Congenital generalized lipodystrophy (CGL) is a rare disorder marked by near-total loss of adipose tissue and severe metabolic disturbances due to leptin deficiency and the inability to store nutrients in adipose tissue effectively. Metreleptin is the only approved leptin replacement therapy for this condition. Here we present the >20-year follow-up of two sisters with CGL type 1 (AGPAT2 deficiency, OMIM# 608594), enrolled in early metreleptin trials. Clinical outcomes, adherence, immunogenicity, and pregnancies were assessed. Both cases showed rapid and sustained metabolic improvement after metreleptin initiation, allowing insulin discontinuation and triglyceride normalization. Menstrual cycles resumed within six months; allowing both to carry successful pregnancies while continuing metreleptin. Both cases experienced reduced treatment adherence over time, linked to psychological distress. One case developed both anti-drug antibodies and neutralizing activity through immune based assay after 14 years, but without significant clinical impact. In conclusion, these cases highlight both the sustained metabolic benefits of therapy and the complex challenges that may arise over time, such as antibody formation and difficulties in maintaining long-term adherence. Documentation of unmet medical needs can provide guidance and impetus for improved therapeutic approaches to achieve optimum quality of life.

Because one in three of all individuals die from atherosclerotic cardiovascular disease (ASCVD), prevention of ASCVD is key to public health worldwide. Lipid clinics provide specialized diagnostic assessment, lifestyle management, and evidence-based lipid-lowering treatment to prevent ASCVD and acute pancreatitis in high-risk individuals. This includes individuals with familial hypercholesterolemia and/or markedly increased lipoprotein(a), statin intolerance, refractory or difficult-to-control low-density lipoprotein (LDL) cholesterol, severe hypertriglyceridaemia, and other rare or complex lipid disorders. Such specialized care not only benefits the individual patients and their families but facilitates dissemination of best practices in lipid disorder management to healthcare professionals in individual nations. Despite this, there is a lack of guidance on standards and metrics needed to establish a well-harmonized national lipid clinic network in most countries capable of offering comprehensive care. This consensus paper from the European Atherosclerosis Society Lipid Clinic Network aims to meet this unmet clinical need. We provide recommendations to enhance education and training on lipid disorders and to harmonize lipid clinics at both national and international levels. Furthermore, we provide guidance on optimal staffing structures and development of registries to improve diagnosis and management of lipid disorders. Finally, we offer recommendations to national and regional policymakers on funding of lipid clinics, with the long-term goal of reducing the overall societal burden and costs of cardiovascular and other lipid-related diseases.

There is a lack of knowledge on the registration of body mass index (BMI) and prevalence of obesity-related complications in the Belgian healthcare system. We therefore evaluated these in Belgians living with overweight or obesity. BMI registration and obesity-related complication prevalences were determined using cross-sectional data from a Belgian general practitioners' morbidity registry (Intego) with 208 891 personal records and from 3605 visitors to an obesity clinic. Two Intego data subsets were used: 53 555 individuals with and 84 017 individuals without registered BMI. Groups were compared using chi-square tests (p-value of < 0.05). For Intego data, BMI was registered in 25.6% of cases. Individuals with registered BMI (mean BMI 27.1 ± 5.5 kg/m2) had a higher prevalence of hypertension (30.1% vs. 17.0%), dyslipidemia (26.9% vs. 14.7%), prediabetes (17.0% vs. 7.9%), type 2 diabetes (12.7% vs. 4.4%) and sleep apnea (3.8% vs. 1.5%) compared to people without registered BMI. People assessed at the obesity clinic (mean BMI 39.0 ± 6.5 kg/m2) had higher prevalences of hypertension (43.1% vs. 37.5%), dyslipidemia (44.4% vs. 32.9%) and sleep apnea (37.9% vs. 5.5%) compared to Intego individuals with BMI ≥ 25 kg/m2(mean BMI 30.3 ± 4.3 kg/m2). BMI is registered only in 25% of patient files in general practice, and people with a registered BMI in general practice have a substantially higher prevalence of the five obesity-related complications than people without registered BMI. When registered, mean BMI is substantially lower than in the obesity clinic, but the prevalence of complications is already substantial, though lower than in the obesity clinic.

Long-term data indicate that patients who underwent metabolic bariatric surgery have a higher risk of developing nutritional complications. Therefore, it is of utmost importance to monitor their nutritional status. A scoping literature search was conducted in MEDLINE, EMBASE, CINAHL, and TRIP database to identify clinical practice guidelines for nutritional screening before and after metabolic bariatric surgery from learned societies. For full coverage, all websites of learned societies affiliated with the World Obesity Federation were searched. Clinical practice guidelines were eligible if they contained recommendations for nutritional screening before and after sleeve gastrectomy or Roux-en-Y gastric bypass. Content was screened by two reviewers for timing, biochemical markers and cut-off values, and biochemical assays for nutritional screening. Nine eligible clinical practice guidelines co-authored by 26 learned societies were identified. All guidelines provided recommendations for both bariatric procedures except for one. Majority of guidelines endorsed nutritional screening before surgery and at 3, 6, 12, and 24 months after surgery, and annually thereafter. Pre- and postoperative screening recommendations were available for iron, vitamin B12, folate, calcium and vitamin D, but in a lesser extent for vitamin A, vitamin E, vitamin K, zinc, vitamin B1, copper and magnesium. Two clinical practice guidelines provided cut-off values for the diagnosis of nutritional deficiencies. The clinical practice guidelines exhibited a high level of consistency for timing of screening, but not for the applied biochemical markers. Going forward, the primary focus should be on harmonizing recommendations for biochemical markers, and cut-off values.

Metabolic and bariatric surgery (MBS) is a proven treatment for obesity but increases risk of nutrient deficiencies. Guidelines recommend vitamin and mineral supplementation after MBS but omits selenium. Adequate selenium status is associated with reduced incidence of chronic diseases, including sarcopenia, yet excess selenium intake is not innocuous. Whilst selenoprotein P is the preferred marker of status, no studies have investigated selenoprotein P after MBS. This cross-sectional study compared Selenoprotein P, plasma selenium and dietary selenium in adults older than 65 years with (BAR) or without previous MBS (CON). Dietary selenium intake was calculated using locally available composition data; Selenoprotein P was categorised as suboptimal, saturated, and supersaturated; and plasma selenium as suboptimal, adequate, and replete. Subgroups were created by selenium supplementation practises (supp vs. none) and linear regression was used to investigate predictors of selenoprotein P. Fifty participants were included per group (BAR 40% male, CON 36%) and BAR participants were two years younger and fewer had diabetes (28% vs 52%). Both selenoprotein P and plasma selenium were higher in BAR-supp compared to BAR-none or CON-none. BAR-supp had a lower prevalence of suboptimal selenoprotein P levels compared to BAR-none (7% vs. 43%) but more participants had supersaturated levels (28% vs 0%). The predictors of selenoprotein P were supplemented selenium, dietary selenium, and total weight loss. Whilst the clinical relevance of Selenoprotein P supersaturated remains uncertain, further studies are needed to investigate the ideal supplement dosage and the impact of surgery type on selenium requirements.

Background:The prevalence of obesity has increased globally over the past few decades for the general population and people with type 2 diabetes. Existing research suggests that the body-mass index (BMI) of individuals living with type 1 diabetes has also increased substantially. This double burden of type 1 diabetes and obesity is concerning and may further increase the risk for microvascular and macrovascular complications associated with type 1 diabetes. We aimed to evaluate trends in BMI (as an indicator for adiposity/obesity) and haemoglobin A1c (HbA1c; as a measure of long-term glucose management) in people with type 1 diabetes, based on clinical trial data. Methods:In this systematic review and meta-analysis, PubMed, Web of Science, Scopus, Embase, Cochrane, and ClinicalTrials.gov were searched for clinical trials involving individuals with type 1 diabetes, covering all publications between January 1, 1993, and May 20, 2025. Randomised controlled trials (RCTs) were included when performed in adults, with baseline data on BMI and HbA1c, and featuring a sample size exceeding 100 participants. Studies were excluded if they applied overly narrow cut-off ranges (difference between upper and lower cut-off) for BMI (<5 kg/m2) or HbA1c (<3%) or if they focused solely on individuals with either overweight or underweight. Spearman correlation and linear regression were applied to evaluate trends in baseline HbA1c and BMI, as the primary outcomes of interest the study. Subgroup analyses were performed for age, diabetes duration, sex and the type of intervention. The Cochrane Risk of Bias tool was used to assess study quality, with disagreements resolved through consultation. Funnel plots were used to evaluate publication bias. The robustness of the study results was checked by performing leave-one-out sensitivity analyses for BMI and HbA1c. Strength of the body of evidence was assessed using GRADE. This work was registered with PROSPERO, CRD42023449198. Findings:12,346 unique studies were identified, of which 148 were RCTs with a combined population of 56,411 participants were included. Included studies represented research conducted in Europe (55 studies), North America (25 studies), Asia (13 studies) and Oceania (2 studies), in addition to 53 multicontinental studies. BMI increased from 25.0 (24.7-25.3) kg/m2 in the first decade studied (1993-2002) to 26.9 (26.4-27.3) kg/m2 in the last decade (2016-2025). Baseline HbA1c was 7.9% (7.6-8.2) for 1993-2002 and 7.9% (7.8-8.0) for 2016-2025. Interpretation:The increasing trend in BMI may indicate that weight gain is also occurring in people with type 1 diabetes. More research is needed on the BMI and HbA1c trends in people with type 1 diabetes, using real-world data on the individual level and investigating these trends in relation to the insulin dose. Funding:The Stratification of Obesity Phenotypes to Optimize Future Obesity Therapy (SOPHIA) project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No. 875534, supported by the European Union's Horizon 2020 research and innovation program and EFPIA, with additional support from T1D Exchange, Breakthrough T1D (former JDRF), and Obesity Action Coalition.

BACKGROUND:Bariatric surgery alters gastrointestinal anatomy and physiology, complicating functional assessments such as gastric emptying. The 13C-octanoic acid breath test is a simple, non-invasive alternative to scintigraphy, though its validity in bariatric populations requires further validation. METHODS:For this proof-of-concept analysis, gastric emptying data were derived from a cross-sectional study including individuals with obesity, sleeve gastrectomy, and Roux-en-Y gastric bypass (RYGB). Gastric emptying was measured simultaneously using the 13C-octanoic breath test and the reference method, scintigraphy. Gastric emptying half-times (GET1/2) were compared between the two methods using Wilcoxon signed-rank tests in each group. Concordance between both methods was assessed using Kendall's tau correlation coefficients, and Bland-Altman plots. RESULTS:No significant inter-method differences were observed for GET1/2 in any group. Mean differences were -26.7 min (95 % CI: -72.3; 18.6) for obesity, -3.92 min (95 % CI: -30.8; 23.0) for sleeve gastrectomy, and -8.55 min (95 % CI: -21.3; 4.18) for RYGB. Kendall's tau coefficients indicated positive rank associations within each group, but were non-significant (Obesity: 0.8, P = 0.16; sleeve gastrectomy: 0.90, P = 0.13; RYGB: 0.57, P = 0.33). Bland-Altman plots demonstrated acceptable agreement between the measurements across all groups. CONCLUSION:This proof-of-concept analysis suggests that the 13C-octanoic acid breath test has potential as a valid, non-invasive method for assessing gastric emptying in post-bariatric surgery patients. However, larger validation studies are warranted to confirm these preliminary findings.

BACKGROUND:Metabolic and bariatric surgery (MBS) is a proven treatment for obesity. Yet weight loss is accompanied by loss of muscle which may predispose to sarcopenia. The prevalence of low muscle mass in older adults after MBS remains unexplored, even though this group is more vulnerable to sarcopenia. METHODS:This cross-sectional study investigated sarcopenia and low muscle mass by comparing adults older than 65 years with previous MBS (BAR) to patients following nonsurgical obesity management (CON). A sample size of 100 was estimated from appendicular lean mass (ALM) in a similar study in younger adults. Patients were recruited from the University Hospitals Leuven Obesity Clinic, Belgium. Study assessments included dual-energy X-ray absorptiometry, handgrip, short battery of physical performance, blood sampling and self-reported dietary intake. Sarcopenia was defined according to the European Working Group on Sarcopenia in Older People (EWGSOP1) criteria using obesity-specific cut-off points and sarcopenic obesity by the European Society for Enteral and Parenteral Nutrition (ESPEN) and the European Association of the Study of Obesity (EASO) consensus definition. Main endpoints were sarcopenia and ALM normalized to body mass index (%ALM/BMI). A multiple linear regression model was fitted to predict ALM. RESULTS:We included 50 participants per group (male, BAR 40%, CON 35%). BAR participants were older (68.3 ± 3.2 years vs. 70.7 ± 3.9, p < 0.01), and more had diabetes (52% vs. 28%). BAR lost more bodyweight after MBS than CON following nonsurgical treatment (BAR 31.6 ± 9.5% vs. CON 12.1 ± 8.42%, p < 0.001). Fat free mass (FFM) was lower for BAR than for CON, but %ALM/BMI was not different (64.7 ± 18.1% vs. 62.6 ± 15.8, p = 0.53). Twenty percent to 56% of participants had low muscle mass, depending on sex and criterium, but only 3% met the criteria for sarcopenia and 9% for sarcopenic obesity. Protein intake tended to be higher in BAR than in CON (1.36 ± 0.36 g/kg FFM/day vs. 1.25 ± 0.27, p = 0.09). Most participants did not meet optimal protein intake recommendations after BMS nor for older adults in general. In the linear regression model, muscle mass increased with male sex, BMI, adiposity and protein intake and decreased with age, (adjusted R2 0.80). Neither BAR compared to CON nor surgery type or other clinical parameters influenced muscle mass. CONCLUSION:Older adults with previous MBS were not more likely to develop sarcopenia than older adults following nonsurgical treatment. Rather, age, adiposity and low protein intake lower muscle mass, predisposing to sarcopenia. TRIAL REGISTRATION:clinicaltrials.gov identifier: NCT05582668.

Funding Arrowhead Pharmaceuticals funded the PALISADE Study. Background/Synopsis FCS causes life-threatening acute pancreatitis (AP) and may be due to genetic defects in the enzyme lipoprotein lipase (LPL) which impair the circulatory clearance of chylomicrons (CMs) and triglycerides (TGs). Other clinical manifestations collectively impair quality of life (QoL). Plozasiran is a siRNA that reduces hepatic apolipoprotein (apo) C-III, thereby effectively lowering extremely high TGs. We describe effects of plozasiran on AP outcomes and QoL in patients with FCS. Objective/Purpose To assess further outcomes of an siRNA therapeutic, plozasiran, an inhibitor of APOC3, under investigation to reduce the risk of acute pancreatitis and to improve patient reported outcomes in familial chylomicronemia syndrome. Methods PALISADE was a Phase 3 double blind, placebo-controlled trial of 75 adults with FCS (59% were genetically confirmed) on best standard-of-care. Patients were randomized to quarterly dosed plozasiran (25 or 50 mg SC) or placebo for 12 months. TG lowering was the primary endpoint and adjudicated rates of AP were a key (alpha-controlled) secondary endpoint. Qualitative patient reported outcomes on composite measures of QoL, EORTC-QLQ-C30, PAN-26 and EQ-5D-5L were exploratory. Results Plozasiran lowered median TG levels from > 2000 to 544 mg/dL at 12 months (p < 0.001), independent of a confirmed FCS genotype. All key secondary endpoints (previously reported) showed significant benefits of plozasiran. Nine AP episodes in 7 patients were positively adjudicated: patients receiving plozasiran achieved an 83% reduction in the risk of developing AP versus placebo, (p < 0.03). Placebo patients with AP transitioned to open label treatment, limiting the ability to assess cumulative events. Plozasiran was well-tolerated. Severe and serious events were less common with Plozasiran than placebo.AP severity differed: 6 severe and 1 moderate event occurred on placebo vs 1 moderate and 1 mild event on Plozasiran. Placebo patients spent 47 days in the hospital vs 10 days with Plozasiran. More patients in placebo experienced abdominal pain leading to AP.Absolute changes in various domain scores of the selected patient reported outcomes correlated with improvements. Most symptom domains improved in the QoL assessments, some with clinically meaningful scores > -10 points, such as significant improvements in appetite loss, -15.9, insomnia, -16.8 (p < 0.05, both). Functional domain scores improved, some with clinically meaningful scores > +10 points, such as improvements in role function, +14.8 and emotional function, +11.8 (p < 0.05, both) as well as health care satisfaction, +14.7. Clinically meaningful improvements were shown for appetite loss, insomnia, cognitive functioning, emotional functioning, and role functioning in the plozasiran treated subjects compared to placebo (nominal p-values of < 0.05). Conclusions Plozasiran significantly reduced TG and AP while improving QoL in the PALISADE trial.

Recent advancements in obesity pharmacotherapy have seen the approval of novel agents, like glucagon-like peptide-1 receptor agonist and dual agonists, offering unprecedented efficacy for obesity management. However, treatment outcomes remain highly variable, necessitating a more personalized approach to pharmacotherapy tailored to individual profiles. This review evaluates the current landscape of obesity pharmacotherapy, while exploring factors influencing variability in treatment response including early response predictors, genetic markers, and physiological traits. Additionally, the potential of combining treatment modalities and some emerging drugs are highlighted. Finally, a stepwise algorithm is proposed for personalized obesity treatment, integrating comorbidities, phenotypes, and responses to medication, paving the way for more effective and efficient obesity management.

Understanding healthcare professionals' perceptions and approaches to obesity management is limited, as are the barriers impeding effective care. A questionnaire was developed to explore the perception, and barriers to obesity management. To ensure content validity, an expert and stakeholder panel evaluated the relevance and comprehension of each item. Consequently, a cross-sectional survey was administered to endocrinologists (Endo), general practitioners (GP), and pharmacists (Pharm). A 46-item questionnaire was developed, validated, and completed by 502 healthcare professionals (Endo: n = 127; GP: n = 138; Pharm: n = 237). The majority agreed that obesity is a chronic disease (Endo = 96%; GP = 92.7%; Pharm = 87%). The conversation about obesity management is mostly initiated by the healthcare professional (Endo = 95.3%; GP = 73.9%; Pharm = 5.9%) instead of the patient (Endo = 55.1%; GP = 21.7%; Pharm = 11.8%). All professionals stated unanimously that there is a need to optimise obesity care in Belgium with identified barriers: motivational (Endo = 90.8%; GP = 90.8%; Pharm = 89.2%), financial (Endo = 96.9%; GP = 88.5%; Pharm = 76.3%), and a lack of structure (Endo = 81.5%; GP = 78.6%; Pharm = 81.5%). A total of 42.4% of the healthcare providers indicated that they did not follow any additional training. These findings highlight that healthcare professionals recognise obesity as a chronic disease, but that barriers need to be addressed to enhance effective care and support for people living with obesity.

AbstractAlthough bariatric surgery is an effective treatment for type 2 diabetes by inducing weight loss and augmenting gut hormone secretion, the immediate effect on beta-cell function itself remains to be elucidated in type 2 diabetes. Therefore, a prospective, randomized trial was performed in 30 patients with insulin-treated type 2 diabetes and a body mass index ≥ 35 kg/m2. Patients were randomly assigned (1:1:1) to Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG) in combination with protein-sparing modified fast (PSMF), or to PSMF alone. Eu- and hyperglycemic clamps were performed before and 3 weeks after surgery and/or PSMF initiation. The primary outcome was the evolution of insulin sensitivity and beta-cell function after surgery, calculated using the composite measures of glucose disposal rate, insulin secretion rate, and disposition index (DI). Results revealed that markers of insulin sensitivity increased similarly in all arms (p = 0.43). A higher marker for maximal beta-cell function was observed when comparing SG to PSMF (p = 0.007). The DI showed a clear positive evolution after RYGB and SG, but not after PSMF alone. Altogether, these findings indicate that bariatric surgery results in an immediate beta-cell function recovery in insulin-treated type 2 diabetes.

BACKGROUND:Familial hypercholesterolaemia (FH) is a genetic disease characterised by hypercholesterolaemia and premature cardiovascular events. Early diagnosis and treatment can reduce the cardiovascular burden. We describe the characteristics of patients with heterozygous FH followed in a tertiary hospital in Belgium.METHODS:We retrospectively studied a population of 321 patients with definite heterozygous FH who visited the UZ Leuven lipid clinic at least once between 1 January 2016 and 31 December 2020. Data are represented as mean ± SD.RESULTS:The age at time of diagnosis of FH was 39 ± 18 years. Patients with atherosclerotic disease (secondary prevention) were older (p < .001), more often male (p < .001), had a higher body mass index (p < .001), prevalence of (pre)diabetes (p < .001) and hypertension (p < .001) and had lower levels of low-density lipoprotein-cholesterol (LDL-C) (p < .001) than individuals without atherosclerotic disease (primary prevention). The average LDL-C in both primary (109 ± 53 mg/dL) and secondary (81 ± 63 mg/dL) prevention did not meet the targets of LDL-C as proposed by the 2019 ESC/EAS guidelines for the management of dyslipidaemias. However, LDL-C levels in the subgroup of patients treated with PCSK9 inhibition therapy, and especially in the triple therapy group (combination of statin, ezetimibe and PCSK9 inhibitor), were markedly lower (p < .001).CONCLUSIONS:In this Belgian population, people with heterozygous FH remain undertreated. Reaching treatment targets in FH seems possible, although this requires combination treatment (with PCSK9-targeted therapy) in most patients. Earlier diagnosis of FH, more extensive lipid-lowering treatment and reimbursement options and a more holistic approach are needed to lower LDL-C and cardiovascular risk in patients with FH.