By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD
The FDA has approved a third long-acting, once-weekly, glucagon-like peptide (GLP-1) receptor agonist for the treatment of type 2 diabetes mellitus, joining exenetide ER and albiglutide. Dulaglutide is made up of two identical human-based GLP-1 analogs linked to a modified human IgG4 Fc fragment. This makes the molecule resistant to degradation by DPP-4, slows absorption, reduces renal clearance, and extends the elimination half-life to approximately 5 days. Dulaglutide is marketed by Eli Lilly as Trulicity.
INDICATIONS
Dulaglutide is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.1
DOSAGE
The recommended starting dose is 0.75 mg given subcutaneously once weekly.1 The dose can be increased to 1.5 mg if additional glycemic control is needed. The drug is administered in the abdomen, thigh, or upper arm. Dulaglutide is available as 0.75 mg and 1.5 mg single-dose pen or prefilled syringes.
POTENTIAL ADVANTAGES
The long elimination half-life allows for once-weekly administration.
POTENTIAL DISADVANTAGES
Dulaglutide is contraindicated in patients with personal or family history of medullary thyroid carcinoma or Multiple Endocrine Neoplasma syndrome type 2.1 It is associated with an increase incidence of thyroid C-cell tumors in rats. Dulaglutide is associated with an increased risk of pancreatitis.1 GLP-1 receptor agonists have been associated with acute renal failure and worsening of chronic renal failure in postmarketing reports.1 Most commonly reported adverse events (% vs placebo) are nausea (12-21% vs 5%), diarrhea (9-13% vs 7%), and vomiting (6-13% vs 2%).1
COMMENTS
Dulaglutide has been evaluated in five pivotal trials as monotherapy as well as an add-on to a number of antidiabetic drugs and drug combinations, including metformin, metformin and sulfonylurea, metformin and pioglitazone, and glargine insulin with or without an oral medication.1-7 Studies were 52 weeks in duration, with efficacy assessment at 26 weeks, 78 weeks, or 104 weeks, with 52-week endpoints. The primary endpoint was reduction in HbA1c from baseline. Non-inferiority and superiority were compared to active comparator across the two doses (0.75 mg and 1.5 mg), with a prespecified non-inferiority margin of 0.4%.2 In the monotherapy study (n = 807), subjects inadequately controlled with diet and exercise or diet and exercise and one anti-diabetic drug at submaximal dose, with an average baseline HbA1c of 7.6%, were randomized to dulaglutide 0.75 mg, 1.5 mg, or metformin (1500 to 2000 mg/day).5 Changes from baseline were -0.7, -0.8, and -0.6. Both doses were non-inferior, as well as superior to metformin. However, as one FDA reviewer pointed out, most subjects failed on a submaximal dose of metformin (median interquartile range, 1000 mg; 850-1250). This means that the active comparator arm had an increase in the dose of metformin, potentially biasing dulaglutide.2 In the add-on studies, dulaglitide was reported to be more effective than sitagliptin 100 mg when added to metformin (52-week endpoint),4 more effective than insulin glargine when added to metformin and glimepiride (52-week) (1.5 mg dose),6 more effective than exenatide when added to metformin and pioglitazone (26 weeks),3 more effective than insulin glargine added to insulin lispro (26 weeks).7 Similarly, the FDA reviewer was concerned about claims of superiority due to selection bias and suboptimal dose titration of the comparator.2 Dulaglutide was shown to be noninferior to once-daily liraglutide with similar side effects.8 There are no comparative studies with the other once-weekly products; however, albiglutite did not meet noninferiority criteria compared to liraglutide.9
CLINICAL IMPLICATIONS
Duluglitide is the third long-acting GLP-1 receptor agonist on the market. The first, exenetide, uses an extended-release microsphere technology, while albiglutide is two tandem copies of a modified human GLP-1 fused to human albumin. Dulaglutide is effective; however, reports of superiority to comparators should be interpreted with caution. Duluglitide, as with other GLP-1 agonists, is not recommended for first-line treatment of type 2 diabetes mellitus. Dulaglutide is the most expensive of the once-weekly drugs with a monthly costs of $482 compared to $440 for exenatide ER and $326 for albiglutide.
REFERENCES
- Trulicity Prescribing Information. Eli Lilly and Company. September 2014.
- Dulaglutide Summary Review. Center for Drug Evaluation and Research. 9/18/2014. accessdata.fda.gov. Accessed 11/20/14.
- Wysham C, et al. Diabetes Care 2014’37:37:2159-2167.
- Nauck M, et al. Diabetes Care 2014;37:2149-2158.
- Umpierrez G, et al. Diabetes Care 2014;37:2168-2176.
- Giorgino F, et al. Diabetes 2014;63(suppl 1):A87.
- Jendle JRJ, et al. Diabetes 2014;63:A246.
- Dungan KM, et al. Lancet 2014;384:1349-1357.Pratley RE, et al. Lancet Diab Endocrinol 2014;2:289-297.
The FDA has approved a third long-acting, once-weekly, glucagon-like peptide (GLP-1) receptor agonist for the treatment of type 2 diabetes mellitus, joining exenetide ER and albiglutide. Dulaglutide is made up of two identical human-based GLP-1 analogs linked to a modified human IgG4 Fc fragment. This makes the molecule resistant to degradation by DPP-4, slows absorption, reduces renal clearance, and extends the elimination half-life to approximately 5 days. Dulaglutide is marketed by Eli Lilly as Trulicity.
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