Differential effects of once‐weekly glucagon‐like peptide‐1 receptor agonist dulaglutide and metformin on pancreatic <i>β</i>‐cell and insulin sensitivity during a standardized test meal in patients with type 2 diabetes

Mari, Andrea; Prato, Stefano Del; Ludvik, Bernhard; Miličević, Zvonko; Peña, Amparo de la; Shurzinske, Linda; Karanikas, Chrisanthi A.; Pechtner, V.

doi:10.1111/dom.12671

Cited by 17 publications

(16 citation statements)

References 21 publications

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“…Similar improvements in beta-cell function with dulaglutide were also reported under fasting conditions, as well as after a standardised test meal. 21 While the mechanism of improved beta-cell function with GLP-1RAs is not fully understood, their stimulation of insulin biosynthesis, excretion, and improvements in glucose sensitivity of betacells, may play an important role. 22 Overall, the glycaemic response to dulaglutide is maintained regardless of differences in baseline beta-cell function.…”

Section: Changes In Pre-meal Glucose 2-hour Ppg and 2-hour Smpgmentioning

confidence: 99%

Effect of once weekly dulaglutide by baseline beta‐cell function in people with type 2 diabetes in the AWARD programme

Mathieu

Prato

Botros

et al. 2018

Diabetes Obesity Metabolism

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Glucagon‐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.

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Section: Changes In Pre-meal Glucose 2-hour Ppg and 2-hour Smpgmentioning

confidence: 99%

Effect of once weekly dulaglutide by baseline beta‐cell function in people with type 2 diabetes in the AWARD programme

Mathieu

Prato

Botros

et al. 2018

Diabetes Obesity Metabolism

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“…1 As such, GLP-1 protected human beta cells from glucose and lipid toxicity. 7,47,49 It could be hypothesized that prolonged stimulation of insulin secretion may not be beneficial in the long-term, as is the case for sulfonylureas, by imposing secretory stress on beta cells. 41,42 Finally, GLP-1 was shown to reduce the expression of several pro-inflammatory cytokines in isolated human islets.…”

Section: Beta-cell Dysfunction In Type 2 Diabetesmentioning

confidence: 99%

“…[44][45][46][47] GLP-1 receptor stimulation, reduce blood glucose levels primarily by around-the-clock (ie, both fasting and postprandial) hyperinsulinaemia, and thus have a markedly different profile compared to GLP-1 peptide. 7,47,49 It could be hypothesized that prolonged stimulation of insulin secretion may not be beneficial in the long-term, as is the case for sulfonylureas, by imposing secretory stress on beta cells. Interestingly, semaglutide, a novel once-weekly GLP-1 receptor agonist currently in development, was shown to decrease the circulating proinsulin/insulin ratio after 12 weeks of treatment 50 ; however, this ratio was increased after 2 years, pointing towards beta-cell stress after more prolonged treatment.…”

Section: -Resistant Glp-1 Receptor Agonists and Dpp-4 Inhibitors Havmentioning

confidence: 99%

Improving glycaemic control in type 2 diabetes: Stimulate insulin secretion or provide beta‐cell rest?

Raalte

Verchere

2017

Diabetes Obesity Metabolism

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Type 2 diabetes (T2D) is characterized by a gradual decline in pancreatic beta cell function that determines the progressive course of the disease. While beta-cell failure is an important contributor to hyperglycaemia, chronic hyperglycaemia itself is also detrimental for beta-cell function, probably by inducing prolonged secretory stress on the beta cell as well as through direct glucotoxic mechanisms that have not been fully defined. For years, research has been carried out in search of therapies targeting hyperglycaemia that preserve long-term beta-cell function in T2D, a quest that is still ongoing. Current strategies aim to improve glycaemic control, either by promoting endogenous insulin secretion, such as sulfonylureas, or by mechanisms that may impact the beta cell indirectly, for example, providing beta-cell rest through insulin treatment. Although overall long-term success is limited with currently available interventions, in this review we argue that strategies that induce beta-cell rest have considerable potential to preserve long-term beta-cell function. This is based on laboratory-based studies involving human islets as well as clinical studies employing intensive insulin therapy, thiazolidinediones, bariatric surgery, short-acting glucagon-like peptide (GLP)-1 receptor agonists and a promising new class of diabetes drugs, sodium-glucose-linked transporter (SGLT)-2 inhibitors. Nevertheless, a lack of long-term clinical studies that focus on beta-cell function for the newer glucose-lowering agents, as well as commonly used combination therapies, preclude a straightforward conclusion; this gap in our knowledge should be a focus of future studies.

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Section: Introductionmentioning

confidence: 99%

“…The pharmacodynamic (PD) effects of dulaglutide have been assessed in several studies in the US [ 4 , 5 ] and Japan (Eli Lilly and Co., unpublished data). In a global phase 3 study (AWARD-3), dulaglutide 0.75 mg and 1.5 mg were found to improve postprandial glycemic control (after a standardized test meal) at 26 and 52 weeks [ 4 ]. In global [ 5 ] and Japanese (Eli Lilly and Co., unpublished data) phase 1 studies, several doses of dulaglutide were found to improve postprandial glycemic control (after a standardized test meal) as early as 2 days after a single dose; however, none of the studies investigated the profile of the PD effects during the first few weeks on dulaglutide at 0.75 mg.…”

Section: Introductionmentioning

confidence: 99%

Effect of Once-Weekly Dulaglutide on Glucose Levels in Japanese Patients with Type 2 Diabetes: Findings from a Phase 4, Randomized Controlled Trial

et al. 2019

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Introduction Dulaglutide is a recombinant glucagon-like peptide-1 immunoglobulin G4 Fc fusion protein approved for treating patients with type 2 diabetes (T2D). The aim of this study was to assess postprandial data over 4 weeks for dulaglutide (0.75 mg) versus placebo after a standardized test meal in Japanese patients with T2D. Methods The pharmacodynamic (PD) effects of once-weekly dulaglutide (0.75 mg) in Japanese patients with T2D on diet and exercise therapy ( N = 12) were evaluated by assessing postprandial data up to week 4 in a phase 4, single-center, randomized, cross-over, single-blind, placebo-controlled study. The primary end point was the change in 4-h glucose area under the concentration versus time curve [AUC (0–4 h)] from baseline to week 4. Secondary end points included changes from baseline in other PD parameters (insulin, C-peptide, glucagon, and triglycerides) at weeks 1, 2, and 4 and the safety and tolerability of dulaglutide 0.75 mg. Continuous glucose monitoring (CGM) during the 1st week was performed as an exploratory measure in each treatment period. Results The decrease in AUC (0–4 h) from baseline to week 4 following dulaglutide administration was statistically significant compared with placebo at weeks 1, 2, and 4 ( P < 0.0001). Insulin and C-peptide levels were also significantly increased ( P < 0.05) with dulaglutide versus placebo at weeks 2 and 4. There were no statistically significant differences between groups in glucagon and triglyceride levels. Daily average glucose concentrations were decreased on the day after the first administration of dulaglutide and remained at similar levels for 4 days. The incidence of treatment-emergent adverse events was slightly higher with dulaglutide versus placebo. Conclusion In conclusion, dulaglutide decreased postprandial glucose from week 1 in Japanese patients with T2D, indicating that dulaglutide treatment is associated with favorable PD effects soon after treatment begins. Trial Registration ClinicalTrials.gov identifier: NCT03315780. Funding Eli Lilly Japan K.K. (Kobe, Japan). Electronic supplementary material The online version of this article (10.1007/s13300-019-0605-7) contains supplementary material, which is available to authorized users.

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Differential effects of once‐weekly glucagon‐like peptide‐1 receptor agonist dulaglutide and metformin on pancreatic β‐cell and insulin sensitivity during a standardized test meal in patients with type 2 diabetes

Cited by 17 publications

References 21 publications

Effect of once weekly dulaglutide by baseline beta‐cell function in people with type 2 diabetes in the AWARD programme

Effect of once weekly dulaglutide by baseline beta‐cell function in people with type 2 diabetes in the AWARD programme

Improving glycaemic control in type 2 diabetes: Stimulate insulin secretion or provide beta‐cell rest?

Effect of Once-Weekly Dulaglutide on Glucose Levels in Japanese Patients with Type 2 Diabetes: Findings from a Phase 4, Randomized Controlled Trial

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