During the past years, targeted therapies for cancer have been developed using drugs that have significant metabolic consequences. Among them, the mammalian target of rapamycin (mTOR) inhibitors and, to a much lesser extent, the tyrosine kinase inhibitors (TKIs) are involved. mTOR plays a key role in the regulation of cell growth as well as lipid and glucose metabolism. Treatment with mTOR inhibitors is associated with a significant increase in plasma triglycerides and LDL cholesterol. mTOR inhibitors seem to increase plasma triglycerides by reducing the activity of the lipoprotein lipase which is in charge of the catabolism of triglyceride-rich lipoproteins. The increase in LDL cholesterol observed with mTOR inhibitors seems to be due to a decrease in LDL catabolism secondary to a reduction of LDL receptor expression. In addition, treatment with mTOR inhibitors is associated with a high incidence of hyperglycemia, ranging from 13 to 50% in the clinical trials. The mechanisms responsible for hyperglycemia with new onset diabetes are not clear, but are likely due to the combination of impaired insulin secretion and insulin resistance. TKIs do not induce hyperlipidemia but alter glucose homeostasis. Treatment with TKIs may be associated either with hyperglycemia or hypoglycemia. The molecular mechanism by which TKIs control glucose homeostasis remains unknown. Owing to the metabolic consequences of these agents used as targeted anti-cancer therapies, a specific and personalized follow-up of blood glucose and lipids is recommended when using mTOR inhibitors and of blood glucose when using TKIs.
Bruno Vergès, Thomas Walter, and Bertrand Cariou
Bruno L Vergès, Jean P Cercueil, Denis Jacob, Geneviève Vaillant, Jean M Brun, and Roger Putelat
Surgery is the usual treatment for primary hyperparathyroidism. However, some patients with high surgical risks are not suitable for surgery. For such patients, we propose, as an alternative treatment, ultrasonically guided percutaneous ethanol injection into parathyroid adenomas, in order to induce necrosis of the tumor. We report, here, the results of ultrasonically guided percutaneous ethanol injection into parathyroid adenomas, during a prolonged follow-up period up to 49 months, in a group of 13 patients (median age 79 years) with primary hyperparathyroidism and contraindications for surgery. In seven patients, complete normalization of plasma calcium, phosphorus and parathyroid hormone (PTH) levels was achieved after ethanol injections, with no recurrence of hypercalcemia during a median follow-up period of 28 months (total success). In these seven patients, plasma calcium, phosphorus and PTH levels were normalized 48 h after the successful ethanol injection. In four patients, a partial success was obtained with clinical improvement and normalization of plasma calcium levels but without complete normalization of plasma PTH levels. This partial success is due to incomplete necrosis of the adenoma, as has been confirmed in one patient by histopathological examination. The ethanol injection treatment failed in only two patients. This treatment was always well tolerated and no major side-effects were observed. In conclusion, our results give evidence that ultrasonically guided percutaneous ethanol injection into parathyroid adenomas can be a very useful alternative therapy in patients not suitable for surgery.
Benjamin Bouillet, Thomas Gautier, Damien Denimal, Maxime Samson, David Masson, Jean Paul Pais de Barros, Guillaume Maquart, Marion Xolin, Alexandra Grosfeld, Héloïse Dalle, Bruno Vergès, Marthe Moldes, and Bruno Fève
Glucocorticoids (GC) are associated with increased cardiovascular morbidity despite increased HDL-C concentration. HDL-mediated cholesterol efflux, a major anti-atherogenic property of HDL particles, is negatively associated with CVD risk. We aimed to determine whether HDL-mediated cholesterol efflux was influenced by GC.
Prospective, observational study.
Lipid parameters, HDL composition, HDL-mediated cholesterol efflux, cholesteryl ester transfer protein, phospholipid transfer protein and lecithin cholesterol acyl-transferase (LCAT) activities were determined in ten patients with giant cell arteritis before and 3 months after GC introduction and in seven control subjects. HDL concentration and composition, HDL-mediated cholesterol efflux and LCAT activity were determined in GC-treated mice.
In patients, HDL-C concentration was higher after than before treatment GC-treatment (P = 0.002), while HDL-mediated cholesterol efflux was decreased (P = 0.008) and negatively associated with the proportion of cholesteryl ester in HDL (P = 0.04), independently of CRP. As well, in mice, HDL-C level was increased after GC exposure (P = 0.04) and HDL-mediated cholesterol efflux decreased (P = 0.04). GC-treated patients had higher cholesteryl ester content in HDL, higher HDL2-to-HDL3 ratio and higher LCAT activity than before treatment (P = 0.008, P = 0.02 and P = 0.004, respectively).
We report, for the first time, that in patients with giant cell arteritis and mice treated with GC, HDL-mediated cholesterol efflux was impaired by GC besides an increased HDL-C level. This impaired HDL functionality, possibly related to HDL enrichment in cholesteryl ester, could contribute to the increased CVD risk observed in GC-treated patients. Further studies are needed in larger populations, to further decipher the effect of GC on HDL.
Blandine Tramunt, Sarra Smati, Sandrine Coudol, Matthieu Wargny, Matthieu Pichelin, Béatrice Guyomarch, Abdallah Al-Salameh, Coralie Amadou, Sara Barraud, Édith Bigot, Lyse Bordier, Sophie Borot, Muriel Bourgeon, Olivier Bourron, Sybil Charriere, Nicolas Chevalier, Emmanuel Cosson, Bruno Fève, Anna Flaus-Furmaniuk, Pierre Fontaine, Amandine Galioot, Céline Gonfroy-Leymarie, Bruno Guerci, Sandrine Lablanche, Jean-Daniel Lalau, Etienne Larger, Adele Lasbleiz, Bruno Laviolle, Michel Marre, Marion Munch, Louis Potier, Gaëtan Prévost, Eric Renard, Yves Reznik, Dominique Seret-begue, Paul Sibilia, Philippe Thuillier, Bruno Vergès, Jean-Francois Gautier, Samy Hadjadj, Bertrand Cariou, Franck Mauvais-Jarvis, and Pierre Gourdy
Male sex is a determinant of severe coronavirus disease-2019 (COVID-19). We aimed to characterize sex differences in severe outcomes in adults with diabetes hospitalized for COVID-19.
We performed a sex-stratified analysis of clinical and biological features and outcomes (i.e. invasive mechanical ventilation [IMV], death, intensive care unit [ICU] admission and home discharge at day 7 [D7] or day 28 [D28]) in 2,380 patients with diabetes hospitalized for COVID-19 and included in the nationwide CORONADO observational study (NCT04324736).
The study population was predominantly male (63.5%). After multiple adjustments, female sex was negatively associated with the primary outcome (IMV and/or death, OR 0.66 [0.49-0.88]), death (OR 0.49 [0.30-0.79]) and ICU admission (OR 0.57 [0.43-0.77]) at D7, but only with ICU admission (OR 0.58 [0.43-0.77]) at D28. Older age and a history of microvascular complications were predictors of death at D28 in both sexes, while chronic obstructive pulmonary disease (COPD) was predictive of death in women only. At admission, CRP, AST and eGFR predicted death in both sexes. Lymphocytopenia was an independent predictor of death in women only, while thrombocytopenia and elevated plasma glucose concentration were predictors of death in men only.
In patients with diabetes admitted for COVID-19, female sex was associated with lower incidence of early severe outcomes, but did not influence the overall in-hospital mortality, suggesting that diabetes mitigates the female protection from COVID-19 severity. Sex-associated biological determinants may be useful to optimize COVID-19 prevention and management in women and men.
Gudmundur Johannsson, Ulla Feldt-Rasmussen, Ida Holme Håkonsson, Henrik Biering, Patrice Rodien, Shigeyuki Tahara, Andrew Toogood, Michael Højby Rasmussen, and the REAL 2 Study Group
Somapacitan is a reversible albumin-binding growth hormone (GH) derivative, developed for once-weekly administration. This study aimed to evaluate the safety of once-weekly somapacitan vs once-daily Norditropin®. Local tolerability and treatment satisfaction were also assessed.
26-week randomized, controlled phase 3 safety and tolerability trial in six countries (Nbib2382939).
Male or female patients aged 18–79 years with adult GH deficiency (AGHD), treated with once-daily GH for ≥6 months, were randomized to once-weekly somapacitan (n = 61) or once-daily Norditropin (n = 31) administered subcutaneously by pen. Both treatments were dose titrated for 8 weeks to achieve insulin-like growth factor I (IGF-I) standard deviation score (SDS) levels within the normal range, and then administered at a fixed dose. Outcome measures were adverse events (AEs), including injection site reactions; occurrence of anti-somapacitan/anti-GH antibodies and change in treatment satisfaction, assessed using the Treatment Satisfaction Questionnaire for Medication-9 (TSQM-9).
Mean IGF-I SDS remained between 0 and 2 SDS throughout the trial in both groups. AEs were mostly mild or moderate and transient in nature. The most common AEs were nasopharyngitis, headache and fatigue in both groups. More than 1500 somapacitan injections were administered and no clinically significant injection site reactions were reported. No anti-somapacitan or anti-GH antibodies were detected. The TSQM-9 score for convenience increased significantly more with somapacitan vs Norditropin (P = 0.0171).
In this 26-week trial in patients with AGHD, somapacitan was well tolerated and no safety issues were identified. Once-weekly somapacitan was reported to be more convenient than once-daily Norditropin.