C Mathieu

University of Leuven, Louvain, Flanders, Belgium

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Publications (190)655.73 Total impact

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    ABSTRACT: Insulin degludec (IDeg) is a new basal insulin with an ultra‐long and stable glucose‐lowering effect. We compared once‐daily IDeg and insulin glargine (IGlar), both in combination with metformin ± dipeptidyl peptidase‐4 inhibitors, in a 52‐week, open‐label, treat‐to‐target trial in patients with type 2 diabetes followed by a 52‐week extension trial in which subjects [n = 725/1030 (70.4%)] maintained their initial randomised treatment. Health status was assessed at baseline and 105 weeks using the Short Form‐36 (SF‐36 v2) questionnaire. SF‐36 scores were analysed (ITT population) using anova, with adjustments for covariates. At 105 weeks, the overall physical component score was significantly better with IDeg versus IGlar [treatment contrast (TC): 1.1 (0.1; 2.1)95%CI, p 95% CI, p 95% CI, p Keywords: SF‐36; hypoglycaemia; insulin degludec; patient‐reported outcomes; quality of life; type 2 diabetes Document Type: Research Article DOI: http://dx.doi.org/10.1111/dom.12271 Publication date: September 1, 2014 $(document).ready(function() { var shortdescription = $(".originaldescription").text().replace(/\\&/g, '&').replace(/\\, '<').replace(/\\>/g, '>').replace(/\\t/g, ' ').replace(/\\n/g, ''); if (shortdescription.length > 350){ shortdescription = "" + shortdescription.substring(0,250) + "... more"; } $(".descriptionitem").prepend(shortdescription); $(".shortdescription a").click(function() { $(".shortdescription").hide(); $(".originaldescription").slideDown(); return false; }); }); Related content In this: publication By this: publisher In this Subject: Internal Medicine By this author: Rodbard, H. W. ; Cariou, B. ; Zinman, B. ; Handelsman, Y. ; Wolden, M. L. ; Rana, A. ; Mathieu, C. GA_googleFillSlot("Horizontal_banner_bottom");
    Diabetes Obesity and Metabolism 09/2014; 16(9). · 5.18 Impact Factor
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    ABSTRACT: Randomised control trials (RCTs) do not always reflect real-life outcomes for glucose-lowering drugs. In this work we compared RCT and real-life data on the efficacy of the dipeptidyl peptidase-IV (DPP-4) inhibitor vildagliptin or sulfonylureas when added to metformin. Data were pooled from five RCTs examining vildagliptin (n = 2,788) and sulfonylureas (glimepiride [n = 1,259] or gliclazide [n = 433]), added to metformin. For real-life conditions, data were extracted from an observational study examining vildagliptin (n = 7,002) or sulfonylureas (n = 3,702), added to metformin monotherapy. Linear regression analyses were performed between the baseline HbA1c and the change in HbA1c (Δ HbA1c) after 24 weeks. Baseline HbA1c correlated to Δ HbA1c (r (2) = 0.36, slope = -0.54 [95% CI -0.55, -0.53; p < 0.0001]) for both treatments. With sulfonylureas, the slope of the correlation was steeper in the observational study than in RCTs (interaction coefficient = -0.327, p < 0.001), whereas for vildagliptin, the slope was virtually identical in the observational study and the RCTs (interaction coefficient = 0.024, p = 0.175). For any given baseline HbA1c, Δ HbA1c with sulfonylureas was smaller in real life than in RCTs, whereas Δ HbA1c with vildagliptin was the same. When comparing RCT to real-life data, the decrease in HbA1c from baseline with sulfonylurea treatment is smaller in real life than in RCTs, whereas the reduction with vildagliptin is essentially the same, suggesting that the full power of treatment is retained in real life for vildagliptin but not for sulfonylureas, possibly due to fear of hypoglycaemia.
    Diabetologia 03/2014; · 6.49 Impact Factor
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    ABSTRACT: Two treatment strategies were compared in patients with type 2 diabetes (T2DM) on basal insulin requiring intensification: addition of once-daily (OD) liraglutide (Lira) or OD insulin aspart (IAsp) with largest meal. Subjects completing 104 weeks (52-week main trial BEGIN ONCE LONG + 52-week extension) on insulin degludec (IDeg) OD + metformin with HbA1c ≥7.0% [≥53 mmol/mol] were randomized to IDeg+Lira (n = 88, mean HbA1c: 7.7% [61 mmol/mol]) or IDeg+IAsp (n = 89, mean HbA1c: 7.7%) for 26 weeks, continuing metformin. Subjects completing 104 weeks with HbA1c <7.0% continued IDeg + metformin in a third, non-randomized arm (n = 236). IDeg+Lira reduced HbA1c (-0.74%-points) significantly more than IDeg+IAsp (-0.39%-points); estimated treatment difference (IDeg+Lira-IDeg+IAsp) -0.32%-points [-0.53; -0.12]95% CI ; p = 0.0024. More IDeg+Lira (49.4%) than IDeg+IAsp (7.2%) subjects achieved HbA1c <7.0% without confirmed hypoglycaemia (plasma glucose <3.1 mmol/l [<56 mg/dl] or severe hypoglycaemia) and without weight gain; estimated odds ratio (IDeg+Lira/IDeg+IAsp) 13.79 [5.24; 36.28]95% CI ; p < 0.0001. IDeg+Lira subjects had significantly less confirmed and nocturnal confirmed hypoglycaemia, and significantly greater weight loss (-2.8 kg) versus IDeg+IAsp (+0.9 kg); ETD (IDeg+Lira-IDeg+IAsp) -3.75 kg [-4.70; -2.79]95% CI ; p < 0.0001. Other than more gastrointestinal side effects with IDeg+Lira, no safety differences occurred. Durability of IDeg was established in the non-randomized arm, as mean HbA1c remained <7.0% (mean 6.5% [48 mmol/mol] at end-of-trial). IDeg+Lira improved long-term glycaemic control, with weight loss and less hypoglycaemia versus adding a single daily dose of IAsp in patients with T2DM inadequately controlled with IDeg + metformin.
    Diabetes Obesity and Metabolism 01/2014; · 5.18 Impact Factor
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    ABSTRACT: Type 1 diabetes is due to destruction of pancreatic β-cells. Lysine deacetylase inhibitors (KDACi) protect β-cells from inflammatory destruction in vitro and are promising immunomodulators. Here we demonstrate that the clinically well-tolerated KDACi vorinostat and givinostat revert diabetes in the nonobese diabetic (NOD) mouse model of type 1 diabetes and counteract inflammatory target cell damage by a mechanism of action consistent with transcription factor-rather than global chromatin-hyperacetylation. Weaning NOD mice received low doses of vorinostat and givinostat in their drinking water until 100-120 d of age. Diabetes incidence was reduced by 38% and 45%, respectively, there was a 15% increase in the percentage of islets without infiltration, and pancreatic insulin content increased by 200%. Vorinostat treatment increased the frequency of functional regulatory T-cell subsets and their transcription factors Gata3 and FoxP3 in parallel to a decrease in inflammatory dendritic cell subsets and their cytokines IL-6, IL-12, and TNF-α. KDACi also inhibited LPS-induced Cox-2 expression in peritoneal macrophages from C57BL/6 and NOD mice. In insulin-producing β-cells, givinostat did not upregulate expression of the anti-inflammatory genes Socs1-3 or sirtuin-1 but reduced levels of IL-1β + IFN-γ-induced proinflammatory Il1a, Il1b, Tnfα, Fas, Cxcl2, and reduced cytokine-induced ERK phosphorylation. Further, NF-κB genomic iNos promoter binding was reduced by 50%, and NF-κB-dependent mRNA expression was blocked. These effects were associated with NF-κB subunit p65 hyperacetylation. Taken together, these data provide a rationale for clinical trials of safety and efficacy of KDACi in patients with autoimmune disease such as type 1 diabetes.
    Proceedings of the National Academy of Sciences 01/2014; · 9.81 Impact Factor
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    ABSTRACT: Apoptosis of pancreatic beta cells is a feature of type 2 diabetes and its prevention may have therapeutic benefit. High glucose concentrations induce apoptosis of islet cells, and this requires the proapoptotic Bcl-2 homology domain 3 (BH3)-only proteins Bim and Puma. We studied the stress pathways induced by glucotoxicity in beta cells that result in apoptosis. High concentrations of glucose or ribose increased expression of the transcription factor CHOP (C/EBP homologous protein) but not endoplasmic reticulum (ER) chaperones, indicating activation of proapoptotic ER stress signaling. Inhibition of ER stress prevented ribose-induced upregulation of Chop and Puma mRNA, and partially protected islets from glucotoxicity. Loss of Bim or Puma partially protected islets from the canonical ER stressor thapsigargin. The antioxidant N-acetyl-cysteine also partially protected islets from glucotoxicity. Islets deficient in both Bim and Puma, but not Bim or Puma alone, were significantly protected from killing induced by the mitochondrial reactive oxygen species donor rotenone. Our data demonstrate that high concentrations of glucose induce ER and oxidative stress, which causes cell death mediated by Bim and Puma. We observed significantly higher Bim and Puma mRNA in islets of human donors with type 2 diabetes. This indicates that inhibition of Bim and Puma, or their inducers, may prevent beta-cell destruction in type 2 diabetes.
    Cell Death & Disease 01/2014; 5:e1124. · 6.04 Impact Factor
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    ABSTRACT: Improvements in the clinical condition of patients with type 2 diabetes are often accompanied by improvements in health-related quality of life and other patient-reported outcomes (PROs), but data assessing injectable treatment initiation from the patient's perspective in routine clinical practice are lacking. We examined PROs in patients initiating injectable treatment in the CHOICE (CHanges to treatment and Outcomes in patients with type 2 diabetes initiating InjeCtablE therapy) study. CHOICE was a 24-month, prospective observational study conducted in six European countries. Patients initiated exenatide twice daily (BID) or insulin based on a physician's clinical judgement. Clinical and PRO data were collected at baseline (injectable therapy initiation) and after approximately 3, 6, 12, 18 and 24 months. The two treatment cohorts had different baseline characteristics; therefore, no statistical comparisons of endpoints between main cohorts were conducted. There were 2388 patients eligible for analysis (exenatide BID cohort, n = 1114; insulin cohort, n = 1274). Mean positive changes in Impact of Weight on Quality of Life-Lite (IWQOL-Lite) total score and EuroQoL5-Dimension (EQ-5D) index and visual analogue scale (VAS) scores were observed in both cohorts with most changes observed during the first 6 months after injectable therapy initiation. Patients who experienced weight loss (>=1 kg) at 24 months appeared to have higher mean improvements in IWQOL-Lite total score than did patients with weight gain or no weight change. Patients who met the composite clinical endpoint of glycated haemoglobin (HbA1c) <7.0%, no weight gain (<=1 kg) and no hypoglycaemia generally experienced higher mean improvements in EQ-5D index and VAS scores (compared with patients who did not meet this endpoint) and Diabetes Health Profile-18 scores (versus the main cohorts). High levels of missing data were observed for all PRO measures in both cohorts compared with those for clinical outcomes. These data from a clinical practice study support those from clinical trials, suggesting that PROs are not adversely affected, and may be improved, by injectable therapy initiation. PRO data may aid appropriate treatment selection for individual patients.Trial registration: ClinicalTrials.gov, NCT00635492.
    Health and Quality of Life Outcomes 12/2013; 11(1):217. · 2.27 Impact Factor
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    ABSTRACT: 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3), and its analogs (i.e. 14,20-bis-epi-19-nor-23-yne-1α,25(OH)2D3 - TX527) have been shown to prevent autoimmunity and prolong islet graft survival in the non-obese diabetic (NOD) mouse. Their effects are mediated by their action on various immune cell types, such as dendritic cells (DC) and T cells. We have previously reported important direct effects of TX527 on human T cells, on their cytokine/chemokine profiles, T regulatory cell markers, homing characteristics and chemotaxis. In order to fully understand the molecular mechanisms underlying the beneficial properties of TX527 on human T cells, we applied here 2-dimensional difference gel electrophoresis (2-D DIGE) to analyze the global protein alterations induced by TX527 on human synchronized T cells. We detected differential expression of 64 protein spots upon TX527 treatment, of which 65.6% could be successfully identified using tandem mass spectrometry (MALDI-TOF/TOF). The identified proteins function in various processes, such as metabolism and energy pathways, cytoskeleton and protein metabolism. When comparing the proteomics data to our previously performed microarray data on the same set of cells, we found an overlap of 17 different mRNAs/proteins. For some of these (e.g. PSME2, HSPA8), the direction of regulation was not similar, hereby reinforcing the important role of post-transcriptional/translational processes in the functionality of proteins. In addition, although 2-D DIGE offers the possibility of picking up post-translational processes, it lacks the ability to detect molecules with extreme molecular weight (MW) and isoelectrical point (pI) values, or very low abundant/hydrophobic proteins. This study highlights therefore the importance of combining different experimental approaches to obtain a complete picture of the underlying mechanisms and general processes being affected in T cells upon TX527 treatment. These processes lead altogether to the generation of T cells with interesting immunomodulatory features for clinical applications in the treatment of autoimmune diseases or in the prevention of graft rejection.
    The Journal of steroid biochemistry and molecular biology 10/2013; · 3.98 Impact Factor
  • Katrien Benhalima, Chantal Mathieu
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    ABSTRACT: To review recently published studies examining new data on screening strategies and diagnostic criteria for gestational diabetes (GDM). Professional organizations continue to have differing recommendations concerning the best screening strategy for GDM. An independent expert panel appointed by the National Institutes of Health has recently recommended to continue with the two-step approach for screening. Recent evidence shows that the glucose challenge test seems acceptable to screen for GDM but that an Hba1c measurement is not a good alternative. The International Association of Diabetes and Pregnancy Study Groups (IADPSG) screening strategy remains controversial with studies showing a high inconsistency in associations with adverse pregnancy outcome and cost-effectiveness analyses show conflicting results. To reduce the number of oral glucose tolerance tests needed, clinical prediction models may be implemented. It is now generally accepted that, especially in high-risk women, overt diabetes should be excluded at first prenatal visit. However, internationally the debate on the best screening strategy for GDM continues. In most populations the implementation of the IADPSG screening strategy will lead to an important increase in the prevalence of GDM and associated costs and workload. Risk stratification in IADPSG-positive women may reduce over-treatment. Using clinical prediction models may be a more cost-effective alternative.
    Current opinion in obstetrics & gynecology 10/2013; · 2.49 Impact Factor
  • Canadian Journal of Diabetes 10/2013; 37S4:S54-S55. · 0.46 Impact Factor
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    ABSTRACT: Insulin degludec (IDeg) is a new basal insulin with an ultra-long and stable glucose-lowering effect. We compared once-daily IDeg and insulin glargine (IGlar), both in combination with metformin ± dipeptidyl peptidase-4 inhibitors, in a 52-week, open-label, treat-to-target trial in patients with type 2 diabetes followed by a 52-week extension trial in which subjects (n = 725/1030 [70.4%]) maintained their initial randomized treatment. Health status was assessed at baseline and 105 weeks using the Short Form 36 (SF-36 v2) questionnaire. SF-36 scores were analyzed (ITT population) using ANOVA, with adjustments for covariates. At 105 weeks, the overall physical component score was significantly better with IDeg versus IGlar (treatment contrast (TC): 1.1 [0.1; 2.1]95% CI , p < 0.05). This was largely due to significantly better physical functioning (TC: 1.1 [0.0; 2.3]95% CI , p < 0.05) and bodily pain sub-domain scores (TC: 1.5 [0.2; 2.9]95% CI , p < 0.05). Improvements in health status with IDeg compared to IGlar were maintained after 2 years.
    Canadian Journal of Diabetes 10/2013; 37S4:S54. · 0.46 Impact Factor
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    ABSTRACT: C-peptide secretion is currently the only available clinical biomarker to measure residual β-cell function in type 1 diabetes. However, the natural history of C-peptide decline after diagnosis can vary considerably dependent upon several variables. We investigated the shape of C-peptide decline over time from type 1 diabetes onset in relation to age at diagnosis, HbA1c levels and insulin dose. We analysed data from 3,929 type 1 diabetes patients recruited from 7 European centres representing all age groups at disease onset (childhood, adolescence, adulthood). The influence of the age at onset on β-cell function was investigated in a longitudinal analysis at diagnosis and up to 5-years follow-up. Fasting C-peptide data at diagnosis were available in 3,668 patients stratified according to age at diagnosis in four groups (<5 yrs, n=344; >5 yrs< 10 yrs, n=668; >10 yrs<18yrs, n=991; >18 yrs, n=1655). Fasting C-peptide levels were positively correlated with age (p<0.001); the subsequent decline in fasting C-peptide over time was log-linear with a greater decline rate in younger age groups (p<0.0001). This study reveals a positive correlation between age at diagnosis of type 1 diabetes and fasting C-peptide with a more rapid decline of β-cell function in the very young patients. These data can inform the design of clinical trials using C-peptide values as an end-point for the effect of a given treatment.
    Diabetes Obesity and Metabolism 10/2013; · 5.18 Impact Factor
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    ABSTRACT: CHOICE (CHanges to treatment and Outcomes in patients with type 2 diabetes initiating InjeCtablE therapy; NCT00635492) assessed, as its primary objective, the time to a 'significant treatment change' (defined within this paper) after patients with type 2 diabetes mellitus initiated their first injectable, glucose-lowering therapy [exenatide twice daily (BID) or insulin] in clinical practice in six European countries and evaluated outcomes during the study. CHOICE was a 24-month, prospective, noninterventional observational study. Patients were invited to participate in CHOICE only after their treating physician had made the clinical decision to initiate first injectable therapy with either exenatide BID or insulin. Clinical data were collected at initiation of first injectable therapy and after approximately 3, 6, 12, 18, and 24 months. A total of 2,515 patients were recruited; 1,114 patients in the exenatide BID cohort and 1,274 patients in the insulin cohort were eligible for the 24-month analysis. During the study, 42.2% and 36.0% of patients from each cohort, respectively, had a significant treatment change. By 24 months, improved mean glycated hemoglobin (p < 0.001 for both cohorts) and reduced severity of several cardiovascular risk factors were observed in both cohorts; additionally, mean weight was reduced in the exenatide BID cohort (p < 0.001) and increased in the insulin cohort (p < 0.001). Hypoglycemia was reported by 18.4% of the exenatide BID cohort and 36.8% of the insulin cohort; 25.9% of the exenatide BID cohort and 10.0% of the insulin cohort had met the secondary endpoint of glycated hemoglobin <7.0%, no weight gain, and no hypoglycemia. CHOICE provided data on exenatide BID and insulin usage patterns and 24-month outcomes in clinical practice. On average, improved glycemic control and reduced severity of cardiovascular risk factors were observed in both cohorts, and those in the exenatide BID cohort also had mean weight loss.
    Diabetes therapy : research, treatment and education of diabetes and related disorders. 09/2013;
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    ABSTRACT: Glucagon-like peptide-1 (GLP-1) is one of the hormones responsible for the incretin effect, a term that refers to the observation that orally administered glucose results in a larger increase in plasma insulin levels and insulin-dependent decrease in blood glucose concentration when compared to the same amount of glucose given intravenously. GLP-1 is secreted mainly by gut endocrine L-cells and is released under the control of carbohydrates, proteins and lipids. Upon secretion, GLP-1 targets different cell types and exerts a wide variety of actions such as potentiation of glucose-stimulated insulin secretion, reduction of appetite, delay of gastric emptying and increase in β-cell mass. These beneficial effects have resulted in the application of GLP-1-based therapies in patients with type 2 diabetes, but also exploitation of its effects in type 1 diabetes is being envisaged. In this review, we focus on the different, short- and long-term action mechanisms of GLP-1 with specific emphasis on its role as a modulator of β-cell function and survival.
    Diabetes Obesity and Metabolism 09/2013; 15(s3). · 5.18 Impact Factor
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    ABSTRACT: Real-life studies are needed to confirm the clinical relevance of findings from randomised controlled trials (RCTs). This study aimed to assess the effectiveness and tolerability of vildagliptin add-on vs. other oral antihyperglycaemic drugs (OADs) added to OAD monotherapy in a real-life setting, and to explore the advantages and limitations of large-scale 'pragmatic' trials. EDGE was a prospective, 1-year, worldwide, real-life observational study in which 2957 physicians reported on the effects of second-line OADs in 45,868 patients with T2DM not reaching glycaemic targets with monotherapy. Physicians could add any OAD, and patients entered either vildagliptin or (pooled) comparator cohort. The primary effectiveness and tolerability end-point (PEP) evaluated proportions of patients decreasing HbA1c > 0.3%, without hypoglycaemia, weight gain, peripheral oedema or gastrointestinal side effects. The most clinically relevant secondary end-point (SEP 3) was attainment of end-point HbA1c < 7% without hypoglycaemia or ≥ 3% increase in body weight. In this large group of T2DM patients, a second OAD was added at mean HbA1c of 8.2 ± 1.3%, with no baseline HbA1c difference between cohorts. Second-line OAD therapy attained the PEP in the majority of patients, with higher attainment in those prescribed a vildagliptin-based regimen. The adjusted odds ratio was 1.49 (95% CI: 1.42, 1.55; p < 0.001). In patients with baseline HbA1c ≥ 7%, SEP 3 was achieved by 35% of patients on a vildagliptin-based combination and by 23% of those receiving comparator combinations. The adjusted odds ratio was 1.96 (95% CI: 1.85, 2.07; p < 0.001). Safety events were reported infrequently and safety profiles of vildagliptin and other OADs were consistent with previous data. EDGE demonstrates that in a 'real-life' setting, vildagliptin as second OAD can lower HbA1c to target without well-recognised OAD side effects, more frequently than comparator OADs. In addition, EDGE illustrates that conducting large-scale, prospective, real-life studies poses challenges but yields valuable clinical information complementary to RCTs.
    International Journal of Clinical Practice 08/2013; · 2.43 Impact Factor
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    ABSTRACT: The aim of this study was to compare long-term safety and efficacy of the basal insulin analogue degludec with glargine in insulin-naive subjects with Type 2 diabetes. This open-label trial included a 52-week core period followed by a 52-week extension. Participants were randomized 3:1 to once-daily degludec or glargine, administered with metformin ± dipeptidyl peptidase-4 inhibitors. Basal insulin was titrated to target pre-breakfast plasma glucose 3.9-4.9 mmol/l. At end of treatment (104 weeks), mean HbA1c reductions were similar for degludec and glargine; estimated treatment difference between degludec and glargine was 1 mmol/mol (95% CI -1 to 3) [0.07% (95% CI -0.07 to 0.22)], P = 0.339 in the extension trial set (degludec 551, glargine 174), comprising subjects who completed core trial and continued into the extension trial. Overall confirmed hypoglycaemia rates (1.72 vs. 2.05 episodes/patient-year), rates of adverse events possibly or probably related to trial product (0.19 events/patient-year), weight gain (2.7 vs. 2.4 kg) and mean daily insulin doses (0.63 U/kg) were similar between treatments in the safety analysis set (degludec 766, glargine 257) comprising all treated subjects. Rates of nocturnal confirmed hypoglycaemia (0.27 vs. 0.46 episodes/patient-year; P = 0.002) and severe hypoglycaemia (0.006 vs. 0.021 episodes/patient-year, P = 0.023) were significantly lower with degludec for the safety analysis set (analysis based on intention-to-treat full analysis set comprising all randomized subjects). In Type 2 diabetes, insulin degludec in combination with oral anti-diabetic drugs, safely and effectively improves long-term glycaemic control, with a significantly lower risk of nocturnal hypoglycaemia as compared with glargine. This article is protected by copyright. All rights reserved.
    Diabetic Medicine 08/2013; · 3.24 Impact Factor
  • J Cuypers, C Mathieu, K Benhalima
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    ABSTRACT: Treatment of type 2 diabetes (T2DM) continues to present challenges, with significant proportion of patients failing to achieve and maintain glycemic targets. Despite the availability of many oral antidiabetic agents, therapeutic efficacy is offset by side effects such as weight gain and hypoglycemia. Therefore, the search for novel therapeutic agents with an improved benefit-risk profile continues. Recent research has focused on the kidney as a potential therapeutic target, especially because maximal renal glucose reabsorption is increased in T2DM. Under normal physiological conditions, nearly all filtered glucose is reabsorbed in the proximal tubule of the nephron, principally via the sodium-glucose cotransporter 2 (SGLT2). SGLT2-inhibitors are a new class of oral antidiabetics, which reduce hyperglycemia by increasing urinary glucose excretion independently of insulin secretion or action. Clinical results are promising with significant lowering of HbA1c without increased risk of hypoglycemia, reduction of body weight and reduction of systolic blood pressure. Dapagliflozin is the first highly selective SGLT2-inhibitor approved by the European Medecine Agency. Canagliflozin and empagliflozin are undergoing phase III trials. Actual safety issues are an increased risk for genital- and urinary tract infections and a possible increased risk for bladder and breast cancer. This led to refusal of dapagliflozin by the Food and Drug Administration (FDA). A large randomized control trial is therefore warranted by the FDA. This review provides an overview of the current evidence available so far on the therapeutic potential of the SGLT2-inhibitors for the treatment of T2DM.
    Acta clinica Belgica 07/2013; 68(4):287-93. · 0.59 Impact Factor
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    ABSTRACT: 1Alpha,25-dihydroxyvitamin D3 [1,25(OH)2D3], the biologically active form of vitamin D3, is a pleiotropic hormone that exerts its effects on a wide range of tissues, resulting in different biological responses such as anticancer activity. It is the ligand of the vitamin D receptor (VDR), a nuclear receptor with transactivating capacity. We demonstrated in this study that 1,25(OH)2D3 induces PDZ-LIM domain-containing protein 2 (PDLIM2) expression. PDLIM2 is an adaptor molecule that links different components of the cytoskeleton, and was recently shown to be repressed in human breast cancer cells by hypermethylation of regulatory promoter regions, leading to enhanced tumorigenicity. We demonstrated that PDLIM2 was a direct target gene of 1,25(OH)2D3; its upregulation was VDR-dependent and a functional VDRE in the promoter was identified. Moreover, 1,25(OH)2D3 induced demethylation of the PDLIM2 promoter, leading to enhanced transcription. Finally, PDLIM2 was found to be crucial for 1,25(OH)2D3-induced cell adhesion and for mediating the ability of 1,25(OH)2D3 to suppress cancer cell migration and invasion. This study provides mechanistic insights into the anticancer activities of 1,25(OH)2D3 in human breast cancer cells.Oncogene advance online publication, 15 April 2013; doi:10.1038/onc.2013.123.
    Oncogene 04/2013; · 8.56 Impact Factor
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    ABSTRACT: BACKGROUND: Evidence on the influence of comorbidity and comedication on clinical outcomes in patients with type 2 diabetes mellitus is scarce. AIM: To ascertain the effect of five chronic diseases (joint disorder, respiratory disease, anaemia, malignancy, depression) and three chronically used drugs (non-steroid anti-inflammatory drugs [NSAIDs], corticosteroids, antidepressants) on treatment for hypoglycaemia in patients with type 2 diabetes. DESIGN AND SETTING: Retrospective cohort study in a variety of practices across Flanders, Belgium. METHOD: A retrospective cohort study was conducted, based on data from Intego, a general practice-based continuous morbidity registry. Multiple logistic regression analysis was used to predict the change in glycosylated haemoglobin (HbA1c) levels related to comorbidity, comedication, and a combination of both in 3416 patients with type 2 diabetes. Adjustments were made for age, sex, and diabetes-treatment group (diet, oral antidiabetic drugs, combination treatment,
    Br.J Gen Pract. 04/2013; 63(609):267-273.
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    ABSTRACT: Evidence on the influence of comorbidity and comedication on clinical outcomes in patients with type 2 diabetes mellitus is scarce. To ascertain the effect of five chronic diseases (joint disorder, respiratory disease, anaemia, malignancy, depression) and three chronically used drugs (non-steroid anti-inflammatory drugs [NSAIDs], corticosteroids, antidepressants) on treatment for hypoglycaemia in patients with type 2 diabetes. Retrospective cohort study in a variety of practices across Flanders, Belgium. A retrospective cohort study was conducted, based on data from Intego, a general practice-based continuous morbidity registry. Multiple logistic regression analysis was used to predict the change in glycosylated haemoglobin (HbA1c) levels related to comorbidity, comedication, and a combination of both in 3416 patients with type 2 diabetes. Adjustments were made for age, sex, and diabetes-treatment group (diet, oral antidiabetic drugs, combination treatment, insulin). Concomitant joint and respiratory disorders, as well as the chronic use of NSAIDs and corticosteroids, either separately or in combination, were significantly associated with the worsening of HbA1c levels. Anaemia, depression, malignancy, and antidepressants had no statistically significant influence on the efficacy of treatment for hypoglycaemia. The presence of some comorbid diseases or drug use can impede the efficacy of treatment for type 2 diabetes. This finding supports the need to develop treatment recommendations, taking into account the presence of both chronic comorbidity and comedication. Further research must be undertaken to ascertain the effect other combinations of chronic diseases have on the efficacy of treatment of this and other diseases.
    British Journal of General Practice 04/2013; 63(609):267-73. · 2.03 Impact Factor
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    Primary Care Diabetes. 04/2013; 7(1):75.

Publication Stats

4k Citations
655.73 Total Impact Points

Institutions

  • 1992–2014
    • University of Leuven
      • • Laboratory for Experimental Medicine and Endocrinology (LEGENDO)
      • • Academic Centre of General Practice
      • • Department of Cellular and Molecular Medicine
      • • Research unit for Experimental Psychology
      Louvain, Flanders, Belgium
  • 2013
    • Belgian Scientific Institute for Public Health
      Bruxelles, Brussels Capital Region, Belgium
    • Karolinska Institutet
      • Department of Molecular Medicine and Surgery
      Stockholm, Stockholm, Sweden
  • 1995–2013
    • Universitair Ziekenhuis Leuven
      • • Department of Endocrinology
      • • Department of Pathology
      Leuven, VLG, Belgium
  • 2012
    • University of Southern Denmark
      • Institute of Clinical Research
      Odense, South Denmark, Denmark
  • 2011–2012
    • Samuel Lunenfeld Research Institute
      Toronto, Ontario, Canada
  • 2003–2011
    • Université Libre de Bruxelles
      • Laboratory of Experimental Medicine (LABOMEDEX)
      Brussels, BRU, Belgium
  • 2001–2009
    • Vrije Universiteit Brussel
      Bruxelles, Brussels Capital Region, Belgium
  • 2005–2008
    • University of Illinois at Chicago
      • Department of Dermatology (Chicago)
      Chicago, IL, United States
  • 2001–2008
    • The Catholic University of America
      Washington, Washington, D.C., United States
  • 1993–1997
    • University of Greifswald
      • Institute of Pathophysiology
      Greifswald, Mecklenburg-Vorpommern, Germany