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See detailLa maladie renale diabetique: prise en charge actuelle et perspectives d'avenir.
Krzesinski, Jean-Marie ULg; Scheen, Andre ULg

in Revue medicale suisse (2015), 11(483), 1534-81540-2

The diabetic kidney disease is the most frequent cause of end stage renal disease in Western countries. Its detection is obtained by simultaneously measuring urinary albumin excretion and estimating ... [more ▼]

The diabetic kidney disease is the most frequent cause of end stage renal disease in Western countries. Its detection is obtained by simultaneously measuring urinary albumin excretion and estimating glomerular filtration rate through serum creatinine dosage. Many type 1 and type 2 diabetic patients can present decreased glomerular filtration rate before the occurrence of increased urinary albumin. While waiting for promising new pharmacological approaches currently evaluated in clinical trials, the best approach to stop the epidemic of diabetic nephropathy remains an early and individual multifactorial approach controlling the glucose level (without inducing hypoglycaemia), blood pressure (using a renin-angiotensin blocker), dyslipidaemia and over-weight. [less ▲]

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See detailGliptines, securite cardio-vasculaire et insuffisance cardiaque: le point apres l'etude TECOS.
Scheen, Andre ULg

in Revue medicale suisse (2015), 11(483), 1526-31

The cardiovascular safety of dipeptidyl peptidase-4 inhibitors (gliptins) has been well studied. Favourable effects of these oral antidiabetic agents have been reported in meta-analyses of phase II-III ... [more ▼]

The cardiovascular safety of dipeptidyl peptidase-4 inhibitors (gliptins) has been well studied. Favourable effects of these oral antidiabetic agents have been reported in meta-analyses of phase II-III randomised controlled trials. Three large prospective trials, which were specifically designed to investigate cardiovascular safety, showed non-inferiority of saxagliptin (SAVOR-TIMI 53), alogliptin (EXA-MINE) and sitagliptin (TECOS) versus placebo as far as major cardiovascular events are concerned, including mortality. The suspected increase in the rate of hospitalisation due to congestive heart failure reported in SAVOR-TIMI 53 was neither found in EXAMINE nor recently confirmed in TECOS. Direct comparative trials, evaluating not only safety but also efficacy, with other oral antidiabetic medications would be of major interest. [less ▲]

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See detailForces et faiblesse des essais cliniques . Evolution en fonction de l'essor de la medecine personnalisee.
Ernest, Ph; Jandrain, B.; Scheen, Andre ULg

in Revue medicale de Liege (2015), 70(5-6), 232-6

Randomised Controlled Trials (RCTs) represent the cornerstone of Evidence-Based Medicine (EBM). Based upon the rules of Good Clinical Practice (GCP), they offer many strengths but also present some ... [more ▼]

Randomised Controlled Trials (RCTs) represent the cornerstone of Evidence-Based Medicine (EBM). Based upon the rules of Good Clinical Practice (GCP), they offer many strengths but also present some weaknesses. The rigorous methodology used allows avoid bias related to confounding factors (through a control group), selection bias (through randomisation) and interpretation bias (through double blinding). However, patients recruited in clinical trials and study experimental conditions markedly differ from the situation in real life. Furthermore, clinical trials recruit a mix of good and poor responders, so that the average therapeutic response is most often mitigated. Clinical trials must evolve according to the new concepts of personalized medicine to become even more performing. In a near future, they must progress from a statistical analysis on large cohorts of patients to a more individualized analysis guided by patient phenotype and genotype characteristics. [less ▲]

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See detailApproche personnalisée du traitement des dyslipidémies
Scheen, Andre ULg; Descamps, O

in Revue medicale de Liege (2015), 70(5-6), 292-8

Individualized therapeutic strategy of dyslipidemias, classically relies upon a phenotypic approach. The pattern of lipid profile allows the choice of the best pharmacological option (statin, fibrate) and ... [more ▼]

Individualized therapeutic strategy of dyslipidemias, classically relies upon a phenotypic approach. The pattern of lipid profile allows the choice of the best pharmacological option (statin, fibrate) and the patient's clinical risk profile allows the definition of therapeutic goals, especially LDL cholesterol target levels. Dyslipidemias have a major genetic component, which is best illustrated by familial hypercholesterolemia, with its two heterozygous and homozygous forms. There is a huge between-subject variability in the response to lipid-lowering therapies (especially to statins) and ongoing pharmacogenetic and pharmacogenomic studies should help to better understand this inter-individual heterogeneity. The recent discovery of mutations in the PCSK9 rene opened new perspectives regarding the understanding of some forms of familial hypercholesterolemia and led to the development of monoclonal antibodies that selectively inhibit PCSK9. These PCSK9 inhibitors allow, when combined to a statin, drastic reductions in LDL cholesterol concentrations, even when familial hypercholesterolemia is present. They are currently tested in large prospective controlled trials aiming to demonstrate a significant reduction in the residual cardiovascular risk in statin-treated patients. [less ▲]

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See detail"Omics" et "big data", avancees majeures vers une medecine personnalisee du futur ?
Scheen, Andre ULg

in Revue medicale de Liege (2015), 70(5-6), 262-8

The increasing interest for personalized medicine evolves together with two major technological advances. First, the new-generation, rapid and less expensive, DNA sequencing method, combined with ... [more ▼]

The increasing interest for personalized medicine evolves together with two major technological advances. First, the new-generation, rapid and less expensive, DNA sequencing method, combined with remarkable progresses in molecular biology leading to the post-genomic era (transcriptomics, proteomics, metabolomics). Second, the refinement of computing tools (IT), which allows the immediate analysis of a huge amount of data (especially, those resulting from the omics approaches) and, thus, creates a new universe for medical research, that of <<big data>> analyzed by computerized modelling. This article for scientific communication and popularization briefly describes the main advances in these two fields of interest. These technological progresses are combined with those occurring in communication, which makes possible the development of artificial intelligence. These major advances will most probably represent the grounds of the future personalized medicine. [less ▲]

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See detailMédecine personalisée: nouveaux defis pour le praticien.
Scheen, Andre ULg

in Revue medicale de Liege (2015), 70(5-6), 242-6

The clinician has to cope with new advances in medicine. Traditional medicine, which is based upon pathophysiological reasoning and clinical experience, has been reinforced by evidence-based medicine ... [more ▼]

The clinician has to cope with new advances in medicine. Traditional medicine, which is based upon pathophysiological reasoning and clinical experience, has been reinforced by evidence-based medicine, which relies on levels of evidence provided by controlled clinical trials carried out on cohorts of patients. Since a few years, personalized medicine has been put at the forefront. A therapy tailored to every patient, if possible characterized by biomarkers, among which, since the achievement of the whole human genome sequencing, an increasing number of genetic markers. Personalized medicine should be used as a complement of traditional and evidence-based medicine. Physicians should progressively integrate this new strategy in their therapeutic approach. Hence, clinicians have to face new challenges as far as scientific knowledge, practical applications and physician-patient relationship are concerned. [less ▲]

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See detailDiabètes iatrogènes : importance d’une analyse critique du rapport bénéfices/risques des traitements en cause
SCHEEN, André ULg

in Médecine des Maladies Métaboliques (2015), 9(3), 1-3

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See detailMédecine personalisée: tout bénéfice pour le patient, mais nouveau challenge pour la relation médecin-malade.
Scheen, Andre ULg; Giet, Didier ULg

in Revue medicale de Liege (2015), 70(5-6), 247-50

Personalized medicine should lead to major advances for patient care since it contributes to deliver the <<right drug to the right patient>>. In curative medicine, this approach should improve the ... [more ▼]

Personalized medicine should lead to major advances for patient care since it contributes to deliver the <<right drug to the right patient>>. In curative medicine, this approach should improve the efficacy of medications by initial selection of "good responders", and should reduce adverse events due to poor tolerance or toxicity by a better pharmacological choice and a more appropriate individualized dose adjustment. Over recent years, considerable technical advances have increasingly linked personalized medicine with predictive and preventive medicine. This progress raises hopes for major advancements in medicine, but may also cause some concern among the lay public. The patient should actively be involved in the decisions related to his/her health, in a true model of participatory medicine. Finally, personalized medicine should leave its strict technical nature and become more interested in the person as a whole, within a holistic approach also integrating psychosocial aspects that are so important in the physician-patient relationship. [less ▲]

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See detailUn nouveau florilege estival de cas cliniques.
Scheen, Andre ULg

in Revue Médicale de Liège (2015), 70(7-8), 349-50

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See detailL'industrie pharmaceutique face à la médecine personalisée: changement de paradigme dans le développement des nouveaux medicaments.
Scheen, Andre ULg

in Revue medicale de Liege (2015), 70(5-6), 237-41

The cost of pharmacotherapy is increasing in the health care budget. The pharmaceutical industry is facing the exhaustion of medications that are largely prescribed and have a high profitability ... [more ▼]

The cost of pharmacotherapy is increasing in the health care budget. The pharmaceutical industry is facing the exhaustion of medications that are largely prescribed and have a high profitability (blockbusters). Because of patient heterogeneity, there is a great interindividual variability of the responses to drug therapy. Thus, it is essential to better detect potential <<good responders>> to avoid waste of resources resulting from the prescription of expensive drugs to poor responders. The development of personalized medicine, or precision medicine, certainly offers opportunities to the pharmaceutical industry, but also exposes it to new big challenges. [less ▲]

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See detailMedecine conventionnelle, medecine factuelle, medecine personnalisee: trois approches complementaires.
Scheen, Andre ULg

in Revue medicale de Liege (2015), 70(5-6), 221-4

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See detailCardiovascular safety of albiglutide and other glucagon-like peptide-1 receptor agonists.
Scheen, Andre ULg

in The lancet. Diabetes & endocrinology (2015), 3(9), 667-9

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See detailPharmacokinetics, Pharmacodynamics and Clinical Use of SGLT2 Inhibitors in Patients with Type 2 Diabetes Mellitus and Chronic Kidney Disease.
Scheen, André ULg

in Clinical pharmacokinetics (2015), 54

Inhibitors of sodium-glucose cotransporters type 2 (SGLT2) are proposed as a novel approach for the management of type 2 diabetes mellitus. SGLT2 cotransporters are responsible for reabsorption of 90 % of ... [more ▼]

Inhibitors of sodium-glucose cotransporters type 2 (SGLT2) are proposed as a novel approach for the management of type 2 diabetes mellitus. SGLT2 cotransporters are responsible for reabsorption of 90 % of the glucose filtered by the kidney. The glucuretic effect resulting from SGLT2 inhibition contributes to reduce hyperglycaemia and also assists weight loss and blood pressure reduction. Several SGLT2 inhibitors are already available in many countries (dapagliflozin, canagliflozin, empagliflozin) and in Japan (ipragliflozin, tofogliflozin). These SGLT2 inhibitors share similar pharmacokinetic characteristics with a rapid oral absorption, a long elimination half-life allowing once-daily administration, an extensive hepatic metabolism mainly via glucuronidation to inactive metabolites and a low renal elimination as a parent drug. Pharmacokinetic parameters are slightly altered in the case of chronic kidney disease (CKD). While no dose adjustment is required in the case of mild CKD, SGLT2 inhibitors may not be used or only at a lower daily dose in patients with moderate CKD. Furthermore, the pharmacodynamic response to SGLT2 inhibitors as assessed by urinary glucose excretion declines with increasing severity of renal impairment as assessed by a reduction in the estimated glomerular filtration rate. Nevertheless, the glucose-lowering efficacy and safety of SGLT2 inhibitors are almost comparable in patients with mild CKD as in patients with normal kidney function. In patients with moderate CKD, the efficacy tends to be dampened and safety concerns may occur. In patients with severe CKD, the use of SGLT2 inhibitors is contraindicated. Thus, prescribing information should be consulted regarding dosage adjustments or restrictions in the case of renal dysfunction for each SGLT2 inhibitor. The clinical impact of SGLT2 inhibitors on renal function and their potential to influence the course of diabetic nephropathy deserve attention because of preliminary favourable results in animal models. [less ▲]

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See detailTowards a genotype-based approach for a patient-centered pharmacologic therapy of type 2 diabetes.
Scheen, André ULg

in Annals of translational medicine (2015), 3(Suppl 1), 36

The recent data reported by Tang and colleagues in Science Translational Medicine suggest that alpha-2 adrenoceptors (alpha2AAR) genetic heterogeneity may explain diverging results regarding the effects ... [more ▼]

The recent data reported by Tang and colleagues in Science Translational Medicine suggest that alpha-2 adrenoceptors (alpha2AAR) genetic heterogeneity may explain diverging results regarding the effects of alpha2AAR antagonists on insulin secretion and glucose control in patients with type 2 diabetes. They first confirmed that the risk variant for rs553668 (the A allele for a single-nucleotide polymorphism in ADRA2A) is likely to cause defective insulin secretion in human pancreatic islets. Second they showed that blocking alpha2AAR with yohimbine dose-dependently improves the reduced insulin secretion during an oral glucose tolerance test in patients with the risk variant. The successful translation of genomic information into clinical intervention in patients with type 2 diabetes provides proof of concept for the feasibility of individualized treatment based on genotype. [less ▲]

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See detailLe medicament du mois. L'albiglutide (Eperzan): nouvel agoniste des recepteurs du glucagon-like peptide-1 en injection hebdomadaire.
Scheen, André ULg

in Revue medicale de Liege (2015), 70(4), 207-14

Albiglutide (Eperzan) is a new once-weekly agonist of Glucagon-Like Peptide-1 (GLP-1) receptors that is indicated in the treatment of type 2 diabetes. Two doses are available, 30 mg and 50 mg, to be ... [more ▼]

Albiglutide (Eperzan) is a new once-weekly agonist of Glucagon-Like Peptide-1 (GLP-1) receptors that is indicated in the treatment of type 2 diabetes. Two doses are available, 30 mg and 50 mg, to be injected subcutaneously once a week. It has been extensively evaluated in the HARMONY programme of eight large randomised controlled trials that were performed at different stages of type 2 diabetes, in comparison with placebo or an active comparator. The endocrine and metabolic effects of albiglutide are similar to those of other GLP-1 receptor agonists: stimulation of insulin secretion (incretin effect) and inhibition of glucagon secretion, both in a glucose-dependent manner, retardation of gastric emptying and increase of satiety. These effects lead to a reduction in glycated haemoglobin (HbA(1c)) levels, combined with a weight reduction. The overall tolerance profile is good. Albiglutide is currently reimbursed in Belgium after failure (HbA(1c) > 7.5%) of and in combination with a dual therapy with metformin and a sulfonylurea as well as in combination with a basal insulin (with or without oral antidiabetic drugs). To avoid hypoglycaemia, a reduction in the dose of sulfonylurea or insulin may be recommended. A once-weekly administration should increase patient's acceptance of injectable therapy and improve compliance. [less ▲]

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See detailIndividualizing treatment of type 2 diabetes by targeting postprandial or fasting hyperglycaemia: Response to a basal vs a premixed insulin regimen by HbA quartiles and ethnicity.
Scheen, André ULg; Schmitt, H.; Jiang, H. H. et al

in Diabetes & metabolism (2015), 41(3), 216-222

AIM: This study evaluated the proportions of prandial (PHG) vs fasting hyperglycaemia (FHG) over 24h in a group of patients with type 2 diabetes (overall and for Caucasian vs Asian patients), and tested ... [more ▼]

AIM: This study evaluated the proportions of prandial (PHG) vs fasting hyperglycaemia (FHG) over 24h in a group of patients with type 2 diabetes (overall and for Caucasian vs Asian patients), and tested the hypothesis that an insulin regimen with a prandial component allows a greater response than basal insulin at low glycated haemoglobin (HbA1c) levels with a higher proportion of PHG than FHG. METHODS: Relative contributions of PHG and FHG to overall hyperglycaemia were analyzed by baseline HbA1c quartiles and by ethnicity at baseline and after 24-week treatment with either insulin glargine or insulin lispro mix 25 in the DURABLE study. RESULTS: With increasing baseline HbA1c, the mean relative contribution of PHG to the total area under the curve decreased (from 41% to 27%) while FHG was increased (from 59% to 73%). Both insulins decreased FHG, but only insulin lispro mix 25 decreased PHG. More patients with baseline HbA1c<9%, where PHG was more relevant, achieved the target HbA1c of<7% at endpoint with insulin lispro mix 25 compared with glargine. On average, Asians had a 10% larger contribution of PHG at all HbA1c quartiles, and a lower proportion of Asians reached the HbA1c target of<7% with either insulin treatment compared with Caucasians. CONCLUSION: At baseline, the contribution of FHG to overall hyperglycaemia predominated at all HbA1c quartiles, whereas PHG was more clinically relevant at lower HbA1c levels and with a greater response to insulin lispro mix 25. Asians had a greater proportion of PHG and a lesser response to either insulins compared with Caucasians. Thus, responses to diabetes drugs by baseline HbA1c and ethnicity are worth investigating to better target and individualize treatment. [less ▲]

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See detailInhibiting or Antagonizing Glucagon: A Progress in Diabetes Care ?
LEFEBVRE, Pierre ULg; Paquot, Nicolas ULg; Scheen, André ULg

in Diabetes, obesity & metabolism (2015)

Absolute or relative hyperglucagonemia has been recognized for years in all experimental or clinical forms of diabetes. It has been suggested that excess secretion of glucagon by the islet alpha-cells is ... [more ▼]

Absolute or relative hyperglucagonemia has been recognized for years in all experimental or clinical forms of diabetes. It has been suggested that excess secretion of glucagon by the islet alpha-cells is a direct consequence of intra-islet insulin secretory defects. Recent studies have demonstrated that knock-out of the glucagon receptor or administration of a monoclonal specific glucagon receptor antibody make insulin deficient type 1 diabetic rodents thrive without insulin. These observations suggest that glucagon plays an essential role in the pathophysiology of diabetes and that targeting the alpha-cell and glucagon are innovative approaches in the management of diabetes. Despite active research and identification of promising compounds, no one selective glucagon antagonist is presently used in the treatment of diabetes. Interestingly, besides insulin, several drugs used today in the management of diabetes appear to exert their effects in part by inhibiting glucagon secretion (GLP-1 receptor agonists, DPP-4 inhibitors, alpha glucosidase inhibitors and, maybe, sulfonylureas) or glucagon action (metformin). The potential risks associated with total glucagon suppression include alpha-cell hyperplasia, increased mass of the pancreas, increased susceptibility to hepatosteatosis and hepatocellular injury and increased risk of hypoglycaemia and should be considered in the search and development of new compounds reducing glucagon receptor signalling. In conclusion, more than 40 years after its initial description, the hyperglucagonemia of diabetes can no longer be ignored or minimized and its correction represents an attractive way for improving diabetes management. [less ▲]

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