Risk of pancreatic adverse events associated with the use of glucagon-like peptide-1 receptor agonist and dipeptidyl peptidase-4 inhibitor drugs: A systematic review and meta-analysis of randomized trials

Table 2 Quality assessment of glucagon-like peptide-1 based agents in randomized controlled trials included in analysis of pancreatic events

Ref.	Sequence generation	Blinding	Allocation concealment	Was Pancreatitis an AE or SAE?	Adverse event monitoring	Arms	Withdrawal rate (%)	Loss to follow- up (%)
Ross et al[21]	Central computer based; randomization: block in a 5:5:1 ratio	Double blind	Adequate	AE	Safety and tolerability end-points were the incidence of adverse events (including adverse changes observed during physical examinations or ECGs), protocol-specified significant AEs, hypoglycemia and changes from baseline in vital signs, clinical laboratory parameters and body weight	Linagliptin 2.5 mg bid	7.2	0
						Linagliptin 5 mg qd	4.5	0
						Placebo	2.3	0
Haak et al[22]	NR	Double blind	Adequate	AE	Incidence of AEs, serious AEs, discontinuation due to AEs,12-lead ECGs, vital signs and clinical laboratory parameters. The causal relationships between study medications and AEs were evaluated by the investigators at the site	Linagliptin 5 mg qd	14.8	2.1
						Metformin 500 mg bid	11.8	2.1
						Metformin 1000 mg bid	14.3	2.7
						Linagliptin 2.5 mg qd + Metformin 500 mg bid	11.2	2.8
						Linagliptin 2.5 mg qd + Metformin 1000 mg bid	7.7	0
						Placebo	25.0	1.4
NCT00328172[23]	NR	Double blind	NR	SAE	NR	Linagliptin 0.5 mg	24.1	1.7
						Linagliptin 2.5 mg	17.5	3.5
						Linagliptin 5.0 mg	23.6	1.8
						Metformin	7.7	1.5
						Placebo	32.8	1.5
Yki-Jarvinen et al[24,25]	NR	Double blind	NR	SAE	NR	Linagliptin 5.0 mg	13.9	2.2
						Placebo	17.5	1.3
NCT00654381[26]	NR	Double blind	NR	SAE	NR	Linagliptin 5.0 mg	1.89	0
						Linagliptin 10.0 mg	3.13	0
						Voglibose	2.5	0
						Placebo	7.5	0
NCT00622284[27]	NR	Double blind	NR	SAE	NR	Linagliptin	24.4	1.4
						Glimepiride	22.1	1.7
BI Trial No: 1218.15/ U09-2519-01[28]	Randomized into 1;2 ratio to receive either placebo or linagliptin	Double blind	Adequate	SAE	Incidence and intensity of AEs, withdrawals due to AEs, physical examination, 12-lead ECG, vital signs, clinical laboratory parameters	Linagliptin 5 mg + Pioglitazone 30 mg	5.8	NR
						Pioglitazone 30 mg + Placebo	14.6	NR
BI Trial No: 1218.52/U11-1782-01[29]	NR	Double blind	NR	SAE	Safety endpoints were the incidence and intensity of AEs, withdrawals due to AEs, clinically relevant new or worsening findings in physical examination, 12-lead ECG, vital signs and clinical laboratory parameters	Linagliptin 2.5 mg + Metformin (500 mg and 1000 mg bid)	0.0	NR
						Metformin 1000 mg bid	0.6	NR
BI Trial No: 1218.63/U11-1781-02[30]	NR	Double blind	NR	SAE	Incidence and intensity of AEs, withdrawals due to AEs, physical examination, 12-lead ECG, vital signs, clinical laboratory parameters	Linagliptin 5 mg	1.23	NR
						Placebo	1.26	NR
BI Trial No: 1218.75/U12-3204-01[31]	NR	Double blind	NR	AE	Incidence and intensity of AEs, withdrawals due to AEs, clinically relevant changes from baseline in vital signs (blood pressure and pulse rate), clinically relevant new or worsening findings in 12-lead ECG as reported as AEs, clinically relevant changes from baseline in clinical laboratory assessments, cardiac and cerebrovascular events adjudicated CEC	Linagliptin 5 mg	12.3	NR
						Placebo	12.5	NR
BI Trial No: 1218.61/U13-3124-01[32]	NR	Double blind	NR	AE	Incidence and intensity of AEs, primarily based on spontaneous AEs; withdrawal due to AEs; clinically relevant new or worsening findings in physical examination reported as AEs; changes from baseline in vital signs (BP and pulse); clinically relevant new or worsening findings in 12 lead ECG reported as AEs; changes from baseline in clinical lab assessments; and hypoglycemic events	Linagliptin 5 mg	2.2	NR
						Placebo	0.0	NR
BI Trial No: 1218.65/U12-2143-01[33]	NR	Double blind	NR	SAE	Incidence and intensity of adverse events, withdrawals due to AEs, physical examination, ECGs, change from baseline in clinical lab parameters and cardiovascular events (Clinical Event Committee adjudication results)	Linagliptin 5 mg	0.98	NR
						Placebo	3.0	NR
BI Trial No: 1218.64/U13-1283-01[34]	NR	Double blind	NR	AE	Incidence and intensity of adverse events (AEs), withdrawals due to AEs, physical examination, vital signs, 12 lead ECG, change from baseline in clinical lab parameters	Linagliptin 5 mg	0.0	NR
						Placebo (first 12 wk)/ Glimepiride (next 40 wk)	1.64	NR
BI Trial No: 1218.66/U12-2076-01[35]	NR	Double blind	NR	SAE	Incidence and intensity of adverse events, withdrawals due to AEs, physical examination and vital signs, 12-lead ECG, clinical laboratory assessments	Linagliptin 5 mg	5.1	NR
						Placebo	2.0	NR
Rosenstock et al[36]	Automated interactive voice response system using a randomization schedule	Double blind	NR	SAE	During the treatment period, patients were reviewed for adverse event evaluations. Further safety assessments included clinical examination of skin and digits. Hematology, serum chemistry, vital signs, physical exam and ECG parameters were done	Alogliptin 12.5 mg	36.6	3.05
						Alogliptin 25 mg	40.3	2.33
						Placebo	57.7	1.54
White et al[37]	NR	Double blind	NR	SAE	The principal secondary safety end point was the primary composite end point with the addition of urgent revascularization due to unstable angina within 24 h after hospital admission. Additional safety end points included angioedema, hypoglycemia, pancreatitis, cancer, and the results of laboratory testing	Alogliptin	NR	NR
						Placebo	NR	NR
NCT01318135[38]	NR	Open Label	Inadequate	SAE (Pancreatic cancer only)		Alogliptin 12.5 mg qd + Glimepiride 1-6 mg qd or bid	NR	NR
						Alogliptin 25 mg qd + Glimepiride 1-6 mg qd or bid	NR	NR
NCT01289119[39]	NR	Double blind	NR	SAE	TEAE were defined as any adverse events that started on or after the date of the first dose of double-blind study drug and within 14 d after the date of the last dose of double-blind study drug	Alogliptin monotherapy	9.78	3.26
						Metformin	9.18	0
						Metformin + Alogliptin Add-on Therapy	6.06	0
						Pioglitazone	7.94	0
						Pioglitazone + Alogliptin Add-on Therapy	6.56	1.64
						Placebo	9.78	0
NCT01263496[40]	NR	Open Label	Inadequate	SAE	A TEAE is defined as an adverse event with an onset that occurs after receiving study drug and within 30 d after receiving the last dose of study drug	Alogliptin 6.25 mg qd	NR	NR
						Alogliptin 12.5 mg qd	NR	NR
						Alogliptin 25 mg qd	NR	NR
						Alogliptin 50 mg qd	NR	NR
						Voglibose 0.2 mg tid	NR	NR
NCT00328627[41]	NR	Double blind	NR	SAE	NR	Alogliptin 12.5 mg + Placebo	24.2	1.56
						Alogliptin 25 mg + Placebo	21.7	1.55
						Placebo	45.7	3.1
NCT00395512[42]	NR	Double blind	Adequate	SAE	NR	Alogliptin 25 mg + Pioglitazone 30 mg	17.1	3.05
						Alogliptin 12.5 mg + Pioglitazone 30 mg	23.2	3.05
						Pioglitazone 30 mg	22.7	3.68
Kikuchi et al[43]	Dynamic randomization	Double blind	NR	SAE	Adverse events were recorded at each visit, and these AEs were assessed for severity and suspected relationship to the study drug. Hematology, biochemistry and urinalysis were performed at each scheduled visit. All laboratory assessments were processed at a central testing to ensure consistency	Vildagliptin 50 mg bid + glimepiride	2.9	NR
						Placebo + glimepiride	4	NR
Lukashevich et al[44]	NR	Double blind	NR	SAE	All treatment emergent AEs were recorded and assessed by the investigator as to severity and potential relationship to study drug. Particular attention was paid to hepatic, infections, skin, pancreatitis as well as edema and cardiovascular safety	Vildagliptin 50 mg qd (moderate RI)	10.3	2.4
						Placebo (moderate RI)	10.9	1.6
						Vildagliptin 50 mg qd (severe RI)	13.7	1.6
						Placebo (severe RI)	13.4	2.1
Strain et al[45]	Validated automated system	Double blind	Adequate	AE	All AEs and their severity, serious AEs, and their presumed relation with the study drug were monitored and recorded at each study visit	Vildagliptin	5.8	0.72
						Placebo	5.8	0
NCT00106340[46] (CLAF237A2308)	NR	Double blind	NR	SAE	Safety assessments included monitoring and recording all AEs, SAEs and pregnancies; regular monitoring of hematology, blood chemistry, and urine (performed at a central lab); and regular assessments of vital signs, ECG, physical condition and body weight. Severity and relationship to study drug were recorded for all AEs and SAEs	Vildagliptin 50 mg bid + Metformin	36.4	0
						Glimepiride up to 6 mg qd + Metformin	38.8	0
NCT00300287[47]	NR	Double blind	NR	SAE	Safety assessments included monitoring and recording all AEs, SAEs with their severity and presumed relationship to study drug and pregnancies, recording of hypoglycemic events, the regular monitoring of hematology, blood chemistry and urine, and regular assessments of vital signs, physical condition, body weight, and ECGs	Vildagliptin 50 mg qd	14.7	0.6
						Placebo	12.7	0.7
(CLAF237A2307) CLAF237A1301[48]	NR	Double blind	NR	AE (elevated pancreatic enzymes)	Safety assessments included monitoring and recording all AEs, SAEs with their severity and presumed relationship to study drug and pregnancies, recording of hypoglycemic events, the regular monitoring of hematology, blood chemistry and urine, and regular assessments of vital signs, physical condition, body weight, and ECGs	Vildagliptin	4.8	NR
						50 mg bid Voglibose 0.2 mg tid	5.2	NR
CLAF237A23119[49]	NR	Open Label	NA	SAE	Safety assessments included monitoring and recording all AEs, SAEs with their severity and presumed relationship to study drug and pregnancies, recording of hypoglycemic events, the regular monitoring of hematology, blood chemistry and urine, and regular assessments of vital signs, physical condition, body weight, and ECGs	Vildagliptin 100 mg + Metformin	10.4	2.5
						Thiazolinedione + Metformin	11.8	2.1
NCT00110240[50] (CLAF237A2323)	NR	Double Blind	NR	SAE	Safety assessments included adverse events, hypoglycemic events and serious adverse events, physical examination, vital signs, laboratory evaluations, and ECGs	Vildagliptin 50 mg bid	9.5	1.6
						Acarbose up to 100 mg tid	12.7	1.4
NCT00327015[51]	NR	Double Blind	NR	SAE	Safety and tolerability end-points included incidence of AEs, SAEs, discontinuation due to AEs, physical and ECG examinations, vital signs and results of clinical laboratory tests	Saxagliptin 5 mg + Metformin 500 mg	28.4	6.9
						Saxagliptin 10 mg + Metformin 500 mg	28.5	7.1
						Metformin 500 mg + Placebo	33.2	6.7
Hollander et al[52] (NCT00295633)	NR	Double Blind	NR	SAE	Safety assessments included incidence of AEs, SAEs and discontinuation due to AEs, changes from baseline lab parameters; changes from baseline vital signs; and incidence of marked clinical laboratory abnormalities	Saxagliptin 2.5 mg + TZD	31.8	NR
						Saxagliptin 5 mg + TZD	36	NR
						Placebo + TZD	41.3	NR
NCT00757588[53]	Interactive voice response system	Double Blind	NR	SAE	Safety end points included AEs, hypoglycemia and weight gain	Saxagliptin 5 mg + Insulin	11.8	0.98
						Placebo + Insulin	11.3	3.31
Scirica et al[54]	Central computerized telephone or web based system	Double Blind	NR	NR (Safety End Point)	A clinical events committee comprising specialists in cardiovascular and pancreatic medicine, all of whom were unaware of the study group assignments, adjudicated	Saxagliptin	NR	NR
						Placebo	NR	NR
Goke et al[55]	NR	Double Blind	NR	SAE	Safety and tolerability assessments included AEs and SAEs, lab measurements, vital signs, physical examination and ECG testing	Saxagliptin + Metformin	61.4	0.23
						Glipizide + Metformin	65.8	0.69
NCT00316082[56]	NR	Double Blind	NR	SAE	NR	Saxagliptin 2.5/5 mg QAM	38.0	9.9
						Saxagliptin 2.5 mg QAM	44.6	9.5
						Saxagliptin 5 mg QAM	29.7	8.1
						Saxagliptin 5 mg QPM	36.1	11.1
						Placebo	35.1	8.1
NCT00614939[57]	Interactive voice response system	Double Blind	NR	SAE	Safety and tolerability assessments included AEs, SAEs, treatment-related AEs, discontinuations of randomized study medication because of AEs, deaths, AEs of special interest and hypoglycemic events	Saxagliptin	71.8	NR
						Placebo	80.0	NR
Chan et al[58,59]	Computer generated randomization schedule	Double Blind	Adequate	SAE	Assessment of safety and tolerability included evaluation of the data from physical examinations, vital signs and ECGs collected at specified study visits. All adverse experiences were rated by the investigators for intensity and relationship to study drug	Sitagliptin 50 mg or 25 mg once daily	29.2	NR
						Placebo/Glipizide	23.1	NR
Kojima et al[60]	Random allocation sequence performed centrally	Open label	NA	AE	NR	Sitagliptin	NR	NR
						Nateglinide	NR	NR
NCT00509262 (Arjona Ferreira JC et al[61,62])	Computer generated randomization schedule	Double	NR	SAE	Safety measurements included evaluation of AEs, physical exam and vital signs, and ECG. Lab safety studies included serum chemistry, hematology and urinalysis. All AEs were rated by the investigator for intensity and relationship to study drug	Sitagliptin	210
						Glipizide	212
Henry RR et al[63,64]	NR	Blind Double blind	NR	SAE	Safety and tolerability were evaluated throughout the study by physical examination, monitoring of vital signs and safety lab measurements that included serum chemistry, hematology and urinalysis. AEs were monitored and evaluated by the investigators for intensity (severity), duration, outcome and relationship to study drug	Sitagliptin 100 mg/Pioglitazone 15 mg	20.9	3.5
						Sitagliptin 100 mg/Pioglitazone 30 mg	22.9	6.9
						Sitagliptin 100 mg/Pioglitazone 45 mg	22.2	5.7
						Pioglitazone 15 mg	31.3	6.1
						Pioglitazone 30 mg	27.9	9
						Pioglitazone 45 mg	27.4	5.7
Raz I et al[65,66]	Computer generated schedule	Double blind	NR	SAE	Safety and tolerability were evaluated by physical examination, vital signs and lab measurements that included routine serum chemistry, hematology, urinalysis and pregnancy testing. AEs were monitored through the study for intensity, duration, outcome, relationship to study drug and level of severity	Sitagliptin 100 mg	17.7
								3.13
						Placebo	14.9	3.19
NCT01131182[67]	NR	Open label	NA	SAE	NR	Sitagliptin	NR	NR
						Sulfonylurea	NR	NR
Goldstein et al[68,69]	NR	Double blind	NR	SAE	Data were collected regarding AEs, physical exam, vital signs, ECGs and body weight throughout the study. All AEs were rated by investigators for intensity and relationship to study drug	Sitagliptin 50 mg bid + Metformin 500 mg bid	22.1	2.6
						Sitagliptin 50 mg bid + Metformin 1000 mg bid	22.5	5.5
						Sitagliptin 50 mg bid + Metformin 1000 mg bid (OLC)	32.5	2.6
						Metformin 500 mg bid	30.8	2.2
						Metformin 1000 mg bid	25.8	3.8
						Placebo/Metformin 1000 mg bid	34.7	5.1
Arechavaleta et al[70,71]	Concealed computer-generated allocation schedule	Double blind	Adequate	SAE	Safety and tolerability were assessed by a review of all safety parameters including adverse experiences, laboratory safety parameters, body weight and vital signs	Sitagliptin	9.3	1.7
						Glimepiride	9.8	1.7
NCT00086515 et al[72,73]	NR	Double blind	NR	SAE	Safety and tolerability were assessed throughout the study. Monitoring for adverse experiences, physical examinations, vital signs, body weight, 12-lead ECGs (read at a central reading laboratory), and safety laboratory measurements comprising routine hematology, serum chemistry, and urinalysis were performed	Sitagliptin 100 mg	10.6	0.86
						Placebo/Glipizide 5 mg	18.9	2.11
Bergenstal et al[74,75]	Interactive voice response system	Double blind	Adequate	SAE	NR	Exenatide once weekly	26.9	5
						Sitagliptin	16.9	5.4
						Pioglitazone	24.8	7.8
NCT00094757[76]	NR	Double blind	NR	SAE	Data for adverse experiences, physical examinations, vital signs, ECGs, and body weight were collected throughout the study	Sitagliptin 100 mg	25.8	1.5
						Sitagliptin 200 mg	30.1	2.4
						Placebo/Pioglitazone	27.3	5.4
NCT00094770[77]	NR	Double blind	NR	SAE	Data on adverse experiences, physical examinations, vital signs, ECGs and body weight were collected throughout the study. All adverse experiences were rated by the study site investigators for intensity and relationship to study drug. Laboratory safety evaluations included blood chemistry, haematology and urinalysis	Sitagliptin 100 mg	34.4	3.2
						Glipizide	29.5	1.7
NCT01137812[78,79]	Interactive Voice Response System/Interactive Web Response System	Double blind	Adequate	SAE	Safety evaluations included AEs, clinical laboratory tests, vital sign measurements, physical examinations, self-monitored blood glucose, 12-lead electrocardiograms, and documentation of hypoglycemic episodes	Sitagliptin 100 mg	44.4	2.1
						Canagliflozin 300 mg	32.6	1.6
NCT00482729[80]	NR	Double blind	NR	SAE	NR	Sitagliptin/Meformin-Fixed Dose Combination	34.7 (217/626)	13.7 (86/626)
						Metformin	34.9 (218/624)	10.6 (66/624)
Bunck et al[81]	NR	Open label	NA	SAE	NR	Exenatide	16.7	0
						Insulin glargine	9.1	3.03
Diamant et al[82]	Computer generated randomization sequence	Open label	NA	SAE	Safety endpoints were adverse events, clinical lab assessments, vital signs, and hypoglycemia. We defined adverse events as those occurring at or after randomization or worsening during the study	Exenatide	10.3	0.86
						Insulin glargine	6.3	0.45
Inagaki et al[83]	Computer generated randomization sequence	Open label	NA	AE	Safety profile end points included AEs and hypoglycemia	Exenatide once weekly	10.2	0.47
						Insulin glargine once daily	5.2	0
Russell-Jones et al[84]	Computer generated randomization sequence	Double blind	Adequate	SAE	Safety end points were adverse events, clinical lab assessments, vital signs, hypoglycemia and antibodies to exenatide. Treatment emergent adverse events were defined as those occurring or worsening after the first dose of study drug	Exenatide 2 mg once weekly + Oral placebo	15.3	1.6
						Sitagliptin 100 mg/d + SC placebo	14.1	2.4
						Metformin starting at 1000 mg/d + SC placebo	13.4	0.4
						Pioglitazone starting at 30 mg/d + SC placebo	1.8	1.8
NCT01003184[85]	NR	Open label	NR	SAE	NR	Exenatide once weekly	17.1	0.9
						Insulin Detemir twice daily	11.4	0
Astrup et al[86]	NR	Double blind (first 20 wk) Weeks 20-104: Open label	NR	SAE	Safety assessments included adverse events, recorded at every visit, standard lab tests and serum liraglutide antibodies. A safety committee for data surveillance was established	Liraglutide 1.2 mg	10.5	0
						Liraglutide 1.8 mg	17.8	0
						Liraglutide 2.4 mg	21.5	0
						Liraglutide 3.0 mg	11.8	0
						Placebo	19.4	0
Garber et al[87]	Telephone based or web-based systems	Double blind	Adequate	SAE	Key safety assessments were tolerability (including nausea and other gastrointestinal adverse events), serum calcitonin and hypoglycemic episodes	Liraglutide 1.2 mg	35.5	NR
						Liraglutide 1.8 mg	29.7	NR
						Glimepiride 8 mg	38.7	NR
Nauck et al[88]	Telephone based or web-based randomization systems	Double blind	Adequate	SAE	Safety variables included adverse events, vital signs, ECG, biochemical and hematology measures and subject reported hypoglycemic episodes	Once daily Liraglutide (0.6 mg)	14.0	0
						Once daily Liraglutide (1.2 mg)	18.0	0.4
						Once daily Liraglutide (1.8 mg)	21.0	0
						Once daily Glimepiride (4 mg)	14.0	0
						Placebo	39.0	0
Marre et al[89]	NR	Double blind	NR	SAE	Safety variables included hypoglycemic episodes, liraglutide antibodies, tolerability (gastrointestinal complaints) and pulse. AEs, vital signs, ECG, biochemical and hematology measures including calcitonin were also monitored	Liraglutide 0.6 mg	10.7	NR
						Liraglutide 1.2 mg	14.0	NR
						Liraglutide 1.8 mg	8.9	NR
						Placebo	27.2	NR
Zinman et al[90]	Telephone based or web-based randomization systems	Double blind	Adequate	SAE	Safety variables included AEs, vital signs, ECG, biochemical and hematology measures and subject reported hypoglycemic episodes	Liraglutide 1.2 mg	14.0	NR
						Liraglutide 1.8 mg	25.0	NR
						Placebo	32.0	NR
Raz et al[91]	NR	Double blind	NR	SAE	Safety assessments included AEs, vital signs, physical examinations, clinical lab tests, ECG and hypoglycemia	Taspoglutide 10 mg	11.2	NR
						Taspoglutide 20 mg	13.2	NR
						Placebo	3.3	NR
Rosenstock et al[92]	NR	Double blind	NR	SAE	Adverse event assessments and safety analyses were conducted throughout the study	Albiglutide 4 mg weekly	48.6	5.7
						Albiglutide 15 mg weekly	31.4	8.6
						Albiglutide 30 mg weekly	32.3	3.2
						Albiglutide 15 mg biweekly	45.5	9.1
						Albiglutide 30 mg biweekly	24.2	0
						Albiglutide 50 mg biweekly	42.9	2.9
						Albiglutide 50 mg monthly	14.3	2.9
						Albiglutide 100 mg monthly	44.1	2.9
						Placebo	23.5	0
Seino et al[93]	Interactive voice response system	Double blind	Adequate	SAE	Safety and tolerability included reported AEs and other safety information such as symptomatic hypoglycemia	Lixisenatide (10 ug for 1 wk, 15 ug for 1 wk, then 20 ug-maintenance dose)	NR	NR
						Placebo	NR	NR
Umpierrez et al[94]	Computer generated random sequence	Double blind	Adequate	SAE	Safety measures included AEs, vital signs, hypoglycemia events and lab tests	LY2189265 (LY 0.5/1.0)	12.1	1.5
						LY2189265 (LY 1.0/1.0)	10.8	1.5
						LY2189265 (LY 1.0/2.0)	13.8	1.5
						Placebo	9.1	1.5

NR: Not reported; AE: Adverse event; SAE: Serious adverse event; ECGs: Electrocardiograms; TEAE: Treatment-emergent adverse events; CEC: Clinical events committee.