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Many people with type 2 diabetes mellitus (T2DM) fail to achieve glycaemic control promptly after diagnosis and do not receive timely treatment intensification. This may be in part due to 'clinical inertia', defined as the failure of healthcare providers to initiate or intensify therapy when indicated. Physician-, patient- and healthcare-system-related factors all contribute to clinical inertia. However, decisions that appear to be clinical inertia may, in fact, be only 'apparent' clinical inertia and may reflect good clinical practice on behalf of the physician for a specific patient. Delay in treatment intensification can happen at all stages of treatment for people with T2DM, including prescription of lifestyle changes after diagnosis, introduction of pharmacological therapy, use of combination therapy where needed and initiation of insulin. Clinical inertia may contribute to people with T2DM living with suboptimal glycaemic control for many years, with dramatic consequences for the patient in terms of quality of life, morbidity and mortality, and for public health because of the huge costs associated with uncontrolled T2DM. Because multiple factors can lead to clinical inertia, potential solutions most likely require a combination of approaches involving fundamental changes in medical care. These could include the adoption of a person-centred model of care to account for the complex considerations influencing treatment decisions by patients and physicians. Better patient education about the progressive nature of T2DM and the risks inherent in long-term poor glycaemic control may also reinforce the need for regular treatment reviews, with intensification when required.

OBJECTIVE This study compared the efficacy and safety of once-weekly dulaglutide, a glucagon-like peptide-1 receptor agonist, with daily insulin glargine, both combined with maximally tolerated doses of metformin and glimepiride in patients with type 2 diabetes. The primary objective was noninferiority of dulaglutide 1.5 mg to glargine in the HbA1c change from baseline at 52 weeks. RESEARCH DESIGN AND METHODS In this 78-week, open-label study, 810 patients were randomized to dulaglutide 1.5 mg, dulaglutide 0.75 mg, or glargine. RESULTS The baseline mean ± SD HbA1c was 8.1 ± 1.0% (65.5 ± 10.8 mmol/mol). The least squares mean ± SE HbA1c change from baseline to the primary end point was −1.08 ± 0.06% (−11.8 ± 0.7 mmol/mol) for dulaglutide 1.5 mg, −0.76 ± 0.06% (−8.3 ± 0.7 mmol/mol) for dulaglutide 0.75 mg, and −0.63 ± 0.06% (−6.9 ± 0.7 mmol/mol) for glargine, with an end point mean ± SD dose of 29 ± 26 units (0.33 ± 0.24 units/kg), and a fasting plasma glucose (mean ± SD) of 118 ± 23 mg/dL from self-monitored plasma glucose. Statistical criteria for superiority were met with dulaglutide 1.5 mg and for noninferiority with dulaglutide 0.75 mg. More patients on dulaglutide 1.5 mg achieved HbA1c targets CONCLUSIONS Once-weekly dulaglutide 1.5 mg, compared with daily insulin glargine without forced titration, demonstrated greater HbA1c reduction and weight loss, with a higher incidence of gastrointestinal adverse events and a lower risk of hypoglycemia.

Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) are an important class of drugs with a well-established efficacy and safety profile in patients with type 2 diabetes mellitus. Agents in this class are derived from either exendin-4 (a compound present in Gila monster venom) or modifications of human GLP-1 active fragment. Differences among these drugs in duration of action (ie, short-acting vs long-acting), effects on glycaemic control and weight loss, immunogenicity, tolerability profiles, and administration routes offer physicians several options when selecting the most appropriate agent for individual patients. Patient preference is also an important consideration. The aim of this review is to discuss the differences between and similarities of GLP-1 RAs currently approved for clinical use, focusing particularly on the properties characterising the single short-acting and long-acting GLP-1 RAs rather than on their individual efficacy and safety profiles. The primary pharmacodynamic difference between short-acting (ie, exenatide twice daily and lixisenatide) and long-acting (ie, albiglutide, dulaglutide, exenatide once weekly, liraglutide, and semaglutide) GLP-1 RAs is that short-acting agents primarily delay gastric emptying (lowering postprandial glucose) and long-acting agents affect both fasting glucose (via enhanced glucose-dependent insulin secretion and reduced glucagon secretion in the fasting state) and postprandial glucose (via enhanced postprandial insulin secretion and inhibition of glucagon secretion). Other advantages of long-acting GLP-1 RAs include smaller fluctuations in plasma drug concentrations, improved gastrointestinal tolerability profiles, and simpler, more convenient administration schedules (once daily for liraglutide and once weekly for albiglutide, dulaglutide, the long-acting exenatide formulation, and semaglutide), which might improve treatment adherence and persistence.

OBJECTIVE Compare the efficacy and safety of monotherapy with dulaglutide, a once-weekly GLP-1 receptor agonist, to metformin-treated patients with type 2 diabetes. The primary objective compared dulaglutide 1.5 mg and metformin on change from baseline glycosylated hemoglobin A1c (HbA1c) at 26 weeks. RESEARCH DESIGN AND METHODS This 52-week double-blind study randomized patients to subcutaneous dulaglutide 1.5 mg, dulaglutide 0.75 mg, or metformin. Patients (N = 807) had HbA1c ≥6.5% (≥48 mmol/mol) and ≤9.5% (≤80 mmol/mol) with diet and exercise alone or low-dose oral antihyperglycemic medication (OAM) monotherapy; OAMs were discontinued at beginning of lead-in period. RESULTS At 26 weeks, changes from baseline HbA1c (least squares [LS] mean ± SE) were: dulaglutide 1.5 mg, −0.78 ± 0.06% (−8.5 ± 0.70 mmol/mol); dulaglutide 0.75 mg, −0.71 ± 0.06% (−7.8 ± 0.70 mmol/mol); and metformin, −0.56 ± 0.06% (−6.1 ± 0.70 mmol/mol). Dulaglutide 1.5 and 0.75 mg were superior to metformin (LS mean difference): −0.22% (−2.4 mmol/mol) and −0.15% (−1.6 mmol/mol) (one-sided P < 0.025, both comparisons), respectively. Greater percentages reached HbA1c targets CONCLUSIONS Dulaglutide improves glycemic control and is well tolerated as monotherapy in patients with early stage type 2 diabetes.

Objectifs Evaluer selon leur âge, les preferences des patients diabetiques de type 2 (DT2) pour les caracteristiques des GLP-1RAs au Royaume-Uni. Methodes C’etait un modele de choix discret (MDC) chez des patients DT2 adultes naifs de traitement injectable. Les parametres du MDC comprenaient : frequence d’administration, variation de l’HbA1c, variation du poids, type de dispositif d’administration, frequence des nausees et frequence des hypoglycemies. Les utilites partielles ont ete estimees par un modele logit a effets aleatoires et utilisees pour calculer l’importance relative (IR) de chaque parametre. Des tests du Chi 2 ont ete utilises pour tester les differences d’IR pour chaque parametre par groupe d’âge ( 65 ans). Resultats Un total de 243 participants ont termine l’etude ( n = 68 ; 55–65 ans, n = 95 ; > 65 ans, n = 80). Dans tous les groupes, frequence d’administration, type de dispositif d’administration et frequence des nausees etaient les trois parametres les plus importants par ordre de preference. Des differences d’IR ont ete observees entre les groupes pour le type de dispositif d’administration ( 65 ans, IR = 37,9 % ; p = 0,0477) et la frequence des hypoglycemies ( 65 ans, IR = 7,6 % ; p = 0,0384). Discussion Dans cette etude, quel que soit l’âge, l’ordre d’IR des caracteristiques des GLP-1RA est globalement similaire, avec la frequence d’administration classee en tete de maniere constante. Lorsque des differences etaient observees, le type de dispositif d’administration et la frequence des hypoglycemies etaient plus importants pour les patients plus âges.

Objectif Evaluer la tolerance, la PK et la PD du dulaglutide chez le patient âge. Patients et Methodes Etude en double aveugle, parallele, chez 37 hommes et femmes (≥ 65 ans) atteints de DT2, randomises pour recevoir dulaglutide 0,5, 0,75, 1,5mg ou un placebo en sous-cutane hebdomadaire pendant 6 semaines. Prelevements sanguins realises pour analyses de PK et PD. Les analyses PD (glucose, peptide-C, insuline et HbA 1c ), ont ete realisees sur les valeurs absolues et les variations a partir de J-1. Resultats Les patients etaient âges de 65-76 ans (26 de 65-69 ans ; 10 de 70 – 75 ans ; 1>75 ans). Les doses de dulaglutide ont ete bien tolerees. La majorite des evenements indesirables (EIs) etaient digestifs, d'intensite legere et resolus sans intervention. L'incidence des EIs etait generalement similaire a toutes les doses et comparable au placebo. La PK du dulaglutide chez les patients âges atteints de DT2 correspondait a celle rapportee precedemment chez les patients 1c comparees au placebo. Conclusions Sur la base des donnees de tolerance de PK et de PD, le dulaglutide 1,5 mg hebdomadaire peut etre administre aux patients ≥ 65 ans sans ajustement de dose.

Objectif Le dulaglutide, un agoniste du recepteur du GLP-1 a administration hebdomadaire, a ete evalue dans les d'essais cliniques du programme AWARD, chez des patients adultes atteints d'un diabete de type 2. Dans 6 essais comparatifs (head to head) de phase 3, le dulaglutide a entraine une reduction significative de l'HbA 1c et des effets sur le poids. L'objectif de cette analyse a ete d'evaluer la relation entre la variation du poids et le controle glycemique chez des patients traites par dulaglutide. Patients et Methodes Les donnees d'HbA 1c et du poids a 26 semaines dans les six essais AWARD ont ete analysees. En raison des differences dans les schemas des etudes, des traitements de fond et des caracteristiques des patients a l'inclusion, les analyses ont ete conduites par essai et non pas combinees. Resultats Dans les etudes, une reduction de l'HbA 1c a ete observee chez 87 % – 97 % et 83 % – 95 % des patients traites par dulaglutide 1,5mg et 0,75mg, respectivement. Parmi les patients avec une reduction de l'HbA 1c , la majorite des patients ayant recu le dulaglutide 1,5mg a presente aussi une perte de poids (55 % – 83 %), ainsi que 41 % – 79 % du bras dulaglutide 0,75mg. La correlation entre les variations de l'HbA 1c et le poids etait minime ((− 0,3 1c , le poids et l'IMC a l'inclusion n'etaient pas correlees aux reponses ponderales. Conclusions Le dulaglutide a demontre un effet dose-dependant sur la perte de poids et la reduction d'HbA 1c . Le dulaglutide est une option therapeutique efficace, dans l'eventail des traitements du diabete, qui apporte a la fois une reduction d'HbA 1c et une perte de poids.

Objectifs DU, agoniste hebdomadaire du recepteur du GLP-1 (glucagon-like peptide-1) etait superieur a l’EX BID et non inferieur au LIR OD sur la reduction de l’HbA1c dans deux essais AWARD, dont nous presentons ici des donnees supplementaires d’auto-surveillance glycemique (ASG). Patients et methodes Des patients DT2 ont recu aleatoirement DU1,5 mg, DU0,75 mg, EX BID, ou placebo, associes avec metformine et pioglitazone (AWARD-1, n = 976), et DU1,5 mg ou LIR1,8 mg, associes avec metformine (AWARD-6, n = 599) (populations en intention de traiter). Dans les deux etudes, les variations de la glycemie plasmatique (GP) par ASG a la semaine 26 ont ete analysees selon un modele mixte de mesures repetees. Resultats DU a entraine une reduction des moyennes des moindres carres (MMC) de toutes les GP mesurees. Dans AWARD-1, les variations de la MMC de la totalite des 8 points de la GP etaient respectivement de -46,8, -42,1 et -37,5 mg/dL pour DU1,5 mg, DU0,75 mg et EX (p Discussion DU en prise hebdomadaire entraine une amelioration des profils d’ASG plus importante qu’EX en prise biquotidienne et comparable au LIR1,8 mg en prise quotidienne. DU est efficace sur la reduction de la GP pre et post-prandiale.

Objectif Determiner l'impact de la duree du diabete (DD) sur l'efficacite et la securite du dulaglutide et de l'insuline glargine chez des patients DT2. Patients et methodes Analyses post-hoc en sous-groupes de DD ( Resultats Les groupes etaient comparables a l'inclusion, dans les sous-groupes de DD. Pour chaque traitement (dulaglutide 1,5mg, dulaglutide 0,75mg et glargine) les variations de la moyenne (erreur type) des moindres carres de l'HbA1c par rapport au taux initial etaient (MMRM): DD p p p vs glargine). L'incidence des hypoglycemies totales (evenements/patient/an) etait respectivement (dulaglutide 1,5mg, dulaglutide 0,75mg et glargine): DD 10 ans: 6,68 ; 5,92 ; 7,99. Conclusion Dans l'etude AWARD-2, le traitement par dulaglutide en comparaison a l'insuline glargine ameliorait l'HbA1c et le poids sans augmenter le risque d'hypoglycemie, independamment de la DD. Declaration d’interet Les auteurs declarent avoir un interet avec un organisme prive, industriel ou commercial en relation avec le sujet presente. Jiten Vora: Research Support. Advisory Boards, Speaker Bureau: Sanofi-Aventis, Lilly, Novo Nordisk, MSD, BMS, Astra-Zeneca, Novartis, Boehringer Ingleheim, Takeda, GSK, Roche. Abbott Omolara Adetunji, Nan Jia, Valeria Pechtner, Rimma Shaginian: salaries de Ely Lilly.

Objectif Comparer les doses hebdomadaires de dulaglutide 1,5 mg et 0,75 mg au placebo a 26 semaines, exenatide 10 μg 2 fois par jour (AWARD-1) et a sitagliptine 100 mg/jour (AWARD-5) a 26 et 52 semaines chez des patients atteints de diabete de type 2 ayant un taux initial d’HbA1c moyen d’environ 8 %. Patients et methodes Les donnees des bras dulaglutide 1,5 mg, dulaglutide 0,75 mg et placebo ont ete poolees par traitement. Des comparaisons des variations d’HbA1c (moyenne des moindres carres [MMC] ± erreur-type) et du pourcentage de patients atteignant les valeurs cibles d’HbA1c Resultats A 26 semaines, dulaglutide 1,5 mg et 0,75 mg ont presente respectivement des reductions d’HbA1c de – 1,34 (0,05) % et de – 1,12 (0,05) %, significativement superieures a celles de l’exenatide (– 0,80 [0,06] %), sitagliptine (– 0,74 [0,06] %) et placebo (– 0,15 [0,06] %) (p Conclusion Compare aux autres traitements de la voie des incretines habituellement utilises, le dulaglutide hebdomadaire a presente une efficacite superieure jusqu’a 52 semaines. Ces reductions importantes d’HbA1c ont ete observees malgre un taux initial moyen d’HbA1c relativement bas.

This Phase 3, randomized, double-blind, parallel-arm, monotherapy study compared the efficacy and safety of 2 doses of dulaglutide (DU), a long-acting GLP-1-receptor agonist, to metformin (MET) in patients with early type 2 diabetes (mean 2.6 years) treated with diet and exercise alone or in combination with 1 oral antidiabetic medication (low dose for ≥ 3 months before screening).

Background: Information is lacking on the potential effect of n3 polyunsaturatedfattyacids(PUFAs)ontheadiposetissueofpatients with type 2 diabetes. Objective: We evaluated whether n3 PUFAs have additional effects on adiposity, insulin sensitivity, adipose tissue function (production of adipokines and inflammatory and atherogenic factors), and gene expression in type 2 diabetes. Design: Twenty-seven women with type 2 diabetes without hypertriglyceridemia were randomly allocated in a double-blind parallel design to 2 mo of 3 g/d of either fish oil (1.8 g n3 PUFAs) or placebo (paraffin oil). Results: Although body weight and energy intake measured by use of a food diary were unchanged, total fat mass (P 0.019) and subcutaneous adipocyte diameter (P 0.0018) were lower in the fish oil group than in the placebo group. Insulin sensitivity was not significantlydifferentbetweenthe2groups(measuredbyhomeostasis model assessment in all patients and by euglycemichyperinsulinemic clamp in a subgroup of 5 patients per group). By contrast, atherogenic risk factors, including plasma triacylglycerol (P 0.03), the ratio of triacylglycerol to HDL cholesterol (atherogenic index, P 0.03), and plasma plasminogen activator inhibitor-1 (P 0.01), were lower in the fish oil group than in the placebo group. In addition, a subset of inflammation-related genes wasreducedinsubcutaneousadiposetissueafterthefishoil,butnot the placebo, treatment. Conclusions: A moderate dose of n3 PUFAs for 2 mo reduced adiposity and atherogenic markers without deterioration of insulin sensitivity in subjects with type 2 diabetes. Some adipose tissue inflammation-related genes were also reduced. These beneficial effects could be linked to morphologic and inflammatory changes in adipose tissue. This trial was registered at clinicaltrials.gov as NCT0037. Am J Clin Nutr 2007;86:1670–9.