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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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See detailL’ÉTUDE CLINIQUE DU MOIS TECOS : confirmation de la sécurité cardiovasculaire de la sitagliptine
SCHEEN, André ULg; PAQUOT, Nicolas ULg

in Revue Médicale de Liège (2015), 70

Summary : The cardiovascular safety of sitagliptin has been evaluated in TECOS («Trial Evaluating Cardiovascular Outcomes with Sitagliptin»). TECOS recruited patients with type 2 diabetes and a history of ... [more ▼]

Summary : The cardiovascular safety of sitagliptin has been evaluated in TECOS («Trial Evaluating Cardiovascular Outcomes with Sitagliptin»). TECOS recruited patients with type 2 diabetes and a history of cardiovascular disease who received, as add-on to their usual therapy, either sitagliptin (n = 7.257) or placebo (n = 7.266), with a median follow-up of 3 years. The primary cardiovascular outcome was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina. Sitagliptin was noninferior to placebo for the primary composite cardiovascular outcome (hazard ratio, 0.98; 95 % confidence interval, 0.88 to 1.09; P<0.001). Rates of hospitalization for heart failure did not differ between the two groups (hazard ratio, 1.00; 95 % CI, 0.83 to 1.20; P=0.98). The cardiovascular safety of sitagliptin, which was already shown in meta-analyses of phase II-III randomised controlled trials and in observational cohort studies in real life, is now confirmed in the landmark prospective cardiovascular outcome study TECOS. [less ▲]

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See detailPharmacokinetics and clinical evaluation of the alogliptin plus pioglitazone combination for type 2 diabetes.
Scheen, André ULg

in Expert opinion on drug metabolism & toxicology (2015), 11(6), 1005-20

INTRODUCTION: Type 2 diabetes is a complex disease with multiple defects, which generally requires a combination of several pharmacological approaches to reach glucose control targets. A unique fixed-dose ... [more ▼]

INTRODUCTION: Type 2 diabetes is a complex disease with multiple defects, which generally requires a combination of several pharmacological approaches to reach glucose control targets. A unique fixed-dose combination combines a thiazolidinedione (pioglitazone) and a dipeptidyl peptidase-4 inhibitor (alogliptin). Area covered: An extensive literature search was performed to analyze the pharmacokinetics of pioglitazone and alogliptin when used separately and in combination as well as to summarize clinical and toxicological considerations about the combined therapy. Expert opinion: Pioglitazone, a potent insulin sensitizer, and alogliptin, an incretin-based agent that potentiates post-meal insulin secretion and reduces glucagon secretion, have complementary mechanisms of action. The clinical efficacy of a combined therapy is superior to any single therapy in patients treated with diet or with metformin (with or without sulphonylurea). These two drugs can be administered once daily, with or without a meal. No clinically relevant pharmacokinetic interactions between the two agents have been described and the fixed-dose combination has shown bioequivalence with alogliptin and pioglitazone given separately. Combining alogliptin with pioglitazone does not alter the safety profile of each compound. Weight gain observed with pioglitazone may be limited with the addition of alogliptin. The concern of an increased risk of heart failure remains to be better investigated. [less ▲]

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See detailFacteurs génétiques et risque de dysglycémie dans des familles de diabétiques de type 2: l’étude DESCENDANCE
Franc, S; Cauchi, S; Yengo, L et al

in Diabètes & Métabolism (2015, April), 41(s1), 10-35

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See detailA review of gliptins for 2014.
Scheen, André ULg

in Expert opinion on pharmacotherapy (2015), 16(1), 43-62

Introduction: Dipeptidyl peptidase-4 (DPP-4) inhibitors (gliptins) occupy an increasing place in the armamentarium of drugs used for the management of hyperglycaemia and offer new opportunities for a ... [more ▼]

Introduction: Dipeptidyl peptidase-4 (DPP-4) inhibitors (gliptins) occupy an increasing place in the armamentarium of drugs used for the management of hyperglycaemia and offer new opportunities for a personalized medicine in patients with Type 2 diabetes. Areas covered: An updated review providing an analysis of available recent data with commercialized DPP-4 inhibitors, with a special focus on: differences between the various molecules, novelties regarding their mechanism of action, clinical efficacy in mono- and various combined therapies, comparison with other new therapies, efficacy-safety profile in at risk patients, concern about pancreatic safety, perspectives in cardiovascular prevention and, finally, a selection of remaining unanswered important questions for the clinician. Expert opinion: DPP-4 inhibitors offer various advantages when compared to other glucose-lowering agents. Despite they have been commercialized since a few years only, available data obtained in randomised controlled trials are of better quality compared to those available with ancient classical glucose-lowering agents, especially in more fragile populations such as elderly people, individuals with renal impairment or at high cardiovascular risk and patients at higher risk of hypoglycaemia. However, there remain uncertainties and controversies that should be resolved by further ongoing large prospective controlled trials and increasing clinical experience combined with a careful post-marketing surveillance. [less ▲]

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See detailInflammatory markers and cardiometabolic diseases.
ESSER, Nathalie ULg; Paquot, Nicolas ULg; Scheen, André ULg

in Acta clinica Belgica (2015), 70(3), 193-9

OBJECTIVES: A growing body of evidence emerges that obesity, metabolic syndrome, type 2 diabetes and cardiovascular disease are intimately related to chronic inflammation. METHODS: A narrative review ... [more ▼]

OBJECTIVES: A growing body of evidence emerges that obesity, metabolic syndrome, type 2 diabetes and cardiovascular disease are intimately related to chronic inflammation. METHODS: A narrative review summarizing the most recent data of the literature describing the pathological implications of inflammation in obese patients with cardiometabolic disorders. RESULTS: Besides high-sensitive C-reactive protein, various circulating or in situ inflammatory markers have been identified, presumably reflecting the presence of inflammation in various key-organs (visceral adipose tissue, skeletal muscle, pancreatic islets, liver, intestine, arterial wall). Available data support the concept that targeting inflammation, not only reduces systemic inflammatory markers, but also improves insulin sensitivity and ameliorates glucose control in insulin-resistant patients, thus potentially reducing the risk of cardiovascular complications. CONCLUSION: These observations confirm the role of inflammation in cardiometabolic diseases and support the development of pharmacological strategies that aim at reducing inflammation, especially in patients with type 2 diabetes. [less ▲]

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See detailAntidiabetic agents: Potential anti-inflammatory activity beyond glucose control.
Scheen, André ULg; ESSER, Nathalie ULg; Paquot, Nicolas ULg

in Diabetes & metabolism (2015)

A growing body of evidence is emerging to show that abdominal obesity, the metabolic syndrome, type 2 diabetes, cardiovascular disease and microvascular diabetic complications are intimately related to ... [more ▼]

A growing body of evidence is emerging to show that abdominal obesity, the metabolic syndrome, type 2 diabetes, cardiovascular disease and microvascular diabetic complications are intimately related to chronic inflammation. These observations pave the way to the development of new pharmacological strategies that aim to reduce silent inflammation. However, besides specific anti-inflammatory agents, glucose-lowering medications may also exert anti-inflammatory effects that could contribute to improved outcomes in diabetic patients. Most studies have used metformin, an AMP-activated protein kinase (AMPK) activator, and thiazolidinediones (TZDs), which act as peroxisome proliferator-activated receptor-gamma (PPARgamma) agonists. Both pharmacological classes (considered insulin-sparing agents or insulin sensitizers) appear to have greater anti-inflammatory activity than insulin-secreting agents such as sulphonylureas or glinides. In particular, TZDs have shown the widest range of evidence of lowered tissue (visceral fat and liver) and serum inflammation. In contrast, despite reducing postprandial hyperglycaemia, the effect of alpha-glucosidase inhibitors on inflammatory markers appears rather modest, whereas dipeptidyl peptidase-4 (DPP-4) inhibitors (gliptins) and glucagon-like peptide-1 (GLP-1) receptor agonists appear more promising in this respect. These incretin-based therapies exert pleiotropic effects, including reports of anti-inflammatory activity. No human data are available so far regarding sodium-glucose cotransporter type 2 (SGLT2) inhibitors. Although they may have indirect effects due to reduced glucotoxicity, their specific mode of action in the kidneys does not suggest systemic anti-inflammatory activity. Also, in spite of the complex relationship between insulin and atherosclerosis, exogenous insulin may also exert anti-inflammatory effects. Nevertheless, for all these glucose-lowering agents, it is essential to distinguish between anti-inflammatory effects resulting from better glucose control and potential anti-inflammatory effects related to intrinsic actions of the pharmacological class. Finally, it would also be of major clinical interest to define what role the anti-inflammatory effects of these glucose-lowering agents may play in the prevention of macrovascular and microvascular diabetic complications. [less ▲]

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See detailEffect of brivaracetam on CYP3A activity, measured by oral midazolam.
Stockis, Armel; Watanabe, Shikiko; Scheen, André ULg

in Journal of clinical pharmacology (2015)

Brivaracetam is a synaptic vesicle protein 2A ligand in phase III development for epilepsy. A phase I, open-label, randomized study was conducted in 42 healthy male participants to assess the effect of ... [more ▼]

Brivaracetam is a synaptic vesicle protein 2A ligand in phase III development for epilepsy. A phase I, open-label, randomized study was conducted in 42 healthy male participants to assess the effect of brivaracetam on CYP3A activity using midazolam as a probe. Participants were randomized to oral brivaracetam 5, 50, or 150 mg/day from Day 8 to Day 14. A single oral dose (7.5 mg) of midazolam was administered on Days 1, 13, and 20, and full pharmacokinetic profiles were obtained. For all brivaracetam doses, the areas under the plasma concentration-time curves from 0 to infinity (AUCinf ) for midazolam and 1'-hydroxymidazolam were similar on Days 13 and 20 compared with Day 1. Following brivaracetam 150 mg/day, the Day 13/Day 1 AUCinf ratio (90% confidence interval) was 1.09 (0.97, 1.21) and 1.04 (0.93, 1.17) for midazolam and 1'-hydroxymidazolam, respectively. For the Day 20/Day 1 comparison, the corresponding AUCinf ratios were 1.10 (0.98, 1.23) and 1.07 (0.97, 1.18). Maximum midazolam plasma concentration was increased on both Day 13 and Day 20 vs. Day 1 but the relevance of this finding was unclear. This study indicates that brivaracetam up to 150 mg/day has no significant inducing or inhibiting effect on CYP3A activity. [less ▲]

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See detailRelations entre gain baro-réflexe et autres marqueurs de risque chez le patient diabétique de type 2
SCHEEN, André ULg; MARCHAND, Monique ULg; PHILIPS, Jean-Christophe ULg

in Annales de Cardiologie et d'Angeiologie (2015), 64(s1),

André J. Scheen, Monique Marchand, Jean-Christophe Philips (1) (1) Service de Diabétologie, Nutrition et Maladies métaboliques, CHU Sart Tilman, Université de Liège, Liège, Belgique. Relations entre gain ... [more ▼]

André J. Scheen, Monique Marchand, Jean-Christophe Philips (1) (1) Service de Diabétologie, Nutrition et Maladies métaboliques, CHU Sart Tilman, Université de Liège, Liège, Belgique. Relations entre gain baro-réflexe et autres marqueurs de risque chez le patient diabétique de type 2 Relationships between baroreflex gain and other risk markers in patients with type 2 diabetes Objectifs : Le gain baro-réflexe (GBR) est un marqueur de la neuropathie autonome cardiovasculaire (NAC) qui s’avère plus discriminant que le classique R-R E/I ratio. Le but du travail est d’étudier les relations entre le GBR et d’autres marqueurs de risque comme la pression pulsée (PP) et la diminution du débit de filtration glomérulaire (DFG) chez le patient diabétique de type 2 (DT2). Méthodes : Au total, 64 patients DT2 ont été étudiés par enregistrement continu de la pression artérielle (PA) et de la fréquence cardiaque (FC) lors d’un test postural standardisé (test de «squatting» : 1min debout – 1min accroupi – 1min debout). GBR est calculé par la pente de la relation entre les espaces R-R et PA systolique lors du redressement. PP (PAS-PAD) est analysée pendant tout le test et par son augmentation durant l’accroupissement (delta PP). Le DFG est calculé par la formule MDRD avant et après un suivi moyen de 12±5 années. Résultats : Les patients ont été séparés en deux groupes en fonction de la valeur médiane du GBR : G1 (n=34) : </=1,36 msec/mm Hg (moyenne ± SD : 0,77±0,40) vs G2 (n=30) : >1,36 (3,05±0,35). Les sujets de G1 sont légèrement plus âgés (58±7 vs 54±8 ans; p=0,04), mais ont un sexe ratio, une durée du DT2, un taux d’HbA1c et des valeurs de PA comparables aux valeurs de G2. Les patients de G1 ont une FC de base plus élevée (88±15 vs 82±14 bpm; p=0,0462) et un DFG plus bas (79±19 vs 95±19 ml/min; p=0,0479). Si la PP en position debout est comparable (59±15 vs 54±15 mmHg; p=0,1983), elle devient plus élevée en position accroupie (73±18 vs 65±16 mmHg; p=0,0395) chez G1 que chez G2. Lors du redressement, la chute de PA moyenne est significativement plus importante (-46±12 vs -38±12 mmHg; p=0,0079), avec un retard à la récupération des valeurs de base (29±19 vs 21±19 sec; p=0,0107) et une tachycardisation moindre (17±8 vs 23±9 bpm; p=0,0359) chez G1. Par contre, la diminution du DFG durant le suivi est comparable chez G1 vs G2 (-13±21 vs -13±21 ml/min; p=0,8561). Conclusion : Un GBR abaissé, marqueur de la NAC, est associé à une PP élevée en position accroupie (un marqueur indirect de rigidité artérielle) et une diminution du DFG. Par contre, la seule valeur de GBR ne permet pas de prédire l’ampleur de la dégradation de la fonction rénale lors d’un suivi ultérieur de 12 années [less ▲]

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