. Conclusions: This is the first systematic review that compiles all GKD cases reported to date including 4 novel cases, and examine the differential GKD phenotype compared to other types of HTG. The proposed score would have a broad utility in clinical practice to avoid unwarranted lipid lowering treatment in GKD patients