Treating homozygous familial hypercholesterolemia in a real-world setting: Experiences with lomitapide

Homozygous familial hypercholesterolaemia (HoFH) is a rare genetic disease characterised by markedly elevated plasma levels of low-density lipoprotein-cholesterol (LDL-C). Lomitapide is a microsomal triglyceride transfer protein (MTP) inhibitor approved as an adjunct to other lipid-lowering therapies (LLTs), with or without lipoprotein apheresis (LA), for the treatment of adult HoFH. Diet with <20% calories from fat is required. Due to a varying genetic and phenotypic profile of patients with HoFH, individual patients may respond to therapy differently; therefore examining individual cases in a 'real-world' setting provides valuable information on the effective day-to-day management of HoFH cases. Four HoFH cases were selected for analysis and discussion: a 20-year-old female compound heterozygote; a 62-year old female homozygote; a 42-year-old female compound heterozygote; and a 36-year-old male homozygote. Each patient was commenced on lomitapide according to the prescribed protocol and subjected to routine follow-up. All four patients experienced clinically meaningful reductions in LDL-C levels of 35-73%. Three of the patients had evidence of steatosis or mildly elevated liver function tests) before lomitapide was started, but effects of lomitapide on hepatic function were not universal. Three of the patients experienced gastrointestinal adverse events, but were managed with appropriate dietary control. Lomitapide is an effective adjunct LLT in the management of patients with HoFH, with or without LA. Real-world use of lomitapide has a side-effect profile consistent with clinical trials and one that can be managed by adherence to recommendations on dose escalation, dietary modification and dietary supplements

The effect of diet-induced weight loss on circulating homocysteine levels in people with obesity and type 2 diabetes

Background/aims: Having type 2 diabetes (T2D) in combination with being overweight results in an additional increase in cardiovascular disease (CVD) risk. In addition, T2D and obesity are associated with increased levels of total homocysteine (tHcy), possibly contributing to the CVD risk. Weight loss dieting has positive effects on several CVD risk factors, but whether it affects tHcy remains unclear. Therefore, the aim of this study was to determine the effect of a calorie restricted diet on tHcy in overweight people with T2D. Methods:In this post-hoc analysis of the POWER study, adults with T2D and a BMI greater than 27 kg/m² were included from the outpatient diabetes clinic of the Erasmus Medical Center, Rotterdam. The patients were subjected to a very low-calorie diet with fortified meal replacements for 20 weeks. Before and after this intervention, blood samples were collected to measure tHcy and other CVD risk factors like glycaemic and lipid parameters. Results: 161 overweight participants with T2D were included, with a mean age of 54 years (range 26–74), mean weight of 104.6 ± 19.9 kg and mean HbA1c of 62.7 ± 14.3 mmol/mol. At baseline, men displayed higher tHcy than women, and tHcy level was positively correlated with body weight and triglyceride levels, while it was negatively correlated with renal function and HDL cholesterol. During the intervention, bodyweight was reduced by a mean of 9.7% (from 104.6 ± 19.9 to 94.5 ± 18.1 kg p &lt; 0.001), and all measured glycaemic and lipid blood parameters improved significantly. However, tHcy remained unchanged (from 12.1 ± 4.1 to 12.1 ± 4.2 umol/L, p = 0.880). The change in tHcy during the intervention was negatively associated with the change in weight and BMI (p = 0.01 and p = 0.008, respectively). People who lost &lt; 10 kg (n = 92) had a mean tHcy change of -0.47 umol/L, while people who lost more than ≥ 10 kg (n = 69) had a mean tHcy change of 0.60 umol/L (p = 0.021). Conclusion: In conclusion, our data show that a calorie restricted diet does not affect tHcy in people with T2D and obesity, despite the use of meal replacements fortified with folic acid and vitamin B12. Our data showed a negative correlation between change in tHcy levels and weight loss, suggesting that people who lost more weight (&gt; 10 kg) showed an increase in tHcy. Future studies should explore the potential increase in tHcy induced by weight loss dieting and target the question if tHcy reduction strategies during weight loss could be clinically beneficial.</p

Preventing cardiovascular disease after hypertensive disorders of pregnancy: Searching for the how and when

Background: Women with a history of a hypertensive disorder during pregnancy (HDP) have an increased risk of cardiovascular events. Guidelines recommend assessment of cardiovascular risk factors in these women later in life, but provide limited advice on how this follow-up should be organized. Design: Systematic review and meta-regression analysis. Methods: The aim of our study was to provide an overview of existing knowledge on the changes over time in three major modifiable components of cardiovascular risk assessment after HDP: blood pressure, glucose homeostasis and lipid levels. Data from 44 studies and up to 6904 women with a history of a HDP were compared with risk factor levels reported for women of corresponding age in the National Health And Nutrition Examination Survey, Estudio Epidemiólogico de la Insuficiencia Renal en España and Hong Kong cohorts (N = 27,803). Results: Compared with the reference cohort, women with a HDP presented with higher mean blood pressure. Hypertension was present in a higher rate among women with a previous HDP from 15 years postpartum onwards. At 15 years postpartum (±age 45), one in five women with a history of a HDP suffer from hypertension. No differences in glucose homeostasis parameters or lipid levels were observed. Conclusions: Based on our analysis, it is not possible to point out a time point to commence screening for cardiovascular risk factors in women after a HDP. We recommend redirection of future research towards the development of a stepwise approach identifying the women with the highest cardiovascular risk

Long-term cardiometabolic disease risk in women with PCOS:a systematic review and meta-analysis

BACKGROUND: Polycystic ovary syndrome (PCOS) is associated with cardiometabolic disease, but recent systematic reviews and meta-analyses of longitudinal studies that quantify these associations are lacking. OBJECTIVE AND RATIONALE: Is PCOS a risk factor for cardiometabolic disease? SEARCH METHODS: We searched from inception to September 2019 in MEDLINE and EMBASE using controlled terms (e.g. MESH) and text words for PCOS and cardiometabolic outcomes, including cardiovascular disease (CVD), stroke, myocardial infarction, hypertension (HT), type 2 diabetes (T2D), metabolic syndrome and dyslipidaemia. Cohort studies and case-control studies comparing the prevalence of T2D, HT, fatal or non-fatal CVD and/or lipid concentrations of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and triglycerides (TGs) between women with and without PCOS of ≥18 years of age were eligible for this systematic review and meta-analysis. Studies were eligible regardless of the degree to which they adjusted for confounders including obesity. Articles had to be written in English, German or Dutch. Intervention studies, animal studies, conference abstracts, studies with a follow-up duration less than 3 years and studies with less than 10 PCOS cases were excluded. Study selection, quality assessment (Newcastle-Ottawa Scale) and data extraction were performed by two independent researchers. OUTCOMES: Of the 5971 identified records, 23 cohort studies were included in the current systematic review. Women with PCOS had increased risks of HT (risk ratio (RR): 1.75, 95% CI 1.42 to 2.15), T2D (RR: 3.00, 95% CI 2.56 to 3.51), a higher serum concentration of TC (mean difference (MD): 7.14 95% CI 1.58 to 12.70 mg/dl), a lower serum concentration of HDL-C (MD: -2.45 95% CI -4.51 to -0.38 mg/dl) and increased risks of non-fatal cerebrovascular disease events (RR: 1.41, 95% CI 1.02 to 1.94) compared to women without PCOS. No differences were found for LDL-C (MD: 3.32 95% CI -4.11 to 10.75 mg/dl), TG (MD 18.53 95% CI -0.58 to 37.64 mg/dl) or coronary disease events (RR: 1.78, 95% CI 0.99 to 3.23). No meta-analyses could be performed for fatal CVD events due to the paucity of mortality data. WIDER IMPLICATIONS: Women with PCOS are at increased risk of cardiometabolic disease. This review quantifies this risk, which is important for clinicians to inform patients and to take into account in the cardiovascular risk assessment of women with PCOS. Future clinical trials are needed to assess the ability of cardiometabolic screening and management in women with PCOS to reduce future CVD morbidity

Early Pregnancy Cardiovascular Health and Subclinical Atherosclerosis

Background: Assessing and optimizing cardiovascular health (CVH) early in life, such as in pregnancy, could lead to a longer lifetime spent in better CVH and reduce the risk of cardiovascular disease. This might especially benefit women with a hypertensive disorder of pregnancy (HDP) who are more likely to develop atherosclerosis and cardiovascular disease. We hypothesized that CVH in pregnancy is related to later life CVH and carotid intima-media thickness (CIMT), and that these associations differ between women with a normotensive pregnancy and women with an HDP. Methods and Results: This study was conducted within the prospective population-based Generation R Study. CVH in pregnancy was based on 5 metrics (blood pressure, total-cholesterol, glucose, smoking, and body mass index). Postpartum CVH additionally included physical activity and diet scores, according to the American Heart Association classification. Postpartum CVH

Efficacy and Safety of High Potent P2Y12 Inhibitors Prasugrel and Ticagrelor in Patients With Coronary Heart Disease Treated With Dual Antiplatelet Therapy: A Sex-Specific Systematic Review and Meta-Analysis

Background Sex differences in efficacy and safety of dual antiplatelet therapy remain uncertain because of the underrepresentation of women in cardiovascular trials. The aim of this study was to perform a sex-specific analysis of the pooled efficacy and safety data of clinical trials comparing a high potent P2Y12 inhibitor+aspirin with clopidogrel+aspirin in patients with acute coronary syndrome. Methods and Results A systematic literature search was performed. Randomized clinical trials that compared patients following percutaneous coronary intervention/acute coronary syndrome who were taking high potent P2Y12 inhibitors+aspirin versus clopidogrel+aspirin were selected. Random effects estimates were calculated and relative risks with 95% CIs on efficacy and safety end points were determined per sex. We included 6 randomized clinical trials comparing prasugrel/ticagrelor versus clopidogrel in 43 990 patients (13 030 women), with a median follow-up time of 1.06 years. Women and men had similar relative risk (RR) reduction for major cardiovascular events (women: RR, 0.89 [95% CI, 0.80-1.00; men: RR, 0.84 [95% CI, 0.79-0.91) (P for interaction=0.39). Regarding safety, women and men had similar risk of major bleeding by high-potency dual antip

Differences between Men and Women in Treatment and Outcome after Traumatic Brain Injury

Traumatic brain injury (TBI) is a significant cause of disability, but little is known about sex and gender differences after TBI. We aimed to analyze the association between sex/gender, and the broad range of care pathways, treatment characteristics, and outcomes following mild and moderate/severe TBI. We performed mixed-effects regression analyses in the prospective multi-center Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study, stratified for injury severity and age, and adjusted for baseline characteristics. Outcomes were various care pathway and treatment variables, and 6-month measures of functional outcome, health-related quality of life (HRQoL), post-concussion symptoms (PCS), and mental health symptoms. The study included 2862 adults (36% women) with mild (mTBI; Glasgow Coma Scale [GCS] score 13-15), and 1333 adults (26% women) with moderate/severe TBI (GCS score 3-12). Women were less likely to be admitted to the intensive care unit (ICU; odds ratios [OR] 0.6, 95% confidence interval [CI]: 0.4-0.8) following mTBI. Following moderate/severe TBI, women had a shorter median hospital stay (OR 0.7, 95% CI: 0.5-1.0). Following mTBI, women had poorer outcomes; lower Glasgow Outcome Scale Extended (GOSE; OR 1.4, 95% CI: 1.2-1.6), lower generic and disease-specific HRQoL, and more severe PCS, depression, and anxiety. Among them, women under age 45 and above age 65 years showed worse 6-month outcomes compared with men of the same age. Following moderate/severe TBI, there was no difference in GOSE (OR 0.9, 95% CI: 0.7-1.2), but women reported more severe PCS (OR 1.7, 95% CI: 1.1-2.6). Men and women differ in care pathways and outcomes following TBI. Women generally report worse 6-month outcomes, but the size of differences depend on TBI severity and age. Future studies should examine factors that explain these differences.</p