Publications by authors named "Elise Gand"

35 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

Intraglomerular Dysfunction Predicts Kidney Failure in Type 2 Diabetes.

Diabetes 2021 Oct 13;70(10):2344-2352. Epub 2021 Jul 13.

University of Colorado, Denver, CO

No longitudinal data link intraglomerular hemodynamic dysfunction with end-stage kidney disease (ESKD) in people with type 2 diabetes (T2D). Afferent (R) and efferent (R) arteriolar resistance and intraglomerular pressure (P) are not directly measurable in humans but are estimable from glomerular filtration rate (GFR), renal plasma flow (RPF), blood pressure, hematocrit, and plasma oncotic pressure. We examined the association of the R-to-R ratio and P with ESKD incidence in 237 Pima Indian individuals with T2D who underwent serial measures of GFR (iothalamate) and RPF (-aminohippurate). Their association with kidney structural lesions was also examined in a subset of 111 participants. Of the 237 participants (mean age 42 years, diabetes duration 11 years, and GFR 153 mL/min and median urine albumin-to-creatinine ratio 36 mg/g), 69 progressed to ESKD during a median follow-up of 17.5 years. In latent class analysis, distinct trajectories characterized by increasing R-to-R ratio (HR 4.60, 95% CI 2.55-8.31) or elevated P followed by a rapid decline (HR 2.96, 95% CI 1.45-6.02) strongly predicted incident ESKD. P ( = 21%, < 0.0001) and R-to-R ratio ( = 15%, < 0.0001) also correlated with mesangial fractional volume, a structural predictor of DKD progression. In conclusion, intraglomerular hemodynamic parameters associated strongly with incident ESKD and correlated with structural lesions of DKD.
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http://dx.doi.org/10.2337/db21-0154DOI Listing
October 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

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

Comparison of a new versus standard removable offloading device in patients with neuropathic diabetic foot ulcers: a French national, multicentre, open-label randomized, controlled trial.

BMJ Open Diabetes Res Care 2020 05;8(1)

Department of Endocrinology, Diabetology and Nutrition, CHU Bordeaux, Haut Lévèque Hospital, Pessac, France.

Introduction: The offloading is crucial to heal neuropathic diabetic foot ulcer (DFU). Removable offloading are the most used devices. is a new customized removable knee-high offloading device immobilizing foot and ankle joints, with some specific and innovative features that may improve offloading. We aimed to evaluate the efficiency of in DFU healing.

Research, Design And Methods: The evaluation of Offloading using a new removable ORTHOsis in DIABetic foot study is a French multicenter (13 centers) randomized controlled trial with blinded end points evaluation. Adults with neuropathic DFU were randomly assigned to either ), or any type of conventional (usually used in France) removable offloading devices (control group). The primary outcome was the 3-month proportion of patients with fully healed DFU.

Results: Among 112 randomized patients (men 78%, age 62±10 years), the primary outcome occurred in 19 (33%) participants using conventional device vs 19 (35%) users (p=0.79). Study groups were also comparable in terms of prespecified secondary end points including occurrence of new DFU (25% vs 27% in conventional and experimental groups), ipsilateral lower-limb amputation (4% vs 10%) or infectious complications (14% vs 13%) (p>0.05 for all). Adverse events were comparable between groups, including 4 deaths unrelated to study allocation (1 sudden death, 2 ventricular arrhythmias and 1 pancreatic cancer). Adverse events believed to be related to the device were higher in the group than in the control group (15% vs 4%). was less frequently worn than conventional devices (46% vs 66%, p=0.04).

Conclusions: , a new removable offloading orthosis immobilizing foot and ankle joints did not show superiority compared with conventional removable devices in neuropathic DFU healing and cannot be recommended to heal DFU.

Trial Registration Number: NCT01956162.
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http://dx.doi.org/10.1136/bmjdrc-2019-000954DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7223015PMC
May 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

Serum tenascin-C is independently associated with increased major adverse cardiovascular events and death in individuals with type 2 diabetes: a French prospective cohort.

Diabetologia 2020 05 10;63(5):915-923. Epub 2020 Feb 10.

INSERM, Centre d'Investigation Clinique CIC1402, Université de Poitiers, CHU de Poitiers, Poitiers, France.

Aims/hypothesis: Tenascin-C (TN-C) is an extracellular matrix glycoprotein highly expressed in inflammatory and cardiovascular (CV) diseases. Serum TN-C has not yet been specifically studied in individuals with type 2 diabetes, a condition associated with chronic low-grade inflammation and increased CV disease risk. In this study, we hypothesised that elevated serum TN-C at enrolment in participants with type 2 diabetes would be associated with increased risk of death and major adverse CV events (MACE) during follow-up.

Methods: We used a prospective, monocentric cohort of consecutive type 2 diabetes participants (the SURDIAGENE [SUivi Rénal, DIAbète de type 2 et GENEtique] cohort) with all-cause death as a primary endpoint and MACE (CV death, non-fatal myocardial infarction or stroke) as a secondary endpoint. We used a proportional hazard model after adjustment for traditional risk factors and the relative integrated discrimination improvement (rIDI) to assess the incremental predictive value of TN-C for these risk factors.

Results: We monitored 1321 individuals (58% men, mean age 64 ± 11 years) for a median of 89 months. During follow-up, 442 individuals died and 497 had MACE. Multivariate Cox analysis showed that serum TN-C concentrations were associated with an increased risk of death (HR per 1 SD: 1.27 [95% CI 1.17, 1.38]; p < 0.0001) and MACE (HR per 1 SD: 1.23 [95% CI 1.13, 1.34]; p < 0.0001). Using TN-C concentrations on top of traditional risk factors, prediction of the risk of all-cause death (rIDI: 8.2%; p = 0.0006) and MACE (rIDI: 6.7%; p = 0.0014) improved significantly, but modestly.

Conclusions/interpretation: In individuals with type 2 diabetes, increased serum TN-C concentrations were independently associated with death and MACE. Therefore, including TN-C as a prognostic biomarker could improve risk stratification in these individuals.
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http://dx.doi.org/10.1007/s00125-020-05108-5DOI Listing
May 2020

Frailty and diabetes status in older patients with cancer: impact on mortality in the ANCRAGE cohort.

Aging Clin Exp Res 2020 Sep 2;32(9):1809-1819. Epub 2020 Jan 2.

Department of Geriatrics, CHU Poitiers, 2 rue de la Milétrie, 86021, Poitiers Cedex, France.

Background: Frailty, diabetes and cancer are associated with aging, but the relationship between these conditions is not well defined.

Aims: We studied older patients with cancer from the prospective single-center cohort ANCRAGE (ANalyses of CanceR in AGEd) aiming to determine the impact of type 2 diabetes (T2D) and its vascular complications (VC) on frailty and adverse outcomes (mortality, unplanned readmission) during follow-up.

Methods: Analysis of cohort patients ≥ 75 years, included between 2009 and 2017, who underwent a comprehensive geriatric assessment (CGA). Variables of interest were history of T2D and VC, tumor site and metastatic status, CGA including eight domains (social environment, functional status, mobility, nutrition, mood, cognition, polypharmacy and comorbidities) and frailty.

Results: Among 1092 patients (47% female, mean age 82 ± 5 years), 219 (20%) had a reported diagnosis of T2D at baseline including 152 (69%) with VC. The most common tumor sites were prostate (15%), breast (15%), skin (12%), and colorectum (11%); 29% of patients had a metastatic disease. Frailty was highly prevalent (84%). During follow-up (median of 15.3 months), 653 (60%) patients died (60% no T2D, 43% T2D without VC, 66% with VC). After adjustment for age, gender and metastatic status, diabetics with VC had a higher risk of all-cause death (aHR1.89, 1.24-2.86, p = 0.004). Death was more frequently due to a non-cancer cause (p < 0.001). No difference in unplanned readmissions was observed in the three groups. Frailty was an independent risk factor for mortality and unplanned readmissions (p < 0.001 both).

Conclusion: In older cancer patients from the prospective ANCRAGE cohort, all-cause mortality was significantly higher in frail patients and those with complicated T2D, a finding questioning the quality of care management in such vulnerable patients, and stimulating further research in this multidisciplinary field.
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http://dx.doi.org/10.1007/s40520-019-01362-9DOI Listing
September 2020

Association between sleep disturbances, fear of hypoglycemia and psychological well-being in adults with type 1 diabetes mellitus, data from cross-sectional VARDIA study.

Diabetes Res Clin Pract 2020 Feb 19;160:107988. Epub 2019 Dec 19.

Institut MITOVASC, UMR CNRS 6015, INSERM 1083, Université d'Angers, 3 rue Roger Amsler, 49100 Angers, France; Diabetes Department, CHU d'Angers, 4 rue Larrey, 49100 Angers, France. Electronic address:

Aim: To assess the relationship between sleep quality, fear of hypoglycemia, glycemic variability and psychological well-being in type 1 diabetes mellitus.

Methods: Our data were provided by the VARDIA Study, a multicentric cross-sectional study conducted between June and December 2015. Sleep characteristics were assessed by the Pittsburgh Sleep Quality Index (PSQI). Fear of hypoglycemia and psychological well-being were measured with the Hypoglycemia Fear Survey version II (HFS-II) and the Hospital Anxiety and Depression Scale (HADS), respectively. Glycemic variability (GV) was determined using the CV of three 7-point self-monitoring blood glucose profiles and the mean amplitude of glycemic excursion (MAGE).

Results: 315 patients were eligible for PSQI questionnaire analysis: 54% women, mean age 47 ± 15, mean diabetes duration of 24 ± 13 years, HbA1c of 7.6 ± 0.9% (60 ± 7,5mmol/mol). Average PSQI score was 6.0 ± 3.3 and 59.8% of the patients had a PSQI score > 5. HFS-II score and HADS were significantly higher among "poor" sleepers (p < 0.0001) and PSQI score was positively associated with HADS (β = 0.22; 95% CI = 0.08;0.35). GV evaluated by CV or MAGE did not differ between "poor" and "good" sleepers (p = 0.28 and 0.54, respectively).

Conclusions: Adult patients with type 1 diabetes have sleep disturbances which correlate with psychological well-being. This study suggests that psychological management can be a target to improve sleep quality in adults with type 1 diabetes mellitus.
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http://dx.doi.org/10.1016/j.diabres.2019.107988DOI Listing
February 2020

Association of Urine Haptoglobin With Risk of All-Cause and Cause-Specific Mortality in Individuals With Type 2 Diabetes: A Transethnic Collaborative Work.

Diabetes Care 2020 03 20;43(3):625-633. Epub 2019 Dec 20.

L'institut du thorax, INSERM, CNRS, University of Nantes, CHU Nantes, Nantes, France

Objective: Haptoglobin is an acute-phase reactant with pleiotropic functions. We aimed to study whether urine haptoglobin may predict risk of mortality in people with type 2 diabetes.

Research Design And Methods: We employed a transethnic approach with a cohort of Asian origin (Singapore) ( = 2,061) and a cohort of European origin (France) ( = 1,438) included in the study. We used survival analyses to study the association of urine haptoglobin with risk of all-cause and cause-specific mortality.

Results: A total of 365 and 525 deaths were registered in the Singapore cohort (median follow-up 7.5 years [interquartile range 3.5-12.8]) and French SURDIAGENE cohort (median follow-up 6.8 years [interquartile range 4.3-10.5], respectively. Singapore participants with urine haptoglobin in quartiles 2 to 4 had higher risk for all-cause mortality compared with quartile 1 (unadjusted hazard ratio [HR] 1.47 [95% CI 1.02-2.11], 2.28 [1.62-3.21], and 4.64 [3.39-6.35], respectively). The association remained significant in quartile 4 after multiple adjustments (1.68 [1.15-2.45]). Similarly, participants in the French cohort with haptoglobin in quartile 4 had significantly higher hazards for all-cause mortality compared with quartile 1 (unadjusted HR 2.67 [2.09-3.42] and adjusted HR 1.49 [1.14-1.96]). In both cohorts, participants in quartile 4 had a higher risk of mortality attributable to cardiovascular disease and infection but not malignant tumor.

Conclusions: Urine haptoglobin predicts risk of mortality independent of traditional risk factors, suggesting that it may potentially be a novel biomarker for risk of mortality in patients with type 2 diabetes.
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http://dx.doi.org/10.2337/dc19-1295DOI Listing
March 2020

Comparison of the removal of uraemic toxins with medium cut-off and high-flux dialysers: a randomized clinical trial.

Nephrol Dial Transplant 2020 02;35(2):328-335

Department of Nephrology, Poitiers University Hospital, Poitiers, France.

Background: Accumulation of middle-weight uraemic toxins in haemodialysis (HD) patients results in increased morbidity and mortality. Whether medium cut-off HD (MCO-HD) improves removal of middle-weight uraemic toxins remains to be demonstrated.

Methods: This cross-over prospective study included 40 patients randomly assigned to receive either 3 months of MCO-HD followed by 3 months of high-flux HD (HF-HD), or vice versa. The primary endpoint was myoglobin reduction ratio (RR) after 3 months of MCO-HD. Secondary endpoints were the effect of MCO-HD on other middle-weight toxins and protein-bound toxins, and on parameters of nutrition, inflammation, anaemia and oxidative stress.

Results: Compared with HF-HD, MCO-HD provided higher mean RR of myoglobin (36 ± 8 versus 57 ± 13%, P < 0.0001), beta2-microglobulin (68 ± 6 versus 73 ± 15%, P = 0.04), prolactin (32 ± 13 versus 59 ± 11%, P < 0.0001), fibroblast growth factor 23 (20 ± 21 versus 41 ± 22%, P = 0.0002), homocysteine (43 ± 7 versus 46 ± 9%, P = 0.03) and higher median RR of kappa [54 (48-58) versus 70 (63-74)%, P < 0.0001] and lambda free light chain (FLC) [15 (9-22) versus 44 (38-49)%, P < 0.0001]. Mean ± SD pre-dialysis levels of beta2-microglobulin (28.4 ± 5.6 versus 26.9 ± 5.1 mg/L, P = 0.01) and oxidized low-density lipoprote (6.9 ± 4.4 versus 5.5 ± 2.5 pg/mL, P = 0.04), and median (interquartile range) kappa FLC [145 (104-203) versus 129 (109-190) mg/L, P < 0.03] and lambda FLC [106 (77-132) versus 89 (62-125) mg/L, P = 0.002] were significantly lower. Mean albumin levels decreased significantly (38.2 ± 4.1 versus 36.9 ± 4.3 g/L, P = 0.004), without an effect on nutritional status as suggested by unchanged normalized protein catabolic rate and transthyretin level.

Conclusions: Compared with HF-HD, MCO-HD provides higher myoglobin and other middle molecules RR and is associated with moderate hypoalbuminemia. The potential benefits of this strategy on long-term clinical outcomes deserve further evaluation.
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http://dx.doi.org/10.1093/ndt/gfz189DOI Listing
February 2020

[Interest of the multidimensional prognostic index (MPI) as an assessment tool in hospitalized patients in geriatrics].

Geriatr Psychol Neuropsychiatr Vieil 2019 12;17(4):386-392

Service de gériatrie, CHU La Milétrie, Poitiers, France, Centre d'investigation clinique, CIC Inserm 1402, CHU La Milétrie, Poitiers, France.

The collection of prognostic information in the elderly is essential. The main objective was to perform a replication of the multidimensional prognostic index (MPI), to predict mortality at one-year in patients hospitalized in geriatric wards. Secondary objectives were to evaluate if the MPI was predictive of the length of hospital stay, and of rehospitalization in the following year.

Methods: Prospective study conducted from February 2015 to November 2016 at the University Hospital of Poitiers (Geriatrics department). A comprehensive geriatric assessment (number of treatment, lifestyle, autonomy, comorbidities, risk of pressure sore, nutritional and cognitive status) was used to calculate the MPI score and to categorize patients into three groups: low (MPI-1), moderate (MPI-2) and high (MPI-3) risk of mortality.

Results: 153 patients were included, with mean age 85.9 ± 5.4 years. Twenty-one patients (13.7%) belonged to MPI-1 group, 98 (64.1%) to MPI-2 group, and 34 (22.2%) to MPI-3 group. The number of deaths at one-year according to the MPI group was different (p < 0.01). The one-year prognostic performance of MPI was good (AUC at 0.76). MPI was also predictive of hospital length stay (p < 0.05).

Conclusion: MPI appears to be a relevant prognostic tool in the stratification of one-year mortality risk in elderly patients hospitalized in geriatrics.
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http://dx.doi.org/10.1684/pnv.2019.0823DOI Listing
December 2019

No association between fear of hypoglycemia and blood glucose variability in type 1 diabetes: The cross-sectional VARDIA study.

J Diabetes Complications 2019 08 10;33(8):554-560. Epub 2019 May 10.

L'institut du thorax, INSERM, CNRS, UNIV Nantes, CHU Nantes, Nantes, France.

Aims: In type 1 diabetes (T1D), treatment efficacy is limited by the unpredictability of blood glucose results and glycemic variability (GV). Fear of Hypoglycemia (FOH) remains a major brake for insulin treatment optimization. We aimed to assess the association of GV with FOH in participants with T1D in an observational cross-sectional study performed in 9 French Diabetes Centres (NCT02790060).

Methods: Participants were T1D for ≥5 years, aged 18-75 years, on stable insulin therapy for ≥3 months. The coefficient of variation (CV) of blood glucose and mean amplitude of glycemic excursions (MAGE) were used to assess GV from 7-point self-monitoring of blood glucose (SMBG). FOH was assessed using the validated French version of the Hypoglycemia Fear Survey-II (HFS-II) questionnaire.

Results: Among a total of 570 recruited participants, 298 were suitable for analysis: 46% women, 58% on continuous subcutaneous insulin infusion [CSII], mean age 49 ± 16 years, HbA1c 7.5 ± 0.9%, HFS-II score 67 ± 18 and 12% with recent history of severe hypoglycemia during the previous 6 months, mean CV 39.8 ± 9.7% and MAGE 119 ± 42 mg/dL. CV and MAGE did not significantly correlate with HFS-II score (R = -0.05;P = 0.457 and R = 0.08;P = 0.170). Participants with severe hypoglycemia in the previous 6 months had higher HFS scores. Participants with higher HFS scores presented more hypoglycemias during follow-up.

Conclusions: FOH as determined using the HFS-II questionnaire was not associated with 7-point SMBG variability in participants with T1D, but was associated with a positive history of severe hypoglycemia. Higher FOH was associated with higher frequency of hypoglycemia during follow-up.
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http://dx.doi.org/10.1016/j.jdiacomp.2019.05.003DOI Listing
August 2019

Clinicopathological spectrum of renal parenchymal involvement in B-cell lymphoproliferative disorders.

Kidney Int 2019 07 15;96(1):94-103. Epub 2019 Mar 15.

Department of Nephrology and Renal Transplantation, Centre Hospitalier Universitaire, Université de Poitiers, Poitiers, France; CNRS UMR 7276, INSERM UMR 1262, Université de Limoges, Limoges, France; INSERM CIC 1402, Centre Hospitalier Universitaire, Poitiers, France.

The clinicopathological characteristics of kidney infiltration in B-cell lymphoproliferative disorders remain poorly described. We retrospectively studied 52 adults with biopsy-proven malignant B-cell kidney infiltration, including Waldenström's macroglobulinemia (n=21), chronic lymphocytic leukemia (n=11), diffuse large B-cell lymphoma (DLBCL) (n=8), other lymphoma (n=11), and multiple myeloma (n=1). Kidney disease varied according to the underlying lymphoproliferative disorder. In DLBCL, malignant kidney infiltration was prominent, resulting in acute kidney injury (AKI, 75%) and kidney enlargement (88%). In the other types, associated immunoglobulin-related nephropathy (most commonly AL amyloidosis) was more common (45%), and chronic kidney disease with proteinuria was the primary presentation. All patients received chemotherapy. Over a median follow-up of 31 months, 20 patients died and 21 reached end-stage kidney disease. Renal response, achieved in 25 patients (48%), was associated with higher overall survival (97 vs. 37 months in non-renal responders). In univariate analysis, percentage of sclerotic glomeruli, kidney enlargement, and complete hematological response at 6 months were predictive of renal response. In multivariate analysis, concomitant immunoglobulin-related nephropathy was the sole independent predictor of poor renal outcome. In conclusion, clinical presentation of renal lymphomatous infiltration depends on the nature of the underlying lymphoproliferative disorder. In DLBCL, massive renal infiltration manifests with enlarged kidneys and AKI, and the diagnosis primarily relies on lymph node biopsy. In other B-cell lymphoproliferative disorders, the clinicopathological spectrum is more heterogeneous, with a high frequency of immunoglobulin-related nephropathy that may affect renal outcome; thus kidney biopsy is required for early diagnosis and prognostic assessment.
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http://dx.doi.org/10.1016/j.kint.2019.01.027DOI Listing
July 2019

Unilateral benign multinodular versus solitary goiter: Long-term contralateral reoperation rates after lobectomy.

Surgery 2019 01 8;165(1):75-79. Epub 2018 Nov 8.

Department of Visceral and Endocrine Surgery, CHU Poitiers, Poitiers, France. Electronic address:

Background: Few long-term studies define the appropriate extent of surgery and recurrence rates for unilateral multinodular goiter. We compared the rate and time to reoperation in patients with multinodular goiter who underwent lobectomy to that of patients with benign solitary nodule.

Methods: Retrospective study of a prospective database of all patients who underwent lobectomy for multinodular goiter or solitary nodule from 1991 to 2017. We analyzed reoperation rates and time to reoperation. Reoperation was defined as the need for completion thyroidectomy determined the following citeria: nodule greater than 3 cm, multiple nodules, nodule growth or suspicion for malignancy by ultrasound or fine-needle aspiration biopsy, or compressive symptoms.

Results: Included in the study were 2,675 lobectomies; 852 (31.85%) for multinodular goiter. In total, 394 patients (14.7%) underwent reoperation: 261 (30.6%) with a previous multinodular goiter and 133 (7.29%) with solitary nodule (P < .0001). A total of 80% of the patients with multinodular goiter and 67.66% with solitary nodule recurred as multinodular goiter; 3.5% of all recurrences were carcinomas. The mean time to reoperation was 14.8 years, without difference between groups (P = .5765). Patients without reoperation were younger (47 ± 15 vs 54 ± 13 years of age, P < .0001) and more likely to be male (P < .0001).

Conclusion: Lobectomy for unilateral multinodular goiter is the procedure of choice given the length of time to reoperation. Patients and surgeons should be aware of the need for long-term surveillance.
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http://dx.doi.org/10.1016/j.surg.2018.04.074DOI Listing
January 2019

Prognostic value of plasma MR-proADM vs NT-proBNP for heart failure in people with type 2 diabetes: the SURDIAGENE prospective study.

Diabetologia 2018 12 19;61(12):2643-2653. Epub 2018 Sep 19.

Centre d'Investigation Clinique, CHU de Poitiers, Poitiers, France.

Aims/hypothesis: N-terminal pro-B-type natriuretic peptide (NT-proBNP) is the gold standard prognostic biomarker for diagnosis and occurrence of heart failure. Here, we compared its prognostic value for the occurrence of congestive heart failure with that of plasma mid-region pro-adrenomedullin (MR-proADM), a surrogate for adrenomedullin, a vasoactive peptide with vasodilator and natriuretic properties, in people with type 2 diabetes.

Methods: Plasma MR-proADM concentration was measured in baseline samples of a hospital-based cohort of consecutively recruited participants with type 2 diabetes. Our primary endpoint was heart failure requiring hospitalisation.

Results: We included 1438 participants (age 65 ± 11 years; 604 women and 834 men). Hospitalisation for heart failure occurred during follow-up (median 64 months) in 206 participants; the incidence rate of heart failure was 2.5 (95% CI 2.2, 2.9) per 100 person-years. Plasma concentrations of MR-proADM and NT-proBNP were significantly associated with heart failure in a Cox multivariable analysis model when adjusted for age, diabetes duration, history of coronary heart disease, proteinuria and baseline eGFR (HR [95%CI] 1.83 [1.51, 2.21] and 2.20 [1.86, 2.61], respectively, per 1 SD log increment, both p < 0.001). MR-proADM contributed significant supplementary information to the prognosis of heart failure when we considered the clinical risk factors (integrated discrimination improvement [IDI, mean ± SEM] 0.021 ± 0.007, p = 0.001) (Table 3). Inclusion of NT-proBNP in the multivariable model including MR-proADM contributed significant complementary information on prediction of heart failure (IDI [mean ± SEM] 0.028 ± 0.008, p < 0.001). By contrast, MR-proADM did not contribute supplementary information on prediction of heart failure in a model including NT-proBNP (IDI [mean ± SEM] 0.003 ± 0.003, p = 0.27), with similar results for heart failure with reduced ejection fraction and preserved ejection fraction.

Conclusions/interpretation: MR-proADM is a prognostic biomarker for heart failure in people with type 2 diabetes but gives no significant complementary information on prediction of heart failure compared with NT-proBNP.
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http://dx.doi.org/10.1007/s00125-018-4727-7DOI Listing
December 2018

Prognostic Values of Inflammatory and Redox Status Biomarkers on the Risk of Major Lower-Extremity Artery Disease in Individuals With Type 2 Diabetes.

Diabetes Care 2018 10 2;41(10):2162-2169. Epub 2018 Aug 2.

UFR de Médecine et Pharmacie, Université de Poitiers, Poitiers, France.

Objective: Inflammation and oxidative stress play an important role in the pathogenesis of lower-extremity artery disease (LEAD). We assessed the prognostic values of inflammatory and redox status biomarkers on the risk of LEAD in individuals with type 2 diabetes.

Research Design And Methods: Plasma concentrations of tumor necrosis factor-α receptor 1 (TNFR1), angiopoietin-like 2, ischemia-modified albumin (IMA), fluorescent advanced glycation end products, protein carbonyls, and total reductive capacity of plasma were measured at baseline in the SURDIAGENE (Survie, Diabete de type 2 et Genetique) cohort. Major LEAD was defined as the occurrence during follow-up of peripheral revascularization or lower-limb amputation.

Results: Among 1,412 participants at baseline (men 58.2%, mean [SD] age 64.7 [10.6] years), 112 (7.9%) developed major LEAD during 5.6 years of follow-up. High plasma concentrations of TNFR1 (hazard ratio [95% CI] for second vs. first tertile 1.12 [0.62-2.03; = 0.71] and third vs. first tertile 2.16 [1.19-3.92; = 0.01]) and of IMA (2.42 [1.38-4.23; = 0.002] and 2.04 [1.17-3.57; = 0.01], respectively) were independently associated with an increased risk of major LEAD. Plasma concentrations of TNFR1 but not IMA yielded incremental information, over traditional risk factors, for the risk of major LEAD as follows: C-statistic change (0.036 [95% CI 0.013-0.059]; = 0.002), integrated discrimination improvement (0.012 [0.005-0.022]; < 0.001), continuous net reclassification improvement (NRI) (0.583 [0.294-0.847]; < 0.001), and categorical NRI (0.171 [0.027-0.317]; = 0.02).

Conclusions: Independent associations exist between high plasma TNFR1 or IMA concentrations and increased 5.6-year risk of major LEAD in people with type 2 diabetes. TNFR1 allows incremental prognostic information, suggesting its use as a biomarker for LEAD.
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http://dx.doi.org/10.2337/dc18-0695DOI Listing
October 2018

Influence of micro- and macro-vascular disease and Tumor Necrosis Factor Receptor 1 on the level of lower-extremity amputation in patients with type 2 diabetes.

Cardiovasc Diabetol 2018 06 8;17(1):81. Epub 2018 Jun 8.

Centre d'Investigation Clinique CIC1402, INSERM, Université de Poitiers, CHU de Poitiers, Poitiers, France.

Background: Patients with type 2 diabetes (T2D) face a high amputation rate. We investigated the relationship between the level of amputation and the presence of micro or macro-vascular disease and related circulating biomarkers, Tumor Necrosis Factor Receptor 1 (TNFR1) and Angiopoietin like-2 protein (ANGPTL2).

Methods: We have analyzed data from 1468 T2D participants in a single center prospective cohort (the SURDIAGENE cohort). Our outcome was the occurrence of lower limb amputation categorized in minor (below-ankle) or major (above ankle) amputation. Microvascular disease was defined as a history of albuminuria [microalbuminuria: uACR (urinary albumine-to-creatinine ratio) 30-299 mg/g or macroalbuminuria: uACR ≥ 300 mg/g] and/or severe diabetic retinopathy or macular edema. Macrovascular disease at baseline was divided into peripheral arterial disease (PAD): peripheral artery revascularization and/or major amputation and in non-peripheral macrovascular disease: coronary artery revascularization, myocardial infarction, carotid artery revascularization, stroke. We used a proportional hazard model considering survival without minor or major amputation.

Results: During a median follow-up period of 7 (0.5) years, 79 patients (5.5%) underwent amputation including 29 minor and 50 major amputations. History of PAD (HR 4.37 95% CI [2.11-9.07]; p < 0.001), severe diabetic retinopathy (2.69 [1.31-5.57]; p = 0.0073), male gender (10.12 [2.41-42.56]; p = 0.0016) and serum ANGPTL2 concentrations (1.25 [1.08-1.45]; p = 0.0025) were associated with minor amputation outcome. History of PAD (6.91 [3.75-12.72]; p < 0.0001), systolic blood pressure (1.02 [1.00-1.03]; p = 0.004), male gender (3.81 [1.67-8.71]; p = 0.002), and serum TNFR1 concentrations (HR 13.68 [5.57-33.59]; p < 0.0001) were associated with major amputation outcome. Urinary albumin excretion was not significantly associated with the risk of minor and major amputation.

Conclusions: This study suggests that the risk factors associated with the minor vs. major amputation including biomarkers such as TNFR1 should be considered differently in patients with T2D.
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http://dx.doi.org/10.1186/s12933-018-0725-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5992642PMC
June 2018

Predictive factors of endocrine and exocrine insufficiency after resection of a benign tumour of the pancreas.

Ann Endocrinol (Paris) 2018 Apr 8;79(2):53-61. Epub 2018 Mar 8.

CHU de Poitiers, service de chirurgie viscérale, 2, rue de la Milétrie, 86000 Poitiers, France.

Background: The aim of the present study is to evaluate the risk factors of endocrine and exocrine insufficiency occurring few years after pancreatic resections in a consecutive series of patients who underwent pancreatoduodenectomy (PD), left pancreatectomy (LP) or enucleation for benign neoplasms at a referral centre.

Methods: Pancreatic exocrine insufficiency (PEI) was defined by the onset of steatorrhea associated with weight loss, and endocrine insufficiency was determinate by fasting plasma glucose. Association between pancreatic insufficiency and clinical, pathological, and perioperative features was studied using univariate and multivariate Cox regression analysis.

Results: A prospective cohort of 92 patients underwent PD (48%), LP (44%) or enucleation (8%) for benign tumours, from 2005 to 2016 in the University Hospital in Poitiers (France). The median follow-up was 68.6±42.4months. During the following, 54 patients developed exocrine insufficiency whereas 32 patients presented endocrine insufficiency. In the Cox model, a BMI>28kg/m, being a man and presenting a metabolic syndrome were significantly associated with a higher risk to develop postoperative diabetes. The risks factors for the occurrence of PEI were preoperative chronic pancreatitis, a BMI<18.5kg/m, tumours located in the pancreatic head, biological markers of chronic obstruction and fibrotic pancreas. Undergoing LP or enucleation were protective factors of PEI. Histological categories such as neuroendocrine tumours and cystadenomas were also associated with a decreased incidence of PEI.

Conclusion: Men with metabolic syndrome and obesity should be closely followed-up for diabetes, and patients with obstructive tumours, pancreatic fibrosis or chronic pancreatitis require a vigilant follow up on their pancreatic exocrine function.
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http://dx.doi.org/10.1016/j.ando.2017.10.003DOI Listing
April 2018

Circulating Concentrations of Redox Biomarkers Do Not Improve the Prediction of Adverse Cardiovascular Events in Patients With Type 2 Diabetes Mellitus.

J Am Heart Assoc 2018 02 25;7(5). Epub 2018 Feb 25.

Centre d'Investigation Clinique, CHU de Poitiers, France.

Background: Despite pathophysiological relevance and promising experimental data, the usefulness of biomarkers of oxidative stress for cardiac risk prediction is unclear. The aim of our study was to investigate the prognostic value of 6 biomarkers exploring different pathways of oxidative stress for predicting adverse cardiovascular outcomes in patients with type 2 diabetes mellitus beyond established risk factors.

Methods And Results: The SURDIAGENE (Survie, Diabete de type 2 et Genetique) prospective cohort study consecutively recruited 1468 patients with type 2 diabetes mellitus. Assays were performed at baseline, and incident cases of major adverse cardiovascular events (MACE)-first occurrence of cardiovascular death, nonfatal myocardial infarction, or stroke-were recorded during a median of 64 months. Advanced oxidation protein products, oxidative hemolysis inhibition assay, ischemia-modified albumin, and total reductive capacity of plasma were not associated with the risk of MACE in univariate analyses. Fluorescent advanced glycation end products and carbonyls were associated with MACE (hazard ratio=1.38 per SD, 95% confidence interval 1.24-1.54, <0.001 and hazard ratio=1.15 per SD, 95% confidence interval 1.04-1.27, =0.006, respectively) in univariate analysis, but when added to a multivariate predictive model including traditional risk factors for MACE, these markers did not significantly improve c-statistics or integrated discrimination index of the model.

Conclusions: These plasma concentrations of 6 markers, which cover a broad spectrum of oxidative processes, were not significantly associated with MACE occurrence and were not able to improve MACE risk discrimination and classification beyond classical risk factors in type 2 diabetes mellitus patients.
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http://dx.doi.org/10.1161/JAHA.117.007397DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5866317PMC
February 2018

Urinary Sodium Concentration Is an Independent Predictor of All-Cause and Cardiovascular Mortality in a Type 2 Diabetes Cohort Population.

J Diabetes Res 2017 1;2017:5327352. Epub 2017 Feb 1.

CHU de Poitiers, Centre d'Investigation Clinique, Poitiers, France; Université de Poitiers, UFR Médecine Pharmacie, CIC1402, Poitiers, France; Inserm, CIC1402, Poitiers, France; CHU Poitiers, Pole DUNE, Poitiers, France; Inserm, U1082, Poitiers, France.

Objective: Sodium intake is associated with cardiovascular outcomes. However, no study has specifically reported an association between cardiovascular mortality and urinary sodium concentration (U). We examined the association of U with mortality in a cohort of type 2 diabetes (T2D) patients.

Methods: Patients were followed for all-cause death and cardiovascular death. Baseline U was measured from second morning spot urinary sample. We used Cox proportional hazard models to identify independent predictors of mortality. Improvement in prediction of mortality by the addition of U to a model including known risk factors was assessed by the relative integrated discrimination improvement (rIDI) index.

Results: Participants ( = 1,439) were followed for a median of 5.7 years, during which 254 cardiovascular deaths and 429 all-cause deaths were recorded. U independently predicted all-cause and cardiovascular mortality. An increase of one standard deviation of U was associated with a decrease of 21% of all-cause mortality and 22% of cardiovascular mortality. U improved all-cause and cardiovascular mortality prediction beyond identified risk factors (rIDI = 2.8%, = 0.04 and rIDI = 4.6%, = 0.02, resp.).

Conclusions: In T2D, U was an independent predictor of mortality (low concentration is associated with increased risk) and improved modestly its prediction in addition to traditional risk factors.
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http://dx.doi.org/10.1155/2017/5327352DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5309403PMC
June 2017

Association of Circulating Biomarkers (Adrenomedullin, TNFR1, and NT-proBNP) With Renal Function Decline in Patients With Type 2 Diabetes: A French Prospective Cohort.

Diabetes Care 2017 Mar 20;40(3):367-374. Epub 2016 Dec 20.

Centre Investigation Clinique 1402, University of Poitiers, Poitiers, France.

Objective: We explored the prognostic value of three circulating candidate biomarkers-midregional-proadrenomedullin (MR-proADM), soluble tumor necrosis factor receptor 1 (sTNFR1), and N-terminal prohormone brain natriuretic peptide (NT-proBNP)-for change in renal function in patients with type 2 diabetes.

Research Design And Methods: Outcomes were defined as renal function loss (RFL), ≥40% decline of estimated glomerular filtration rate (eGFR) from baseline, and rapid renal function decline (RRFD), absolute annual eGFR slope <-5 mL/min/year. We used a proportional hazard model for RFL and a logistic model for RRFD. Adjustments were performed for established risk factors (age, sex, diabetes duration, HbA, blood pressure, baseline eGFR, and urinary albumin-to-creatinine ratio [uACR]). C-statistics were used to assess the incremental predictive value of the biomarkers to these risk factors.

Results: Among 1,135 participants (mean eGFR 76 mL/min, median uACR 2.6 mg/mmol, and median GFR slope -1.6 mL/min/year), RFL occurred in 397, RRFD developed in 233, and 292 died during follow-up. Each biomarker predicted RFL and RRFD. When combined, MR-proADM, sTNFR1, and NT-proBNP predicted RFL independently from the established risk factors (adjusted hazard ratio 1.59 [95% CI 1.34-1.89], < 0.0001; 1.33 [1.14-1.55], 0.0003; and 1.22 [1.07-1.40], 0.004, respectively) and RRFD (adjusted odds ratio 1.56 [95% CI 1.7-2.09], = 0.003; 1.72 [1.33-2.22], < 0.0001; and 1.28 [1.03-1.59], 0.02, respectively). The combination of the three biomarkers yielded the highest discrimination (difference in C-statistic = 0.054, < 0.0001; 0.067, < 0.0001 for RFL; and 0.027, < 0.0001 for RRFD).

Conclusions: In addition to established risk factors, MR-proADM, sTNFR1, and NT-proBNP improve risk prediction of loss of renal function in patients with type 2 diabetes.
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http://dx.doi.org/10.2337/dc16-1571DOI Listing
March 2017

Glycaemic control influences the relationship between plasma PCSK9 and LDL cholesterol in type 1 diabetes.

Diabetes Obes Metab 2017 03 8;19(3):448-451. Epub 2016 Dec 8.

Department of Endocrinology, l'Institut du Thorax, INSERM, CNRS, CHU Nantes, Nantes University, Nantes, France.

Pro-protein convertase subtilisin/kexin type 9 (PCSK9) is a critical regulator of LDL cholesterol metabolism. Little is known, however, about the regulation of PCSK9 in patients with type 1 diabetes (T1D). In the present study, we aimed to determine the relationship between circulating PCSK9 and metabolic variables in T1D. Plasma PCSK9 levels were measured in 195 people with T1D (mean age 38.8 years, mean diabetes duration 17.2 years, mean glycated haemoglobin [HbA1c] 8.3%), who were free of any lipid-lowering agent. Plasma PCSK9 was positively correlated with LDL cholesterol (P = .0007), triglycerides (P = .004), apolipoprotein B (P = .005), HbA1c (P = .003), systolic (P = .003) and diastolic (P = .001) blood pressure and body mass index (0.02). In multivariate analysis, PCSK9 concentration was independently associated with HbA1c (P = .02) and LDL cholesterol (P = .03). After classifying patients according to HbA1c tertile, the correlation between PCSK9 and LDL cholesterol was only observed in the highest tertile (P = .0006; Rho = 0.43), whereas no correlation was found in the lowest and intermediate tertiles. This study suggests that good glycaemic control abolishes the positive relationship between PCSK9 and LDL cholesterol in patients with T1D; however, the underlying molecular mechanisms remain to be established.
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http://dx.doi.org/10.1111/dom.12819DOI Listing
March 2017

ANGPTL2 is associated with an increased risk of cardiovascular events and death in diabetic patients.

Diabetologia 2016 11 4;59(11):2321-2330. Epub 2016 Aug 4.

CHU de Poitiers Centre d'Investigation Clinique, Poitiers, France.

Aims/hypothesis: A high serum angiopoietin-like 2 (ANGPTL2) concentration is an independent risk factor for developing diabetes and is associated with insulin resistance and atherosclerosis. In this work, we have examined the impact of serum ANGPTL2 on improving cardiovascular (CV) risk stratification in patients with type 2 diabetes.

Methods: A prospective, monocentric cohort of consecutive type 2 diabetes patients (the SURDIAGENE cohort; total of 1353 type 2 diabetes patients; 58% men, mean ± SD age 64 ± 11 years) was followed for a median of 6.0 years for death as primary endpoint and major adverse CV events (MACE; i.e. CV death, myocardial infarction or stroke) as a secondary endpoint. Patients with end-stage renal disease, defined as a requirement for dialysis or a history of kidney transplantation, were excluded. Patients were grouped into quartiles according to ANGPTL2 concentrations at inclusion: <11.2 (Q1), 11.2-14.7 (Q2), 14.8-19.5 (Q3) or >19.5 (Q4) ng/ml.

Results: During follow up, 367 patients (representing 4.5% of the total person-years) died and 290 patients (representing 3.7% of the total person-years) presented with MACE. Both the survival and MACE-free survival rates were significantly different between ANGPTL2 quartiles (logrank 82.12, p < 0.0001 for death; and logrank 65.14, p < 0.0001 for MACE). Patients with ANGPTL2 concentrations higher than 19.5 ng/ml (Q4) had a significantly higher risk of death and MACE than those with ANGPTL2 levels of 19.5 ng/ml or less (Q1-3) (HR for death 2.44 [95% CI 1.98, 3.00], p < 0.0001; HR for MACE 2.43 [95% CI 1.92, 3.06], p < 0.0001) after adjustment for sex, age and established CV risk factors. Using ANGPTL2 concentrations, prediction of the risk of mortality, as assessed by integrated discrimination improvement (IDI), was significantly improved (IDI 0.006 ± 0.002, p = 0.0002).

Conclusions/interpretation: In patients with type 2 diabetes, serum ANGPTL2 concentrations were independently associated with death and MACE. Therefore, ANGPTL2 is a promising candidate biomarker for improving risk stratification in type 2 diabetes patients, and may prove to be a valuable therapeutic target.
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http://dx.doi.org/10.1007/s00125-016-4066-5DOI Listing
November 2016

Dynamic Changes in Renal Function Are Associated With Major Cardiovascular Events in Patients With Type 2 Diabetes.

Diabetes Care 2016 Jul 23;39(7):1259-66. Epub 2016 May 23.

INSERM CIC 1402, Poitiers, France UFR Médecine Pharmacie, Université de Poitiers, Poitiers, France Centre d'Investigation Clinique, CHU de Poitiers, Poitiers, France INSERM U1082 IRTOMIT, Poitiers, France.

Objective: The pattern of renal function decline prior to cardiovascular (CV) events in type 2 diabetes is not well known. Our aim was to describe the association between renal function trajectories and the occurrence of a CV event.

Research Design And Methods: We considered patients with type 2 diabetes from the SURDIAGENE (Survie, Diabete de type 2 et Genetique) study (discovery cohort) and the DIABHYCAR (Non-Insulin-Dependent Diabetes, Hypertension, Microalbuminuria or Proteinuria, Cardiovascular Events, and Ramipril) study (replication cohort). Global patterns of estimated glomerular filtration rate (eGFR) (Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI]) and serum creatinine (SCr) prior to a major CV event (MACE) or last update were determined using a linear mixed-effects model and annual individual slopes computed by simple linear regression.

Results: In the 1,040 participants of the discovery cohort, establishment of global patterns including 22,227 SCr over 6.3 years of follow-up showed an annual eGFR decline and an annual SCr increase that were significantly greater in patients with MACE compared with patients without (-3.0 and -1.7 mL/min/1.73 m(2)/year and +10.7 and +4.0 μmol/L/year, respectively; P < 0.0001 for both). Median annual individual slopes were also significantly steeper in patients with MACE, and adjusted risk of MACE was 4.11 times higher (3.09-5.45) in patients with rapid decline in eGFR (change less than -5 mL/min/1.73 m(2)/year). Consideration of renal function trajectories provided significant additive information helping to explain the occurrence of MACE for both SCr and eGFR (PIDI < 0.0001 and P = 0.0005, respectively). These results were confirmed in the replication cohort.

Conclusions: Renal function decline was associated with a higher risk of MACE. The pattern of renal function decline, beyond baseline kidney function, is an independent factor of CV risk.
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http://dx.doi.org/10.2337/dc15-2607DOI Listing
July 2016

Minimization of maintenance immunosuppressive therapy after renal transplantation comparing cyclosporine A/azathioprine or cyclosporine A/mycophenolate mofetil bitherapy to cyclosporine A monotherapy: a 10-year postrandomization follow-up study.

Transpl Int 2016 Jan;29(1):23-33

Service de Néphrologie-Hémodialyse-Transplantation rénale, CHU de Poitiers, Poitiers, France.

Long-term outcomes in renal transplant recipients withdrawn from steroid and submitted to further minimization of immunosuppressive regimen after 1 year are lacking. In this multicenter study, 204 low immunological risk kidney transplant recipients were randomized 14.2 ± 3.7 months post-transplantation to receive either cyclosporine A (CsA) + azathioprine (AZA; n = 53), CsA + mycophenolate mofetil (MMF; n = 53), or CsA monotherapy (n = 98). At 3 years postrandomization, the occurrence of biopsy for graft dysfunction was similar in bitherapy and monotherapy groups (21/106 vs. 26/98; P = 0.25). At 10 years postrandomization, patients' survival was 100%, 94.2%, and 95.8% (P = 0.25), and death-censored graft survival was 94.9%, 94.7%, and 95.2% (P = 0.34) in AZA, MMF, and CsA groups, respectively. Mean estimated glomerular filtration rate was 70.4 ± 31.1, 60.1 ± 22.2, and 60.1 ± 19.0 ml/min/1.73 m(2), respectively (P = 0.16). The incidence of biopsy-proven acute rejection was 1.4%/year in the whole cohort. None of the patients developed polyomavirus-associated nephropathy. The main cause of graft loss (n = 12) was chronic antibody-mediated rejection (n = 6). De novo donor-specific antibodies were detected in 13% of AZA-, 21% of MMF-, and 14% of CsA-treated patients (P = 0.29). CsA monotherapy after 1 year is safe and associated with prolonged graft survival in well-selected renal transplant recipient (ClinicalTrials.gov number: 980654).
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http://dx.doi.org/10.1111/tri.12627DOI Listing
January 2016

Acute Kidney Injury Predicts Major Adverse Outcomes in Diabetes: Synergic Impact With Low Glomerular Filtration Rate and Albuminuria.

Diabetes Care 2015 Dec 28;38(12):2333-40. Epub 2015 Oct 28.

Service de Néphrologie, CHU de Tours, Tours, France Université François-Rabelais, EA4245, Faculté de Médecine, Tours, France

Objective: Subjects with diabetes are prone to the development of cardiovascular and noncardiovascular complications. In separate studies, acute kidney injury (AKI), albuminuria, and low estimated glomerular filtration rate (eGFR) were shown to predict adverse outcomes, but, when considered together, their respective prognostic value is unknown.

Research Design And Methods: Patients with type 2 diabetes consecutively recruited in the SURDIAGENE cohort were prospectively followed up for major diabetes-related events, as adjudicated by an independent committee: death (with cause), major cardiovascular events (myocardial infarction, stroke, congestive heart failure, amputation, and arterial revascularization), and renal failure (i.e., sustained doubling of serum creatinine level or end-stage renal disease).

Results: Intrahospital AKI occurred in 411 of 1,371 patients during the median follow-up period of 69 months. In multivariate analyses, AKI was significantly associated with cardiovascular and noncardiovascular death, including cancer-related death. In multivariate analyses, AKI was a powerful predictor of major adverse cardiovascular events, heart failure requiring hospitalization, myocardial infarction, stroke, lower-limb amputation or revascularization, and carotid artery revascularization. AKI, eGFR, and albuminuria, even when simultaneously considered in multivariate models, predicted all-cause and cardiovascular deaths. All three renal biomarkers were also prognostic of most adverse outcomes and of the risk of renal failure.

Conclusions: AKI, low eGFR, and elevated albuminuria, separately or together, are compelling biomarkers of major adverse outcomes and death in diabetes.
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http://dx.doi.org/10.2337/dc15-1222DOI Listing
December 2015

Death, end-stage renal disease and renal function decline in patients with diabetic nephropathy in French cohorts of type 1 and type 2 diabetes.

Diabetologia 2016 Jan;59(1):208-216

Université Paris Diderot, Sorbonne Paris Cité, Paris, France.

Aims/hypothesis: Microvascular complications are a common feature of diabetes but additional research is needed regarding diabetic nephropathy endpoints in type 1 and type 2 diabetes.

Methods: We compared 277 type 1 diabetes patients with 942 type 2 diabetes patients, with clinical proteinuria and no endstage renal disease (ESRD) at baseline, prospectively followed for death, ESRD and decline in estimated glomerular filtration rate (eGFR, all available measures).

Results: The incidence rate of death was 67.0 (95% CI 59.2, 74.8) vs. 24.6 (95% CI, 19.0, 30.2) per 1,000 patient-years, in type 2 diabetes and type 1 diabetes, respectively. Unadjusted risk for death was greater for type 2 diabetes patients (HR 3.423; 95% CI, 2.501, 4.683; p<0.0001), but the difference did not persist after adjustment for age (HRage-adj 0.859; 95% CI 0.581, 1.269; p=0.445). The incidence rate of ESRD was 18.4 (95% CI 14.2, 22.5) vs. 47.1 (95%CI 38.4, 55.9) per 1,000 patient-years, in type 2 diabetes and type 1 diabetes, respectively. Unadjusted risk for ESRD was lower in type 2 diabetes (HR 0.399; 95% CI 0.287, 0.554; p<0.0001), but the difference did not persist after adjustment for sex, age and baseline serum creatinine (HRadj 0.989; 95% CI 0.597, 1.639; p=0.965). In a mixed linear model, eGFR decline was not significantly different in type 2 vs. type 1 diabetes (difference in slope −0.19 [0.28] ml min(−1) 1.73 m(−2) year(−1); p=0.512).

Conclusions/interpretation: In diabetic nephropathy, once baseline risk factors were taken into account the risk for death, ESRD and renal function decline did not significantly differ between type 1 diabetes and type 2 diabetes.
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http://dx.doi.org/10.1007/s00125-015-3785-3DOI Listing
January 2016

Association Between Diabetic Macular Edema and Cardiovascular Events in Type 2 Diabetes Patients: A Multicenter Observational Study.

Medicine (Baltimore) 2015 Aug;94(33):e1220

From the Department of ophthalmology, University Hospital of Poitiers, France (NL, OL, JG, M-FR, MB); University of Poitiers, UFR Médecine et Pharmacie, France (NL, RM); U1084, Inserm, Poitiers, France (NL); Centre d'investigation clinique, University of Poitiers, Poitiers, France (SR, P-JS, SH); CIC1402, Inserm, France (SR, P-JS, SH); Centre d'investigation clinique, University Hospital of Poitiers, Poitiers, France (SR, P-JS, SH); Endocrinology and Diabetology Department, pole DUNE, University Hospital of Poitiers, Poitiers, France (EG, XP, RM, SH); Department of Nephrology-immunology, University Hospital of Tours, François Rabelais University, Tours, France (JMH); Diabetology Department, Rangueuil Hospital, University Hospital of Toulouse, France (PG); Endocrinology Department Hospital of Sud Francilien, Corbeil Essonnes, France (DD); UMRS1138, Inserm, Paris, France (RR); University Paris 7 Denis Diderot, UMRS1138, Paris, France (RR); Diabetology, endocrinology and Nutrition Department, Groupe Hospitalier Bichat Claude Bernard, Assistance Public-Hopitaux de Paris (AP-HP), Paris, France (RR); Diabetology Department Bégin Armed Forces Hospital, Saint Mandé, France (OD); U1082, Inserm, Poitiers, France (SH).

Diabetic macular edema (DME) is the main cause of visual loss associated with diabetes but any association between DME and cardiovascular events is unclear.This study aims to describe the possible association between DME and cardiovascular events in a multicenter cross-sectional study of patients with type 2 diabetes.Two thousand eight hundred seven patients with type 2 diabetes were recruited from diabetes and nephrology clinical institutional centers participating in the DIAB 2 NEPHROGENE study focusing on diabetic complications. DME (presence/absence) and diabetic retinopathy (DR) classification were based on ophthalmological report and/or on 30° color retinal photographs. DR was defined as absent, nonproliferative (background, moderate, or severe) or proliferative. Cardiovascular events were stroke, myocardial infarction, and lower limb amputation.Details regarding associations between DME and cardiovascular events were evaluated.The study included 2807 patients with type 2 diabetes, of whom 355 (12.6%) had DME. DME was significantly and independently associated with patient age, known duration of diabetes, HbA1c, systolic blood pressure, and DR stage. Only the prior history of lower limb amputation was strongly associated with DME in univariate and multivariate analyses, whereas no association was found with regard to myocardial infarction or stroke. Moreover, both major (n = 32) and minor lower limb (n = 96) amputations were similarly associated with DME, with respective odds ratio of 3.7 (95% confidence interval [CI], 1.77-7.74; P = 0.0012) and of 4.29 (95% CI, 2.79-6.61; P < 0.001).DME is strongly and independently associated with lower limb amputation in type 2 diabetic patients.
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http://dx.doi.org/10.1097/MD.0000000000001220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4616429PMC
August 2015

Cardiovascular events in chronic hepatitis C: prognostic value of liver stiffness evolution.

Eur J Gastroenterol Hepatol 2015 Nov;27(11):1286-92

aHepatology and Gastroenterology Unit, University Hospital bLaboratoire Inflammation, Tissus Epithéliaux et Cytokines, Pôle Biologie Santé, Poitiers University, Poitiers, France.

Background And Aims: Chronic hepatitis C is also a metabolic disease that may increase cardiovascular events. FibroScan is a diagnostic tool for fibrosis and a prognostic tool for cirrhosis complications and mortality. The aim of our study was to investigate the prognostic value of liver stiffness evolution and initial stiffness in cardiovascular events occurring in patients with chronic hepatitis C.

Patients And Methods: Between 2006 and 2013, chronic hepatitis C patients followed in a reference center with two valid liver stiffness measurements by FibroScan were included. Cardiovascular events occurring after the initial FibroScan were collected retrospectively. 'Rapid stiffness progression' was defined as an evolution of at least 0.3 kPa/year and 'high initial stiffness' as at least 7 kPa.

Results: Among 561 patients with chronic hepatitis C, 135 were included, mean follow-up 5.2 years, 56% men, mean age 55.3 years, infected with genotype 1 (71%). Among these, 27 were overweight, 12 had type 2 diabetes, 41 had steatosis, and 89 had been treated. During follow-up, seven patients had a cardiovascular event (four myocardial infarctions, three strokes). Among the 35 patients with rapid stiffness progression, 6% had a cardiovascular event compared with 5% of 100 patients with slow progression (P=1.0). Among the 57 patients with high initial stiffness, 11% had a cardiovascular event compared with 1% of the 78 patients with low initial stiffness (P=0.04).

Conclusion: In chronic hepatitis C, initial stiffness of at least 7 kPa was associated with cardiovascular events. Rapid progression of liver stiffness does not seem to be associated with these events.
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http://dx.doi.org/10.1097/MEG.0000000000000453DOI Listing
November 2015
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