39 research outputs found
Efficacy and safety of dulaglutide in the treatment of type 2 diabetes: A comprehensive review of the dulaglutide clinical data focusing on the AWARD phase 3 clinical trial program
No full textDulaglutide (DU) is a once weekly glucagon-like peptide-1 receptor agonist (GLP-1 RA) approved for the treatment of type 2 diabetes mellitus (T2DM). Glycaemic efficacy and safety characteristics of dulaglutide have been assessed in six Phase 3 studies in the AWARD program. The objective of this review article is to summarize these results from the six completed AWARD studies. At the primary endpoint, in five of the six studies, once weekly dulaglutide 1.5 mg was superior to the active comparator [exenatide, insulin glargine (two studies), metformin, and sitagliptin], with a greater proportion of patients reaching glycated hemoglobin A1c (HbA1c) targets of <7.0% (53.0 mmol/mol) and ≤6.5% (47.5 mmol/mol). Dulaglutide 1.5 mg was non-inferior to liraglutide in AWARD-6. Once weekly dulaglutide 0.75 mg was evaluated in five of these trials and demonstrated superiority to the active comparator in four of five AWARD studies (exenatide, glargine, metformin, and sitagliptin), and non-inferiority to glargine in the AWARD-2 study. Similar to other GLP-1 receptor agonists, treatment with dulaglutide was associated with weight loss or attenuation of weight gain and low rates of hypoglycaemia when used alone or with non-insulin-secretagogue therapy. The most frequently reported adverse events were gastrointestinal, including nausea, vomiting, and diarrhea. The incidence of dulaglutide antidrug antibody formation was 1-2.8% with rare injection site reactions. In conclusion, dulaglutide is an effective treatment for T2DM and has an acceptable tolerability and safety profile
Effect of once weekly dulaglutide by baseline beta-cell function in people with type 2 diabetes in the AWARD programme
No full textGlucagon-like peptide-1 receptor agonists lower blood glucose in type 2 diabetes (T2D) partially through glucose-dependent stimulation of insulin secretion. The aim of this study was to investigate whether beta-cell function (as measured by HOMA2-%B) at baseline affects the glycaemic response to dulaglutide. Dulaglutide-treated patients from AWARD-1, AWARD-3 and AWARD-6 clinical studies were categorised based on their homeostatic model assessment of beta-cell function (HOMA2-%B) tertiles. Changes in glycaemic measures in response to treatment with once-weekly dulaglutide were evaluated in each HOMA2-%B tertile. Patients with low HOMA2-%B had higher baseline glycated haemoglobin (HbA1c), fasting and postprandial blood glucose, and longer duration of diabetes (P <.001, all) (mean low, middle and high tertiles with dulaglutide 1.5 mg: HOMAB-2%B, 31%, 58%, 109%; HbA1c, 8.7%, 7.7%, 7.3%, respectively). At 26 weeks, the low tertile experienced larger reductions in HbA1c compared to the high tertile with dulaglutide 1.5 mg (mean; −1.55% vs. −0.98% [−16.94 vs. −10.71 mmol/mol]). Differences between low and high tertiles disappeared when adjusted for baseline HbA1c (LSM; −1.00 vs. −1.18% [−10.93 vs. −12.90 mmol/mol]). Greater decreases in fasting blood glucose and greater increases in fasting C-peptide were observed in the low tertile. Similar increases in HOMA2-%B were observed in all tertiles. Dulaglutide demonstrated clinically relevant HbA1c reduction irrespective of estimated baseline beta-cell function
Interaction between endogenously produced carbon monoxide and nitric oxide in regulation of renal afferent arterioles
No full textRenal Heme Oxygenase-1 Induction with Hemin Augments Renal Hemodynamics, Renal Autoregulation, and Excretory Function
No full textHeme oxygenases (HO-1; HO-2) catalyze conversion of heme to free iron, carbon monoxide, and biliverdin/bilirubin. To determine the effects of renal HO-1 induction on blood pressure and renal function, normal control rats (n=7) and hemin-treated rats (n=6) were studied. Renal clearance studies were performed on anesthetized rats to assess renal function; renal blood flow (RBF) was measured using a transonic flow probe placed around the left renal artery. Hemin treatment significantly induced renal HO-1. Mean arterial pressure and heart rate were not different (115±5 mmHg versus 112±4 mmHg and 331±16 versus 346±10 bpm). However, RBF was significantly higher (9.1±0.8 versus 7.0±0.5 mL/min/g, P<0.05), and renal vascular resistance was significantly lower (13.0±0.9 versus 16.6±1.4 [mmHg/(mL/min/g)], P<0.05). Likewise, glomerular filtration rate was significantly elevated (1.4±0.2 versus 1.0±0.1 mL/min/g, P<0.05), and urine flow and sodium excretion were also higher (18.9±3.9 versus 8.2±1.0 μL/min/g, P<0.05 and 1.9±0.6 versus 0.2±0.1 μmol/min/g, P<0.05, resp.). The plateau of the autoregulation relationship was elevated, and renal vascular responses to acute angiotensin II infusion were attenuated in hemin-treated rats reflecting the vasodilatory effect of HO-1 induction. We conclude that renal HO-1 induction augments renal function which may contribute to the antihypertensive effects of HO-1 induction observed in hypertension models
Increase in heme oxygenase-1 levels ameliorates renovascular hypertension
No full textIncrease in heme oxygenase-1 levels ameliorates renovascular hypertensionBackgroundThe heme oxygenase system (HO-1 and HO-2) catalyzes the conversion of heme to free iron, carbon monoxide (CO), a vasodepressor, and biliverdin, which is further converted to bilirubin, an antioxidant. HO-1 induction has been shown to suppress arachidonic acid metabolism by cytochrome P450 (CYP450) monooxygenases and cyclooxygenases (COX), and to decrease blood pressure in spontaneously hypertensive rats (SHR). The Goldblatt 2K1C model is a model of renovascular hypertension in which there is increased expression of COX-2 in the macula densa and increased renin release from the juxtaglomerular apparatus of the clipped kidney. We examined whether HO-1 overexpression, as a prophylactic approach, would attenuate renovascular hypertension and evaluated potential mechanisms that may account for its effect.Methods2K1C rats were treated with cobalt protoporphyrin (CoPP) or tin mesoporphyrin (SnMP) one day before surgery and weekly for three weeks thereafter. We measured systolic blood pressure, HO activity, HO-1, HO-2, COX-1 and COX-2 protein expression, heme content, and nitrotyrosine levels as indices of oxidative stress. Urinary prostaglandin excretion (PGE2), plasma renin activity (PRA), and plasma aldosterone levels were also measured.ResultsCoPP administration induced renal HO-1 expression by 20-fold and HO activity by 6-fold. This was associated with a reduction in heme content, nitrotyrosine levels, COX-2 expression and urinary PGE2 excretion, and attenuation of the development of hypertension in the 2K1C rats. There was no decrease in plasma renin activity; however, plasma aldosterone levels were significantly lower. In the 2K1C SnMP-treated rats, blood pressure was significantly higher than that of untreated 2K1C rats throughout the study, and the difference in the size of the smaller left clipped kidney compared to the nonclipped right kidney was significantly increased.ConclusionThese findings define an action of prolonged HO-1 induction to interrupt and counteract the influence of the renin-angiotensin-aldosterone system (RAAS) to increase in blood pressure in the 2K1C model of renovascular hypertension. Multiple mechanisms include a decrease in oxidative stress as indicated by the decrease in cellular heme and nitrotyrosine levels, an anti-inflammatory action as evidenced by a decrease in COX-2 and PGE2, interference with the action of angiontensin II (Ang II) as evidenced by an increase in PRA in the face of a decrease in PGE2 and aldosterone, as well as the inhibition of aldosterone synthesis
Cardiovascular safety for once-weekly dulaglutide in type 2 diabetes: a pre-specified meta-analysis of prospectively adjudicated cardiovascular events
No full textGlucagon-Like Peptide-1 Receptor Agonist Use and Renal Impairment: A Retrospective Analysis of Electronic Health Records Database in the US Population
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Baseline factors associated with glycaemic response to treatment with once‐weekly dulaglutide in patients with type 2 diabetes
No full textGlucagon-Like Peptide-1 Receptor Agonist Use and Renal Impairment: A Retrospective Analysis of an Electronic Health Records Database in the U.S. Population
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