Publications by authors named "Michel Marre"

257 Publications

Efficacy and safety of finerenone in patients with chronic kidney disease and type 2 diabetes by GLP-1RA treatment: A subgroup analysis from the FIDELIO-DKD trial.

Diabetes Obes Metab 2021 Sep 28. Epub 2021 Sep 28.

Department of Medicine, University of Chicago Medicine, Chicago, Illinois, USA.

Aims: Finerenone significantly reduced the risk of kidney and cardiovascular (CV) outcomes in patients with chronic kidney disease and type 2 diabetes in the FIDELIO-DKD trial (NCT02540993). This exploratory subgroup analysis investigates the effect of glucagon-like peptide-1 receptor agonist (GLP-1RA) use on the treatment effect of finerenone.

Materials And Methods: Patients with type 2 diabetes, urine albumin-to-creatinine ratio (UACR) 30-5000 mg/g and estimated glomerular filtration rate 25-<75 ml/min per 1.73 m receiving optimized renin-angiotensin system blockade were randomized to finerenone or placebo.

Results: Of the 5674 patients analysed, overall, 394 (6.9%) received GLP-1RAs at baseline. A reduction in UACR with finerenone was observed with or without baseline GLP-1RA use; ratio of least-squares means 0.63 (95% confidence interval 0.56, 0.70) with GLP-1RA use and 0.69 (95% confidence interval 0.67, 0.72) without GLP-1RA use (p value for interaction .20). Finerenone also significantly reduced the primary kidney (time to kidney failure, sustained decrease in estimated glomerular filtration rate ≥40% from baseline, or renal death) and key secondary CV outcomes (time to CV death, non-fatal myocardial infarction, non-fatal stroke, or hospitalization for heart failure) versus placebo, with no clear difference because of GLP-1RA use at baseline (p value for interaction .15 and .51 respectively) or any time during the trial. The safety profile of finerenone was similar between subgroups.

Conclusions: This exploratory subgroup analysis suggests that finerenone reduces UACR in patients with or without GLP-1RA use at baseline, and the effects on kidney and CV outcomes are consistent irrespective of GLP-1RA use.
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http://dx.doi.org/10.1111/dom.14558DOI Listing
September 2021

Polygenic risk scores predict diabetes complications and their response to intensive blood pressure and glucose control.

Diabetologia 2021 Sep 6;64(9):2012-2025. Epub 2021 Jul 6.

Ontario Institute for Cancer Research, Toronto, ON, Canada.

Aims/hypothesis: Type 2 diabetes increases the risk of cardiovascular and renal complications, but early risk prediction could lead to timely intervention and better outcomes. Genetic information can be used to enable early detection of risk.

Methods: We developed a multi-polygenic risk score (multiPRS) that combines ten weighted PRSs (10 wPRS) composed of 598 SNPs associated with main risk factors and outcomes of type 2 diabetes, derived from summary statistics data of genome-wide association studies. The 10 wPRS, first principal component of ethnicity, sex, age at onset and diabetes duration were included into one logistic regression model to predict micro- and macrovascular outcomes in 4098 participants in the ADVANCE study and 17,604 individuals with type 2 diabetes in the UK Biobank study.

Results: The model showed a similar predictive performance for cardiovascular and renal complications in different cohorts. It identified the top 30% of ADVANCE participants with a mean of 3.1-fold increased risk of major micro- and macrovascular events (p = 6.3 × 10 and p = 9.6 × 10, respectively) and a 4.4-fold (p = 6.8 × 10) higher risk of cardiovascular death. While in ADVANCE overall, combined intensive blood pressure and glucose control decreased cardiovascular death by 24%, the model identified a high-risk group in whom it decreased the mortality rate by 47%, and a low-risk group in whom it had no discernible effect. High-risk individuals had the greatest absolute risk reduction with a number needed to treat of 12 to prevent one cardiovascular death over 5 years.

Conclusions/interpretation: This novel multiPRS model stratified individuals with type 2 diabetes according to risk of complications and helped to target earlier those who would receive greater benefit from intensive therapy.
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http://dx.doi.org/10.1007/s00125-021-05491-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8382653PMC
September 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

The Impact of Frailty on the Effectiveness and Safety of Intensive Glucose Control and Blood Pressure-Lowering Therapy for People With Type 2 Diabetes: Results From the ADVANCE Trial.

Diabetes Care 2021 Jul 25;44(7):1622-1629. Epub 2021 May 25.

Westmead Applied Research Centre, Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia

Objective: To develop a frailty index (FI) and explore the relationship of frailty to subsequent adverse outcomes on the effectiveness and safety of more intensive control of both blood glucose and blood pressure (BP), among participants with type 2 diabetes in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial.

Research Design And Methods: Cox proportional hazard models were used to estimate the effectiveness and safety of intensive glucose control and BP intervention according to frailty (defined as FI >0.21) status. The primary outcomes were macro- and microvascular events. The secondary outcomes were all-cause mortality, cardiovascular mortality, severe hypoglycemia, and discontinuation of BP treatment due to hypotension/dizziness.

Results: There were 11,140 participants (mean age, 65.8 years; 42.5% women, 25.7% frail). Frailty was an independent predictor of all primary outcomes and secondary outcomes. The effect of intensive glucose treatment on primary outcomes showed some evidence of attenuation in the frail: hazard ratios for combined major macro- and microvascular events 1.03 (95% CI 0.90-1.19) in the frail versus 0.84 (95% CI 0.74-0.94) in the nonfrail ( = 0.02). A similar trend was observed with BP intervention. Severe hypoglycemia rates (per 1,000 person-years) were higher in the frail: 8.39 (6.15-10.63) vs. 4.80 (3.84-5.76) in nonfrail ( < 0.001). There was no significant difference in discontinuation of BP treatment between frailty groups.

Conclusions: It was possible to retrospectively estimate frailty in a trial population, and this FI identified those at higher risk of poor outcomes. Participants with frailty had some attenuation of benefit from intensive glucose-lowering and BP-lowering treatments.
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http://dx.doi.org/10.2337/dc20-2664DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8323181PMC
July 2021

Combination blood pressure lowering in the presence or absence of background statin and aspirin therapy: a combined analysis of PROGRESS and ADVANCE Trials.

J Hypertens 2021 08;39(8):1689-1696

The George Institute for Global Health, University of New South Wales.

Objectives: To assess the effects of combination BP lowering on cardiovascular events and mortality in the presence of aspirin and/or statin therapy in a combined analysis of the ADVANCE and PROGRESS trials.

Methods: We conducted an analysis of 14 682 participants allocated combination therapy with perindopril and indapamide or placebo followed up for a mean of 4.2 years. Participants were stratified into four groups defined by background use of medications at baseline: statin, aspirin, both or neither. Linear mixed effect models were used to assess differences in BP and Cox proportional hazard models were used to estimate the risks of major cardiovascular events, all-cause mortality and treatment discontinuation.

Results: At baseline, 14% of patients were on both aspirin and statin, 35% on aspirin, 9% on statins and 42% on neither aspirin/statins. Compared with placebo, combination BP therapy reduced mean SBP by 5.7 mmHg in ADVANCE and 12.1 mmHg in PROGRESS, with no difference (P > 0.447) between patients by baseline use of aspirin/statin. Combination BP therapy reduced the risk of major cardiovascular events (hazard ratio 0.78, 95% CI 0.71-0.86), with no significant difference (P = 0.600) between aspirin/statin subgroups. Rates of treatment discontinuation were similar with combination BP therapy compared with placebo (18.4 versus 18%), with no evidence of difference across the subgroups (P = 0.340).

Conclusion: BP lowering with perindopril and indapamide reduces the risk of major cardiovascular events independent of baseline use of aspirin and/or statins.
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http://dx.doi.org/10.1097/HJH.0000000000002862DOI Listing
August 2021

I/D Polymorphism, Plasma ACE Levels, and Long-term Kidney Outcomes or All-Cause Death in Patients With Type 1 Diabetes.

Diabetes Care 2021 06 7;44(6):1377-1384. Epub 2021 Apr 7.

Centre de Recherche des Cordeliers, INSERM, Université de Paris, Sorbonne Université, Paris, France

Objective: The deletion (D) allele of the insertion/deletion (I/D) polymorphism is a risk factor for diabetic kidney disease. We assessed its contribution to long-term kidney outcomes and all-cause death in patients with long-standing type 1 diabetes.

Research Design And Methods: A total of 1,155 participants from three French and Belgian cohorts were monitored for a median duration of 14 (interquartile range 13) years. The primary outcome was the occurrence of end-stage kidney disease (ESKD) or a 40% drop in the estimated glomerular filtration rate (eGFR). Secondary outcomes were the individual components of the primary outcome, rapid decline in eGFR (steeper than -3 mL/min/1.73 m per year), incident albuminuria, all-cause death, and a composite ESKD or all-cause death. Hazard ratios (HRs) for XD versus II genotype and for baseline plasma ACE levels were computed by Cox analysis. Genotype performance in stratifying the primary outcome was tested.

Results: Genotype distribution was 954 XD and 201 II. The primary outcome occurred in 20% of XD and 13% of II carriers: adjusted HR 2.07 (95% CI 1.32-3.40; 0.001). Significant associations were also observed for rapid decline in eGFR, incident albuminuria, ESKD, all-cause death, and ESKD or all-cause death. Baseline plasma ACE levels were higher in XD carriers and significantly associated with an increased risk of the primary outcome. The genotype enhanced net reclassification improvement (0.154, 95% CI 0.007-0.279; 0.04) and integrated discrimination improvement (0.012, 95%CI 0.001-0.021; 0.02) for primary outcome stratification.

Conclusions: The D-allele of the I/D polymorphism was associated with an increased risk of major kidney events and all-cause death in patients with long-standing type 1 diabetes.
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http://dx.doi.org/10.2337/dc20-3036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8247517PMC
June 2021

Variability in estimated glomerular filtration rate and the risk of major clinical outcomes in diabetes: Post hoc analysis from the ADVANCE trial.

Diabetes Obes Metab 2021 06 4;23(6):1420-1425. Epub 2021 Mar 4.

The George Institute for Global Health, University of New South Wales, Sydney, New South Wales, Australia.

There are limited data on whether estimated glomerular filtration rate (eGFR) variability modifies the risk of future clinical outcomes in type 2 diabetes (T2D). We assessed the association between 20-month eGFR variability and the risk of major clinical outcomes in T2D among 8241 participants in the ADVANCE trial. Variability in eGFR (coefficient of variation [CV ]) was calculated from three serum creatinine measurements over 20 months. Participants were classified into three groups by thirds of CV : low (≤6.4; reference), moderate (>6.4 to ≤12.1) and high (>12.1). The primary outcome was the composite of major macrovascular events, new or worsening nephropathy and all-cause mortality. Cox regression models were used to estimate hazard ratios (HRs). Over a median follow-up of 2.9 years following the 20-month period, 932 (11.3%) primary outcomes were recorded. Compared with low variability, greater 20-month eGFR variability was independently associated with higher risk of the primary outcome (HR for moderate and high variability: 1.07, 95% CI: 0.91-1.27 and 1.22, 95% CI: 1.03-1.45, respectively) with evidence of a positive linear trend (p = .015). These data indicate that eGFR variability predict changes in the risk of major clinical outcomes in T2D.
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http://dx.doi.org/10.1111/dom.14351DOI Listing
June 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

The comparative effects of intensive glucose lowering in diabetes patients aged below or above 65 years: Results from the ADVANCE trial.

Diabetes Obes Metab 2021 06 19;23(6):1292-1300. Epub 2021 Feb 19.

George Institute for Global Health, University of New South Wales, Sydney, New South Wales, Australia.

Aims: For relatively old patients with diabetes, current guidelines recommend adjustment of glycaemic goals based on patients' cognitive function, or coexisting chronic illnesses. However, the evidence which supports the efficacy and safety of intensive glucose lowering in older patients with diabetes is scarce. The objective of the present study was to compare the efficacy and safety of intensive glucose lowering in patients with type 2 diabetes stratified by age (<65 and ≥ 65 years), and examine whether the effects differ according to patients' characteristics in the older patient group.

Materials And Methods: The effects of intensive glucose lowering (to a target glycated haemoglobin [HbA1c] concentration of ≤48 mmol/mol [6.5%]) on major clinical outcomes were evaluated by Cox regression models according to subgroups defined by baseline age of <65 or ≥ 65 years in the ADVANCE trial (n = 11 140).

Results: Over a median follow-up of 5 years, intensive glucose lowering significantly decreased the risk of the composite of major macrovascular and microvascular events (hazard ratio 0.90, 95% confidence interval 0.82-0.98), with no heterogeneity in the effects across age subgroups (p for heterogeneity = 0.44). Relative effects on all-cause death, cardiovascular death, and components of major vascular events were also similar (P for heterogeneity ≥0.06), except for severe hypoglycaemia, which was of greater risk for patients aged <65 years. Absolute benefits and harms were broadly consistent across subgroups. Among patients aged ≥65 years, randomized treatment effects did not differ significantly across different levels of cognitive function or coexisting chronic illnesses.

Conclusions: Our results suggest that an intensive glycaemic control strategy to reduce HbA1c to 48 mmol/mol (6.5%) provided broadly similar benefits and harms and may be recommended for older, as well as younger, patients.
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http://dx.doi.org/10.1111/dom.14339DOI Listing
June 2021

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

Diabetologia 2021 03 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

History of lower-limb complications and risk of cancer death in people with type 2 diabetes.

Cardiovasc Diabetol 2021 01 4;20(1). Epub 2021 Jan 4.

The George Institute for Global Health, Sydney, NSW, Australia.

Background: Individuals with diabetes and lower-limb complications are at high risk for cardiovascular and all-cause mortality, but uncertainties remain in terms of cancer-related death in this population. We investigated this relationship in a large cohort of people with type 2 diabetes.

Methods: We used data from the Action in Diabetes and Vascular Disease: PreterAx and DiamicroN Modified-Release Controlled Evaluation (ADVANCE) study. The primary outcome was adjudicated cancer death; secondary outcomes were overall and site-specific incident cancers, determined according to the International Classification of Diseases Code (ICD-10). We compared outcomes in individuals with (versus without) a baseline history of lower-limb complications (peripheral artery disease (PAD) or sensory peripheral neuropathy) using Cox regression models.

Results: Among 11,140 participants (women 42%, mean age 66 years), lower-limb complications were reported at baseline in 4293 (38%) individuals: 2439 (22%) with PAD and 2973 (27%) with peripheral neuropathy. Cancer death occurred in 316 (2.8%) participants during a median of 5.0 (25th-75th percentile, 4.7-5.1) years of follow-up corresponding to 53,550 person-years and an incidence rate of 5.9 (95% CI 5.3-6.6) per 1000 person-years. The risk of cancer death was higher in individuals with (versus without) lower-limb complication [hazard ratio 1.53 (95% CI, 1.21-1.94), p = 0.0004], PAD [1.32 (1.02-1.70), p = 0.03] or neuropathy (1.41 (1.11-1.79), p = 0.004], adjusting for potential confounders and study allocations. PAD, but not neuropathy, was associated with excess risk of incident cancers.

Conclusions: PAD and peripheral neuropathy were independently associated with increased 5-year risk of cancer death in individuals with type 2 diabetes. PAD was also associated with increased risk of incident cancers. Our findings provide new evidence on the non-cardiovascular prognostic burden of lower-limb complications in people with type 2 diabetes.
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http://dx.doi.org/10.1186/s12933-020-01198-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7784290PMC
January 2021

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

Diabetes Metab 2021 09 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
September 2021

Monogenic diabetes characteristics in a transnational multicenter study from Mediterranean countries.

Diabetes Res Clin Pract 2021 Jan 24;171:108553. Epub 2020 Nov 24.

Inserm UMR1283, CNRS UMR8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur Lille, Univ. Lille, Lille University Hospital, Lille, France; Department of Metabolism, Section of Genomics of Common Disease, Imperial College London, London, United Kingdom.

Background: Diagnosis of monogenic diabetes has important clinical implications for treatment and health expenditure. However, its prevalence remains to be specified in many countries, particularly from South Europe, North Africa and Middle-East, where non-autoimmune diabetes in young adults is increasing dramatically.

Aims: To identify cases of monogenic diabetes in young adults from Mediterranean countries and assess the specificities between countries.

Methods: We conducted a transnational multicenter study based on exome sequencing in 204 unrelated patients with diabetes (age-at-diagnosis: 26.1 ± 9.1 years). Rare coding variants in 35 targeted genes were evaluated for pathogenicity. Data were analyzed using one-way ANOVA, chi-squared test and factor analysis of mixed data.

Results: Forty pathogenic or likely pathogenic variants, 14 of which novel, were identified in 36 patients yielding a genetic diagnosis rate of 17.6%. The majority of cases were due to GCK, HNF1A, ABCC8 and HNF4A variants. We observed highly variable diagnosis rates according to countries, with association to genetic ancestry. Lower body mass index and HbA1c at study inclusion, and less frequent insulin treatment were hallmarks of pathogenic variant carriers. Treatment changes following genetic diagnosis have been made in several patients.

Conclusions: Our data from patients in several Mediterranean countries highlight a broad clinical and genetic spectrum of diabetes, showing the relevance of wide genetic testing for personalized care of early-onset diabetes.
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http://dx.doi.org/10.1016/j.diabres.2020.108553DOI Listing
January 2021

Plasma total adiponectin and changes in renal function in a cohort from the community: the prospective Data from an Epidemiological Study on the Insulin Resistance Syndrome study.

Nephrol Dial Transplant 2021 Nov;36(11):2058-2065

Centre de Recherche des Cordeliers UMR-S 1138, Université de Paris, INSERM, Paris, France.

Background: High adiponectin levels are associated with diabetic nephropathy. Nevertheless, it is not known whether plasma adiponectin is associated with renal function decline in the general population. We evaluated whether adiponectin concentrations were associated with changes in renal function in a community cohort, the Data from an Epidemiological Study on the Insulin Resistance Syndrome (DESIR) study.

Methods: Plasma adiponectin concentrations were measured in a random sample of 3284 people from the DESIR study, a 9-year prospective cohort from the general population. Data were analysed for three endpoints during follow-up: incidence of Stage 3 chronic kidney disease (CKD); the Kidney Disease: Improving Global Outcomes (KDIGO) criterion 'certain drop in eGFR' and rapid kidney function decline [estimated glomerular filtration rate (eGFR) slope steeper than -3 mL/min/1.73 m2/year].

Results: After exclusion of participants with an eGFR <60 mL/min/1.73 m2 at baseline and those with type 2 diabetes or impaired fasting glycaemia at any time during follow-up (remaining n = 2174), there was a 113% higher risk for a rapid decline in kidney function in participants with adiponectin above the third tertile (T3) versus below the first tertile (T1) (Ptrend = 0.004) and a 53% higher risk for kidney function decline as defined by the KDIGO criterion (Ptrend = 0.04). In a cross-sectional analysis, adiponectin was positively associated with urinary albumin:creatinine ratio at baseline (P = 0.009).

Conclusions: In a healthy cohort from the general population, higher levels of plasma adiponectin were associated with decreased renal function at baseline and at follow-up. This result is similar to what is observed in people with diabetic nephropathy, in contrast with animal models of nephropathy.
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http://dx.doi.org/10.1093/ndt/gfaa228DOI Listing
November 2021

Superior weight loss with once-weekly semaglutide versus other glucagon-like peptide-1 receptor agonists is independent of gastrointestinal adverse events.

BMJ Open Diabetes Res Care 2020 10;8(2)

Department of Cardiovascular and Metabolic Medicine, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, UK.

Introduction: Gastrointestinal (GI) adverse events (AEs) are the most common AEs with glucagon-like peptide-1 receptor agonists (GLP-1RAs). Weight loss (WL) is slightly greater in people who experience GI AEs than those who do not. A previous mediation analysis of the SUSTAIN 1-5 trials indicated minor contribution of nausea/vomiting to the greater WL with once-weekly semaglutide versus comparators. Semaglutide demonstrated superior glycated hemoglobin and body weight (BW) reductions versus other GLP-1RAs in SUSTAIN 3 (versus exenatide extended release 2.0 mg), SUSTAIN 7 (versus dulaglutide) and SUSTAIN 10 (liraglutide 1.2 mg). The objective of this analysis was to assess if significantly greater WL with semaglutide versus other GLP-1RAs is mediated by nausea/vomiting and other GI AEs (diarrhea, constipation, dyspepsia) during dose escalation (baseline to week 12, when GI AEs are generally most prevalent) and from baseline to end of treatment (EOT: week 56 (SUSTAIN 3), 40 (SUSTAIN 7) or 30 (SUSTAIN 10)).

Research Design And Methods: Subjects within trials were subdivided into those who reported (yes/no) nausea/vomiting or any other GI AE. Change from baseline in BW was assessed within each trial and subgroup. A mediation analysis separated WL into direct or indirect (mediated by GI AEs) effects.

Results: From baseline to week 12 or EOT, the nausea/vomiting-mediated difference in WL was, respectively: 0.05 or 0.09 kg of 3.78 kg at EOT (SUSTAIN 3); 0.06 or 0.03 kg of 2.26 kg at EOT (low-dose comparison) and 0.08 or 0.04 kg of 3.55 kg at EOT (high-dose comparison) (SUSTAIN 7) and 0.05 or 0.09 kg of 3.82 kg at EOT (SUSTAIN 10).

Conclusions: In SUSTAIN 3, 7 and 10, nausea/vomiting by week 12 (end of dose escalation) or throughout treatment contributed minimally (<0.1 kg) to the superior WL with semaglutide versus GLP-1RA comparators at EOT.
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http://dx.doi.org/10.1136/bmjdrc-2020-001706DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7594204PMC
October 2020

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

Pathogenic variants in actionable MODY genes are associated with type 2 diabetes.

Nat Metab 2020 10 12;2(10):1126-1134. Epub 2020 Oct 12.

Inserm UMR1283, CNRS UMR8199, European Genomic Institute for Diabetes (EGID), Université de Lille, Institut Pasteur de Lille, Lille University Hospital, Lille, France.

Genome-wide association studies have identified 240 independent loci associated with type 2 diabetes (T2D) risk, but this knowledge has not advanced precision medicine. In contrast, the genetic diagnosis of monogenic forms of diabetes (including maturity-onset diabetes of the young (MODY)) are textbook cases of genomic medicine. Recent studies trying to bridge the gap between monogenic diabetes and T2D have been inconclusive. Here, we show a significant burden of pathogenic variants in genes linked with monogenic diabetes among people with common T2D, particularly in actionable MODY genes, thus implying that there should be a substantial change in care for carriers with T2D. We show that, among 74,629 individuals, this burden is probably driven by the pathogenic variants found in GCK, and to a lesser extent in HNF4A, KCNJ11, HNF1B and ABCC8. The carriers with T2D are leaner, which evidences a functional metabolic effect of these mutations. Pathogenic variants in actionable MODY genes are more frequent than was previously expected in common T2D. These results open avenues for future interventions assessing the clinical interest of these pathogenic mutations in precision medicine.
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http://dx.doi.org/10.1038/s42255-020-00294-3DOI Listing
October 2020

Alternative kidney filtration markers and the risk of major macrovascular and microvascular events, and all-cause mortality in individuals with type 2 diabetes in the ADVANCE trial.

J Diabetes 2020 Dec 27;12(12):929-941. Epub 2020 Jul 27.

Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.

Background: Creatinine-based estimated glomerular filtration rate (eGFR) is biased in the setting of obesity and other conditions. Alternative kidney filtration markers may be useful in adults with diabetes, but few studies examined the associations with risk of clinical outcomes.

Methods: In the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial, we evaluated whether baseline levels and change in eGFR based on creatinine (Cr), cystatin c (Cys), β -microglobulin (B2M), eGFR , and the average of three estimates (eGFR ) assessed in 7217 participants at baseline and a random sample of 640 participants at the 1-year visit are associated with clinical outcomes. We examined associations with major macrovascular and microvascular events together and separately and all-cause mortality using Cox regression models, adjusting for established risk factors.

Results: Over a median follow-up of 5 years, 1313 major macrovascular (n = 748) and microvascular events (n = 637), and 743 deaths occurred. Lower levels of eGFR based on all filtration markers individually and combined were associated with 1.4 to 3.0 times higher risk of major macrovascular and microvascular events (combined and separately) and all-cause mortality. Per 30% decline in eGFR , eGFR , and eGFR were associated with a >2-fold higher risk of all clinical outcomes.

Conclusions: In adults with type 2 diabetes, baseline levels of eGFR based on alternative filtration markers and per 30% decline in eGFR , eGFR , and eGFR were associated with clinical outcomes. Measurement of alternative filtration markers, particularly B2M in adults with type 2 diabetes may be warranted.
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http://dx.doi.org/10.1111/1753-0407.13083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7775276PMC
December 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

Importance of intensive blood pressure control in type 2 diabetes: Mechanisms, treatments and current guidelines.

Authors:
Michel Marre

Diabetes Obes Metab 2020 04;22 Suppl 2:33-42

INSERM U1138, Centre de Recherches des Cordeliers, Paris, France.

Observational and interventional studies have shown that intensified blood pressure (BP) reduction can benefit people with diabetes. Because of their special haemodynamic properties, renin-angiotensin-aldosterone system (RAAS) blockers are recommended. The results of the BP arm of the ADVANCE study strongly support the recently updated European Society of Cardiology/European Association of Diabetes recommendations for the treatment of BP in people with diabetes, which recommend a target systolic/diastolic BP of 130/80 mmHg with few exceptions, and a fixed combination of an RAAS blocker with a diuretic or a calcium channel blocker as first-line treatment.
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http://dx.doi.org/10.1111/dom.13975DOI Listing
April 2020

Leukocyte Telomere Length, DNA Oxidation, and Risk of Lower-Extremity Amputation in Patients With Long-standing Type 1 Diabetes.

Diabetes Care 2020 04 27;43(4):828-834. Epub 2020 Jan 27.

INSERM, UMRS 1138, Centre de Recherche des Cordeliers, Paris, France.

Objective: Telomere shortening and DNA oxidation are associated with premature vascular aging, which may be involved in lower-extremity amputation (LEA). We sought to investigate whether leukocyte telomere length (LTL) and plasma 8-hydroxy-2'-deoxyguanosine (8-OHdG), a biomarker of DNA oxidation, were associated with LEA in subjects with type 1 diabetes at high vascular risk.

Research Design And Methods: LTL (quantitative PCR) and plasma 8-OHdG concentrations (immunoassay method) were assessed at baseline in the GENEDIAB (Génétique de la Néphropathie Diabétique) type 1 diabetes cohort. Logistic and Cox proportional hazards regression models were fitted to estimate odds ratio (OR) (at baseline) and hazard ratio (HR) (during follow-up), with related 95% CI, by increasing biomarker tertiles (T1, T2, T3).

Results: Among 478 participants (56% male, mean ± SD age 45 ± 12 years and diabetes duration 29 ± 10 years), 84 patients had LEA at baseline. Baseline history of LEA was associated with shorter LTL (OR for T2 vs. T1 0.62 [95% CI 0.32-1.22] and for T3 vs. T1 0.41 [0.20-0.84]) but not with plasma 8-OHdG (1.16 [0.56-2.39] and 1.24 [0.61-2.55], respectively). New cases of LEA occurred in 34 (12.3%) participants during the 10-year follow-up. LTL were shorter (HR T2 vs. T1 0.25 [95% CI 0.08-0.67] and T3 vs. T1 0.29 [0.10-0.77]) and plasma 8-OHdG higher (2.20 [0.76-7.35] and 3.11 [1.07-10.32]) in participants who developed LEA during follow-up compared with others. No significant interaction was observed between biomarkers on their association with LEA.

Conclusions: We report the first independent association between LTL shortening and excess risk of LEA in type 1 diabetes. High plasma 8-OHdG was also associated with incident LEA but partly dependent on cofounding variables.
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http://dx.doi.org/10.2337/dc19-0973DOI Listing
April 2020

Plasma Apelin and Risk of Type 2 Diabetes in a Cohort From the Community.

Diabetes Care 2020 02 5;43(2):e15-e16. Epub 2019 Dec 5.

INSERM Research Unit 1138, Cordeliers Research Center, Sorbonne Université, Paris, France.

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http://dx.doi.org/10.2337/dc19-1865DOI Listing
February 2020

Loss-of-function mutations in MRAP2 are pathogenic in hyperphagic obesity with hyperglycemia and hypertension.

Nat Med 2019 11 7;25(11):1733-1738. Epub 2019 Nov 7.

CNRS UMR 8199, European Genomic Institute for Diabetes, Institut Pasteur de Lille, University of Lille, Lille, France.

The G-protein-coupled receptor accessory protein MRAP2 is implicated in energy control in rodents, notably via the melanocortin-4 receptor. Although some MRAP2 mutations have been described in people with obesity, their functional consequences on adiposity remain elusive. Using large-scale sequencing of MRAP2 in 9,418 people, we identified 23 rare heterozygous variants associated with increased obesity risk in both adults and children. Functional assessment of each variant shows that loss-of-function MRAP2 variants are pathogenic for monogenic hyperphagic obesity, hyperglycemia and hypertension. This contrasts with other monogenic forms of obesity characterized by excessive hunger, including melanocortin-4 receptor deficiency, that present with low blood pressure and normal glucose tolerance. The pleiotropic metabolic effect of loss-of-function mutations in MRAP2 might be due to the failure of different MRAP2-regulated G-protein-coupled receptors in various tissues including pancreatic islets.
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http://dx.doi.org/10.1038/s41591-019-0622-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6858878PMC
November 2019

New roles for prokineticin 2 in feeding behavior, insulin resistance and type 2 diabetes: Studies in mice and humans.

Mol Metab 2019 11 28;29:182-196. Epub 2019 Aug 28.

Université de Paris, Paris, France; Unité de Biologie Fonctionnelle et Adaptative, CNRS UMR8251, Paris, France. Electronic address:

Objective: Prokineticin 2 (PROK2) is a hypothalamic neuropeptide that plays a critical role in the rhythmicity of physiological functions and inhibits food intake. PROK2 is also expressed in the main olfactory bulb (MOB) as an essential factor for neuro-and morphogenesis. Since the MOB was shown to be strongly involved in eating behavior, we hypothesized that PROK2 could be a new target in the regulation of food intake and energy homeostasis, through its effects in the MOB. We also asked whether PROK2 could be associated with the pathophysiology of obesity, the metabolic syndrome (MetS), and type 2 diabetes (T2D) in humans.

Methods: We assessed in wild type mice whether the expression of Prok2 in the MOB is dependent on the nutritional status. We measured the effect of human recombinant PROK2 (rPROK2) acute injection in the MOB on food intake and olfactory behavior. Then, using a lentivirus expressing Prok2-shRNA, we studied the effects of Prok2 underexpression in the MOB on feeding behavior and glucose metabolism. Metabolic parameters and meal pattern were determined using calorimetric cages. In vivo 2-deoxyglucose uptake measurements were performed in mice after intraperitoneally insulin injection. Plasmatic PROK2 dosages and genetic associations studies were carried out respectively on 148 and more than 4000 participants from the D.E.S.I.R. (Data from an Epidemiologic Study on the Insulin Resistance Syndrome) cohort.

Results: Our findings showed that fasting in mice reduced Prok2 expression in the MOB. Acute injection of rPROK2 in the MOB significantly decreased food intake whereas Prok2-shRNA injection resulted in a higher dietary consumption characterized by increased feeding frequency and decreased meal size. Additionally, Prok2 underexpression in the MOB induced insulin resistance compared to scrambled shRNA-injected mice. In the human D.E.S.I.R. cohort, we found a significantly lower mean concentration of plasma PROK2 in people with T2D than in those with normoglycemia. Interestingly, this decrease was no longer significant when adjusted for Body Mass Index (BMI) or calorie intake, suggesting that the association between plasma PROK2 and diabetes is mediated, at least partly, by BMI and feeding behavior in humans. Moreover, common Single Nucleotide Polymorphisms (SNPs) in PROK2 gene were genotyped and associated with incident T2D or impaired fasting glycemia (IFG), MetS, and obesity.

Conclusions: Our data highlight PROK2 as a new target in the MOB that links olfaction with eating behavior and energy homeostasis. In humans, plasma PROK2 is negatively correlated with T2D, BMI, and energy intake, and PROK2 genetic variants are associated with incident hyperglycemia (T2D/IFG), the MetS and obesity.
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http://dx.doi.org/10.1016/j.molmet.2019.08.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6812023PMC
November 2019

The Risks of Cardiovascular Disease and Mortality Following Weight Change in Adults with Diabetes: Results from ADVANCE.

J Clin Endocrinol Metab 2020 01;105(1)

Department of Epidemiology and Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 21205.

Context: Weight loss is strongly recommended for overweight and obese adults with type 2 diabetes. Unintentional weight loss is associated with increased risk of all-cause mortality, but few studies have examined its association with cardiovascular outcomes in patients with diabetes.

Objective: To evaluate 2-year weight change and subsequent risk of cardiovascular events and mortality in established type 2 diabetes.

Design And Setting: The Action in Diabetes and Vascular Disease: Preterax and Diamicron-MR Controlled Evaluation was an international, multisite 2×2 factorial trial of intensive glucose control and blood pressure control. We examined 5 categories of 2-year weight change: >10% loss, 4% to 10% loss, stable (±<4%), 4% to 10% gain, and >10% gain. We used Cox regression with follow-up time starting at 2 years, adjusting for intervention arm, demographics, cardiovascular risk factors, and diabetes medication use from the 2-year visit.

Results: Among 10 081 participants with valid weight measurements, average age was 66 years. By the 2-year examination, 4.3% had >10% weight loss, 18.4% had 4% to 10% weight loss, and 5.3% had >10% weight gain. Over the following 3 years of the trial, >10% weight loss was strongly associated with major macrovascular events (hazard ratio [HR], 1.75; 95% confidence interval [CI], 1.26-2.44), cardiovascular mortality (HR, 2.76; 95% CI, 1.87-4.09), all-cause mortality (HR, 2.79; 95% CI, 2.10-3.71), but not major microvascular events (HR, 0.91; 95% CI, 0.61-1.36), compared with stable weight. There was no evidence of effect modification by baseline body mass index, age, or type of diabetes medication.

Conclusions: In the absence of substantial lifestyle changes, weight loss may be a warning sign of poor health meriting further workup in patients with type 2 diabetes.
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http://dx.doi.org/10.1210/clinem/dgz045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6936964PMC
January 2020

Plasma Copeptin and Risk of Lower-Extremity Amputation in Type 1 and Type 2 Diabetes.

Diabetes Care 2019 12 3;42(12):2290-2297. Epub 2019 Oct 3.

INSERM, UMRS 1138, Cordeliers Research Center, Paris, France.

Objective: Diabetes is the leading cause of nontraumatic lower-extremity amputations (LEAs). Identification of patients with foot ulcers at risk for amputation remains clinically challenging. Plasma copeptin, a surrogate marker of vasopressin, is associated with the risk of cardiovascular and renal complications in diabetes.

Research Design And Methods: We assessed the association between baseline plasma copeptin and risk of LEA during follow-up in four cohorts of people with type 1 (GENESIS, = 503, and GENEDIAB, = 207) or type 2 diabetes (DIABHYCAR, = 3,101, and SURDIAGENE, = 1,452) with a median duration of follow-up between 5 and 10 years. Copeptin concentration was measured in baseline plasma samples by an immunoluminometric assay.

Results: In the pooled cohorts with type 1 diabetes ( = 710), the cumulative incidence of LEA during follow-up by increasing tertiles (tertile 1 [TER1], TER2, and TER3) of baseline plasma copeptin was 3.9% (TER1), 3.3% (TER2), and 10.0% (TER3) ( = 0.002). Cox regression analyses confirmed the association of copeptin with LEA: hazard ratio (HR) for 1 SD increment of log[copeptin] was 1.89 (95% CI 1.28-2.82), = 0.002. In the pooled cohorts of type 2 diabetes ( = 4,553), the cumulative incidence of LEA was 1.1% (TER1), 2.9% (TER2), and 3.6% (TER3) ( < 0.0001). In Cox regression analyses, baseline plasma copeptin was significantly associated with LEA: HR for 1 SD increment of log[copeptin] was 1.42 (1.15-1.74), = 0.001. Similar results were observed in the cohort with type 2 diabetes for lower-limb revascularization (HR 1.20 [95% CI 1.03-1.39], = 0.02).

Conclusions: Baseline plasma copeptin is associated with cumulative incidence of LEA in cohorts of people with both type 1 and type 2 diabetes and may help to identify patients at risk for LEA.
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http://dx.doi.org/10.2337/dc19-1062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6973542PMC
December 2019

Genome-Wide Association Study of Diabetic Kidney Disease Highlights Biology Involved in Glomerular Basement Membrane Collagen.

J Am Soc Nephrol 2019 10 19;30(10):2000-2016. Epub 2019 Sep 19.

Department of Biostatistics and.

Background: Although diabetic kidney disease demonstrates both familial clustering and single nucleotide polymorphism heritability, the specific genetic factors influencing risk remain largely unknown.

Methods: To identify genetic variants predisposing to diabetic kidney disease, we performed genome-wide association study (GWAS) analyses. Through collaboration with the Diabetes Nephropathy Collaborative Research Initiative, we assembled a large collection of type 1 diabetes cohorts with harmonized diabetic kidney disease phenotypes. We used a spectrum of ten diabetic kidney disease definitions based on albuminuria and renal function.

Results: Our GWAS meta-analysis included association results for up to 19,406 individuals of European descent with type 1 diabetes. We identified 16 genome-wide significant risk loci. The variant with the strongest association (rs55703767) is a common missense mutation in the collagen type IV alpha 3 chain ( gene, which encodes a major structural component of the glomerular basement membrane (GBM). Mutations in are implicated in heritable nephropathies, including the progressive inherited nephropathy Alport syndrome. The rs55703767 minor allele (Asp326Tyr) is protective against several definitions of diabetic kidney disease, including albuminuria and ESKD, and demonstrated a significant association with GBM width; protective allele carriers had thinner GBM before any signs of kidney disease, and its effect was dependent on glycemia. Three other loci are in or near genes with known or suggestive involvement in this condition ( or renal biology ( and ).

Conclusions: The 16 diabetic kidney disease-associated loci may provide novel insights into the pathogenesis of this condition and help identify potential biologic targets for prevention and treatment.
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http://dx.doi.org/10.1681/ASN.2019030218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6779358PMC
October 2019

Intensive glucose-lowering and the risk of vascular events and premature death in patients with decreased kidney function: The ADVANCE trial.

Diabetes Obes Metab 2020 03 30;22(3):452-457. Epub 2019 Oct 30.

The George Institute for Global Health, University of New South Wales, Sydney, New South Wales, Australia.

To assess the effects of intensive glucose control on the risk of major clinical outcomes according to estimated glomerular filtration rate (eGFR) levels in people with type 2 diabetes. Of 11 140 ADVANCE trial participants, 11 096 with baseline eGFR measurements were included, and classified into three eGFR groups: ≥90 mL/min/1.73 m ; 60 to 89 mL/min/1.73 m ; and < 60 mL/min/1.73 m . Relative risk reduction of randomized intensive glucose control with regard to the composite outcome of major macro- and microvascular events, all-cause death and cardiovascular death did not significantly vary by eGFR level (P for heterogeneity ≥0.49). The risk of severe hypoglycaemia increased with intensive glucose control; however, this risk did not vary across eGFR groups (P for heterogeneity = 0.83). The risk-benefit profile of intensive glucose control in patients with type 2 diabetes and impaired kidney function appears similar to that observed in those with preserved kidney function.
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http://dx.doi.org/10.1111/dom.13878DOI Listing
March 2020
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