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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 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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See detailWeight Management in Type 2 Diabetes: Current and Emerging Approaches to Treatment.
Van Gaal, Luc; Scheen, André ULg

in Diabetes care (2015), 38(6), 1161-1172

Diabetes is a growing global health concern, as is obesity. Diabetes and obesity are intrinsically linked: obesity increases the risk of diabetes and also contributes to disease progression and ... [more ▼]

Diabetes is a growing global health concern, as is obesity. Diabetes and obesity are intrinsically linked: obesity increases the risk of diabetes and also contributes to disease progression and cardiovascular disease. Although the benefits of weight loss in the prevention of diabetes and as a critical component of managing the condition are well established, weight reduction remains challenging for individuals with type 2 diabetes due to a host of metabolic and psychological factors. For many patients, lifestyle intervention is not enough to achieve weight loss, and alternative options, such as pharmacotherapy, need to be considered. However, many traditional glucose-lowering medications may lead to weight gain. This article focuses on the potential of currently available pharmacological strategies and on emerging approaches in development to support the glycemic and weight-loss goals of individuals with type 2 diabetes. Two pharmacotherapy types are considered: those developed primarily for blood glucose control that have a favorable effect on body weight and those developed primarily to induce weight loss that have a favorable effect on blood glucose control. Finally, the potential of combination therapies for the management of obese patients with type 2 diabetes is discussed. [less ▲]

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See detailObesity: A new paradigm for treating obesity and diabetes mellitus.
Scheen, André ULg; Paquot, Nicolas ULg

in Nature reviews. Endocrinology (2015), 11(4), 196-198

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See detailOnce-weekly DPP-4 inhibitors: do they meet an unmet need?
Scheen, André ULg

in Lancet Diabetes & Endocrinology (2015), 3(3), 162-164

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See detailLa vignette therapeutique de l'etudiant. Instaurer, surveiller et interrompre des traitements medicamenteux: un exercice pratique en vie reelle.
Scheen, André ULg

in Revue medicale de Liege (2015), 70(1), 49-53

Some patients are exposed to complex clinical situations, which impose a careful analysis of both the indications and contraindications of ongoing pharmacological treatments as well as of the dosing or ... [more ▼]

Some patients are exposed to complex clinical situations, which impose a careful analysis of both the indications and contraindications of ongoing pharmacological treatments as well as of the dosing or drug adjustments to be proposed. This article illustrates some problems encountered when a new drug therapy is initiated, when medications with narrow therapeutic window should be supervised and when some drugs should be stopped mainly for safety reasons. The clinical case relates the story of a patient with type 2 diabetes, arterial hypertension and coronary heart disease, who presents a congestive heart failure associated with an episode of atrial fibrillation and a severe renal insufficiency. [less ▲]

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See detailQuels medecins pour quelle medecine?
Scheen, André ULg

in Revue medicale de Liege (2015), 70(1), 1-4

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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 detailAntidiabétiques oraux dans le traitement du diabète de type 2 : perspectives historique et médico-économique
SCHEEN, André ULg

in Médecine des Maladies Métaboliques (2015), 9(2), 186-197

Oral therapy of type 2 diabetes (T2D) is becoming increasingly complex during the last decade, with first the launch of glitazones, then that of gliptins and finally, very recently, that of gliflozins ... [more ▼]

Oral therapy of type 2 diabetes (T2D) is becoming increasingly complex during the last decade, with first the launch of glitazones, then that of gliptins and finally, very recently, that of gliflozins. However, the two oral glucose-lowering agents developed more than 50 years ago, metformin and sulfonylureas, still remain the leaders in the market. After failure of metformin monotherapy, the choice of antidiabetic medications is difficult and should be made taking into account the benefit-risk balance, with a special attention to cost of therapy and a focus on a patient-centered approach. This strategy is recommended in the recently updated joint ADA-EASD position statement, in January 2015. If the main principles of T2D therapy are universal, particularities should probably be discussed regarding regional situations, and the African continent obviously presents specificities in this respect. [less ▲]

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