Trulicity ® (dulaglutid) injektion

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Trulicity® (dulaglutid): Pankreatit

Bedömning bekräftade 3 fall av akut pankreatit hos patienter som tar dulaglutid (0,85/1000 poäng år) jämfört med 1 i placebogruppen (3,52/1000 poäng år).

Information from the label

Use of GLP‑1 receptor agonists has been associated with a risk of developing acute pancreatitis. In clinical trials, acute pancreatitis has been reported in association with dulaglutide.1

Patients should be informed of the characteristic symptoms of acute pancreatitis. If pancreatitis is suspected, dulaglutide should be discontinued. If pancreatitis is confirmed, dulaglutide should not be restarted. In the absence of other signs and symptoms of acute pancreatitis, elevations in pancreatic enzymes alone are not predictive of acute pancreatitis.1

Detailed Information

Dulaglutide has not been studied in patients with a history of pancreatitis. Consider other antihyperglycemic therapies in patients with a history of pancreatitis.2

After initiation of dulaglutide, observe patients carefully for signs and symptoms of pancreatitis, including persistent severe abdominal pain.2

If pancreatitis is suspected after initiation of dulaglutide, promptly discontinue dulaglutide. If pancreatitis is confirmed, dulaglutide should not be restarted.2

Pancreatitis 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 T2DM.3 

In the integrated analysis, a total of 203 events were adjudicated in 151 patients. Pancreatitis was confirmed in 9 patients, which included

  • 5 patients treated with dulaglutide

  • 3 patients treated with sitagliptin, and

  • 1 patient receiving placebo.3

All 5 patients with confirmed pancreatitis who were being treated with dulaglutide had elevated pancreatic enzymes at baseline prior to initiation of dulaglutide.3

Acute Pancreatitis

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.3

The type of pancreatitis was indeterminate in 1 of the 3 patients receiving dulaglutide. For the purpose of data analysis, this case was conservatively categorized as “acute.” In the assessment of risk factors for acute pancreatitis, this patient had cholelithiasis.3

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.3

Chronic Pancreatitis

In addition to the 3 adjudicated events of acute 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.3

Pancreatic Enzymes

During dulaglutide treatment, changes in pancreatic enzymes were dose dependent and greater for dulaglutide 1.5 mg than dulaglutide 0.75 mg.3

The median changes in lipase with dulaglutide 1.5 mg ranged from 5.0 to 7.0 units/L. The median changes in lipase with dulaglutide 0.75 mg ranged from 3.0 to 5.0 units/L. Median levels in lipase also increased with sitagliptin, exenatide twice daily, and metformin. A small decrease in the median level in lipase was noted with IGlar. A small decrease to no change was noted with placebo.3

The median changes in p-amylase were lower than the median changes in lipase and ranged from 3.0 to 5.0 units/L with dulaglutide 1.5 mg and 2.0 to 4.0 units/L with dulaglutide 0.75 mg. Median levels in p-amylase also increased with sitagliptin, exenatide twice daily, metformin, and IGlar. The median level in p-amylase was not changed with placebo.3

In patients receiving dulaglutide, increased pancreatic enzymes returned to near baseline levels at the last visit, which was 4 weeks after discontinuation of treatment. Routine pancreatic enzyme testing in asymptomatic patients in the clinical setting had limited clinical value and did not predict the onset of acute pancreatitis.3

Pancreatitis in the REWIND Study

The REWIND study was an event-driven, randomized, double-blind, phase 3 study evaluating once-weekly dulaglutide 1.5 mg treatment compared with placebo when added to standard of care on a composite endpoint of MACE-3 in adults with T2DM and established CV disease and/or risk factors.4,5

Dulaglutide 1.5 mg significantly reduced MACE-3 when compared to placebo: (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 AEs, such as pancreatitis, did not differ significantly between the dulaglutide and placebo treatment groups (Table 1).5

Table 1. Acute Pancreatitis in the Dulaglutide REWIND Study5

 

Dulaglutide
(n=4949)

Placebo
(n=4952)

P Value

Acute pancreatitisa

23

13

.11

Imaging and enzymesb

4

3

.71

Imaging, enzymes, and symptomsc

4

3

.71

Abbreviation: REWIND = Researching cardiovascular Events with a Weekly INcretin in Diabetes.

a Based 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.

b Subset of patients with acute pancreatitis who also had both elevated pancreatic enzymes and an abnormal pancreatic image.

c Subset of patients with acute pancreatitis who had elevated pancreatic enzymes, an abnormal pancreatic image, and symptoms.

References

1. Trulicity [summary of product characteristics]. Eli Lilly Nederland B.V., The Netherlands.

2. Data on file, Eli Lilly and Company and/or one of its subsidiaries.

3. Nauck 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

4. Gerstein HC, Colhoun HM, Dagenais GR, et al. REWIND Trial Investigators. Design and baseline characteristics of participants in the Researching cardiovascular Events with a Weekly INcretin in Diabetes (REWIND) trial on the cardiovascular effects of dulaglutide. Diabetes Obes Metab. 2018;20(1):42-49. https://doi.org/10.1111/dom.13028

5. Gerstein HC, Colhoun HM, Dagenais GR, et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. The Lancet. 2019;394(10193):121-130. https://doi.org/10.1016/S0140-6736(19)31149-3

Glossary

AE = adverse event

CV = cardiovascular

GLP-1 = glucagon-like peptide-1

HR = hazard ratio

IGlar = insulin glargine

MACE-3 = major adverse cardiovascular events (death due to cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke)

REWIND = Researching cardiovascular Events with a Weekly INcretin in Diabetes

T2DM = type 2 diabetes mellitus

Datum fӧr senaste ӧversyn 2019 M11 06


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