Cardiovascular safety of albiglutide and other glucagon-like peptide-1 receptor agonists.
in The lancet. Diabetes & endocrinology (2015), 3(9), 667-9Detailed reference viewed: 18 (0 ULg)
A Randomized, Double-Blind, Parallel Study to Evaluate the Dose-Response of Three Different Vitamin D Treatment Schemes on the 25-Hydroxyvitamin D Serum Concentration in Patients with Vitamin D Deficiency
SCHLECK, Marie-Louise ; ; JANDRAIN, Bernard et al
in Nutrients (2015), 7Detailed reference viewed: 48 (8 ULg)
Pharmacokinetics, Pharmacodynamics and Clinical Use of SGLT2 Inhibitors in Patients with Type 2 Diabetes Mellitus and Chronic Kidney Disease.
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 ▲]Detailed reference viewed: 61 (6 ULg)
Towards a genotype-based approach for a patient-centered pharmacologic therapy of type 2 diabetes.
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 ▲]Detailed reference viewed: 46 (0 ULg)
Le medicament du mois. L'albiglutide (Eperzan): nouvel agoniste des recepteurs du glucagon-like peptide-1 en injection hebdomadaire.
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 ▲]Detailed reference viewed: 33 (0 ULg)
Metformin should not be contraindicated in patients with type 2 diabetes and mild to moderate renal impairment.
in Evidence-based medicine (2015), 20(3), 115Detailed reference viewed: 24 (0 ULg)
Individualizing 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 ; ; 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 ▲]Detailed reference viewed: 29 (0 ULg)
Inhibiting or Antagonizing Glucagon: A Progress in Diabetes Care ?
LEFEBVRE, Pierre ; Paquot, Nicolas ; Scheen, André
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 ▲]Detailed reference viewed: 29 (3 ULg)
Weight Management in Type 2 Diabetes: Current and Emerging Approaches to Treatment.
; Scheen, André
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 ▲]Detailed reference viewed: 16 (1 ULg)
Obesity: A new paradigm for treating obesity and diabetes mellitus.
Scheen, André ; Paquot, Nicolas
in Nature reviews. Endocrinology (2015), 11(4), 196-198Detailed reference viewed: 66 (4 ULg)
Once-weekly DPP-4 inhibitors: do they meet an unmet need?
in Lancet Diabetes & Endocrinology (2015), 3(3), 162-164Detailed reference viewed: 23 (2 ULg)
La vignette therapeutique de l'etudiant. Instaurer, surveiller et interrompre des traitements medicamenteux: un exercice pratique en vie reelle.
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 ▲]Detailed reference viewed: 82 (6 ULg)
Antidiabétiques oraux dans le traitement du diabète de type 2 : perspectives historique et médico-économique
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 ▲]Detailed reference viewed: 83 (13 ULg)
Anti-inflammatory agents to treat or prevent type 2 diabetes, metabolic syndrome and cardiovascular disease.
Esser, Nathalie ; Paquot, Nicolas ; Scheen, André
in Expert opinion on investigational drugs (2015), 24(3), 283-307
Introduction: There is a growing body of evidence to suggest that chronic silent inflammation is a key feature in abdominal obesity, metabolic syndrome, type 2 diabetes (T2DM) and cardiovascular disease ... [more ▼]
Introduction: There is a growing body of evidence to suggest that chronic silent inflammation is a key feature in abdominal obesity, metabolic syndrome, type 2 diabetes (T2DM) and cardiovascular disease (CVD). These observations suggest that pharmacological strategies, which reduce inflammation, may be therapeutically useful in treating obesity, type 2 diabetes and associated CVD. Area covered: The article covers novel strategies, using either small molecules or monoclonal antibodies. These strategies include: approaches targeting IKK-b-NF-kB (salicylates, salsalate), TNF-alpha (etanercept, infliximab, adalimumab), IL-1beta (anakinra, canakinumab) and IL-6 (tocilizumab), AMP-activated protein kinase activators, sirtuin-1 activators, mammalian target of rapamycin inhibitors and C-C motif chemokine receptor 2 antagonists. Expert opinion: The available data supports the concept that targeting inflammation improves insulin sensitivity and beta-cell function; it also ameliorates glucose control in insulin-resistant patients with inflammatory rheumatoid diseases as well in patients with metabolic syndrome or T2DM. Although promising, the observed metabolic effects remain rather modest in most clinical trials. The potential use of combined anti-inflammatory agents targeting both insulin resistance and insulin secretion appears appealing but remains unexplored. Large-scale prospective clinical trials are underway to investigate the safety and efficacy of different anti-inflammatory drugs. Further evidence is needed to support the concept that targeting inflammation pathways may represent a valuable option to tackle the cardiometabolic complications of obesity. [less ▲]Detailed reference viewed: 76 (11 ULg)
Author's Reply to De Ponti et al.: "Pharmacokinetics in Patients with Chronic Liver Disease and Hepatic Safety of Incretin-Based Therapies for the Management of Type 2 Diabetes Mellitus"
in Clinical pharmacokinetics (2015)Detailed reference viewed: 16 (1 ULg)
Clinical inertia in general practice, a matter of debate: a qualitative study with 114 general practitioners in Belgium.
; ; et al
in BMC family practice (2015), 16(1), 13
BackgroundPrescribing that is not concordant with guidelines is increasingly referred to as clinical inertia (CI). However, CI may be only apparent, and the absence of decision may actually reflect ... [more ▼]
BackgroundPrescribing that is not concordant with guidelines is increasingly referred to as clinical inertia (CI). However, CI may be only apparent, and the absence of decision may actually reflect appropriate inaction as a result of good clinical reasoning. Our study aimed to: (i) elucidate GPs inverted question mark beliefs regarding CI and the risk of CI in their own practice, (ii) identify modifiable provider-related factors associated with CI.MethodsWe conducted 8 group interviews with 114 general practitioners (GP) in Belgium, and used an integrated approach of thematic analysis.ResultsOur results call for a redefinition of CI, in order to take into account the GPs inverted question mark extended health-promoting role, and acknowledge that inaction or delayed action follows a process of clinical reasoning that takes into account the patients inverted question mark preferences, and that is appropriate most of the time. However, the participants in our study did acknowledge that the risk of CI exists in practice. The main factor of such a risk is when GPs feel overwhelmed and disempowered, due to characteristics of either the patients or the health care system, including contradictions between guidelines and reimbursement policies.ConclusionsAlthough situations of clinical inertia exist in practice and need to be prevented or corrected, the term clinical inertia could potentially increase the already existing gap between general practice and specialised care, whereas sustained efforts toward more collaborative work and integrated care are called for. [less ▲]Detailed reference viewed: 25 (1 ULg)
Safety of dipeptidyl peptidase-4 inhibitors for treating type 2 diabetes.
in Expert opinion on drug safety (2015), epub
Introduction: Dipeptidyl peptidase-4 (DPP-4) inhibitors (gliptins) occupy a growing place in the armamentarium of drugs used for the management of hyperglycemia in type 2 diabetes, although some safety ... [more ▼]
Introduction: Dipeptidyl peptidase-4 (DPP-4) inhibitors (gliptins) occupy a growing place in the armamentarium of drugs used for the management of hyperglycemia in type 2 diabetes, although some safety concerns have been raised in recent years. Areas covered: An updated review providing an analysis of available safety data (meta-analyses, randomized controlled trials, observational cohort and case-control studies and pharmacovigilance reports) with five commercialized DPP-4 inhibitors (sitagliptin, vildagliptin, saxagliptin, alogliptin, linagliptin). A special focus is given to overall safety profile; pancreatic adverse events (AEs) (acute pancreatitis, pancreatic cancer); overall cardiovascular safety (myocardial infarction and stroke); congestive heart failure concern and finally, safety in special populations (elderly, renal impairment). Expert opinion: The good tolerance/safety profile of DPP-4 inhibitors has been largely confirmed, including in more fragile populations (elderly, renal impairment) with almost no increased risk of infection or gastrointestinal AEs, no weight gain and a minimal risk of hypoglycemia. Although an increased risk of acute pancreatitis and pancreatic cancer was suspected, the complete set of available data appears reassuring so far. Cardiovascular safety of DPP-4 inhibitors has been proven but an unexpected increased risk of heart failure has been reported which should be confirmed in ongoing trials and better understood. Further postmarketing surveillance is recommended. [less ▲]Detailed reference viewed: 67 (7 ULg)
Pharmacodynamics, Efficacy and Safety of Sodium-Glucose Co-Transporter Type 2 (SGLT2) Inhibitors for the Treatment of Type 2 Diabetes Mellitus.
in Drugs (2015), 75(1), 33-59
Inhibitors of sodium-glucose co-transporter type 2 (SGLT2) are proposed as a novel approach for the management of type 2 diabetes mellitus (T2DM). Several compounds are already available in many countries ... [more ▼]
Inhibitors of sodium-glucose co-transporter type 2 (SGLT2) are proposed as a novel approach for the management of type 2 diabetes mellitus (T2DM). Several compounds are already available in many countries (dapagliflozin, canagliflozin, empagliflozin and ipragliflozin) and some others are in a late phase of development. The available 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, the absence of clinically relevant drug-drug interactions and a low renal elimination as parent drug. SGLT2 co-transporters are responsible for reabsorption of most (90 %) of the glucose filtered by the kidneys. The pharmacological inhibition of SGLT2 co-transporters reduces hyperglycaemia by decreasing renal glucose threshold and thereby increasing urinary glucose excretion. The amount of glucose excreted in the urine depends on both the level of hyperglycaemia and the glomerular filtration rate. Results of numerous placebo-controlled randomised clinical trials of 12-104 weeks duration have shown significant reductions in glycated haemoglobin (HbA1c), resulting in a significant increase in the proportion of patients reaching HbA1c targets, and a significant lowering of fasting plasma glucose when SGLT2 inhibitors were administered as monotherapy or in addition to other glucose-lowering therapies including insulin in patients with T2DM. In head-to-head trials of up to 2 years, SGLT2 inhibitors exerted similar glucose-lowering activity to metformin, sulphonylureas or sitagliptin. The durability of the glucose-lowering effect of SGLT2 inhibitors appears to be better; however, this remains to be more extensively investigated. The risk of hypoglycaemia was much lower with SGLT2 inhibitors than with sulphonylureas and was similarly low as that reported with metformin, pioglitazone or sitagliptin. Increased renal glucose elimination also assists weight loss and could help to reduce blood pressure. Both effects were very consistent across the trials and they represent some advantages for SGLT2 inhibitors when compared with other oral glucose-lowering agents. The pharmacodynamic response to SGLT2 inhibitors declines with increasing severity of renal impairment, and prescribing information for each SGLT2 inhibitor should be consulted regarding dosage adjustments or restrictions in moderate to severe renal dysfunction. Caution is also recommended in the elderly population because of a higher risk of renal impairment, orthostatic hypotension and dehydration, even if the absence of hypoglycaemia represents an obvious advantage in this population. The overall effect of SGLT2 inhibitors on the risk of cardiovascular disease is unknown and will be evaluated in several ongoing prospective placebo-controlled trials with cardiovascular outcomes. The impact of SGLT2 inhibitors on renal function and their potential to influence the course of diabetic nephropathy also deserve more attention. SGLT2 inhibitors are generally well-tolerated. The most frequently reported adverse events are female genital mycotic infections, while urinary tract infections are less commonly observed and generally benign. In conclusion, with their unique mechanism of action that is independent of insulin secretion and action, SGLT2 inhibitors are a useful addition to the therapeutic options available for the management of T2DM at any stage in the natural history of the disease. Although SGLT2 inhibitors have already been extensively investigated, further studies should even better delineate the best place of these new glucose-lowering agents in the already rich armamentarium for the management of T2DM. [less ▲]Detailed reference viewed: 104 (3 ULg)
Programme EDUDORA²: quelles leçons tirer de l'étude des représentations au sein de la triade patient/soignant/famille pour la prévention et le traitement du diabète et de l’obésité ?
Degrange, Sophie ; PETRE, Benoit ; et al
Poster (2014, December)Detailed reference viewed: 76 (12 ULg)