Diet and Cardiovascular Disease Risk Among Individuals with Familial Hypercholesterolemia: Systematic Review and Meta-Analysis

Background: Although a cholesterol-lowering diet and the addition of plant sterols and stanols are suggested for the lipid management of children and adults with familial hypercholesterolemia, there is limited evidence evaluating such interventions in this population. Objectives: To investigate the impact of cholesterol-lowering diet and other dietary interventions on the incidence or mortality of cardiovascular disease and lipid profile of patients with familial hypercholesterolemia. Search methods: Relevant trials were identified by searching US National Library of Medicine National Institutes of Health Metabolism Trials Register and clinicaltrials.gov.gr using the following terms: diet, dietary, plant sterols, stanols, omega-3 fatty acids, fiber and familial hypercholesterolemia. Selection criteria: Randomized controlled trials evaluating the effect of cholesterol-lowering diet or other dietary interventions in children and adults with familial hypercholesterolemia were included. Data collection and analysis: Two authors independently assessed the eligibility of the included trials and their bias risk and extracted the data which was independently verified by other colleagues. Results: A total of 17 trials were finally included, with a total of 376 participants across 8 comparison groups. The included trials had either a low or unclear bias risk for most of the assessed risk parameters. Cardiovascular incidence or mortality were not evaluated in any of the included trials. Among the planned comparisons regarding patients’ lipidemic profile, a significant difference was noticed for the following comparisons and outcomes: omega-3 fatty acids reduced triglycerides (mean difference (MD): −0.27 mmol/L, 95% confidence interval (CI): −0.47 to −0.07, p < 0.01) when compared with placebo. A non-significant trend towards a reduction in subjects’ total cholesterol (MD: −0.34, 95% CI: −0.68 to 0, mmol/L, p = 0.05) and low-density lipoprotein cholesterol (MD: −0.31, 95% CI: −0.61 to 0, mmol/L, p = 0.05) was noticed. In comparison with cholesterol-lowering diet, the additional consumption of plant stanols decreased total cholesterol (MD: −0.62 mmol/L, 95% CI: −1.13 to −0.11, p = 0.02) and low-density lipoprotein cholesterol (MD: −0.58 mmol/L, 95% CI: −1.08 to −0.09, p = 0.02). The same was by plant sterols (MD: −0.46 mmol/L, 95% CI: −0.76 to −0.17, p < 0.01 for cholesterol and MD: −0.45 mmol/L, 95% CI: −0.74 to −0.16, p < 0.01 for low-density lipoprotein cholesterol). No heterogeneity was noticed among the studies included in these analyses. Conclusions: Available trials confirm that the addition of plant sterols or stanols has a cholesterol-lowering effect on such individuals. On the other hand, supplementation with omega-3 fatty acids effectively reduces triglycerides and might have a role in lowering the cholesterol of patients with familial hypercholesterolemia. Additional studies are needed to investigate the efficacy of cholesterol-lowering diet or the addition of soya protein and dietary fibers to a cholesterol-lowering diet in patients with familial hypercholesterolemia

Συσχέτιση κλασικών και νεότερων παραγόντων κινδύνου με την εμφάνιση καρδιαγγειακής νόσου σε ασθενείς με δυσλιπιδαιμία

Introduction: Despite available therapies used for cardiovascular (CV) prevention and their increased prescription rates during the last decade, cardiovascular disease (CVD) remains the leading mortality cause worldwide. There are limited data regarding CV and metabolic risk in dyslipidemic patients treated in the setting of CV prevention. Aims: To study CVD incidence in dyslipidemic patients taking multifactorial CV therapy and identify potential factors for residual CV and metabolic risk. Methods: This was a retrospective study including consecutive adult patients with dyslipidemia who attended the Outpatient Lipid Clinic of the University Hospital of Ioannina in Greece for ≥3 years (from 1999 to 2015). A complete assessment of their clinical and laboratory profile was performed at baseline visit, after 6 months and most recent visit. Concomitant therapies were recorded, with a particular emphasis on lipid-lowering drugs. We depicted the incidence of atherosclerotic cardiovascular disease (ASCVD) and identified possible risk factors. We evaluated and compared prognostic values of tools estimating the risk of ASCVD and atrial fibrillation (AF). We also evaluated whether an association between lipid parameters and ventricular repolarization indices (QTc interval, the Tpe interval, and the Tpe/QT ratio) exists. We captured the rates of proposed lipid, blood pressure (BP) and glycemic target attainment, along with rate of eligibility for treatment with proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. We assessed the correlations (r2) of apolipoprotein B (apoB) with low-density lipoprotein cholesterol (LDL-C) and non-high-density lipoprotein cholesterol (non-HDL-C) according to the presence of high triglyceride (TG) levels, type 2 diabetes mellitus (T2DM) and metabolic syndrome (MetS). We recorded the rate of adverse effects related with lipid-lowering treatment and identified the corresponding risk factors. We assessed the overall effect of proton pump inhibitors (PPI) administration on LDL-C lowering and we investigated whether a statin escape phenomenon exists (as defined as an increase in low-density lipoprotein cholesterol (LDL-C) levels at the most recent visit by >10% compared with the value at 6 months following initiation of statin treatment). Also, we evaluated which factors were associated with incident chronic kidney disease (CKD) and hyponatremia in our study population. Results: A total of 1,334 subjects were included in the present study and followed-up for a median of 6 years (4-10). During follow-up, lipid-lowering therapy was prescribed to the majority of study participants (94%) with statins being the cornerstone therapy (91%), whereas 70% of those were on antihypertensive therapy. During 6-year follow-up, a total of 95 subjects (7%) were diagnosed with incident ASCVD (rate of ASCVD incidence: 10.4/1,000 patient-years). ASCVD incidence in our cohort was similar to that of a Hellenic cohort (ATTICA study) representative of the general population (10.4 vs 15.7/1,000 patient-years, respectively). T2DM (HR: 2.09, 95% CI: 1.18-3.70, p 0.05). An additional analysis showed that among prediabetic subjects, atherogenic dyslipidemia increased T2DM risk (adjusted OR: 3.44, 95% CI: 1.31-9.04, p=0.01). The same was true for overweight/obese status (adjusted OR: 5.60, 95% CI: 2.19-14.30, p 0.05). Metabolically unhealthy obese (MUO) patients had greater T2DM risk than MHNO (adjusted OR: 7.87, 95% CI: 4.02-15.42, p 200 mg/dL). Επιπλέον, καταγράψαμε τα ποσοστά των ανεπιθύμητων ενεργειών που σχετίζονται με τις θεραπείες καρδιαγγειακής πρόληψης, με ιδιαίτερη έμφαση στην υπολιπιδαιμική αγωγή. Συγκρίναμε τη μείωση της LDL-C σε άτομα που λαμβάνουν στατίνη + αναστολείς αντλίας πρωτονίων (ΡΡΙ) με εκείνα στα οποία χορηγήθηκαν μόνο στατίνη και ερευνήσαμε εάν υπάρχει το φαινόμενο της διαφυγής της δράσης των στατινών στην κλινική πράξη (δηλαδή αύξηση των επιπέδων της LDL-C κατά την πιο πρόσφατη επίσκεψη κατά >10% συγκριτικά με την τιμή στους 6 μήνες μετά την έναρξη της θεραπείας με στατίνη). Διερευνήσαμε τους παράγοντες κινδύνου για την εμφάνιση χρόνιας νεφρικής νόσου (ΧΝΝ) και υπονατριαιμίας στον πληθυσμό της μελέτης μας. Αποτελέσματα: Συνολικά 1,334 άτομα συμμετείχαν στην παρούσα μελέτη, τα οποία παρακολουθήθηκαν για 6 έτη (4-10 έτη). Κατά τη διάρκεια της παρακολούθησης συνταγογραφήθηκε υπολιπιδαιμική αγωγή στην πλειοψηφία των συμμετεχόντων στη μελέτη (94%), με τις στατίνες να αποτελούν τον ακρογωνιαίο λίθο της (91%), ενώ το 70% ελάμβανε αντιϋπερτασική θεραπεία. Κατά τη διάρκεια της παρακολούθησής, 95 άτομα (7%) εμφάνισαν ΚΑΝ. Η επίπτωση της ΚΑΝ στη μελέτη μας ήταν παρόμοια με την αντίστοιχη μίας ελληνικής μελέτης (ΑΤΤΙΚΗ), αντιπροσωπευτικής του γενικού πληθυσμού (10.4 vs 15.7/1,000 ανθρωπο-έτη, αντίστοιχα). Το ιστορικό ΣΔ2 (HR: 2.09, 95% CI: 1.18-3.70, p 0.05). Σε μια επιπρόσθετη ανάλυση μεταξύ των ατόμων με προδιαβήτη η αθηρογόνος δυσλιπιδαιμία (προσαρμοσμένος OR: 3.44, 95% CI: 1.31-9.04, p=0.01) και ο δείκτης μάζας σώματος >25 Kg/m2 (προσαρμοσμένος OR: 2.54, 95% CI: 1.14-5.66, p 0.05). Οι μεταβολικά μη υγιείς παχύσαρκοι (MUO) ασθενείς είχαν υψηλότερο κίνδυνο εμφάνισης ΣΔ2 από τους MHNO (προσαρμοσμένος OR: 7.87, 95% CI: 4.02-15.42, p <0.01), τους MHO (προσαρμοσμένος OR: 5.45, 95% CI: 2.47-12.04, p <0.01) και τους μεταβολικά μη υγιείς μη παχύσαρκους (MUNO) ασθενείς (προσαρμοσμένος OR: 2.68, 95% CI: 1.28-5.64, p <0.01). Τα άτομα που έλαβαν στατίνη + PPI είχαν υψηλότερη μείωση της LDL-C κατά 6.4% σε σύγκριση με εκείνα που έλαβαν μόνο στατίνη (p <0.01). Από τα 181 άτομα που συμμετείχαν στην ανάλυση, ένα ποσοστό 31% εμφάνισε το φαινόμενο της διαφυγής της δράσης των στατινών. Κατά τη διάρκεια της παρακολούθησης (6 έτη, IQR: 4-10), το 11.9% των ασθενών εμφάνισε ΧΝΝ, ενώ η μέση ετήσια μείωση του eGFR ήταν 0.69 mL/min/1.73 m2 (IQR: 0.45-2.33). Η πολυπαραγοντική ανάλυση έδειξε ότι τα αρχικά επίπεδα ουρικού οξέος (HR: 1.26, 95% CI: 1.09-1.45, p=0.001), το θήλυ φύλο (HR: 1.74, 95% CI: 1.14-2.65, p=0.01), η ηλικία (HR: 1.10, 95% CI: 1.07-1.12, p<0.001), o ΣΔ2 (HR: 1.67, 95% CI: 1.05-2.65, p<0.05), η ΚΑΝ (HR: 1.62, 95% CI: 1.02-2.58, p<0.05),

The Effect of Upadacitinib on Lipid Profile and Cardiovascular Events: A Meta-Analysis of Randomized Controlled Trials

Background: Our aim was to systematically investigate the effect of upadacitinib, an oral JAK-1 selective inhibitor, on lipid profile and cardiovascular disease risk. Methods: PubMed, PubMed Central and ClinicalTrials.gov databases were searched for relevant randomized controlled trials (RCTs) up to 31 July 2022. We performed a qualitative synthesis of published RCTs to investigate the associations of upadacitinib with lipoprotein changes, along with a quantitative synthesis of MACE and mean lipoprotein changes where there were available data. Results: Nineteen RCTs were eligible for the present systematic review, which included 10,656 patients with a mean age of 51 years and a follow-up period of 12–52 weeks. Increases in low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) were noted upon upadacitinib administration (3–48 mg/day) in 15 studies, while the LDL-C:HDL-C ratio remained unchanged. The pooled analyses of three placebo-controlled RCTs (n = 2577) demonstrated that upadacitinib at 15 mg increased the LDL-C by 15.18 mg/dL (95% CI: 7.77–22.59) and HDL-C by 7.89 mg/dL (95% CI: 7.08–8.69). According to the pooled analysis of 15 placebo-controlled RCTs (n = 7695), upadacitinib had no effect on MACE (risk ratio, RR: 0.62; 95% CI: 0.24–1.60). A sub-analysis focusing on upadacitinib at 15 mg (12 studies, n = 5395) demonstrated similar results (RR: 0.67; 95% CI: 0.19–2.36). Conclusions: Treatment with upadacitinib increases both LDL-C and HDL-C levels. Nevertheless, upadacitinib had no significant effect on the cardiovascular disease risk during a ≤52-week follow-up