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

Jendle, Johan; Grunberger, George; Blevins, Thomas; Giorgino, Francesco; Hietpas, Ryan T.; Botros, Fady T.

doi:10.1002/dmrr.2810

Cited by 123 publications

(93 citation statements)

References 58 publications

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“…Further, and unlike those with metformin, the GI side effects usually are mild to moderate, waning over the first 4–6 weeks of initiating therapy. The percentage of patients who discontinue long-acting GLP-1 RAs because of GI side effects is significantly lower than that of metformin (67). Some postmarketing reports have suggested an increased risk of acute pancreatitis with GLP-1 RA use.…”

Section: Glp-1 Ras Not Metformin Should Be the First-line Therapy Imentioning

confidence: 99%

Is It Time to Change the Type 2 Diabetes Treatment Paradigm? Yes! GLP-1 RAs Should Replace Metformin in the Type 2 Diabetes Algorithm

Abdul‐Ghani

2017

Diabetes Care

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Most treatment guidelines, including those from the American Diabetes Association/European Association for the Study of Diabetes and the International Diabetes Federation, suggest metformin be used as the first-line therapy after diet and exercise. This recommendation is based on the considerable body of evidence that has accumulated over the last 30 years, but it is also supported on clinical grounds based on metformin’s affordability and tolerability. As such, metformin is the most commonly used oral antihyperglycemic agent in the U.S. However, based on the release of newer agents over the recent past, some have suggested that the modern approach to disease management should be based upon identification of its etiology and correcting the underlying biological disturbances. That is, we should use interventions that normalize or at least ameliorate the recognized derangements in physiology that drive the clinical manifestation of disease, in this circumstance, hyperglycemia. Thus, it is argued that therapeutic interventions that target glycemia but do not correct the underlying pathogenic disturbances are unlikely to result in a sustained benefit on the disease process. In our field, there is an evolving debate regarding the suggested first step in diabetes management and a call for a new paradigm. Given the current controversy, we provide a Point-Counterpoint debate on this issue. In the point narrative below that precedes the counterpoint narrative, Drs. Abdul-Ghani and DeFronzo provide their argument that a treatment approach for type 2 diabetes based upon correcting the underlying pathophysiological abnormalities responsible for the development of hyperglycemia provides the best therapeutic strategy. Such an approach requires a change in the recommendation for first-line therapy from metformin to a GLP-1 receptor agonist. In the counterpoint narrative that follows Drs. Abdul-Ghani and DeFronzo’s contribution, Dr. Inzucchi argues that, based on the medical community’s extensive experience and the drug’s demonstrated efficacy, safety, low cost, and cardiovascular benefits, metformin should remain the “foundation therapy” for all patients with type 2 diabetes, barring contraindications.—William T. CefaluChief Scientific, Medical & Mission Officer, American Diabetes Association

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Section: Glp-1 Ras Not Metformin Should Be the First-line Therapy Imentioning

confidence: 99%

Is It Time to Change the Type 2 Diabetes Treatment Paradigm? Yes! GLP-1 RAs Should Replace Metformin in the Type 2 Diabetes Algorithm

Abdul‐Ghani

2017

Diabetes Care

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“…6 In the AWARD-7 study, dulaglutide treatment was associated with smaller decline in eGFR and reduction in BW compared to insulin glargine (glargine) treatment in participants with T2D and moderate-to-severe CKD. 6 In the AWARD-7 study, dulaglutide treatment was associated with smaller decline in eGFR and reduction in BW compared to insulin glargine (glargine) treatment in participants with T2D and moderate-to-severe CKD.…”

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

Body weight and eGFR during dulaglutide treatment in type 2 diabetes and moderate‐to‐severe chronic kidney disease (AWARD‐7)

Lakshmanan

Rayner

Zimmermann

et al. 2019

Diabetes Obesity Metabolism

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In patients with type 2 dibetes and moderate-to-severe chronic kidney disease, dulaglutide treatment led to body weight (BW) loss and lesser eGFR decline compared to insulin glargine.As BW may affect muscle mass, creatinine-based eGFR can be altered independently of kidney function. Cystatin C-based eGFR is not affected by muscle mass. The objective of this post-hoc analysis was to determine whether the lesser eGFR decline with dulaglutide was related to BW loss. Baseline characteristics were similar between treatments ([mean ± SD] age, 64.6 ± 8.6 years; women, 48%; BW, 89.1 ± 17.7 kg; eGFR [CKD-EPI-cystatin C] 38 ± 14 mL/min/1.73m 2 ). BW decreased with dulaglutide 1.5 and 0.75 mg and increased with insulin glargine ([LSM change (SE)], −2.66 [0.47] kg and −1.71 [0.45] vs 1.57 [0.43] kg; P < 0.001). Changes in eGFR were not significant with dulaglutide 1.5 and 0.75 mg, but eGFR significantly decreased with insulin glargine (eGFR-CKD-EPI-cystatin C [LSM change (95%CI)], −0.7 [−2.5, 1.0] and −0.7 [−2.4, 1.1] vs −3.3 [−5.1, −1.6] mL/min/1.73 m 2 ; P ≤ 0.037 vs glargine). Changes in BW did not correlate with changes in eGFR-CKD-EPI-cystatin C (r = −0.041; n = 471; P = 0.379) or eGFR-CKD-EPIcreatinine (r = −0.074; n = 473; P = 0.106). In conclusion, the lesser decline in eGFR observed with dulaglutide was not influenced by BW loss. K E Y W O R D S GLP-1, type 2 diabetes | INTRODUCTIONThe leading cause of chronic kidney disease (CKD) worldwide is diabetes. 1,2 Patients with moderate-to-severe CKD (eGFR of <60 to ≥15 mL/min/1.73m 2 ) and type 2 diabetes (T2D) have limited treatment options for hyperglycaemia. 2,3 Furthermore, evaluation of the effects of anti-hyperglycaemic agents on kidney function is crucial for patient safety. 2,4 Direct measurement of the glomerular filtration rate (GFR) by administration of exogenous clearance markers is laborious and not widely available in clinical settings. In daily practice, the estimated GFR (eGFR) is typically based on serum creatinine, but is subject to certain provisos. The serum creatinine level must be in steady-state when rates of production from muscle and elimination by the kidney are equilibrated. As production of serum creatinine is highly dependent on muscle mass, changes in body weight (BW) driven by alterations in muscle mass affect serum creatinine levels. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) cause BW loss, raising the concern that serum creatinine may not accurately reflect eGFR if there are associated changes in muscle mass. As cystatin C is a marker for eGFR that is not dependent on muscle, it may provide a more accurate eGFR in this context. 5Dulaglutide is a once-weekly GLP-1 RA that demonstrates glycaemic efficacy and BW loss. 6 In the AWARD-7 study, dulaglutide treatment was associated with smaller decline in eGFR and reduction in BW compared to insulin glargine (glargine) treatment in participants with T2D and moderate-to-severe CKD. 7 In the AWARD-7 study, eGFR was evaluated with both creatinine and cystatin C. The

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“…This finding suggests that increased dissemination of information to targeted groups of physicians may be useful for ensuring that all appropriate treatment options are considered. Hence, although there have already been published primary manuscripts and reviews [25], this review article is intended to provide practicing physicians with an updated overview of dulaglutide efficacy data, safety profile, and key patientreported outcomes (PROs) from the clinical program.…”

Section: Introductionmentioning

confidence: 99%

Dulaglutide in the treatment of adult type 2 diabetes: a perspective for primary care providers

Anderson¹,

Thieu

Boye

et al. 2016

Postgraduate Medicine

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Approximately 90% of T2D patients in the US are diagnosed and treated in the primary care setting, and the majority of the burden of disease management falls to primary care providers. Here, we discuss the clinical data for once weekly dulaglutide, e.g. the results of seven completed Phase 3 trials, patient preference studies, patient reported outcomes (PRO), and clinical data surrounding the dulaglutide administration device. Dulaglutide 1.5 mg once weekly demonstrated superiority to placebo, metformin, sitagliptin, exenatide BID, and insulin glargine (in 2 trials), and non-inferiority to liraglutide in reduction of HbA1c from baseline, with an acceptable safety profile. Dulaglutide-treated patients achieved the composite endpoint of an HbA1c <7.0% with no hypoglycemia, no severe hypoglycemia, and no weight gain significantly more than metformin, sitagliptin, exenatide BID or insulin glargine treated patients. Dulaglutide consistently showed an early onset of glycemic control, lasting up to 104 weeks. Additionally, PRO and patient preference data support the benefit of once weekly dulaglutide for the treatment of T2D. ARTICLE HISTORY

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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

Cited by 123 publications

References 58 publications

Is It Time to Change the Type 2 Diabetes Treatment Paradigm? Yes! GLP-1 RAs Should Replace Metformin in the Type 2 Diabetes Algorithm

Is It Time to Change the Type 2 Diabetes Treatment Paradigm? Yes! GLP-1 RAs Should Replace Metformin in the Type 2 Diabetes Algorithm

Body weight and eGFR during dulaglutide treatment in type 2 diabetes and moderate‐to‐severe chronic kidney disease (AWARD‐7)

Dulaglutide in the treatment of adult type 2 diabetes: a perspective for primary care providers

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