References of "SCHEEN, André"
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See detailSGLT2 Inhibitors: Benefit/Risk Balance.
Scheen, André ULg

in Current Diabetes Reports (2016), 16(10), 92

Inhibitors of sodium-glucose cotransporters type 2 (SGLT2) reduce hyperglycemia by increasing urinary glucose excretion. They have been evaluated in patients with type 2 diabetes treated with diet ... [more ▼]

Inhibitors of sodium-glucose cotransporters type 2 (SGLT2) reduce hyperglycemia by increasing urinary glucose excretion. They have been evaluated in patients with type 2 diabetes treated with diet/exercise, metformin, dual oral therapy or insulin. Three agents are available in Europe and the USA (canagliflozin, dapagliflozin, empagliflozin) and others are commercialized in Japan or in clinical development. SGLT2 inhibitors reduce glycated hemoglobin, with a minimal risk of hypoglycemia. They exert favorable effects beyond glucose control with consistent body weight, blood pressure, and serum uric acid reductions. Empagliflozin showed remarkable reductions in cardiovascular/all-cause mortality and in hospitalization for heart failure in patients with previous cardiovascular disease. Positive renal outcomes were also shown with empagliflozin. Mostly reported adverse events are genital mycotic infections, while urinary tract infections and events linked to volume depletion are rather rare. Concern about a risk of ketoacidosis and bone fractures has been recently raised, which deserves caution and further evaluation. [less ▲]

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See detailPrecision medicine: The future in diabetes care?
Scheen, André ULg

in Diabetes Research & Clinical Practice (2016), 117

Personalized medicine aims at better targeting therapeutic intervention to the individual to maximize benefit and minimize harm. Type 2 diabetes (T2D) is a heterogeneous disease from a genetic ... [more ▼]

Personalized medicine aims at better targeting therapeutic intervention to the individual to maximize benefit and minimize harm. Type 2 diabetes (T2D) is a heterogeneous disease from a genetic, pathophysiological and clinical point of view. Thus, the response to any antidiabetic medication may considerably vary between individuals. Numerous glucose-lowering agents, with different mechanisms of action, have been developed, a diversified armamentarium that offers the possibility of a patient-centred therapeutic approach. In the current clinical practice, a personalized approach is only based upon phenotype, taking into account patient and disease individual characteristics. If this approach may help increase both efficacy and safety outcomes, there remains considerable room for improvement. In recent years, many efforts were taken to identify genetic and genotype SNP's (Single Nucleotide Polymorphism's) variants that influence the pharmacokinetics, pharmacodynamics, and ultimately the therapeutic response of oral glucose-lowering drugs. This approach mainly concerns metformin, sulphonylureas, meglitinides and thiazolidinediones, with only scarce data concerning gliptins and gliflozins yet. However, the contribution of pharmacogenetics and pharmacogenomics to personalized therapy still needs to mature greatly before routine clinical implementation is possible. This review discusses both opportunities and challenges of precision medicine and how this new paradigm may lead to a better individualized treatment of T2D. [less ▲]

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See detailDiabetes: Time for reconciliation between cardiologists and diabetologists.
Scheen, André ULg

in Nature Reviews. Cardiology (2016)

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See detailDPP-4 inhibitor plus SGLT-2 inhibitor as combination therapy for type 2 diabetes: from rationale to clinical aspects.
Scheen, André ULg

in Expert Opinion on Drug Metabolism & Toxicology (2016)

INTRODUCTION: Type 2 diabetes (T2D) is a complex disease with multiple defects, which generally require a combination of several pharmacological approaches to control hyperglycemia. Combining a dipeptidyl ... [more ▼]

INTRODUCTION: Type 2 diabetes (T2D) is a complex disease with multiple defects, which generally require a combination of several pharmacological approaches to control hyperglycemia. Combining a dipeptidyl peptidase-4 inhibitor (DPP-4i) and a sodium-glucose cotransporter type 2 inhibitor (SGT2i) appears to be an attractive approach. AREA COVERED: An extensive literature search was performed to analyze the pharmacokinetics, pharmacodynamics and clinical experience of different gliptin-gliflozin combinations. EXPERT OPINION: There is a strong rationale for combining a DPP-4i and a SGLT2i in patients with T2D because the two drugs exert different and complementary glucose-lowering effects. Dual therapy (initial combination or stepwise approach) is more potent than either monotherapy in patients treated with diet and exercise or already treated with metformin. Combining the two pharmacological options is safe and does not induce hypoglycemia. The additional glucose-lowering effect is more marked when a gliflozin is added to a gliptin than when a gliptin is added to a gliflozin. Two fixed-dose combinations (FDCs) are already available (saxagliptin-dapagliflozin and linagliptin-empagliflozin) and others are in current development. Bioequivalence of the two compounds given as FDC tablets was demonstrated when compared with coadministration of the individual tablets. FDCs could simplify the anti-hyperglycaemic therapy and improve drug compliance. [less ▲]

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See detailAssessment of cardiovascular risk of new drugs for the treatment of diabetes mellitus: risk assessment vs. risk aversion.
Zannad, Faiez; Stough, Wendy Gattis; Lipicky, Raymond J. et al

in European heart journal. Cardiovascular pharmacotherapy (2016), 2(3), 200-205

The Food and Drug Administration issued guidance for evaluating the cardiovascular risk of new diabetes mellitus drugs in 2008. Accumulating evidence from several completed trials conducted within this ... [more ▼]

The Food and Drug Administration issued guidance for evaluating the cardiovascular risk of new diabetes mellitus drugs in 2008. Accumulating evidence from several completed trials conducted within this framework raises questions as to whether requiring safety outcome studies for all new diabetes mellitus therapies remains justified. Given the burden of cardiovascular disease in patients with diabetes, the focus should shift towards cardiovascular outcome studies designed to evaluate efficacy (i.e. to determine the efficacy of a drug over placebo or standard care) rather than demonstrating that risk is not increased by a pre-specified safety margin. All stakeholders are responsible for ensuring that new drug approvals occur under conditions of appropriate safety and effectiveness. It is also a shared responsibility to avoid unnecessary hurdles that may compromise access to useful drugs and threaten the sustainability of health systems. It is critical to renew this debate so that stakeholders can collectively determine the optimal approach for developing new drugs to treat type 2 diabetes mellitus. [less ▲]

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See detailLE MEDICAMENT DU MOIS. Le liraglutide a la dose de 3 mg (Saxenda): indication dans le traitement de l'obesite.
Scheen, André ULg

in Revue Médicale de Liège (2016), 71(5), 256-61

Liraglutide is an analogue of Glucagon-Like Peptide-1 (GLP-1) already indicated under the trade name of Victoza for the treatment of type 2 diabetes, at usual doses of 1.2 or 1.8 mg as once daily ... [more ▼]

Liraglutide is an analogue of Glucagon-Like Peptide-1 (GLP-1) already indicated under the trade name of Victoza for the treatment of type 2 diabetes, at usual doses of 1.2 or 1.8 mg as once daily subcutaneous injection. It is henceforth indicated at a dose of 3.0 mg, also as once daily subcutaneous injection, for the treatment of obesity or overweight with comorbidities under the trade name of Saxenda, in combination with diet and exercise. Besides a specific action on the endocrine pancreas, mainly responsible for the antihyperglycaemic effect, liraglutide helps controlling appetite at the hypothamalic level. A specific programme of controlled trials (especially SCALE studies) demonstrated both efficacy and safety of the 3.0 mg dose of liraglutide in obese or overweight patients with various comorbidities. [less ▲]

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See detailCombinaison fixe atorvastatine-ezetimibe (Atozet(R)).
Scheen, André ULg

in Revue medicale de Liege (2016), 71(1), 47-52

Cardiovascular prevention in subjects at high or very high risk requires a drastic reduction in LDL cholesterol according to the concept "the lower, the better". The combination of an inhibitor of ... [more ▼]

Cardiovascular prevention in subjects at high or very high risk requires a drastic reduction in LDL cholesterol according to the concept "the lower, the better". The combination of an inhibitor of cholesterol synthesis and a selective inhibitor of intestinal absorption results in a complementary and synergistic LDL-lowering activity. Besides a first fixed combination ezetimibe-simvastatin (Inegy(R)), a new fixed combination is presented, Atozet(R) that combines atorvastatin and ezetimibe. Because atorvastatin is more potent than simvastatin, this novel fixed combination should facilitate reaching therapeutic goals in terms of LDL cholesterol amongst patients with severe hypercholesterolaemia and/or at high or very high cardiovascular risk. [less ▲]

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See detailEffect of rifampin on the disposition of brivaracetam in human subjects: further insights into brivaracetam hydrolysis.
Stockis, Armel; Watanabe, Shikiko; Scheen, André ULg et al

in Drug metabolism and disposition: the biological fate of chemicals (2016), 44(6), 792-799

Brivaracetam (BRV) is a high-affinity synaptic vesicle protein 2A ligand developed for the treatment of uncontrolled partial-onset seizures. The present Phase I open-label two-way crossover study was ... [more ▼]

Brivaracetam (BRV) is a high-affinity synaptic vesicle protein 2A ligand developed for the treatment of uncontrolled partial-onset seizures. The present Phase I open-label two-way crossover study was designed to assess the effect of rifampin on the pharmacokinetics of BRV and its hydroxy (BRV-OH); acid (BRV-AC); and hydroxy acid (BRV OHAC) metabolites. Twenty-six healthy subjects received BRV 150mg single oral dose, either alone or following 5 days of rifampin 600 mg/day. BRV and its metabolites were examined for their plasma profiles and urinary excretion. Pharmacokinetic modeling was developed to estimate the rate constants of the various metabolic routes. Parallel in vitro assays were conducted to characterize the hydrolysis of BRV to BRV-AC as well as to identify any potential effect of rifampin on the hydrolysis reaction. Rifampin did not significantly affect the maximum plasma concentration (Cmax) of BRV but decreased its area under the curve (AUC) by 45%. In addition, rifampin significantly increased the AUC of BRV-OH (+109%), decreased the AUC of BRV-AC (-53%), but had little effect on BRV-OHAC (-10%). In vitro assays showed that the major urinary metabolite BRV-AC (33% of the dose) was likely to be formed by amidase EC 3.5.1.4. In vitro data indicated that the enzyme was not significantly inhibited nor induced by rifampin. Modeling confirmed that all the observed changes in vivo were secondary to the induction of the CYP2C19-mediated hydroxylation of BRV to BRV-OH (3.7-fold increase in the rate constant). [less ▲]

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See detailReduction in cardiovascular and all-cause mortality in the EMPA-REG OUTCOME trial: A critical analysis.
SCHEEN, André ULg

in Diabetes & metabolism (2016), 42(2), 71-6

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See detailCreatinine-based equations for the adjustment of drug dosage in an obese population.
BOUQUEGNEAU, Antoine ULg; Vidal-Petiot, E; Moranne, O et al

in British Journal of Clinical Pharmacology (2016), 81(2), 349-361

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See detailWill delayed release metformin provide better management of diabetes type 2?
Scheen, André ULg

in Expert opinion on pharmacotherapy (2016), 17(5), 627-30

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See detailDulaglutide (LY-2189265) for the treatment of type 2 diabetes.
Scheen, André ULg

in Expert review of clinical pharmacology (2016), 9(3), 385-99

Dulaglutide is a new once-weekly glucagon-like peptide-1 receptor agonist for the management of hyperglycemia in adult patients with type 2 diabetes. It stimulates dose-dependent insulin secretion and ... [more ▼]

Dulaglutide is a new once-weekly glucagon-like peptide-1 receptor agonist for the management of hyperglycemia in adult patients with type 2 diabetes. It stimulates dose-dependent insulin secretion and reduces glucagon secretion, both in a glucose-dependent manner. Efficacy on blood glucose control and safety were demonstrated in the large AWARD program in type 2 diabetic patients treated with diet, metformin, dual oral therapy or insulin lispro with or without metformin, confirming findings of pilot studies in Caucasian patients and data in Japanese patients. Dulaglutide 1.5 mg once weekly was superior to metformin, sitagliptin, insulin glargine and exenatide twice daily, and non-inferior to liraglutide 1.8 mg once daily regarding the reduction in glycated hemoglobin. A modest but significant weight loss was consistently observed. Most frequent adverse events were transient and generally mild gastrointestinal disturbances. Clinical outcomes of dulaglutide will not be known until the large prospective cardiovascular outcome trial REWIND is complete. [less ▲]

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See detailInvestigational insulin secretagogues for type 2 diabetes.
SCHEEN, André ULg

in Expert opinion on investigational drugs (2016), 25(4), 405-22

INTRODUCTION: Insulin secretory defects are a key feature in the pathophysiology of type 2 diabetes (T2D). Classical insulin-secreting agents such as sulfonlyureas stimulate insulin secretion independent ... [more ▼]

INTRODUCTION: Insulin secretory defects are a key feature in the pathophysiology of type 2 diabetes (T2D). Classical insulin-secreting agents such as sulfonlyureas stimulate insulin secretion independent of glucose and cause hypoglycemia. Despite the advantages offered by incretin-based therapies, there is still a medical need for developing new insulin secretagogues for treating T2D. AREA COVERED: This article discusses: the new advances in the field of incretin-based therapies, glucokinase (GK) activators, free fatty acid receptor (FFAR) or G protein-coupled receptor (GPR) agonists (GPR40, GPR119, GPR120), imeglimin and some other insulin secretagogues with diverse mechanisms of action still in preclinical development. EXPERT OPINION: New insulin secretagogues should offer major advantages over sulfonylureas and gliptins. The challenge is to avoid uncontrolled insulin secretion and minimize the risk of hypoglycemia, to protect cells from progressive loss of mass and function for a better durability of glucose control, and to offer a good safety profile. Numerous approaches are in development. However, it is too early to decide whether one new pharmacological class will emerge as a clinically useful insulin secretagogue in the near feature. [less ▲]

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See detailInsulinosensibilisateurs (metformine/glitazones) : niveau de preuve et controverse
SCHEEN, André ULg

in Médecine des Maladies Métaboliques (2015), 9

Summary Because of the deleterious role attributed to insulin resistance, insulin sensitizing agents should theoretically reduce the incidence of cardiovascular complications in type 2 diabetes. In the ... [more ▼]

Summary Because of the deleterious role attributed to insulin resistance, insulin sensitizing agents should theoretically reduce the incidence of cardiovascular complications in type 2 diabetes. In the UKPDS, metformin reduced the risk of myocardial infarction and cardiovascular mortality in a rather small group of recently diagnosed patients at a low cardiovascular risk. These results deserve confirmation in a larger study with patients a high cardiovascular risk. Glitazones, as more specific insulin sensitizers, raised much hope. However, rosiglitazone fell from its pedestal after the suspicion of an increased risk of myocardial infarction. In PROactive among patients at high cardiovascular risk, pioglitazone gave positive but questionable results: statistical significance was not reached regarding the large composite primary endpoint, but well regarding the prespecified more focused principal secondary endpoint or in various post-hoc analyses. Thus, even if data with insulin sensitizers appear globally rather promising, evidence is rather weak, therefore leading to recurrent controversy. [less ▲]

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See detailComment je traite ... A propos du positionnement des inhibiteurs de la DPP-4 (gliptines) dans le traitement du diabète de type 2
SCHEEN, André ULg

in Revue Médicale de Liège (2015), 70

Summary : Dipeptidyl peptidase-4 (DPP-4) inhibitors (gliptins) are more and more prominent medications in the management of type 2 diabetes (T2D), with five molecules commercialized and as many fixed-dose ... [more ▼]

Summary : Dipeptidyl peptidase-4 (DPP-4) inhibitors (gliptins) are more and more prominent medications in the management of type 2 diabetes (T2D), with five molecules commercialized and as many fixed-dose combinations with metformin. After failure of metformin monotherapy, gliptins compete with old medications such as sulphonylureas, on the one hand, or with new oral antidiabetic agents such as inhibitors of renal sodium-glucose cotransporters type 2 (SGLT2) (gliflozines), on the other hand. Another alternative is the use of an incretin mimetic (agonist of glucagon-like peptide-1 receptors, to be injected subcutaneously) rather than an incretin enhancer such as a gliptin, before considering insulin therapy. This article analyses the arguments in favour of DPP-4 inhibitors. We will mainly consider the use of gliptins in patients with recently diagnosed T2D, in elderly and frail patients and in those with chronic kidney disease. To illustrate the discussion, we will analyze the results of both interventional and observational studies with vildagliptin. Obviously, these various groups of patients represent a large proportion of T2D population. [less ▲]

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See detailL’ETUDE CLINIQUE DU MOIS EMPA-REG OUTCOME : L’empagliflozine réduit la mortalité chez le patient diabétique de type 2 à haut risque cardiovasculaire
SCHEEN, André ULg

in Revue Médicale de Liège (2015), 70

Summary : EMPA-REG OUTCOME is an international, prospective, placebo-controlled clinical trial investigating the cardiovascular outcomes of empagliflozin, an inhibitor of sodium-glucose cotransporters ... [more ▼]

Summary : EMPA-REG OUTCOME is an international, prospective, placebo-controlled clinical trial investigating the cardiovascular outcomes of empagliflozin, an inhibitor of sodium-glucose cotransporters type 2 (SGLT2), in patients with type 2 diabetes mellitus and known cardiovascular disease. The trial succeeded in reaching the primary objective of non-inferiority and, in addition, showed, after a median follow up of 3.1 years, a superiority of empagliflozin (10 or 25 mg/day) versus placebo as regards the primary composite cardiovascular endpoint (hasard ratio or HR = 0.86; 95% CI 0.74-0.99; P = 0.04), hospitalisations for heart failure (- 35 %), cardiovascular mortality (- 38 %) and all-cause mortality (- 32 %, each p< 0.001). The reduction in mortality appeared early (< 6 months) and concerned all subgroups, without any obvious heterogeneity. This reduction in mortality does not seem to be fully explained by the concomitant slight reductions in HbA1c, body weight, waist circumference, blood pressure and serum uric acid levels in the empagliflozin groups versus the placebo group. Finally, the tolerance and safety profile of empagliflozin was good, with only a moderate increase in benign mycotic genital infections, a well-known adverse event with SGLT2 inhibitors. The remarkable effects of empagliflozin in the EMPA-REG OUTCOME trial, especially on mortality, should modify the management of patients with type 2 diabetes and a high cardiovascular risk in a near future. [less ▲]

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See detailLe médicament du mois. Humalog® 200 U/ml KwikPenTM
SCHEEN, André ULg

in Revue Médicale de Liège (2015), 70

Summary : Insulin lispro (Humalog®) was the first short-acting insulin analogue to be indicated for the treatment of diabetes mellitus requiring insulin therapy. After subcutaneous injection, insulin ... [more ▼]

Summary : Insulin lispro (Humalog®) was the first short-acting insulin analogue to be indicated for the treatment of diabetes mellitus requiring insulin therapy. After subcutaneous injection, insulin lispro has a more favourable pharmacokinetics/pharmacodynamics profile than human insulin, characterized by a faster resorption and a more rapid and less prolonged glucose-lowering activity. These properties allow a better control of postprandial hyperglycaemia and a reduction of the risk of delayed hypoglycaemia, especially at night. The patient’s quality of life is also improved because insulin lispro can be injected within the 15 minutes before meal and even possibly after meal when the amount of food intake is unpredictable. Already commercialized as Humalog® 100 U/ml, insulin lispro is now also available as Humalog® 200 U/ml. A pharmacokinetics/pharmacodynamics study confirmed the bioequivalence of the two formulations, based upon the analysis of both plasma free insulin concentrations and glucose infusion rates to maintain normoglycaemia. Humalog® 200 U/ml is available in a novel disposable 3 ml pen (KwikPenTM), with lower glide force and injection volume; thus this new pen is more convenient for the patient compared with the current pen used to inject Humalog® 100 U/ml. The new formulation Humalog® 200 U/ml is indicated in Europe for adult patients with type 1 or type 2 diabetes who require more than 20 units of prandial insulin per day to cover their meals. [less ▲]

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