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Alirocumab in Pediatric Patients With Heterozygous Familial Hypercholesterolemia: A Randomized Clinical Trial.
Santos, RD, Wiegman, A, Caprio, S, Cariou, B, Averna, M, Poulouin, Y, Scemama, M, Manvelian, G, Garon, G, Daniels, S
JAMA pediatrics. 2024;(3):283-293
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Abstract
IMPORTANCE Many pediatric patients with heterozygous familial hypercholesterolemia (HeFH) cannot reach recommended low-density lipoprotein cholesterol (LDL-C) concentrations on statins alone and require adjunct lipid-lowering therapy (LLT); the use of alirocumab in pediatric patients requires evaluation. OBJECTIVE To assess the efficacy of alirocumab in pediatric patients with inadequately controlled HeFH. DESIGN, SETTING, AND PARTICIPANTS This was a phase 3, randomized clinical trial conducted between May 2018 and August 2022 at 43 centers in 24 countries. Pediatric patients aged 8 to 17 years with HeFH, LDL-C 130 mg/dL or greater, and receiving statins or other LLTs were included. Following consecutive enrollment into dosing cohorts, 25 of 99 patients screened for dosing every 2 weeks (Q2W) failed screening; 25 of 104 patients screened for dosing every 4 weeks (Q4W) failed screening. A total of 70 of 74 Q2W patients (95%) and 75 of 79 Q4W patients (95%) completed the double-blind period. INTERVENTIONS Patients were randomized 2:1 to subcutaneous alirocumab or placebo and Q2W or Q4W. Dosage was based on weight (40 mg for Q2W or 150 mg for Q4W if <50 kg; 75 mg for Q2W or 300 mg for Q4W if ≥50 kg) and adjusted at week 12 if LDL-C was 110 mg/dL or greater at week 8. After the 24-week double-blind period, patients could receive alirocumab in an 80-week open-label period. MAIN OUTCOMES AND MEASURES The primary end point was percent change in LDL-C from baseline to week 24 in each cohort. RESULTS Among 153 patients randomized to receive alirocumab or placebo (mean [range] age, 12.9 [8-17] years; 87 [56.9%] female), alirocumab showed statistically significant reductions in LDL-C vs placebo in both cohorts at week 24. Least squares mean difference in percentage change from baseline was -43.3% (97.5% CI, -56.0 to -30.7; P < .001) Q2W and -33.8% (97.5% CI, -46.4 to -21.2; P < .001) Q4W. Hierarchical analysis of secondary efficacy end points demonstrated significant improvements in other lipid parameters at weeks 12 and 24 with alirocumab. Two patients receiving alirocumab Q4W experienced adverse events leading to discontinuation. No significant difference in adverse event incidence was observed between treatment groups. Open-label period findings were consistent with the double-blind period. CONCLUSIONS AND RELEVANCE The findings in this study indicate that alirocumab Q2W or Q4W significantly may be useful for reducing LDL-C and other lipid parameters and be well tolerated in pediatric patients with HeFH inadequately controlled with statins. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT03510884.
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Increased FH-Risk-Score and Diabetes Are Cardiovascular Risk Equivalents in Heterozygous Familial Hypercholesterolemia.
Paquette, M, Cariou, B, Bernard, S, Hegele, RA, Gallo, A, Genest, J, Trinder, M, Brunham, LR, Béliard, S, Baass, A
Arteriosclerosis, thrombosis, and vascular biology. 2024;(2):505-512
Abstract
BACKGROUND Familial hypercholesterolemia (FH) is a genetic condition causing premature atherosclerotic cardiovascular disease (ASCVD). It is well established that patients with FH should be treated with statin therapy. However, there exists discordance concerning low-density lipoprotein cholesterol-lowering goals in the management of these patients between different guidelines worldwide. The objective was to compare the 10-year ASCVD risk of different subgroups of patients with and without FH including those with diabetes or a history of ASCVD and patients with FH within different FH-Risk-Score categories. METHODS This multinational observational study used data from 3 different prospective cohorts. A total of 3383 FH and 6917 non-FH controls matched for age and sex were included (104 363 person-years of follow-up). The 10-year incident ASCVD risk was assessed using Kaplan-Meier estimates, whereas the relative risk was estimated using Cox proportional hazards regression models. RESULTS FH patients with a high (score >20%) FH-Risk-Score (hazard ratio, 8.45 [95% CI, 6.69-10.67]; P<0.0001), FH patients with diabetes (hazard ratio, 7.67 [95% CI, 4.82-12.21]; P<0.0001), and non-FH patients with ASCVD (hazard ratio, 6.78 [95% CI, 5.45-8.42]; P<0.0001) had a significantly higher incident ASCVD risk over 10 years than the reference group (non-FH without ASCVD or diabetes). The observed 10-year risks in these groups were 32.1%, 30.8%, 30.0%, and 5.1%, respectively. The 10-year ASCVD risk associated with both FH and ASCVD was extremely high (observed risk of 50.7%; hazard ratio, 14.53 [95% CI, 12.14-17.38]; P<0.0001). CONCLUSIONS This study strongly suggests that the observed risk of FH patients with diabetes, history of ASCVD, and FH-Risk-Score >20% is as high or higher than non-FH individuals with a history of ASCVD. More aggressive management should be recommended for these patients.
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Associations of microvascular complications with all-cause death in patients with diabetes and COVID-19: The CORONADO, ABCD COVID-19 UK national audit and AMERICADO study groups.
Hadjadj, S, Saulnier, PJ, Ruan, Y, Zhu, X, Pekmezaris, R, Marre, M, Halimi, JM, Wargny, M, Rea, R, Gourdy, P, et al
Diabetes, obesity & metabolism. 2023;(1):78-88
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Abstract
AIM: To provide a detailled analysis of the microvascular burden in patients with diabetes hopitalized for COVD-19. MATERIALS AND METHODS We analysed data from the French CORONADO initiative and the UK Association of British Clinical Diabetologists (ABCD) COVID-19 audit, two nationwide multicentre studies, and the AMERICADO, a multicentre study conducted in New York area. We assessed the association between risk of all-cause death during hospital stay and the following microvascular complications in patients with diabetes hospitalized for COVID-19: diabetic retinopathy and/or diabetic kidney disease and/or history of diabetic foot ulcer. RESULTS Among 2951 CORONADO, 3387 ABCD COVID-19 audit and 9327 AMERICADO participants, microvascular diabetic complications status was ascertained for 1314 (44.5%), 1809 (53.4%) and 7367 (79.0%) patients, respectively: 1010, 1059 and 1800, respectively, had ≥1 severe microvascular complication(s) and 304, 750 and 5567, respectively, were free of any complications. The patients with isolated diabetic kidney disease had an increased risk of all-cause death during hospital stay: odds ratio [OR] 2.53 (95% confidence interval [CI] 1.66-3.83), OR 1.24 (95% CI 1.00-1.56) and OR 1.66 (95% CI 1.40-1.95) in the CORONADO, the ABCD COVID-19 national audit and the AMERICADO studies, respectively. After adjustment for age, sex, hypertension and cardiovascular disease (CVD), compared to those without microvascular complications, patients with microvascular complications had an increased risk of all-cause death during hospital stay in the CORONADO, the ABCD COVID-19 diabetes national audit and the AMERICADO studies: adjusted OR (adj OR) 2.57 (95% CI 1.69-3.92), adj OR 1.22 (95% CI 1.00-1.52) and adj OR 1.33 (95% CI 1.15-1.53), respectively. In meta-analysis of the three studies, compared to patients free of complications, those with microvascular complications had an unadjusted OR for all-cause death during hospital stay of 2.05 (95% CI 1.42-2.97), which decreased to 1.62 (95% CI 1.19-2.119) after adjustment for age and sex, and to 1.50 (1.12-2.02) after hypertension and CVD were further added to the model. CONCLUSION Microvascular burden is associated with an increased risk of death in patients hospitalized for COVID-19.
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Metabolic syndrome predicts cardiovascular risk and mortality in familial hypercholesterolemia.
Paquette, M, Bernard, S, Cariou, B, Hegele, RA, Genest, J, Trinder, M, Brunham, LR, Béliard, S, Baass, A
Journal of clinical lipidology. 2023;(3):376-383
Abstract
BACKGROUND The association between familial hypercholesterolemia (FH) and premature atherosclerotic cardiovascular disease (ASCVD) is well established. Several risk factors other than the cumulative low-density lipoprotein cholesterol (LDL-C) have been shown to modulate the severity of the phenotype in these patients. However, the effect of the metabolic syndrome (MetS) on ASCVD risk in FH remains to be determined. OBJECTIVES The objective was to study the association between the presence of MetS and the incidence of different ASCVD endpoints and all-cause mortality. METHODS This prospective follow up study used data from 5 independent FH cohorts from Europe and North America. We analysed data of 2401 adult heterozygous FH without history of a prior ASCVD event (21,139 person-years of follow-up). Multivariate Cox proportional hazards regression was used to estimate the association between MetS and the incidence of the different endpoints. RESULTS The prevalence of MetS was 14% in the study population. The presence of MetS was a significant predictor of incident 10-year ASCVD after adjustment for traditional cardiovascular risk factors (HR 2.07, 95% CI 1.34-3.19), as well as of 10-year major adverse cardiovascular event (MACE) (HR 4.59, 95% CI 2.27-9.30), 10-year myocardial infarction (MI) (HR 4.29, 95% CI 1.91-9.63), and 30-year all-cause mortality (HR 4.87, 95% CI 1.99-11.89). CONCLUSION Our findings suggests that FH patients with MetS, have an increased cardiovascular risk that is independent from LDL-C and other traditional risk factors. Future studies are required to determine the most appropriate strategy to reduce the cardiovascular burden associated with MetS in this population.
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Lipid-lowering efficacy and safety of alirocumab in a real-life setting in France: Insights from the ODYSSEY APPRISE study.
Henry, P, Cariou, B, Farnier, M, Lakhdari, SL, Detournay, B
Archives of cardiovascular diseases. 2023;(1):3-8
Abstract
BACKGROUND Recently, a multicentre, prospective, single-arm, phase 3b, open-label trial was conducted to determine the safety and efficacy of alirocumab, a proprotein convertase subtilisin/kexin type 9 inhibitor, in a real-life setting. This study enrolled patients at high cardiovascular risk, with heterozygous familial hypercholesterolaemia (HeFH) or non-familial hypercholesterolaemia (non-FH). Results showed that alirocumab was well tolerated and resulted in a clinically significant reduction in low-density lipoprotein cholesterol (LDL-C). AIM: This ancillary analysis aimed to describe the characteristics of the French patients enrolled in the study, the main results observed in this population according to their familial hypercholesterolaemia status, and adherence to treatment. METHODS French data were analysed separately from the original dataset of the study. RESULTS Among 215 French patients in the ODYSSEY APPRISE trial, 63.7% had non-FH, with a mean LDL-C concentration of 5.0±1.8mmol/L at baseline. The mean duration of alirocumab exposure was 72.4±42.5 weeks, with only 48.4% of patients receiving statins concomitantly. At week 12, a mean reduction in LDL-C of 56.5±17.8% was observed: 51.2±22.8% in HeFH; 59.5±13.2% in non-FH. This improvement in LDL-C started from week 4 and remained stable and sustained until week 120 in both populations. The overall incidence of severe treatment-emergent adverse events (TEAEs) was 33.5%. The most frequent TEAEs were myalgia (15.8%) and asthenia (15.3%). No tolerance or efficacy differences were observed between patients with or without established coronary artery disease or other cardiovascular disease, whatever the age of these events or considering the concomitant use of other lipid-lowering therapies. CONCLUSIONS In the French setting, alirocumab was well tolerated, safe and highly effective at reducing LDL-C. These findings support the use of alirocumab to manage hypercholesterolaemia in patients at high cardiovascular risk.
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Nocturnal hypoglycemia is underdiagnosed in older people with insulin-treated type 2 diabetes: The HYPOAGE observational study.
Boureau, AS, Guyomarch, B, Gourdy, P, Allix, I, Annweiler, C, Cervantes, N, Chapelet, G, Delabrière, I, Guyonnet, S, Litke, R, et al
Journal of the American Geriatrics Society. 2023;(7):2107-2119
Abstract
BACKGROUND There is a lack of real-life data regarding the frequency and predictive factors of hypoglycemia in older patients with type 2 diabetes (T2D). This study aimed to determine the frequency and predictors of hypoglycemia in older patients with insulin-treated T2D. METHODS This prospective multicenter study included 155 insulin-treated T2D patients aged 75 years and older with ≥2 self-monitoring of blood glucose (SMBG) daily controls. Participants underwent a geriatric and diabetic assessment and received ambulatory blinded continuous glucose monitoring (CGM) for 28 consecutive days with FreeStyle Libre Pro® sensor. Study population (n = 141) has >70% CGM active time. Multivariable logistic regressions were used to identify factors associated with SMBG confirmed hypoglycemia (≥70 mg/dL) and with nocturnal level 2 time below range (glucose concentration <54 mg/dL during ≥15 consecutive min between 0.00 and 6.00 am). RESULTS The mean age of the 141 analyzed patients was 81.5 ± 5.3 years and 56.7% were male. The mean baseline HbA1c was 7.9% ± 1.0%. After geriatric assessment, 102 participants (72.3%) were considered as complex and 39 (27.7%) as healthy. The primary endpoint (confirmed SMBG <70 mg/dL) occurred in 37.6% patients. In multivariable analysis, the risk of SMBG-confirmed hypoglycemia was positively associated with a longer duration of diabetes (OR (+1 year) =1.04, (1.00-1.08), p = 0.04) and glycemic variability assessed by CGM (CV %) (OR (+1%) = 1.12, [1.05-1.19], p = <0.001). Nighty-two patients (65.2%) experienced nocturnal time in hypoglycemia (i.e., <54 mg/dL during ≥15 consecutive min between midnight and 6 a.m.). In multivariable analyses, cognitive impairment (OR: 9.31 [2.59-33.4]), heart failure (OR: 4.81 [1;48-15.6]), and depressive disorder (OR: 0.19 [0.06-0.53]) were associated with nocturnal time in hypoglycemia. CONCLUSION Nocturnal hypoglycemia is very common and largely underdiagnosed in older patients with insulin-treated T2D. CGM is a promising tool to better identify hypoglycemia and adapt diabetes management in this population.
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A proposal from the liver forum for the management of comorbidities in non-alcoholic steatohepatitis therapeutic trials.
Pais, R, Cariou, B, Noureddin, M, Francque, S, Schattenberg, JM, Abdelmalek, MF, Lalazar, G, Varma, S, Dietrich, J, Miller, V, et al
Journal of hepatology. 2023;(3):829-841
Abstract
The current document has been developed by the Liver Forum who mandated the NAFLD-Associated Comorbidities Working Group - a multistakeholder group comprised of experts from academic medicine, industry and patient associations - to identify aspects of diverse comorbidities frequently associated with non-alcoholic steatohepatitis (NASH) that can interfere with the conduct of therapeutic trials and, in particular, impact efficacy and safety results. The objective of this paper is to propose guidance for the management of relevant comorbidities in both candidates and actual participants in NASH therapeutic trials. We relied on specific guidelines from scientific societies, when available, but adapted them to the particulars of NASH trials with the aim of addressing multiple interacting requirements such as maintaining patient safety, reaching holistic therapeutic objectives, minimising confounding effects on efficacy and safety of investigational agents and allowing for trial completion. We divided the field of action into: first, analysis and stabilisation of the patient's condition before inclusion in the trial and, second, management of comorbidities during trial conduct. For the former, we discussed the concept of acceptable vs. optimal control of comorbidities, defined metabolic and ponderal stability prior to randomisation and weighed the pros and cons of a run-in period. For the latter, we analysed non-hepatological comorbid conditions for changes or acute events possibly occurring during the trial, including changes in alcohol consumption, in order to detail when specific interventions are necessary and how best to manage concomitant drug intake in line with methodological constraints. These recommendations are intended to act as a guide for clinical trialists and are open to further refinement when additional data become available.
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Dulaglutide and insulin microsecretion in people with type 1 diabetes (DIAMOND-GLP-1): A randomized double-blind placebo-controlled trial.
Thivolet, C, Larger, E, Cariou, B, Renard, E, Hanaire, H, Benhamou, PY, Guerci, B, Mathiotte, É, Chikh, K
Diabetes & metabolism. 2023;(2):101433
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A new 165-SNP low-density lipoprotein cholesterol polygenic risk score based on next generation sequencing outperforms previously published scores in routine diagnostics of familial hypercholesterolemia.
Vanhoye, X, Bardel, C, Rimbert, A, Moulin, P, Rollat-Farnier, PA, Muntaner, M, Marmontel, O, Dumont, S, Charrière, S, Cornélis, F, et al
Translational research : the journal of laboratory and clinical medicine. 2023;:119-127
Abstract
Genetic diagnosis of familial hypercholesterolemia (FH) remains unexplained in 30 to 70% of patients after exclusion of monogenic disease. There is now a growing evidence that a polygenic burden significantly modulates LDL-cholesterol (LDL-c) concentrations. Several LDL-c polygenic risk scores (PRS) have been set up. However, the balance between their diagnosis performance and their practical use in routine practice is not clearly established. Consequently, we set up new PRS based on our routine panel for sequencing and compared their diagnostic performance with previously-published PRS. After a meta-analysis, four new PRS including 165 to 1633 SNP were setup using different softwares. They were established using two French control cohorts (MONA LISA n=1082 and FranceGenRef n=856). Then the explained LDL-c variance and the ability of each PRS to discriminate monogenic negative FH patients (M-) versus healthy controls were compared with 4 previously-described PRS in 785 unrelated FH patients. Between all PRS, the 165-SNP PRS developed with PLINK showed the best LDL-c explained variance (adjusted R²=0.19) and the best diagnosis abilities (AUROC=0.77, 95%CI=0.74-0.79): it significantly outperformed all the previously-published PRS (p<1 × 10-4). By using a cut-off at the 75th percentile, 61% of M- patients exhibited a polygenic hypercholesterolemia with the 165-SNP PRS versus 48% with the previously published 12-SNP PRS (p =3.3 × 10-6). These results were replicated using the UK biobank. This new 165-SNP PRS, usable in routine diagnosis, exhibits better diagnosis abilities for a polygenic hypercholesterolemia diagnosis. It would be a valuable tool to optimize referral for whole genome sequencing.
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COVID-19 and Diabetes Outcomes: Rationale for and Updates from the CORONADO Study.
Smati, S, Tramunt, B, Wargny, M, Gourdy, P, Hadjadj, S, Cariou, B
Current diabetes reports. 2022;(2):53-63
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Abstract
PURPOSE OF REVIEW In France, in order to describe the phenotypic characteristics of patients with diabetes hospitalized for coronavirus disease-2019 (COVID-19) and to identify the prognostic factors in this specific population, the CORONADO (CORONAvirus and Diabetes Outcomes) study was launched. This review will summarize the key findings from the CORONADO study and put them in perspectives with others studies published on the subject. RECENT FINDINGS For almost 2 years, the new SARS-CoV-2 (Severe Acute Respiratory Syndrome-CoronaVirus-2), which causes COVID-19, has spread all around the world leading to a pandemic. From the first epidemiological reports, diabetes mellitus has rapidly emerged as a major risk factor associated with severe forms of COVID-19 but few data were available about diabetes characteristics in hospitalized people with COVID-19. Between March 10 and April 10, 2020, 2951 patients were included in 68 centers throughout the national territory, including overseas territories. In the CORONADO study, the primary outcome was a composite endpoint combining invasive mechanical ventilation (IMV) and/or death within day 7 (D7). Secondary outcomes included death, IMV, intensive care unit (ICU) admission, and hospital discharge, all considered within D7 and day 28 (D28). The primary outcome occurred in 29.0% participants within D7 following hospital admission. Within D28, the end of the follow-up period, the mortality rate was 20.6%, while 50.2% of patients were discharged. In multivariable analysis, advanced age, microvascular complications, treatment with insulin or statin prior to admission, dyspnea on admission, as well as biological markers reflecting the severity of the infection (high levels of transaminases, leukocytes and CRP, and low platelet levels) were associated with an increased risk of death. Several exploratory analyses were performed to clarify the influence of some parameters such as weight status, sex, type of diabetes, and some routine drugs, including metformin or statins.