Pub Date : 2024-11-01Epub Date: 2024-09-23DOI: 10.1016/S2213-8587(24)00200-6
André Lacroix, Isabelle Bourdeau, Fanny Chasseloup, Peter Kamenický, Antoine-Guy Lopez, Estelle Louiset, Hervé Lefebvre
Aberrant G-protein coupled receptor (GPCR) expression is highly prevalent in cortisol-secreting primary bilateral macronodular adrenal hyperplasia (PBMAH) and unilateral adenomas. The aberrant expression of diverse GPCRs and their ligands play an important role in the over-function of various endocrine tumours. Examples include aberrant expression of MC2R, 5-HT4R, AVPR1A, LHCGR, and GnRHR in primary aldosteronism; GCGR, LHCGR, and 5-HT4R in phaeochromocytomas and paragangliomas; TRHR, GnRHR, GIPR, and GRP101 in pituitary somatotroph tumours; AVPR2, D2DR, and SSTR5 in pituitary corticotroph tumours; GLP1R, GIPR, and somatostatin receptors in medullary thyroid carcinoma; and SSTRs, GLP1R, and GIPR in other neuroendocrine tumours. The genetic mechanisms causing the ectopic expression of GIPR in cortisol-secreting PBMAHs and unilateral adenomas have been identified, but distinct mechanisms are implicated in other endocrine tumours. Development of functional imaging targeting aberrant GPCRs should be useful for identification and for specific therapies of this wide spectrum of tumours. The aim of this review is to show that the regulation of endocrine tumours by aberrant GPCR is not restricted to cortisol-secreting adrenal lesions, but also occurs in tumours of several other organs.
{"title":"Aberrant hormone receptors regulate a wide spectrum of endocrine tumors.","authors":"André Lacroix, Isabelle Bourdeau, Fanny Chasseloup, Peter Kamenický, Antoine-Guy Lopez, Estelle Louiset, Hervé Lefebvre","doi":"10.1016/S2213-8587(24)00200-6","DOIUrl":"10.1016/S2213-8587(24)00200-6","url":null,"abstract":"<p><p>Aberrant G-protein coupled receptor (GPCR) expression is highly prevalent in cortisol-secreting primary bilateral macronodular adrenal hyperplasia (PBMAH) and unilateral adenomas. The aberrant expression of diverse GPCRs and their ligands play an important role in the over-function of various endocrine tumours. Examples include aberrant expression of MC2R, 5-HT4R, AVPR1A, LHCGR, and GnRHR in primary aldosteronism; GCGR, LHCGR, and 5-HT4R in phaeochromocytomas and paragangliomas; TRHR, GnRHR, GIPR, and GRP101 in pituitary somatotroph tumours; AVPR2, D2DR, and SSTR5 in pituitary corticotroph tumours; GLP1R, GIPR, and somatostatin receptors in medullary thyroid carcinoma; and SSTRs, GLP1R, and GIPR in other neuroendocrine tumours. The genetic mechanisms causing the ectopic expression of GIPR in cortisol-secreting PBMAHs and unilateral adenomas have been identified, but distinct mechanisms are implicated in other endocrine tumours. Development of functional imaging targeting aberrant GPCRs should be useful for identification and for specific therapies of this wide spectrum of tumours. The aim of this review is to show that the regulation of endocrine tumours by aberrant GPCR is not restricted to cortisol-secreting adrenal lesions, but also occurs in tumours of several other organs.</p>","PeriodicalId":48790,"journal":{"name":"The Lancet Diabetes & Endocrinology","volume":" ","pages":"837-855"},"PeriodicalIF":44.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142330471","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-01Epub Date: 2024-09-23DOI: 10.1016/S2213-8587(24)00275-4
Stefano Del Prato
{"title":"Dysglycaemia in cardiovascular disease: what's the best glycaemic risk predictor?","authors":"Stefano Del Prato","doi":"10.1016/S2213-8587(24)00275-4","DOIUrl":"10.1016/S2213-8587(24)00275-4","url":null,"abstract":"","PeriodicalId":48790,"journal":{"name":"The Lancet Diabetes & Endocrinology","volume":" ","pages":"776-777"},"PeriodicalIF":44.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142330472","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-01Epub Date: 2024-08-20DOI: 10.1016/S2213-8587(24)00240-7
Sufyan Hussain, Katarina Braune, Shareen Forbes, Peter A Senior
{"title":"Closed-loop systems: a bridge to cell therapy for type 1 diabetes?","authors":"Sufyan Hussain, Katarina Braune, Shareen Forbes, Peter A Senior","doi":"10.1016/S2213-8587(24)00240-7","DOIUrl":"10.1016/S2213-8587(24)00240-7","url":null,"abstract":"","PeriodicalId":48790,"journal":{"name":"The Lancet Diabetes & Endocrinology","volume":" ","pages":"782-784"},"PeriodicalIF":44.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142047360","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-01Epub Date: 2024-09-05DOI: 10.1016/S2213-8587(24)00281-X
David Beran, Stéphane Besançon
{"title":"International Day of Charity: what does charity mean for diabetes?","authors":"David Beran, Stéphane Besançon","doi":"10.1016/S2213-8587(24)00281-X","DOIUrl":"10.1016/S2213-8587(24)00281-X","url":null,"abstract":"","PeriodicalId":48790,"journal":{"name":"The Lancet Diabetes & Endocrinology","volume":" ","pages":"787-788"},"PeriodicalIF":44.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142156449","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-24DOI: 10.1016/s2213-8587(24)00234-1
Jana Sommer, Sandra Olivia Borgmann, Veronika Gontscharuk, Oana Patricia Zaharia, Haifa Maalmi, Christian Herder, Robert Wagner, Klaus Strassburger, Martin Schön, Volker Burkart, Julia Szendroedi, Andreas F H Pfeiffer, Stefan Bornstein, Matthias Blüher, Jochen Seissler, Andreas L Birkenfeld, Svenja Meyhöfer, Michael Roden, Andrea Icks, Robert Wagner
Background
The subjective experiences of individuals living with diabetes is commonly assessed with patient-reported outcomes (PROs; eg, depression symptoms, wellbeing, health-related quality of life [HRQOL], and diabetes-related distress). Cluster analyses have identified novel diabetes subtypes differing in phenotypic and metabolic characteristics. We aimed to investigate associations between these subtypes and PROs and whether subtype predicted PROs 5 years later.
Methods
Baseline (<12 months after a diabetes diagnosis) and 5-year follow-up data were collected from German Diabetes Study (GDS) participants. Multiple regressions were applied to analyse associations between diabetes subtypes and depression symptoms (Center for Epidemiologic Studies Depression Scale), wellbeing (WHO-5), HRQOL (SF-36), and diabetes-related distress (Problem Areas in Diabetes Scale).
Findings
Cluster analyses at baseline (n=1391) identified participants with severe autoimmune diabetes (SAID, 417 [30%]), severe insulin-deficient diabetes (SIDD, 33 [2%]), severe insulin-resistant diabetes (SIRD, 150 [11%]), mild obesity-related diabetes (MOD, 354 [25%]), and mild age-related diabetes (MARD, 437 [31%]). At baseline, multiple regression analyses showed that participants with SIRD had higher depression symptoms than participants with MARD and lower physical HRQOL than all other subtypes. Participants with SAID reported higher depression symptoms and lower mental HRQOL than participants with MARD, higher physical HRQOL than participants with MARD and MOD, and higher diabetes-related distress than most other subtypes. At the 5-year follow-up, clustering predicted no statistically significant changes in PROs after adjustment for multiple testing, whereas descriptive analyses demonstrated that individuals with SIRD were more likely to experience clinically relevant depression symptoms (16% vs 6%) and low wellbeing (31% vs 14%), respectively, than individuals with MARD.
Interpretation
Diabetes subtypes already differ in PROs at diabetes diagnosis. Our analyses had limited predictive power during follow-up. However, our findings suggest that clustering could predict future changes in depression symptoms.
Funding
The GDS was initiated and financed by the German Diabetes Center, which is funded by the German Federal Ministry of Health, the Ministry of Culture and Science of the state of North Rhine-Westphalia, and by the German Federal Ministry of Education and Research to the German Center for Diabetes Research.
Translation
For the German translation of the abstract see Supplementary Materials section.
背景糖尿病患者的主观体验通常由患者报告的结果（PROs；如抑郁症状、幸福感、健康相关生活质量 [HRQOL] 和糖尿病相关困扰）来评估。聚类分析发现了表型和代谢特征不同的新型糖尿病亚型。我们的目的是研究这些亚型与PROs之间的关系，以及亚型是否能预测5年后的PROs。方法从德国糖尿病研究（GDS）参与者中收集基线（糖尿病诊断后12个月）和5年随访数据。应用多元回归分析糖尿病亚型与抑郁症状（流行病学研究中心抑郁量表）、幸福感（WHO-5）、HRQOL（SF-36）和糖尿病相关困扰（糖尿病问题领域量表）之间的关系。研究结果基线聚类分析（n=1391）发现，参与者患有严重自身免疫性糖尿病（SAID，417 [30%]）、严重胰岛素缺乏性糖尿病（SIDD，33 [2%]）、严重胰岛素抵抗性糖尿病（SIRD，150 [11%]）、轻度肥胖相关性糖尿病（MOD，354 [25%]）和轻度年龄相关性糖尿病（MARD，437 [31%]）。基线多元回归分析显示，SIRD 参与者的抑郁症状高于 MARD 参与者，身体 HRQOL 低于所有其他亚型。SAID 患者的抑郁症状和心理 HRQOL 均高于 MARD 患者，身体 HRQOL 则高于 MARD 和 MOD 患者，与糖尿病相关的困扰则高于大多数其他亚型。在为期5年的随访中，经多重测试调整后，聚类预测PROs没有统计学意义上的显著变化，而描述性分析表明，与MARD患者相比，SIRD患者更有可能出现临床相关的抑郁症状（16% vs 6%）和低幸福感（31% vs 14%）。我们的分析对随访的预测能力有限。GDS由德国糖尿病中心发起和资助，该中心由德国联邦卫生部、北莱茵-威斯特法伦州文化和科学部以及德国联邦教育和研究部资助，并由德国糖尿病研究中心提供资金支持。
{"title":"Depression symptoms, wellbeing, health-related quality of life, and diabetes-related distress in novel subtypes of recent-onset diabetes in Germany: a 5-year observational follow-up study","authors":"Jana Sommer, Sandra Olivia Borgmann, Veronika Gontscharuk, Oana Patricia Zaharia, Haifa Maalmi, Christian Herder, Robert Wagner, Klaus Strassburger, Martin Schön, Volker Burkart, Julia Szendroedi, Andreas F H Pfeiffer, Stefan Bornstein, Matthias Blüher, Jochen Seissler, Andreas L Birkenfeld, Svenja Meyhöfer, Michael Roden, Andrea Icks, Robert Wagner","doi":"10.1016/s2213-8587(24)00234-1","DOIUrl":"https://doi.org/10.1016/s2213-8587(24)00234-1","url":null,"abstract":"<h3>Background</h3>The subjective experiences of individuals living with diabetes is commonly assessed with patient-reported outcomes (PROs; eg, depression symptoms, wellbeing, health-related quality of life [HRQOL], and diabetes-related distress). Cluster analyses have identified novel diabetes subtypes differing in phenotypic and metabolic characteristics. We aimed to investigate associations between these subtypes and PROs and whether subtype predicted PROs 5 years later.<h3>Methods</h3>Baseline (<12 months after a diabetes diagnosis) and 5-year follow-up data were collected from German Diabetes Study (GDS) participants. Multiple regressions were applied to analyse associations between diabetes subtypes and depression symptoms (Center for Epidemiologic Studies Depression Scale), wellbeing (WHO-5), HRQOL (SF-36), and diabetes-related distress (Problem Areas in Diabetes Scale).<h3>Findings</h3>Cluster analyses at baseline (n=1391) identified participants with severe autoimmune diabetes (SAID, 417 [30%]), severe insulin-deficient diabetes (SIDD, 33 [2%]), severe insulin-resistant diabetes (SIRD, 150 [11%]), mild obesity-related diabetes (MOD, 354 [25%]), and mild age-related diabetes (MARD, 437 [31%]). At baseline, multiple regression analyses showed that participants with SIRD had higher depression symptoms than participants with MARD and lower physical HRQOL than all other subtypes. Participants with SAID reported higher depression symptoms and lower mental HRQOL than participants with MARD, higher physical HRQOL than participants with MARD and MOD, and higher diabetes-related distress than most other subtypes. At the 5-year follow-up, clustering predicted no statistically significant changes in PROs after adjustment for multiple testing, whereas descriptive analyses demonstrated that individuals with SIRD were more likely to experience clinically relevant depression symptoms (16% <em>vs</em> 6%) and low wellbeing (31% <em>vs</em> 14%), respectively, than individuals with MARD.<h3>Interpretation</h3>Diabetes subtypes already differ in PROs at diabetes diagnosis. Our analyses had limited predictive power during follow-up. However, our findings suggest that clustering could predict future changes in depression symptoms.<h3>Funding</h3>The GDS was initiated and financed by the German Diabetes Center, which is funded by the German Federal Ministry of Health, the Ministry of Culture and Science of the state of North Rhine-Westphalia, and by the German Federal Ministry of Education and Research to the German Center for Diabetes Research.<h3>Translation</h3>For the German translation of the abstract see Supplementary Materials section.","PeriodicalId":48790,"journal":{"name":"The Lancet Diabetes & Endocrinology","volume":"25 1","pages":""},"PeriodicalIF":44.5,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142489143","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-23DOI: 10.1016/s2213-8587(24)00242-0
Beryl Lin, Ruth L Coleman, Fiona Bragg, Ernesto Maddaloni, Rury R Holman, Amanda I Adler
Background
Younger-onset type 2 diabetes is associated with accelerated complications. We assessed whether complications and mortality rates differed for younger age compared with older age at diagnosis over 30 years of follow-up.
Methods
In this study, we used data from the UKPDS, collected between 1977 and 2007, of participants aged 25–65 years with newly diagnosed type 2 diabetes with younger-onset (younger than 40 years) or later-onset (40 years or older), and without diabetes autoantibodies. We analysed standardised mortality ratios (SMR) using UK general population data, and incidence rates of prespecified outcomes by 10-year age intervals at diagnosis.
Findings
Of 4550 participants testing negative to all measured autoantibodies, 429 (9·4%) had younger-onset type 2 diabetes. 2704 (59·4%) were male, and mean HbA1c was 76 mmol/mol (SD 24·6). The median follow-up was 17·5 years (IQR 12·7–20·8). SMR for younger-onset type 2 diabetes was higher (3·72 [95% CI 2·98–4·64]) compared with later-onset type 2 diabetes (1·54 [1·47–1·61]). The incidence rate was higher for all outcomes in later-onset type 2 diabetes, except for microvascular disease (younger-onset 14·5 (11·9–17·7) vs later-onset 12·1 (11·3–13·0) per 1000 person-years). However, at any given age, the 5-year incidence of any diabetes-related endpoint, all-cause mortality, microvascular disease, and myocardial infarction was higher with younger age at diagnosis. Annual mean HbA1c was higher in the first 20 years in younger-onset compared with later-onset type 2 diabetes. Among participants randomised to intensive versus conventional glycaemic control, we observed no interactions by subgroup of younger-onset versus later-onset type 2 diabetes for any outcome.
Interpretation
The risk of dying relative to the general population is even greater for people diagnosed with type 2 diabetes at younger ages. The increased risk of complications and poorer glycaemic control in younger-onset type 2 diabetes calls for the development of services to identify and manage these individuals.
Funding
National Institute of Health and Care Research's Biomedical Research Centre.
{"title":"Younger-onset compared with later-onset type 2 diabetes: an analysis of the UK Prospective Diabetes Study (UKPDS) with up to 30 years of follow-up (UKPDS 92)","authors":"Beryl Lin, Ruth L Coleman, Fiona Bragg, Ernesto Maddaloni, Rury R Holman, Amanda I Adler","doi":"10.1016/s2213-8587(24)00242-0","DOIUrl":"https://doi.org/10.1016/s2213-8587(24)00242-0","url":null,"abstract":"<h3>Background</h3>Younger-onset type 2 diabetes is associated with accelerated complications. We assessed whether complications and mortality rates differed for younger age compared with older age at diagnosis over 30 years of follow-up.<h3>Methods</h3>In this study, we used data from the UKPDS, collected between 1977 and 2007, of participants aged 25–65 years with newly diagnosed type 2 diabetes with younger-onset (younger than 40 years) or later-onset (40 years or older), and without diabetes autoantibodies. We analysed standardised mortality ratios (SMR) using UK general population data, and incidence rates of prespecified outcomes by 10-year age intervals at diagnosis.<h3>Findings</h3>Of 4550 participants testing negative to all measured autoantibodies, 429 (9·4%) had younger-onset type 2 diabetes. 2704 (59·4%) were male, and mean HbA<sub>1c</sub> was 76 mmol/mol (SD 24·6). The median follow-up was 17·5 years (IQR 12·7–20·8). SMR for younger-onset type 2 diabetes was higher (3·72 [95% CI 2·98–4·64]) compared with later-onset type 2 diabetes (1·54 [1·47–1·61]). The incidence rate was higher for all outcomes in later-onset type 2 diabetes, except for microvascular disease (younger-onset 14·5 (11·9–17·7) <em>vs</em> later-onset 12·1 (11·3–13·0) per 1000 person-years). However, at any given age, the 5-year incidence of any diabetes-related endpoint, all-cause mortality, microvascular disease, and myocardial infarction was higher with younger age at diagnosis. Annual mean HbA<sub>1c</sub> was higher in the first 20 years in younger-onset compared with later-onset type 2 diabetes. Among participants randomised to intensive versus conventional glycaemic control, we observed no interactions by subgroup of younger-onset versus later-onset type 2 diabetes for any outcome.<h3>Interpretation</h3>The risk of dying relative to the general population is even greater for people diagnosed with type 2 diabetes at younger ages. The increased risk of complications and poorer glycaemic control in younger-onset type 2 diabetes calls for the development of services to identify and manage these individuals.<h3>Funding</h3>National Institute of Health and Care Research's Biomedical Research Centre.","PeriodicalId":48790,"journal":{"name":"The Lancet Diabetes & Endocrinology","volume":"14 1","pages":""},"PeriodicalIF":44.5,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142488102","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-23DOI: 10.1016/s2213-8587(24)00282-1
Soon H Song, Brian M Frier
No Abstract
无摘要
{"title":"Young adult-onset type 2 diabetes heralds a poor prognosis","authors":"Soon H Song, Brian M Frier","doi":"10.1016/s2213-8587(24)00282-1","DOIUrl":"https://doi.org/10.1016/s2213-8587(24)00282-1","url":null,"abstract":"No Abstract","PeriodicalId":48790,"journal":{"name":"The Lancet Diabetes & Endocrinology","volume":"17 1","pages":""},"PeriodicalIF":44.5,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142488100","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-16DOI: 10.1016/s2213-8587(24)00233-x
Luis Masana, Alberto Zambon, Claus Peter Schmitt, Christina Taylan, Joenna Driemeyer, Hofit Cohen, Paola Sabrina Buonuomo, Abdullah Alashwal, Mohammed Al-Dubayee, Naji Kholaif, José Luis Diaz-Diaz, Faouzi Maatouk, Sergio Martinez-Hervas, Brian Mangal, Sandra Löwe, Tracy Cunningham
<h3>Background</h3>Homozygous familial hypercholesterolaemia (HoFH) is a rare inherited disorder characterised by extremely high concentrations of LDL cholesterol, leading to early-onset atherosclerosis. Lomitapide is an orally administered microsomal triglyceride transfer protein (MTP) inhibitor that effectively lowers LDL cholesterol and is approved for adults with HoFH. We aimed to investigate the efficacy and safety of lomitapide in paediatric patients with HoFH receiving standard-of-care lipid-lowering therapy.<h3>Methods</h3>APH-19 is an open-label, single-arm, phase 3 trial performed at 12 study centres in Germany, Israel, Italy, Saudi Arabia, Spain, and Tunisia. A 6-week run-in period was followed by a 24-week efficacy phase and an 80-week safety phase. Patients aged 5–17 years, on stable lipid-lowering therapy, with HoFH diagnosed using the criteria from the 2014 European Atherosclerosis Society Consensus Panel on HoFH were titrated to maximum tolerated doses of oral lomitapide, starting at 2 mg (patients aged 5–15 years) or 5 mg (patients aged 16–17 years). The primary endpoint was the percentage change from baseline to week 24 in LDL cholesterol, which was assessed in patients who had received at least one dose of lomitapide, and who had a baseline and at least one post-baseline measurement. The secondary outcomes were the percentage change from baseline at week 24 in total cholesterol, non-HDL cholesterol, VLDL cholesterol, apolipoprotein B, triglycerides, and lipoprotein(a). Safety was assessed in patients who received at least one dose of study drug. This study is registered with <span><span>ClinicalTrials.gov</span><svg aria-label="Opens in new window" focusable="false" height="20" viewbox="0 0 8 8"><path d="M1.12949 2.1072V1H7V6.85795H5.89111V2.90281L0.784057 8L0 7.21635L5.11902 2.1072H1.12949Z"></path></svg></span>, <span><span>NCT04681170</span><svg aria-label="Opens in new window" focusable="false" height="20" viewbox="0 0 8 8"><path d="M1.12949 2.1072V1H7V6.85795H5.89111V2.90281L0.784057 8L0 7.21635L5.11902 2.1072H1.12949Z"></path></svg></span>.<h3>Findings</h3>Between Dec 20, 2020, and Oct 16, 2022, 43 patients were included and treated (24 [56%] were female and 19 [44%] were male, and median age was 10·7 years [7·0–14·0]). Mean change from baseline in LDL cholesterol at week 24 was –53·5% (95% CI –61·6 to –45·4, p<0·0001). Mean percentage reductions were observed at week 24 for non-HDL cholesterol (–53·9%, 95% CI –61·7 to –46·1, p<0·0001), total cholesterol (–50·0%, 95% CI –57·6 to –42·4, p<0·0001), VLDL cholesterol (–50·2%, –59·1 to –41·2, p<0·0001), apolipoprotein B (–52·4%, –60·3 to –44·5, p<0·0001), triglycerides was –49·9% (–58·8 to –41·0, p<0·0001), and lipoprotein(a) (–11·3%, –32·9 to 10·3 [in 21 patients with measurements in mg/dL]; –23·6%, –38·2 to –9·0 [in 22 patients with measurements in nmol/L]; p=0·0070 combined). Adverse events were mostly mild, and gastrointestinal and hepatic in nature. Adve
{"title":"Lomitapide for the treatment of paediatric patients with homozygous familial hypercholesterolaemia (APH-19): results from the efficacy phase of an open-label, multicentre, phase 3 study","authors":"Luis Masana, Alberto Zambon, Claus Peter Schmitt, Christina Taylan, Joenna Driemeyer, Hofit Cohen, Paola Sabrina Buonuomo, Abdullah Alashwal, Mohammed Al-Dubayee, Naji Kholaif, José Luis Diaz-Diaz, Faouzi Maatouk, Sergio Martinez-Hervas, Brian Mangal, Sandra Löwe, Tracy Cunningham","doi":"10.1016/s2213-8587(24)00233-x","DOIUrl":"https://doi.org/10.1016/s2213-8587(24)00233-x","url":null,"abstract":"<h3>Background</h3>Homozygous familial hypercholesterolaemia (HoFH) is a rare inherited disorder characterised by extremely high concentrations of LDL cholesterol, leading to early-onset atherosclerosis. Lomitapide is an orally administered microsomal triglyceride transfer protein (MTP) inhibitor that effectively lowers LDL cholesterol and is approved for adults with HoFH. We aimed to investigate the efficacy and safety of lomitapide in paediatric patients with HoFH receiving standard-of-care lipid-lowering therapy.<h3>Methods</h3>APH-19 is an open-label, single-arm, phase 3 trial performed at 12 study centres in Germany, Israel, Italy, Saudi Arabia, Spain, and Tunisia. A 6-week run-in period was followed by a 24-week efficacy phase and an 80-week safety phase. Patients aged 5–17 years, on stable lipid-lowering therapy, with HoFH diagnosed using the criteria from the 2014 European Atherosclerosis Society Consensus Panel on HoFH were titrated to maximum tolerated doses of oral lomitapide, starting at 2 mg (patients aged 5–15 years) or 5 mg (patients aged 16–17 years). The primary endpoint was the percentage change from baseline to week 24 in LDL cholesterol, which was assessed in patients who had received at least one dose of lomitapide, and who had a baseline and at least one post-baseline measurement. The secondary outcomes were the percentage change from baseline at week 24 in total cholesterol, non-HDL cholesterol, VLDL cholesterol, apolipoprotein B, triglycerides, and lipoprotein(a). Safety was assessed in patients who received at least one dose of study drug. This study is registered with <span><span>ClinicalTrials.gov</span><svg aria-label=\"Opens in new window\" focusable=\"false\" height=\"20\" viewbox=\"0 0 8 8\"><path d=\"M1.12949 2.1072V1H7V6.85795H5.89111V2.90281L0.784057 8L0 7.21635L5.11902 2.1072H1.12949Z\"></path></svg></span>, <span><span>NCT04681170</span><svg aria-label=\"Opens in new window\" focusable=\"false\" height=\"20\" viewbox=\"0 0 8 8\"><path d=\"M1.12949 2.1072V1H7V6.85795H5.89111V2.90281L0.784057 8L0 7.21635L5.11902 2.1072H1.12949Z\"></path></svg></span>.<h3>Findings</h3>Between Dec 20, 2020, and Oct 16, 2022, 43 patients were included and treated (24 [56%] were female and 19 [44%] were male, and median age was 10·7 years [7·0–14·0]). Mean change from baseline in LDL cholesterol at week 24 was –53·5% (95% CI –61·6 to –45·4, p<0·0001). Mean percentage reductions were observed at week 24 for non-HDL cholesterol (–53·9%, 95% CI –61·7 to –46·1, p<0·0001), total cholesterol (–50·0%, 95% CI –57·6 to –42·4, p<0·0001), VLDL cholesterol (–50·2%, –59·1 to –41·2, p<0·0001), apolipoprotein B (–52·4%, –60·3 to –44·5, p<0·0001), triglycerides was –49·9% (–58·8 to –41·0, p<0·0001), and lipoprotein(a) (–11·3%, –32·9 to 10·3 [in 21 patients with measurements in mg/dL]; –23·6%, –38·2 to –9·0 [in 22 patients with measurements in nmol/L]; p=0·0070 combined). Adverse events were mostly mild, and gastrointestinal and hepatic in nature. Adve","PeriodicalId":48790,"journal":{"name":"The Lancet Diabetes & Endocrinology","volume":"29 1","pages":""},"PeriodicalIF":44.5,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142440353","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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