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Efficacy and Safety of Parathyroid Hormone Replacement With TransCon PTH in Hypoparathyroidism: 26-Week Results From the Phase 3 PaTHway Trial.
Khan, AA, Rubin, MR, Schwarz, P, Vokes, T, Shoback, DM, Gagnon, C, Palermo, A, Marcocci, C, Clarke, BL, Abbott, LG, et al
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2023;(1):14-25
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Abstract
Conventional therapy for hypoparathyroidism consisting of active vitamin D and calcium aims to alleviate hypocalcemia but fails to restore normal parathyroid hormone (PTH) physiology. PTH replacement therapy is the ideal physiologic treatment for hypoparathyroidism. The double-blind, placebo-controlled, 26-week, phase 3 PaTHway trial assessed the efficacy and safety of PTH replacement therapy for hypoparathyroidism individuals with the investigational drug TransCon PTH (palopegteriparatide). Participants (n = 84) were randomized 3:1 to once-daily TransCon PTH (initially 18 μg/d) or placebo, both co-administered with conventional therapy. The study drug and conventional therapy were titrated according to a dosing algorithm guided by serum calcium. The composite primary efficacy endpoint was the proportion of participants at week 26 who achieved normal albumin-adjusted serum calcium levels (8.3-10.6 mg/dL), independence from conventional therapy (requiring no active vitamin D and ≤600 mg/d of calcium), and no increase in study drug over 4 weeks before week 26. Other outcomes of interest included health-related quality of life measured by the 36-Item Short Form Survey (SF-36), hypoparathyroidism-related symptoms, functioning, and well-being measured by the Hypoparathyroidism Patient Experience Scale (HPES), and urinary calcium excretion. At week 26, 79% (48/61) of participants treated with TransCon PTH versus 5% (1/21) wiplacebo met the composite primary efficacy endpoint (p < 0.0001). TransCon PTH treatment demonstrated a significant improvement in all key secondary endpoint HPES domain scores (all p < 0.01) and the SF-36 Physical Functioning subscale score (p = 0.0347) compared with placebo. Additionally, 93% (57/61) of participants treated with TransCon PTH achieved independence from conventional therapy. TransCon PTH treatment normalized mean 24-hour urine calcium. Overall, 82% (50/61) treated with TransCon PTH and 100% (21/21) wiplacebo experienced adverse events; most were mild (46%) or moderate (46%). No study drug-related withdrawals occurred. In conclusion, TransCon PTH maintained normocalcemia while permitting independence from conventional therapy and was well-tolerated in individuals with hypoparathyroidism. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
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Frequency of family meals and food consumption in families at high risk of type 2 diabetes: the Feel4Diabetes-study.
Mahmood, L, González-Gil, EM, Schwarz, P, Herrmann, S, Karaglani, E, Cardon, G, De Vylder, F, Willems, R, Makrilakis, K, Liatis, S, et al
European journal of pediatrics. 2022;(6):2523-2534
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UNLABELLED A family meal is defined as a meal consumed together by the members of a family or by having ≥ 1 parent present during a meal. The frequency of family meals has been associated with healthier food intake patterns in both children and parents. This study aimed to investigate in families at high risk for developing type 2 diabetes across Europe the association (i) between family meals' frequency and food consumption and diet quality among parents and (ii) between family meals' frequency and children's food consumption. Moreover, the study aimed to elucidate the mediating effect of parental diet quality on the association between family meals' frequency and children's food consumption. Food consumption frequency and anthropometric were collected cross-sectionally from a representative sample of 1964 families from the European Feel4Diabetes-study. Regression and mediation analyses were applied by gender of children. Positive and significant associations were found between the frequency of family meals and parental food consumption (β = 0.84; 95% CI 0.57, 1.45) and diet quality (β = 0.30; 95% CI 0.19, 0.42). For children, more frequent family meals were significantly associated with healthier food consumption (boys, β = 0.172, p < 0.05; girls, β = 0.114, p < 0.01). A partial mediation effect of the parental diet quality was shown on the association between the frequency of family meals and the consumption of some selected food items (i.e., milk products and salty snacks) among boys and girls. The strongest mediation effect of parental diet quality was found on the association between the frequency of family breakfast and the consumption of salty snacks and milk and milk products (62.5% and 37.5%, respectively) among girls. CONCLUSIONS The frequency of family meals is positively associated with improved food consumption patterns (i.e., higher intake of fruits and vegetables and reduced consumption of sweets) in both parents and children. However, the association in children is partially mediated by parents' diet quality. The promotion of consuming meals together in the family could be a potentially effective strategy for interventions aiming to establish and maintain healthy food consumption patterns among children. TRIAL REGISTRATION The Feel4Diabetes-study is registered with the clinical trials registry (NCT02393872), http://clinicaltrials.gov , March 20, 2015. WHAT IS KNOWN • Parents' eating habits and diet quality play an important role in shaping dietary patterns in children • Family meals frequency is associated with improved diet quality of children in healthy population What is New: • Frequency of family meals was significantly associated with healthier food consumption among parents and children in families at high risk of type 2 diabetes in six European countries. • Parental diet quality mediates the association between family meals frequency and the consumption of some selected food items among children.
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PaTH Forward: A Randomized, Double-Blind, Placebo-Controlled Phase 2 Trial of TransCon PTH in Adult Hypoparathyroidism.
Khan, AA, Rejnmark, L, Rubin, M, Schwarz, P, Vokes, T, Clarke, B, Ahmed, I, Hofbauer, L, Marcocci, C, Pagotto, U, et al
The Journal of clinical endocrinology and metabolism. 2022;(1):e372-e385
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CONTEXT Hypoparathyroidism is characterized by insufficient levels of parathyroid hormone (PTH). TransCon PTH is an investigational long-acting prodrug of PTH(1-34) for the treatment of hypoparathyroidism. OBJECTIVE This work aimed to investigate the safety, tolerability, and efficacy of daily TransCon PTH in adults with hypoparathyroidism. METHODS This phase 2, randomized, double-blind, placebo-controlled 4-week trial with open-label extension enrolled 59 individuals with hypoparathyroidism. Interventions included TransCon PTH 15, 18, or 21 µg PTH(1-34)/day or placebo for 4 weeks, followed by a 22-week extension during which TransCon PTH dose was titrated (6-60 µg PTH[1-34]/day). RESULTS By Week 26, 91% of participants treated with TransCon PTH achieved independence from standard of care (SoC, defined as active vitamin D = 0 μg/day and calcium [Ca] ≤ 500 mg/day). Mean 24-hour urine Ca (uCa) decreased from a baseline mean of 415 mg/24h to 178 mg/24h by Week 26 (n = 44) while normal serum Ca (sCa) was maintained and serum phosphate and serum calcium-phosphate product fell within the normal range. By Week 26, mean scores on the generic 36-Item Short Form Health Survey domains increased from below normal at baseline to within the normal range. The Hypoparathyroidism Patient Experience Scale symptom and impact scores improved through 26 weeks. TransCon PTH was well tolerated with no treatment-related serious or severe adverse events. CONCLUSION TransCon PTH enabled independence from oral active vitamin D and reduced Ca supplements (≤ 500 mg/day) for most participants, achieving normal sCa, serum phosphate, uCa, serum calcium-phosphate product, and demonstrating improved health-related quality of life. These results support TransCon PTH as a potential hormone replacement therapy for adults with hypoparathyroidism.
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Biologic Treatment in Combination with Lifestyle Intervention in Moderate to Severe Plaque Psoriasis and Concomitant Metabolic Syndrome: Rationale and Methodology of the METABOLyx Randomized Controlled Clinical Trial.
Pinter, A, Schwarz, P, Gerdes, S, Simon, JC, Saalbach, A, Rush, J, Melzer, N, Kramps, T, Häberle, B, Reinhardt, M
Nutrients. 2021;(9)
Abstract
Inflammatory diseases including psoriasis are associated with metabolic and cardiovascular comorbidities, including obesity and metabolic syndrome. Obesity is associated with greater psoriasis disease severity and reduced response to treatment. Therefore, targeting metabolic comorbidities could improve patients' health status and psoriasis-specific outcomes. METABOLyx is a randomized controlled trial evaluating the combination of a lifestyle intervention program with secukinumab treatment in psoriasis. Here, the rationale, methodology and baseline patient characteristics of METABOLyx are presented. A total of 768 patients with concomitant moderate to severe plaque psoriasis and metabolic syndrome were randomized to secukinumab 300 mg, or secukinumab 300 mg plus a tailored lifestyle intervention program, over 24 weeks. A substudy of immunologic and metabolic biomarkers is ongoing. The primary endpoint of METABOLyx is PASI90 response at week 24. Other endpoints include patient-reported outcomes and safety. METABOLyx represents the first large scale clinical trial of an immunomodulatory biologic in combination with a standardized lifestyle intervention.
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The trans-ancestral genomic architecture of glycemic traits.
Chen, J, Spracklen, CN, Marenne, G, Varshney, A, Corbin, LJ, Luan, J, Willems, SM, Wu, Y, Zhang, X, Horikoshi, M, et al
Nature genetics. 2021;(6):840-860
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Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 × 10-8), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution.
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Accuracy of 1-Hour Plasma Glucose During the Oral Glucose Tolerance Test in Diagnosis of Type 2 Diabetes in Adults: A Meta-analysis.
Ahuja, V, Aronen, P, Pramodkumar, TA, Looker, H, Chetrit, A, Bloigu, AH, Juutilainen, A, Bianchi, C, La Sala, L, Anjana, RM, et al
Diabetes care. 2021;(4):1062-1069
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OBJECTIVE One-hour plasma glucose (1-h PG) during the oral glucose tolerance test (OGTT) is an accurate predictor of type 2 diabetes. We performed a meta-analysis to determine the optimum cutoff of 1-h PG for detection of type 2 diabetes using 2-h PG as the gold standard. RESEARCH DESIGN AND METHODS We included 15 studies with 35,551 participants from multiple ethnic groups (53.8% Caucasian) and 2,705 newly detected cases of diabetes based on 2-h PG during OGTT. We excluded cases identified only by elevated fasting plasma glucose and/or HbA1c. We determined the optimal 1-h PG threshold and its accuracy at this cutoff for detection of diabetes (2-h PG ≥11.1 mmol/L) using a mixed linear effects regression model with different weights to sensitivity/specificity (2/3, 1/2, and 1/3). RESULTS Three cutoffs of 1-h PG, at 10.6 mmol/L, 11.6 mmol/L, and 12.5 mmol/L, had sensitivities of 0.95, 0.92, and 0.87 and specificities of 0.86, 0.91, and 0.94 at weights 2/3, 1/2, and 1/3, respectively. The cutoff of 11.6 mmol/L (95% CI 10.6, 12.6) had a sensitivity of 0.92 (0.87, 0.95), specificity of 0.91 (0.88, 0.93), area under the curve 0.939 (95% confidence region for sensitivity at a given specificity: 0.904, 0.946), and a positive predictive value of 45%. CONCLUSIONS The 1-h PG of ≥11.6 mmol/L during OGTT has a good sensitivity and specificity for detecting type 2 diabetes. Prescreening with a diabetes-specific risk calculator to identify high-risk individuals is suggested to decrease the proportion of false-positive cases. Studies including other ethnic groups and assessing complication risk are warranted.
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Longitudinal Associations between Food Parenting Practices and Dietary Intake in Children: The Feel4Diabetes Study.
Flores-Barrantes, P, Iglesia, I, Cardon, G, Willems, R, Schwarz, P, Timpel, P, Kivelä, J, Wikström, K, Iotova, V, Tankova, T, et al
Nutrients. 2021;(4)
Abstract
Food parenting practices (FPPs) have an important role in shaping children's dietary behaviors. This study aimed to investigate cross-sectional and longitudinal associations over a two-year follow-up between FPP and dietary intake and compliance with current recommendations in 6- to 11-year-old European children. A total of 2967 parent-child dyads from the Feel4Diabetes study, a randomized controlled trial of a school and community-based intervention, (50.4% girls and 93.5% mothers) were included. FPPs assessed were: (1) home food availability; (2) parental role modeling of fruit intake; (3) permissiveness; (4) using food as a reward. Children's dietary intake was assessed through a parent-reported food frequency questionnaire. In regression analyses, the strongest cross-sectional associations were observed between home availability of 100% fruit juice and corresponding intake (β = 0.492 in girls and β = 0.506 in boys, p < 0.001), and between parental role modeling of fruit intake and children's fruit intake (β = 0.431 in girls and β = 0.448 in boys, p < 0.001). In multilevel logistic regression models, results indicated that improvements in positive FPPs over time were mainly associated with higher odds of compliance with healthy food recommendations, whereas a decrease in negative FPP over time was associated with higher odds of complying with energy-dense/nutrient-poor food recommendations. Improving FPPs could be an effective way to improve children's dietary intake.
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Denosumab vs. zoledronic acid treatment in post-menopausal breast cancer: a 2-year prospective observational study.
Buch-Larsen, K, Jørgensen, NR, Jensen, LT, Andersson, M, Schwarz, P
Scandinavian journal of clinical and laboratory investigation. 2021;(6):425-431
Abstract
Adjuvant treatment for post-menopausal women with early breast cancer (BC) includes aromatase inhibitors (AI), known to decrease bone mineral density (BMD). In this study, we investigate whether denosumab is a valid second option for patients unable to receive standard adjuvant i.v. zoledronic acid (ZA). In total, 212 patients have been evaluated after they did not receive ZA. Of those 194 were included. After evaluation by an endocrinologist, all patients were offered ZA as their first choice and 15% accepted (N = 29). The remaining 85% were offered denosumab (N = 165). All patients were followed prospectively with blood tests up to 24 months. DXA scans were performed at baseline and 24 months. No difference was observed between the two treatment groups at baseline, with regard to anthropometry and standard biochemistry. Markers of bone turnover (p-PINP, p-CTX, p-bone-specific alkaline phosphatase and p-osteocalcin) all showed significant suppression compared to baseline and remained suppressed throughout the 2 years. BMD showed small and significant increases at the spine (0.024 g/cm2) and total hip (0.019 g/cm2) in the denosumab group but no change at the femoral neck(-0.011g/cm2). In the ZA group, we observed no significant change at the spine (0.015 g/cm2) and total hip (-0.001g/cm2) and a small significant decrease at the femoral neck (-0.037 g/cm2). However, when we compared BMD change between the treatment groups, we found no significant difference.Conclusions: Our data indicate that for BC patients in AI treatment who refused or were not able to receive ZA treatment, denosumab might be recommended as a second choice. Regarding markers of bone turnover and BMD denosumab is equal to ZA.Summary: Women with early breast cancer receiving anti-estrogen treatment are at risk of developing osteoporosis.We followed 194 women receiving zoledronic acid (ZA) or denosumab for up to 2 years.We find that with regard to bone protection, denosumab is a viable alternative to ZA and might be recommended as a second choice.
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Different Effects of Lifestyle Intervention in High- and Low-Risk Prediabetes: Results of the Randomized Controlled Prediabetes Lifestyle Intervention Study (PLIS).
Fritsche, A, Wagner, R, Heni, M, Kantartzis, K, Machann, J, Schick, F, Lehmann, R, Peter, A, Dannecker, C, Fritsche, L, et al
Diabetes. 2021;(12):2785-2795
Abstract
Lifestyle intervention (LI) can prevent type 2 diabetes, but response to LI varies depending on risk subphenotypes. We tested whether individuals with prediabetes with low risk (LR) benefit from conventional LI and individuals with high risk (HR) benefit from an intensification of LI in a multicenter randomized controlled intervention over 12 months with 2 years' follow-up. A total of 1,105 individuals with prediabetes based on American Diabetes Association glucose criteria were stratified into an HR or LR phenotype based on previously described thresholds of insulin secretion, insulin sensitivity, and liver fat content. LR individuals were randomly assigned to conventional LI according to the Diabetes Prevention Program (DPP) protocol or control (1:1) and HR individuals to conventional or intensified LI with doubling of required exercise (1:1). A total of 908 (82%) participants completed the study. In HR individuals, the difference between conventional and intensified LI in postchallenge glucose change was -0.29 mmol/L [95% CI -0.54; -0.04], P = 0.025. Liver fat (-1.34 percentage points [95% CI -2.17; -0.50], P = 0.002) and cardiovascular risk (-1.82 percentage points [95% CI -3.13; -0.50], P = 0.007) underwent larger reductions with intensified than with conventional LI. During a follow-up of 3 years, intensified compared with conventional LI had a higher probability of normalizing glucose tolerance (P = 0.008). In conclusion, it is possible in HR individuals with prediabetes to improve glycemic and cardiometabolic outcomes by intensification of LI. Individualized, risk phenotype-based LI may be beneficial for the prevention of diabetes.
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Vitamin D Boosts Alendronate Tail Effect on Bone Mineral Density in Postmenopausal Women with Osteoporosis.
Catalano, A, Bellone, F, Santoro, D, Schwarz, P, Gaudio, A, Basile, G, Sottile, MC, Stoian, SA, Corica, F, Morabito, N
Nutrients. 2021;13(6)
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Post-menopausal women are at an increased risk for bone associated disorders such as osteoporosis. Treatments with drugs known as bisphosphonates aim to increase bone density, bone strength, and reduce bone fractures. However long-term treatment may be associated with poor outcomes and short treatment breaks where use is discontinued, may be of benefit. Vitamin D, which has shown to be of benefit during treatment with bisphosphonates, may be of increased importance during these treatment breaks. This retrospective study of postmenopausal women aimed to determine if vitamin D status influenced bone density after osteoporosis treatment had ceased in 1686 patients. The results showed that in those who discontinued osteoporosis treatment, individuals with the highest levels of vitamin D had a greater increase in bone mineral density. Bone density was also associated with a change in vitamin D level. It was concluded that in those who have discontinued osteoporosis treatment improving vitamin D status may be of benefit to bone density. This study could be used by healthcare professionals to understand how vitamin D supplementation may be of benefit in osteoporotic, post-menopausal women who have stopped treatment due to worries of long-term side effects.
Abstract
Vitamin D modulates bisphosphonate (BP) efficacy, but its contribution to bone mineral density (BMD) after BP discontinuation is not known. To address this topic, we performed a retrospective analysis of postmenopausal women exposed to alendronate (ALN) to treat osteoporosis who regularly continued the supplementation of cholecalciferol or calcifediol at recommended doses. In the ninety-six recruited women (age 61.1 ± 6.9 years), ALN was administered for 31.2 ± 20.6 months and then discontinued for 33.3 ± 18.9 months. The modification of 25(OH)D serum levels over time was associated with a change of alkaline phosphatase (r = -0.22, p = 0.018) and C-terminal collagen type 1 telopeptide (r = -0.3, p = 0.06). Women in the tertile of the highest increase in 25(OH)D level showed a 5.7% BMD gain at lumbar spine, that was twice as great in comparison with participants with a lower 25(OH)D variation. At a multiple regression analysis, BMD change was associated with time since menopause (ß = 2.28, SE 0.44, p < 0.0001), FRAX score for major fracture (ß = -0.65, SE 0.29, p = 0.03), drug holiday duration (ß = -2.17, SE 0.27, p < 0.0001) and change of 25(OH)D levels (ß = 0.15, SE 0.03, p = 0.0007). After ALN discontinuation, improving the vitamin D status boosts the ALN tail effect on BMD.