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Trulicity ® (dulaglutide)
This information is intended for UK registered healthcare professionals only as a scientific exchange in response to your search for information. For current prescribing information for all Lilly products, including Summaries of Product Characteristics, Patient Information Leaflets and Instructions for Use, please visit: www.medicines.org.uk (England, Scotland, Wales) or www.emcmedicines.com/en-GB/northernireland/ (Northern Ireland).
Is there a Risk of Pancreatitis with Trulicity® (dulaglutide)?
Acute pancreatitis has been reported in association with dulaglutide In clinical trials. The use of GLP‑1 receptor agonists have been associated with a risk of developing acute pancreatitis.
Content Overview
How many cases of pancreatitis were reported in the dulaglutide clinical program?
The pancreatic safety of dulaglutide was assessed in an integrated analysis of 4 phase 2 and 5 phase 3 studies in 6005 patients with Type 2 Diabetes (T2D).1
In the integrated analysis, a total of 203 events were adjudicated in 151 patients. Pancreatitis was confirmed in 9 patients that included
- 5 patients treated with dulaglutide
- 3 patients treated with sitagliptin, and
- 1 patient receiving placebo.1
The incidence of acute pancreatitis was
- 0.07 % for dulaglutide compared to
- 0.14 % for placebo.
Acute pancreatitis and pancreatitis have also been reported in the post-marketing setting.2
All 5 patients with confirmed pancreatitis who were being treated with dulaglutide had elevated pancreatic enzymes at baseline prior to initiation of dulaglutide.1
Acute Pancreatitis
An event was adjudicated as confirmed acute pancreatitis if at least 2 of 3 criteria were met, namely,
- severe upper abdominal pain
- serum amylase and/or lipase level ≥3 times the upper limit of normal (ULN) range, or
- imaging results that indicated inflammatory changes in the pancreatic parenchyma.1
The normal reference limits used for evaluation of pancreatic enzymes were
- 0 to 60 units/L for lipase
- 13 to 53 units/L for pancreatic amylase, and
- 20 to 112 units/L for total amylase.1
Of the 9 patients with adjudicated pancreatitis, 7 patients had acute pancreatitis including
- 3 patients treated with dulaglutide
- 3 patients treated with sitagliptin, and
- 1 patient receiving placebo.1
The type of pancreatitis was not determined in 1 of the 3 patients receiving dulaglutide. For data analysis, this case was categorized as “acute.” In the assessment of risk factors for acute pancreatitis, this patient had cholelithiasis.1
The exposure-adjusted incidence rates of acute pancreatitis were
- 0.85 patients/1000 patient-years in the dulaglutide group
- 4.71 patients/1000 patient-years in the sitagliptin group, and
- 3.52 patients/1000 patient-years in the placebo group.1
Chronic Pancreatitis
There were 2 reported events of chronic pancreatitis in patients receiving dulaglutide.
The exposure-adjusted incidence rate of chronic pancreatitis was 0.57 patients/1000 patient-years in the dulaglutide group.1
Pancreatitis in the AWARD-11 Study
The AWARD-11 trial was a phase 3, randomized, double-blind, active-controlled, parallel-arm study that assessed the efficacy and safety of dulaglutide 3.0 mg and dulaglutide 4.5 mg compared to dulaglutide 1.5 mg in patients with inadequately controlled type 2 diabetes on concomitant metformin therapy.3,4
From baseline through week 52 (final endpoint), 6 cases of pancreatitis (all acute) were confirmed by adjudication.4
Pancreatitis was reported in
- 0.2% (1 of 612) of patients in the dulaglutide 1.5 mg arm
- 0.3% (2 of 616) of patients in the dulaglutide 3.0 mg arm, and
- 0.5% (3 of 614) of patients in the dulaglutide 4.5 mg arm.4
Importantly, one patient who was assigned to dulaglutide 4.5 mg, with a confirmed case of acute pancreatitis, had a previously undisclosed history of pancreatitis and would have been excluded from enrollment had this been known at the time of screening.4
Pancreatitis in the REWIND Study
REWIND was an event-driven, randomized, double-blind, phase 3 cardiovascular (CV) outcomes study of dulaglutide.5
The study evaluated the effect on major adverse cardiovascular events (MACE-3, defined as the composite of CV death, nonfatal myocardial infarction, or nonfatal stroke) and other serious outcomes with once-weekly dulaglutide 1.5 mg treatment compared with placebo when added to standard of care in participants 50 years of age and older with type 2 diabetes
- with established CV disease, or
- without established CV disease with multiple CV risk factors.5
Dulaglutide 1.5 mg significantly reduced MACE-3 when compared with placebo (Hazard ratio [HR] = 0.88 [95% CI: 0.79-0.99]; p = .026), demonstrating a decrease in CV events and showing safety in a population that included a majority of participants without established CV disease.5
The instance of prespecified adverse events, such as pancreatitis, did not differ significantly between the dulaglutide and placebo treatment groups (Acute Pancreatitis in the Dulaglutide REWIND Study).5
|
Dulaglutide |
Placebo |
P Value |
Acute pancreatitisa |
23 |
13 |
0.11 |
Imaging and enzymesb |
4 |
3 |
0.71 |
Imaging, enzymes, and symptomsc |
4 |
3 |
0.71 |
Abbreviation: REWIND = Researching cardiovascular Events with a Weekly INcretin in Diabetes.
aBased on the first occurrence of acute pancreatitis diagnosed on the basis of at least 2 of 3 diagnostic criteria which include symptoms, elevated pancreatic enzymes, and an abnormal pancreatic image.
bSubset of patients with acute pancreatitis who also had both elevated pancreatic enzymes and an abnormal pancreatic image.
cSubset of patients with acute pancreatitis who had elevated pancreatic enzymes, an abnormal pancreatic image, and symptoms.
Pancreatitis in Pediatric Patients Taking Dulaglutide: AWARD-PEDS Study
AWARD-PEDS was a phase 3, randomized, placebo-controlled study that assessed the efficacy and safety of dulaglutide 0.75 mg and 1.5 mg in pediatric patients, ages 10 to less than 18 years old, with inadequately controlled type 2 diabetes despite diet and exercise, with or without metformin and/or basal insulin.6
In AWARD-PEDS, patients receiving dulaglutide experienced greater mean changes from baseline in pancreatic enzyme levels through 26 weeks compared with patients receiving placebo (Mean Change in Pancreatic Enzymes From Baseline to 26 Weeks in AWARD-PEDS).6
Parametera |
Pooled Dulaglutide |
Dulaglutide 1.5 mg |
Dulaglutide 0.75 mg |
Placebo |
Pancreatic amylase, IU/L |
2.3 |
2.9 |
1.8 |
0.6 |
Lipase, IU/L |
4.1 |
3.9 |
4.4 |
2.2 |
aData presented as mean change from baseline.
There were no reported cases of pancreatitis in AWARD-PEDS.6
Acute Pancreatitis Among Dulaglutide Initiators: Real-world Data
A multicountry postauthorization safety study (PASS) was conducted to evaluate the incidence of acute pancreatitis during the first 12 months after dulaglutide initiation among patients with type 2 diabetes. A total of 21,907 new users of dulaglutide were identified (2015-2019) from electronic health care databases in Germany (Leibniz Institute for Prevention Research and Epidemiology [BIPS]), the Netherlands (PHARMO), Italy (CASERTA), and England (Drug Safety Research Unit [DSRU]). Of them, approximately 60% had full 12 months of follow-up.7
A total of 30 cases of acute pancreatitis (BIPS, n=22; CASERTA, n=2; DSRU, n=6) were identified during the follow-up. The overall incident risk estimate of acute pancreatitis (without a prior history of acute pancreatitis) during the first 12 months of treatment in the combined cohort was 0.1% (95% CI, 0.1-0.2%).7
The risk estimate remained unchanged when evaluated for patients both with and without a prior history of acute pancreatitis (DSRU data only).7
The risk of developing acute pancreatitis was higher among
- smokers (odds ratio [OR]=3.9), and
- patients with a history of gallstones, biliary colic, or cholecystitis (OR=4.8).7
Patients with a diabetes duration of >10 years had a lower risk of acute pancreatitis than those with a diabetes duration of <4 years (OR=0.3).7
The results of this analysis must be interpreted with caution because of the heterogeneity of the data sources.7
References
1Nauck MA, Frossard JL, Barkin JS, et al. Assessment of pancreas safety in the development program of once-weekly GLP-1 receptor agonist dulaglutide. Diabetes Care. 2017;40(5):647-654. http://dx.doi.org/10.2337/dc16-0984
2Trulicity [summary of product characteristics]. Eli Lilly Nederland B.V., The Netherlands.
3Frias JP, Nevárez Ruiz L, Li YG, et al. Efficacy and safety of higher dulaglutide doses (3.0 mg and 4.5 mg) when added to metformin in patients with type 2 diabetes: a phase 3, randomized, double-blind, parallel arm study (AWARD-11). J Endocr Soc. 2020;4(suppl 1):A1036. Endocrine Society abstract OR26-08. https://doi.org/10.1210/jendso/bvaa046.2057
4Frias JP, Bonora E, Nevarez Ruiz L, et al. Efficacy and safety of dulaglutide 3.0 mg and 4.5 mg versus dulaglutide 1.5 mg in metformin-treated patients with type 2 diabetes in a randomized controlled trial (AWARD-11). Diabetes Care. 2021;44(3):765-773. https://doi.org/10.2337/dc20-1473
5Gerstein HC, Colhoun HM, Dagenais GR, et al; REWIND Investigators. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. Lancet. 2019;394(10193):121-130. https://doi.org/10.1016/S0140-6736(19)31149-3
6Arslanian SA, Hannon T, Zeitler P, et al; AWARD-PEDS Investigators. Once-weekly dulaglutide for the treatment of youths with type 2 diabetes. N Engl J Med. 2022;387(5):433-443. https://doi.org/10.1056/NEJMoa2204601
7Davies M, Hazell L, Dhanda S, et al. Incidence of acute pancreatitis among dulaglutide initiators: Results from a multi-country post authorization safety study (PASS). Pharmacoepidemiol. Drug Saf. 2020;29(SUPPL 3):475-476. https://doi.org/10.1002/pds.5114
Date of Last Review: 02 August 2023