Publications by authors named "Samy Hadjadj"

150 Publications

Do diabetic complications influence cancer-related events in people with type 2 diabetes? A cohort approach.

Diabetes Metab 2021 Oct 10:101289. Epub 2021 Oct 10.

Institut du thorax, INSERM, CNRS, Université de Nantes, CHU Nantes, Nantes, France.

Aim: To investigate whether diabetic micro- and macrovascular complications (mMVC) influence cancer-related events in people with type 2 diabetes.

Methods: People with type 2 diabetes from the SURDIAGENE cohort were characterized (duration of diabetes, HbA1c, mMVC, history of cancer) and prospectively followed-up for death and cancer-related events (occurrence, dissemination and cancer-related death).

Results: Between 2002 and 2012, 1468 participants (58% men, mean age 64.8 ± 10.7 years, mean duration of diabetes 14.5 ± 9.9 years at baseline) were enrolled. At baseline, 119 (8%) had a personal history of cancer. Incident cancer occurred in 207 (14%) patients during a mean follow-up of 7.3 ± 3.7 years and was associated with older age, smoking status and personal history of cancer. mMVC were not associated with cancer-related events, considering cancer occurrence, node/metastasis dissemination and cancer-specific death. Risk of all-cause mortality was increased in diabetic patients cumulating cancer history and mMVC (HR 1.73, 95%CI 1.25-2.38) compared to those with neither cancer nor mMVC. In our cohort, cancer-related death was not associated with mMVC (HR 1.05, 95%CI 0.67-1.64), but conversely history of cancer was significantly associated with cardiovascular-related death (HR 2.41, 95%CI 1.36-4.26).

Conclusion: In our cohort, mMVC were not associated with cancer-related events, while history of cancer was significantly associated with cardiovascular death.
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http://dx.doi.org/10.1016/j.diabet.2021.101289DOI Listing
October 2021

Pituitary adenoma in patients with multiple endocrine neoplasia type 1 - a cohort study.

Eur J Endocrinol 2021 Oct 1. Epub 2021 Oct 1.

S Hadjadj, Service d'Endocrinologie, Diabétologie et Nutrition, CHU de Nantes PHU 2 Institut du thorax et du système nerveux, Nantes, France.

Objective: Pituitary adenoma (PA) is one of the three major components of multiple endocrine neoplasia type 1 (MEN1). Recent studies have suggested that MEN1-associated PAs are less aggressive than initially estimated. We propose an analysis of the outcome of PAs with standard of care treatment in a nationwide cohort of MEN1 patients.

Design: Retrospective observational nationwide cohort study using the MEN1 patient registry from the French Group of Endocrine Tumours (GTE).

Methods: The GTE database population consists of 1,435 patients with MEN1. This analysis focused on 551 patients recruited after 2000 with at least 3 years of follow-up. The study outcome was tumour progression of PA defined by an increase in Hardy classification (HC) during follow-up according to referring physician regular reports.

Results: Among 551 MEN1 patients (index and related), 202 (36.7%) had PA, with 114 (56.4%) diagnosed by MEN1-related screening. PAs were defined according to HC as microadenoma (grade I) in 117 cases (57.9%), macroadenoma in 59 (29.2%) with 20 HC grade II and 39 HC grade III-IV and unspecified in 26 (12.8%). They were prolactinomas in 92 cases (45.5%) and non-secreting in 73 (36.1%). After a median follow-up of 3 years among the 137 patients with HC grades I-II, 4 patients (2.9%) presented tumour progression.

Conclusion: PAs in patients with MEN1 are less aggressive than previously thought. Tumour progression is rare with standard of care monitoring and treatment, especially in related patients who mostly present non-secreting microadenoma. MRI monitoring for asymptomatic MEN1 patients should be reduced accordingly.
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http://dx.doi.org/10.1530/EJE-21-0630DOI Listing
October 2021

History of bariatric surgery and COVID 19 outcomes in patients with type 2 diabetes: results from the CORONADO study.

Obesity (Silver Spring) 2021 Sep 29. Epub 2021 Sep 29.

Université de Nantes, CHU Nantes, CNRS, INSERM, l'institut du thorax, F-44000, Nantes, France.

Objective: The objective of this study is to assess the impact of a history of metabolic and bariatric surgery (MBS) on the clinical outcomes in patients with type 2 diabetes (T2D) and severe obesity hospitalized for COVID-19.

Methods: Post-hoc analysis from the nationwide observational CORONADO study: patients with T2D and history of MBS were matched with patients without MBS for age, sex and body mass index (BMI) either at the time of MBS or on admission for COVID-19. The composite primary outcome (CPO) combined invasive mechanical ventilation and/or death within 7 and 28 days following admission.

Results: Out of 2 398 CORONADO participants, 20 had history of MBS. When matching for BMI at the time of MBS and after adjustment on diabetes duration, the CPO occurred less frequently within 7 days (3 vs 17 events, OR: 0.15 [0.01-0.94], P=0.03) and 28 days (3 vs 19 events, OR: 0.11 (0.01-0.71), P=0.02) in patients with MBS (n=16) vs controls (n=44). There was no difference in CPO rate between patients with MBS and controls when matching for BMI on admission.

Conclusions: These data are reassuring regarding COVID-19 prognosis in patients with diabetes with history of MBS compared to those without MBS.
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http://dx.doi.org/10.1002/oby.23314DOI Listing
September 2021

Association of Coding Variants in Hydroxysteroid 17-beta Dehydrogenase 14 () with Reduced Progression to End Stage Kidney Disease in Type 1 Diabetes.

J Am Soc Nephrol 2021 Oct 14;32(10):2634-2651. Epub 2021 Jul 14.

Research Division, Joslin Diabetes Center, Boston, Massachusetts.

Background: Rare variants in gene coding regions likely have a greater impact on disease-related phenotypes than common variants through disruption of their encoded protein. We searched for rare variants associated with onset of ESKD in individuals with type 1 diabetes at advanced kidney disease stage.

Methods: Gene-based exome array analyses of 15,449 genes in five large incidence cohorts of individuals with type 1 diabetes and proteinuria were analyzed for survival time to ESKD, testing the top gene in a sixth cohort (=2372/1115 events all cohorts) and replicating in two retrospective case-control studies (=1072 cases, 752 controls). Deep resequencing of the top associated gene in five cohorts confirmed the findings. We performed immunohistochemistry and gene expression experiments in human control and diseased cells, and in mouse ischemia reperfusion and aristolochic acid nephropathy models.

Results: Protein coding variants in the hydroxysteroid 17- dehydrogenase 14 gene (), predicted to affect protein structure, had a net protective effect against development of ESKD at exome-wide significance (=4196; value=3.3 × 10). The gene and encoded enzyme were robustly expressed in healthy human kidney, maximally in proximal tubular cells. Paradoxically, gene and protein expression were attenuated in human diabetic proximal tubules and in mouse kidney injury models. Expressed gene and protein levels remained low without recovery after 21 days in a murine ischemic reperfusion injury model. Decreased gene expression was found in other CKD-associated renal pathologies.

Conclusions: gene is mechanistically involved in diabetic kidney disease. The encoded sex steroid enzyme is a druggable target, potentially opening a new avenue for therapeutic development.
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http://dx.doi.org/10.1681/ASN.2020101457DOI Listing
October 2021

Sex disparities in COVID-19 outcomes of inpatients with diabetes: insights from the CORONADO study.

Eur J Endocrinol 2021 Jul 5;185(2):299-311. Epub 2021 Jul 5.

Department of Endocrinology, Diabetology and Nutrition, Strasbourg University Hospitals, Strasbourg, France.

Objective: Male sex is one of the determinants of severe coronavirus diseas-e-2019 (COVID-19). We aimed to characterize sex differences in severe outcomes in adults with diabetes hospitalized for COVID-19.

Methods: 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 2380 patients with diabetes hospitalized for COVID-19 and included in the nationwide CORONADO observational study (NCT04324736).

Results: 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, C-reactive protein (CRP), aspartate amino transferase (AST) and estimated glomerular filtration rate (eGFR), according to the CKD-EPI formula 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.

Conclusions: 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.
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http://dx.doi.org/10.1530/EJE-21-0068DOI Listing
July 2021

Glucose-lowering treatments and COVID-19 mortality in T2DM.

Nat Rev Endocrinol 2021 07;17(7):387-388

Clinique des données, INSERM CIC 1413, CHU Nantes, Nantes, France.

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http://dx.doi.org/10.1038/s41574-021-00509-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8114189PMC
July 2021

Predictors of hospital discharge and mortality in patients with diabetes and COVID-19: updated results from the nationwide CORONADO study.

Diabetologia 2021 04 17;64(4):778-794. Epub 2021 Feb 17.

Service d'Endocrinologie, Diabétologie et Maladies Métaboliques, Groupe Hospitalier Mutualiste Les Portes du Sud, Venissieux, France.

Aims/hypothesis: This is an update of the results from the previous report of the CORONADO (Coronavirus SARS-CoV-2 and Diabetes Outcomes) study, which aims to describe the outcomes and prognostic factors in patients with diabetes hospitalised for coronavirus disease-2019 (COVID-19).

Methods: The CORONADO initiative is a French nationwide multicentre study of patients with diabetes hospitalised for COVID-19 with a 28-day follow-up. The patients were screened after hospital admission from 10 March to 10 April 2020. We mainly focused on hospital discharge and death within 28 days.

Results: We included 2796 participants: 63.7% men, mean age 69.7 ± 13.2 years, median BMI (25th-75th percentile) 28.4 (25.0-32.4) kg/m. Microvascular and macrovascular diabetic complications were found in 44.2% and 38.6% of participants, respectively. Within 28 days, 1404 (50.2%; 95% CI 48.3%, 52.1%) were discharged from hospital with a median duration of hospital stay of 9 (5-14) days, while 577 participants died (20.6%; 95% CI 19.2%, 22.2%). In multivariable models, younger age, routine metformin therapy and longer symptom duration on admission were positively associated with discharge. History of microvascular complications, anticoagulant routine therapy, dyspnoea on admission, and higher aspartate aminotransferase, white cell count and C-reactive protein levels were associated with a reduced chance of discharge. Factors associated with death within 28 days mirrored those associated with discharge, and also included routine treatment by insulin and statin as deleterious factors.

Conclusions/interpretation: In patients with diabetes hospitalised for COVID-19, we established prognostic factors for hospital discharge and death that could help clinicians in this pandemic period.

Trial Registration: Clinicaltrials.gov identifier: NCT04324736.
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http://dx.doi.org/10.1007/s00125-020-05351-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890396PMC
April 2021

Phenotypic characteristics and prognosis of newly diagnosed diabetes in hospitalized patients with COVID-19: Results from the CORONADO study.

Diabetes Res Clin Pract 2021 05 10;175:108695. Epub 2021 Feb 10.

Département de Diabétologie, Maladies Métaboliques et Nutrition, CHU de Toulouse et UMR1048/I2MC, Université de Toulouse, Toulouse, France.

In patients with diabetes hospitalized for COVID-19 in CORONADO study, 2.8% had a newly discovered. 2.8% had a newly discovered diabetes (NDD): mean age 60.2 ± 12.5 years and HbA1C 9.0 ± 2.5%. When compared with center, age and sex-matched patients with established type 2 diabetes, NDD was not significantly associated with a more severe COVID-19 prognosis.
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http://dx.doi.org/10.1016/j.diabres.2021.108695DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7872857PMC
May 2021

Use of dipeptidyl peptidase-4 inhibitors and prognosis of COVID-19 in hospitalized patients with type 2 diabetes: A propensity score analysis from the CORONADO study.

Diabetes Obes Metab 2021 05 16;23(5):1162-1172. Epub 2021 Feb 16.

Département d'Endocrinologie, Diabétologie et Maladies Métaboliques, CHU de Rouen, Université de Rouen, Rouen, France.

Aim: To investigate the association between routine use of dipeptidyl peptidase-4 (DPP-4) inhibitors and the severity of coronavirus disease 2019 (COVID-19) infection in patient with type 2 diabetes in a large multicentric study.

Materials And Methods: This study was a secondary analysis of the CORONADO study on 2449 patients with type 2 diabetes (T2D) hospitalized for COVID-19 in 68 French centres. The composite primary endpoint combined tracheal intubation for mechanical ventilation and death within 7 days of admission. Stabilized weights were computed for patients based on propensity score (DPP-4 inhibitors users vs. non-users) and were used in multivariable logistic regression models to estimate the average treatment effect in the treated as inverse probability of treatment weighting (IPTW).

Results: Five hundred and ninety-six participants were under DPP-4 inhibitors before admission to hospital (24.3%). The primary outcome occurred at similar rates in users and non-users of DPP-4 inhibitors (27.7% vs. 28.6%; p = .68). In propensity analysis, the IPTW-adjusted models showed no significant association between the use of DPP-4 inhibitors and the primary outcome by Day 7 (OR [95% CI]: 0.95 [0.77-1.17]) or Day 28 (OR [95% CI]: 0.96 [0.78-1.17]). Similar neutral findings were found between use of DPP-4 inhibitors and the risk of tracheal intubation and death.

Conclusions: These data support the safety of DPP-4 inhibitors for diabetes management during the COVID-19 pandemic and they should not be discontinued.
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http://dx.doi.org/10.1111/dom.14324DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8013481PMC
May 2021

Pre-term birth in women exposed to Cushing's disease: the baby-cush study.

Eur J Endocrinol 2021 Mar;184(3):469-476

Aix-Marseille Université, Institut National de la Santé et de la Recherche Médicale (INSERM), U1251, Marseille Medical Genetics (MMG), Institut Marseille Maladies Rares (MarMaRa), Marseille, France.

Design: Hypercortisolism during pregnancy is a risk factor for prematurity. Long-term exposure to hypercortisolism may lead to permanent comorbidities, such as hypertension or diabetes, even after remission. Our aim was to determine whether women with a history of Cushing's disease (and being eu-, hypo- or hypercortisolic at the time of pregnancy) had the same risks of comorbidities, and especially prematurity, during pregnancy.

Methods: It was a retrospective multicentric study focusing on mothers with a history of Cushing's disease or diagnosed during pregnancy, followed in French tertiary referral centers. We compared the outcomes of pregnancies depending on the cortisolic status at the time of pregnancy.

Results: A total of 60 patients (78 pregnancies including 21 with hypercortisolism, 32 with hypocortisolism and 25 in eucortisolism in 25) were evaluated. The overall rate of preterm birth was 24.3%, with a peak in women diagnosed during pregnancy (62.5%), a high risk in hypercortisolic (33%) and hypocortisolic (19.3%), and a low risk (8%) in eucortisolic women Gestational diabetes and hypertension were observed in 21% and 10.4% of the whole cohort, with a higher risk in hypercortisolic women. Cesarean delivery was performed in 33.7% of the cohort.

Conclusions: Being non-eucortisolic at the time of pregnancy increases the risk of prematurity and comorbidities compared to the general population. Women with a history of Cushing's disease should thus be carefully monitored during pregnancy. The high rate of cesarean delivery emphasizes the fact that these pregnancies should always be considered at risk.
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http://dx.doi.org/10.1530/EJE-20-1224DOI Listing
March 2021

Plasma concentrations of lipoproteins and risk of lower-limb peripheral artery disease in people with type 2 diabetes: the SURDIAGENE study.

Diabetologia 2021 Mar 6;64(3):668-680. Epub 2021 Jan 6.

Département d'Endocrinologie, Diabétologie, Nutrition, Hôpital Haut-Lévêque, Pessac, Bordeaux, France.

Aims/hypothesis: The lipid profile has not been fully investigated in individuals with peripheral artery disease (PAD). We aimed to evaluate the relationship between plasma concentrations of lipoproteins and the prevalence of lower-limb PAD at baseline and its incidence during follow-up in people with type 2 diabetes.

Methods: Plasma concentrations of total cholesterol, HDL-cholesterol, triacylglycerol and apolipoprotein (Apo) A-I, ApoA-II, ApoB-100 and Apo(a) were measured at baseline using colorimetric or MS methods in the SURDIAGENE cohort. Total cholesterol/HDL-cholesterol ratio, non-HDL-cholesterol and LDL-cholesterol were estimated using computation formulas. Logistic and Cox proportional hazard regression models were fitted to estimate OR or HR, with related 95% CI, for baseline prevalence or incidence of major PAD (lower-limb amputation or requirement of revascularisation) during follow-up by increasing lipoprotein tertiles, after adjustment for key confounders.

Results: Among 1468 participants (women 42%, mean ± SD age 65 ± 11 years, duration of diabetes 14 ± 10 years at baseline), 129 (8.8%) had a baseline history of major PAD. Major PAD was less prevalent at baseline in the highest (vs lowest) tertile of HDL-cholesterol (OR 0.42 [95% CI 0.26, 0.71], p = 0.001) and ApoA-I (OR 0.39 [95% CI 0.23, 0.67], p = 0.0007), and more frequent in the highest tertile of total cholesterol/HDL-cholesterol ratio (OR 1.95 [95% CI 1.18, 3.24], p = 0.01). Among 1339 participants without a history of PAD at baseline, incident PAD occurred in 97 (7.2%) during a median (25th-75th percentile) duration of follow-up of 7.1 (4.4-10.7) years, corresponding to 9685 person-years and an incidence rate of 9.8 (95% CI 8.0, 12.0) per 1000 person-years. The risk of incident PAD was lower in the top (vs bottom) tertile of HDL-cholesterol (HR 0.54 [95% CI 0.30, 0.95], p = 0.03) or ApoA-I (HR 0.50 [95% CI 0.28, 0.86], p = 0.01) and higher in the top tertile of total cholesterol/HDL-cholesterol ratio (HR 2.81 [95% CI 1.61, 5.04], p = 0.0002) and non-HDL-cholesterol (HR 1.80 [95% CI 1.06, 3.12], p = 0.03).

Conclusions/interpretation: We reported independent associations between HDL-cholesterol, ApoA-I, total cholesterol/HDL-cholesterol ratio or non-HDL-cholesterol and the prevalence or the incidence of major PAD in people with type 2 diabetes. Our findings provide a picture of lipoprotein profile in people with type 2 diabetes. Graphical abstract.
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http://dx.doi.org/10.1007/s00125-020-05326-xDOI Listing
March 2021

Meningiomas and cyproterone acetate: a retrospective, monocentric cohort of 388 patients treated by surgery or radiotherapy for intracranial meningioma.

J Neurooncol 2021 Mar 3;152(1):115-123. Epub 2021 Jan 3.

Neurotraumatology, Neurosurgery Department, Hotel-Dieu, CHU Nantes, Nantes, France.

Purpose: Meningiomas are the most common intracranial tumors, accounting for 20-30% of central nervous system tumors. Recently, the European Medicines Agency issued an alert on cyproterone acetate (CPA) based on the results of a study that found an increased risk of meningioma 7 to 20 times higher when a patient is on CPA. The primary objective of this study was to determine the prevalence of CPA exposure in patients who had one or more intracranial meningiomas treated surgically or with radiation therapy. The secondary objectives were to establish a description of the patients who had intracranial meningioma in Nantes and to establish whether there was a difference in the intrinsic and tumoral characteristics of patients exposed to CPA compared with patients who had no hormonal exposure and patients who had been exposed to other hormones.

Methods: Monocentric, retrospective study including all patients treated by surgery or radiotherapy for intracranial meningioma from 2014 to 2017 excluding those with a history of exposure to ionizing radiation or neurofibromatosis type 2.

Results: 388 patients were included, 277 were treated by surgery and 111 by radiotherapy. 3.9% of the patients had a history or current use of CPA, 16.2% were taking other hormonal treatment. Compared with the group without hormonal exposure, the CPA-exposed group had significantly an earlier onset of meningiomas at 48.9 vs. 61.9 years (p = 0.0005) and had more multiple meningiomas, 26.7% vs. 6.1% (p = 0.0115).

Conclusions: In our study, patients with a history or current use of CPA had significantly more meningiomas and were significantly younger at the onset.
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http://dx.doi.org/10.1007/s11060-020-03683-6DOI Listing
March 2021

Metformin use is associated with a reduced risk of mortality in patients with diabetes hospitalised for COVID-19.

Diabetes Metab 2020 Dec 10;47(5):101216. Epub 2020 Dec 10.

Department of Endocrinology, Diabetes Mellitus and Nutrition, Amiens University Hospital, 80054 Amiens, France; PériTox = UMR_I 01, University of Picardie Jules Verne, Amiens, France.

Aims: Metformin exerts anti-inflammatory and immunosuppressive effects. We addressed the impact of prior metformin use on prognosis in patients with type 2 diabetes hospitalised for COVID-19.

Methods: CORONADO is a nationwide observational study that included patients with diabetes hospitalised for COVID-19 between March 10 and April 10, 2020 in 68 French centres. The primary outcome combined tracheal intubation and/or death within 7 days of admission. A Kaplan-Meier survival curve was reported for death up to day 28. The association between metformin use and outcomes was then estimated in a logistic regression analysis after applying a propensity score inverse probability of treatment weighting approach.

Results: Among the 2449 patients included, 1496 were metformin users and 953 were not. Compared with non-users, metformin users were younger with a lower prevalence of diabetic complications, but had more severe features of COVID-19 on admission. The primary endpoint occurred in 28.0% of metformin users (vs 29.0% in non-users, P =  0.6134) on day 7 and in 32.6% (vs 38.7%, P = 0.0023) on day 28. The mortality rate was lower in metformin users on day 7 (8.2 vs 16.1%, P <  0.0001) and on day 28 (16.0 vs 28.6%, P < 0.0001). After propensity score weighting was applied, the odds ratios for primary outcome and death (OR [95%CI], metformin users vs non-users) were 0.838 [0.649-1.082] and 0.688 [0.470-1.007] on day 7, then 0.783 [0.615-0.996] and 0.710 [0.537-0.938] on day 28, respectively.

Conclusion: Metformin use appeared to be associated with a lower risk of death in patients with diabetes hospitalised for COVID-19.
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http://dx.doi.org/10.1016/j.diabet.2020.101216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7832745PMC
December 2020

Impact of Gastric Electrical Stimulation on Economic Burden of Refractory Vomiting: A French Nationwide Multicentre Study.

Clin Gastroenterol Hepatol 2020 Nov 13. Epub 2020 Nov 13.

Nancy University Hospital, Nancy, France.

Background & Aims: Medico-economic data of patients suffering from chronic nausea and vomiting are lacking. In these patients, gastric electrical stimulation (GES) is an effective, but costly treatment. The aim of this study was to assess the efficacy, safety and medico-economic impact of Enterra therapy in patients with chronic medically refractory nausea and vomiting.

Methods: Data were collected prospectively from patients with medically refractory nausea and/or vomiting, implanted with an Enterra device and followed for two years. Gastrointestinal quality of life index (GIQLI) score, vomiting frequency, nutritional status and safety were evaluated. Direct and indirect expenditure data were prospectively collected in diaries.

Results: Complete clinical data were available for142 patients (60 diabetic, 82 non-diabetic) and medico-economic data were available for 96 patients (36 diabetic, 60 non-diabetic), 24 months after implantation. GIQLI score increased by 12.1 ± 25.0 points (p < .001), with a more significant improvement in non-diabetic than in diabetic patients (+15.8 ± 25.0 points, p < .001 versus 7.3 ± 24.5 points, p = .027, respectively). The proportion of patients vomiting less than once per month increased by 25.5% (p < .001). Hospitalisations, time off work and transport were the main sources of costs. Enterra therapy decreased mean overall healthcare costs from 8873 US$ to 5525 US$ /patient/year (p = .001), representing a saving of 3348 US$ per patient and per year. Savings were greater for diabetic patients (4096 US$ /patient/year) than for non-diabetic patients (2900 US$ /patient/year).

Conclusions: Enterra therapy is an effective, safe and cost-effective option for patients with refractory nausea and vomiting. ClinicalTrials.gov Identifier: NCT00903799.
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http://dx.doi.org/10.1016/j.cgh.2020.11.011DOI Listing
November 2020

Routine use of statins and increased COVID-19 related mortality in inpatients with type 2 diabetes: Results from the CORONADO study.

Diabetes Metab 2021 03 19;47(2):101202. Epub 2020 Oct 19.

L'Institut du Thorax, Université de Nantes, CHU Nantes, CNRS, Inserm, Nantes, France.

Aim: Patients with type 2 diabetes mellitus (T2DM) represent a high-risk population for both cardiovascular diseases and severe coronavirus disease 2019 (COVID-19). Recent studies have reported interactions between statin treatment and COVID-19-related outcomes. The study reported here specifically assessed the association between routine statin use and COVID-19-related outcomes in inpatients with T2DM.

Methods: The Coronavirus-SARS-CoV-2 and Diabetes Outcomes (CORONADO) study was a nationwide observational study aiming to describe the phenotypic characteristics and prognosis of T2DM patients with COVID-19 admitted to 68 French hospitals between 10 March and 10 April 2020. The composite primary outcome comprised tracheal intubation and/or death within 7 and 28 days of admission. The association between statin use and outcomes was estimated by logistic regression analysis after applying inverse probability of treatment weighting (IPTW) using a propensity score-weighting approach.

Results: Of the 2449 patients with T2DM (881 women, 1568 men; aged 70.9 ± 12.5 years) suitable for analysis, 1192 (49%) were using statin treatment before admission. In unadjusted analyses, patients using statins had rates of the primary outcome similar to those of non-users within both 7 (29.8% vs 27.0%, respectively; P = 0.1338) and 28 days (36.2% vs 33.8%, respectively; P = 0.2191) of admission. However, mortality rates were significantly higher in statin users within 7 (12.8% vs 9.8%, respectively; P = 0.02) and 28 days (23.9% vs 18.2%, respectively; P < 0.001). After applying IPTW, significant associations were observed with statin use and the primary outcome within 7 days (OR [95% CI]: 1.38 [1.04-1.83]) and with death within both 7 (OR [95% CI]: 1.74 [1.13-2.65]) and 28 days (OR [95% CI]: 1.46 [1.08-1.95]).

Conclusion: Routine statin treatment is significantly associated with increased mortality in T2DM patients hospitalized for COVID-19.
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http://dx.doi.org/10.1016/j.diabet.2020.10.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7572108PMC
March 2021

Relationship Between Diabetic Retinopathy Stages and Risk of Major Lower-Extremity Arterial Disease in Patients With Type 2 Diabetes.

Diabetes Care 2020 11 2;43(11):2751-2759. Epub 2020 Sep 2.

Hôpital Haut-Lévêque, Département d'Endocrinologie, Diabétologie, Nutrition, Pessac, Bordeaux, France

Objective: We evaluated the association between diabetic retinopathy stages and lower-extremity arterial disease (LEAD), its prognostic value, and the influence of potential contributors to this relationship in a prospective cohort of patients with type 2 diabetes.

Research Design And Methods: Diabetic retinopathy was staged at baseline as absent, nonproliferative, or proliferative. A Cox regression model was fitted in order to compute the hazard ratio (HR) (95% CI) for major LEAD (lower-limb amputation or revascularization) during follow-up by baseline retinopathy stages. The retinopathy-LEAD association was assessed in subgroups by age, sex, diabetes duration, HbA, systolic blood pressure, diabetic kidney disease, smoking, and macrovascular disease at baseline. The performance of retinopathy in stratifying LEAD risk was assessed by using the C statistic, integrated discrimination improvement (IDI), and net reclassification improvement (NRI).

Results: Among 1,320 participants without a history of LEAD at baseline, 94 (7.1%) developed a major LEAD during a 7.1-year median follow-up (incidence rate 9.6 per 1,000 person-years [95% CI 7.8-11.7]). The LEAD incidence rate (per 1,000 person-years) increased as retinopathy worsened: it was 5.5 (95% CI 3.9-7.8) in participants in whom retinopathy was absent, 14.6 (11.1-19.3) in those with nonproliferative retinopathy, and 20.1 (11.1-36.3) in those with proliferative retinopathy. Nonproliferative retinopathy (adjusted HR 2.31 [95% CI 1.43-3.81], = 0.0006) and proliferative retinopathy (3.14 [1.40-6.15], = 0.007) remained associated with major LEAD. No heterogeneity was observed across subgroups. Retinopathy enhanced the C statistic (+0.023 [95% CI 0.003-0.044], = 0.02), IDI (0.209 [0.130-0.321], < 0.001), and NRI (0.562 [0.382-0.799], < 0.001) values for risk of LEAD, beyond traditional risk factors.

Conclusions: An independent dose-response relationship was identified between diabetic retinopathy stages and major LEAD. Retinopathy yielded incremental prognostic information for stratifying risk of LEAD, suggesting its usefulness as a predictor of LEAD.
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http://dx.doi.org/10.2337/dc20-1085DOI Listing
November 2020

Relationship between obesity and severe COVID-19 outcomes in patients with type 2 diabetes: Results from the CORONADO study.

Diabetes Obes Metab 2021 02 6;23(2):391-403. Epub 2020 Nov 6.

Département d'Endocrinologie, Diabétologie et Nutrition, L'Institut du Thorax, INSERM, CNRS, University of Nantes, CHU Nantes, Nantes, France.

Aim: To assess the relationship between body mass index (BMI) classes and early COVID-19 prognosis in inpatients with type 2 diabetes (T2D).

Methods: From the CORONAvirus-SARS-CoV-2 and Diabetes Outcomes (CORONADO) study, we conducted an analysis in patients with T2D categorized by four BMI subgroups according to the World Health Organization classification. Clinical characteristics and COVID-19-related outcomes (i.e. intubation for mechanical ventilation [IMV], death and discharge by day 7 [D7]) were analysed according to BMI status.

Results: Among 1965 patients with T2D, 434 (22.1%) normal weight (18.5-24.9 kg/m , reference group), 726 (36.9%) overweight (25-29.9 kg/m ) and 805 (41.0%) obese subjects were analysed, including 491 (25.0%) with class I obesity (30-34.9 kg/m ) and 314 (16.0%) with class II/III obesity (≥35 kg/m ). In a multivariable-adjusted model, the primary outcome (i.e. IMV and/or death by D7) was significantly associated with overweight (OR 1.65 [1.05-2.59]), class I (OR 1.93 [1.19-3.14]) and class II/III obesity (OR 1.98 [1.11-3.52]). After multivariable adjustment, primary outcome by D7 was significantly associated with obesity in patients aged younger than 75 years, while such an association was no longer found in those aged older than 75 years.

Conclusions: Overweight and obesity are associated with poor early prognosis in patients with T2D hospitalized for COVID-19. Importantly, the deleterious impact of obesity on COVID-19 prognosis was no longer observed in the elderly, highlighting the need for specific management in this population.
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http://dx.doi.org/10.1111/dom.14228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7675375PMC
February 2021

Euglycaemic ketoacidosis during gestational diabetes with concomitant COVID-19 infection.

Diabetes Metab 2021 03 29;47(2):101181. Epub 2020 Jul 29.

Département d'Endocrinologie, Diabétologie et Nutrition, l'Institut du Thorax, INSERM, CNRS, UNIV Nantes, CHU Nantes, Nantes, France. Electronic address:

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http://dx.doi.org/10.1016/j.diabet.2020.07.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7387919PMC
March 2021

Phenotypic characteristics and prognosis of inpatients with COVID-19 and diabetes: the CORONADO study.

Diabetologia 2020 08 29;63(8):1500-1515. Epub 2020 May 29.

Département Diabète et Endocrinologie, Hôpital Lariboisière, Assistance Publique Hôpitaux de Paris, Paris, France.

Aims/hypothesis: Coronavirus disease-2019 (COVID-19) is a life-threatening infection caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) virus. Diabetes has rapidly emerged as a major comorbidity for COVID-19 severity. However, the phenotypic characteristics of diabetes in COVID-19 patients are unknown.

Methods: We conducted a nationwide multicentre observational study in people with diabetes hospitalised for COVID-19 in 53 French centres in the period 10-31 March 2020. The primary outcome combined tracheal intubation for mechanical ventilation and/or death within 7 days of admission. Age- and sex-adjusted multivariable logistic regressions were performed to assess the prognostic value of clinical and biological features with the endpoint. ORs are reported for a 1 SD increase after standardisation.

Results: The current analysis focused on 1317 participants: 64.9% men, mean age 69.8 ± 13.0 years, median BMI 28.4 (25th-75th percentile: 25.0-32.7) kg/m; with a predominance of type 2 diabetes (88.5%). Microvascular and macrovascular diabetic complications were found in 46.8% and 40.8% of cases, respectively. The primary outcome was encountered in 29.0% (95% CI 26.6, 31.5) of participants, while 10.6% (9.0, 12.4) died and 18.0% (16.0, 20.2) were discharged on day 7. In univariate analysis, characteristics prior to admission significantly associated with the primary outcome were sex, BMI and previous treatment with renin-angiotensin-aldosterone system (RAAS) blockers, but not age, type of diabetes, HbA, diabetic complications or glucose-lowering therapies. In multivariable analyses with covariates prior to admission, only BMI remained positively associated with the primary outcome (OR 1.28 [1.10, 1.47]). On admission, dyspnoea (OR 2.10 [1.31, 3.35]), as well as lymphocyte count (OR 0.67 [0.50, 0.88]), C-reactive protein (OR 1.93 [1.43, 2.59]) and AST (OR 2.23 [1.70, 2.93]) levels were independent predictors of the primary outcome. Finally, age (OR 2.48 [1.74, 3.53]), treated obstructive sleep apnoea (OR 2.80 [1.46, 5.38]), and microvascular (OR 2.14 [1.16, 3.94]) and macrovascular complications (OR 2.54 [1.44, 4.50]) were independently associated with the risk of death on day 7.

Conclusions/interpretations: In people with diabetes hospitalised for COVID-19, BMI, but not long-term glucose control, was positively and independently associated with tracheal intubation and/or death within 7 days.

Trial Registration: clinicaltrials.gov NCT04324736.
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http://dx.doi.org/10.1007/s00125-020-05180-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7256180PMC
August 2020

Acromegaly is associated with vertebral deformations but not vertebral fractures: Results of a cross-sectional monocentric study.

Joint Bone Spine 2020 Dec 16;87(6):618-624. Epub 2020 May 16.

Department of Rheumatology, CHU de Nantes, Nantes, France.

Objectives: Patients with acromegaly appear to be at increased risk of vertebral fractures despite normal bone mineral density. We investigated the prevalence of vertebral fractures in a cohort of acromegalic patients under 80 years of age.

Methods: Monocentric cross-sectional study performed at Nantes University Hospital from 1988 to 2018. Fifty patients (18 females, 32 males) with a median age of 52.3 years (range: 27-78) were included. Radiological vertebral fractures were evaluated on conventional lumbar and thoracic spine radiographs using Genant's semiquantitative fracture assessment. We studied qualitative abnormalities of the spine using three criteria: osteophytes, disc-space narrowing and wedge-shaped vertebrae. We analysed bone mineral density and endocrine status.

Results: Three patients (6%) had a vertebral fracture: one grade 1 and two grade 2 according to Genant's assessment, with two osteoporotic and one osteopenic patients. They had no unsubstituted pituitary deficiency. Considering the frank deformations (osteophyte or disc narrowing≥grade 2 or wedge-shaped), the thoracic spine was deformed in 22 patients (44%) and the lumbar spine in 21 patients (42%).

Conclusion: Acromegalic patients had a low prevalence of vertebral fractures but had a significant amount of vertebral deformations. We speculate that this high prevalence of frank deformations could explain the previously reported high prevalence of vertebral fractures.
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http://dx.doi.org/10.1016/j.jbspin.2020.04.020DOI Listing
December 2020

A high-throughput mass spectrometry-based assay for large-scale profiling of circulating human apolipoproteins.

J Lipid Res 2020 07 13;61(7):1128-1139. Epub 2020 May 13.

NUN, INRA, CHU Nantes, UMR 1280, PhAN, IMAD, CRNH-O, Nantes, France; CRNH-O Mass Spectrometry Core Facility, Nantes, France.

Apolipoproteins govern lipoprotein metabolism and are promising biomarkers of metabolic and cardiovascular diseases. Unlike immunoassays, MS enables the quantification and phenotyping of multiple apolipoproteins. Hence, here, we aimed to develop a LC-MS/MS assay that can simultaneously quantitate 18 human apolipoproteins [A-I, A-II, A-IV, A-V, B48, B100, C-I, C-II, C-III, C-IV, D, E, F, H, J, L1, M, and (a)] and determined apoE, apoL1, and apo(a) phenotypes in human plasma and serum samples. The plasma and serum apolipoproteins were trypsin digested through an optimized procedure and peptides were extracted and analyzed by LC-MS/MS. The method was validated according to standard guidelines in samples spiked with known peptide amounts. The LC-MS/MS results were compared with those obtained with other techniques, and reproducibility, dilution effects, and stabilities were also assessed. Peptide markers were successfully selected for targeted apolipoprotein quantification and phenotyping. After optimization, the assay was validated for linearity, lower limits of quantification, accuracy (biases: -14.8% to 12.1%), intra-assay variability [coefficients of variation (CVs): 1.5-14.2%], and inter-assay repeatability (CVs: 4.1-14.3%). Bland-Altman plots indicated no major statistically significant differences between LC-MS/MS and other techniques. The LC-MS/MS results were reproducible over five repeated experiments (CVs: 1.8-13.7%), and we identified marked differences among the plasma and serum samples. The LC-MS/MS assay developed here is rapid, requires only small sampling volumes, and incurs reasonable costs, thus making it amenable for a wide range of studies of apolipoprotein metabolism. We also highlight how this assay can be implemented in laboratories.
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http://dx.doi.org/10.1194/jlr.D120000835DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7328037PMC
July 2020

Plasma Trimethylamine N-Oxide and Risk of Cardiovascular Events in Patients With Type 2 Diabetes.

J Clin Endocrinol Metab 2020 07;105(7)

CRNH-O, Plateforme Spectrométrie de Masse (PFSM, Mass Spectrometry Core Facility), Nantes, France.

Objective: Even though trimethylamine N-oxide (TMAO) has been demonstrated to interfere with atherosclerosis and diabetes pathophysiology, the association between TMAO and major adverse cardiovascular events (MACE) has not been specifically established in type 2 diabetes (T2D).

Research Design And Methods: We examined the association of plasma TMAO concentrations with MACE and all-cause mortality in a single-center prospective cohort of consecutively recruited patients with T2D.

Results: The study population consisted in 1463 SURDIENE participants (58% men), aged 65 ± 10 years. TMAO concentrations were significantly associated with diabetes duration, renal function, high-density lipoprotein cholesterol, soluble tumor necrosis factor receptor 1 (sTNFR1) concentrations (R2 = 0.27) and were significantly higher in patients on metformin, even after adjustment for estimated glomerular filtration rate (eGFR): 6.7 (8.5) vs 8.5 (13.6) µmol/L, respectively (PeGFR-adjusted = 0.0207). During follow-up (median duration [interquartile range], 85 [75] months), 403 MACE and 538 deaths were registered. MACE-free survival and all-cause mortality were significantly associated with the quartile distribution of TMAO concentrations, patients with the highest TMAO levels displaying the greatest risk of outcomes (P < 0.0001). In multivariate Cox models, compared with patients from the first 3 quartiles, those from the fourth quartile of TMAO concentration had an independently increased risk for MACE: adjusted hazard ratio (adjHR) 1.32 (1.02-1.70); P = 0.0325. Similarly, TMAO was significantly associated with mortality in multivariate analysis: adjHR 1.75 (1.17-2.09); P = 0.0124, but not when sTNFR1 and angiopoietin like 2 were considered: adjHR 1.16 (0.95-1.42); P = 0.1514.

Conclusions: We revealed an association between higher TMAO concentrations and increased risk of MACE and all-cause mortality, thereby opening some avenues on the role of dysbiosis in cardiovascular risk, in T2D patients.
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http://dx.doi.org/10.1210/clinem/dgaa188DOI Listing
July 2020

Safety of dapagliflozin in a broad population of patients with type 2 diabetes: Analyses from the DECLARE-TIMI 58 study.

Diabetes Obes Metab 2020 08 27;22(8):1357-1368. Epub 2020 Apr 27.

Li Ka Shing Knowledge Institute, Department of Medicine, St Michael's Hospital, University of Toronto, Toronto, Canada.

Aims: To evaluate comprehensively the safety of dapagliflozin in patients with type 2 diabetes (T2DM), with emphasis placed on potential safety concerns related to the sodium-glucose co-transporter-2 inhibitor class.

Methods: In the Dapagliflozin Effect on Cardiovascular Events - Thrombolysis in Myocardial Infarction 58 (DECLARE-TIMI 58) study, 17 160 patients with T2DM were randomized to dapagliflozin or placebo and followed for a median of 4.2 years. Safety was evaluated in 17 143 patients receiving at least one dose of study drug.

Results: Acute kidney injury occurred less frequently with dapagliflozin, and adverse events suggestive of volume depletion were balanced between treatment groups, both irrespective of baseline estimated glomerular filtration rate, blood pressure, diuretic or loop diuretic use (interaction P values >0.05). Fractures and malignancies were balanced between the groups, irrespective of sex, diabetes duration or smoking (interaction P values >0.05) and fewer cases of bladder cancer occurred in the dapagliflozin versus the placebo group. Diabetic ketoacidosis was very rare, but more frequent with dapagliflozin versus placebo (27 vs. 12 patients with events; P = 0.02), yet signs, symptoms and contributing factors were similar in the two groups. Major hypoglycaemia occurred less frequently with dapagliflozin versus placebo, regardless of baseline use of either insulin or sulphonylureas (interaction P values >0.05). There were more adverse events of genital infections leading to discontinuation of study drug in the dapagliflozin versus the placebo group, but serious genital infections were few and balanced between treatment groups. Urinary tract infections, acute pyelonephritis and urosepsis were also balanced between treatment groups.

Conclusions: Dapagliflozin was well tolerated. The long duration and large number of patient-years in DECLARE-TIMI 58 comprehensively addressed previous safety questions, confirming the robust safety profile of dapagliflozin.
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http://dx.doi.org/10.1111/dom.14041DOI Listing
August 2020

VLDL (Very-Low-Density Lipoprotein)-Apo E (Apolipoprotein E) May Influence Lp(a) (Lipoprotein [a]) Synthesis or Assembly.

Arterioscler Thromb Vasc Biol 2020 03 6;40(3):819-829. Epub 2020 Feb 6.

Nephrology Department, CHU Saint-Pierre, La Réunion, France (E.N.-D.).

Objective: To clarify the association between PCSK9 (proprotein convertase subtilisin/kexin type 9) and Lp(a) (lipoprotein [a]), we studied Lp(a) kinetics in patients with loss-of-function and gain-of-function mutations and in patients in whom extended-release niacin reduced Lp(a) and PCSK9 concentrations. Approach and Results: Six healthy controls, 9 heterozygous patients with familial hypercholesterolemia (5 with low-density lipoprotein receptor [] mutations and 4 with gain-of-function mutations) and 3 patients with heterozygous dominant-negative loss-of-function mutations were included in the preliminary study. Eight patients were enrolled in a second study assessing the effects of 2 g/day extended-release niacin. Apolipoprotein kinetics in VLDL (very-low-density lipoprotein), LDL (low-density lipoprotein), and Lp(a) were studied using stable isotope techniques. Plasma Lp(a) concentrations were increased in -gain-of-function and familial hypercholesterolemia- groups compared with controls and -loss-of-function groups (14±12 versus 5±4 mg/dL; =0.04), but no change was observed in Lp(a) fractional catabolic rate. Subjects with -loss-of-function mutations displayed reduced apoE (apolipoprotein E) concentrations associated with a VLDL-apoE absolute production rate reduction. Lp(a) and VLDL-apoE absolute production rates were correlated (=0.50; <0.05). ApoE-to-apolipoprotein (a) molar ratios in Lp(a) increased with plasma Lp(a) (=0.96; <0.001) but not with PCSK9 levels. Extended-release niacin-induced reductions in Lp(a) and VLDL-apoE absolute production rate were correlated (=0.83; =0.015). In contrast, PCSK9 reduction (-35%; =0.008) was only correlated with that of VLDL-apoE absolute production rate (=0.79; =0.028).

Conclusions: VLDL-apoE production could determine Lp(a) production and/or assembly. As PCSK9 inhibitors reduce plasma apoE and Lp(a) concentrations, apoE could be the link between PCSK9 and Lp(a).
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http://dx.doi.org/10.1161/ATVBAHA.119.313877DOI Listing
March 2020
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