Safety and tolerability of exenatide once weekly in patients with type 2 diabetes: an integrated analysis of 4,328 patients

Figures & data

Figure 1 Selection of trials for pooled analysis and patient disposition. Of the 16 completed clinical trials with available data, eight comparator-controlled studies were included.

Abbreviations: ITT, intent-to-treat; Met, metformin; QW, once weekly; SFU, sulfonylurea; TZD, thiazolidinedione; DURATION, Diabetes Therapy Utilization: Researching Changes in A1C, Weight, and Other Factors Through Intervention With Exenatide Once Weekly.

Table 1 Baseline demographics

Characteristic	DURATION-1–6 and Asian studies^Citation14^–^Citation21			DURATION-6^Citation19
	Pooled exenatide QW (n=1,934)	Pooled exenatide BID (n=606)	Pooled non-GLP-1RA comparators (n=1,338)	Exenatide QW (n=461)	Liraglutide QD (n=450)
Male, %	56	54	58	55	54
Mean age, years	55	56	54	56	56
Race/ethnicity, %
Black/African American	2	5	4	0.7	0.7
White	48	29	51	66	64
Hispanic	13	10	12	21	22
Asian	37	57	32	12	12
Other	0.2	0	0.9	0.2	1
Mean HbA1c, % (SD)	8.48 (1.06)	8.52 (1.08)	8.48 (1.11)	8.45 (1.01)	8.44 (1.00)
Mean BMI, kg/m^2 (SD)	30.7 (5.8)	30.0 (5.7)	30.8 (5.5)	32.3 (5.6)	32.3 (5.4)
Mean duration of diabetes, years (SD)	7.1 (5.6)	7.8 (5.6)	5.3 (5.5)	8.0 (5.8)	8.8 (6.5)

Abbreviations: BID, twice daily; BMI, body mass index; GLP-1RA, glucagon-like peptide-1 receptor agonist; HbA_1c, glycosylated hemoglobin; QD, once daily; QW, once weekly; SD, standard deviation; DURATION, Diabetes Therapy Utilization: Researching Changes in A1C, Weight, and Other Factors Through Intervention With Exenatide Once Weekly.

Table 2 Summary of serious AEs, discontinuations, and deaths for DURATION-1–6 and Asian studies

	DURATION-1–6 and Asian studies^Citation14^–^Citation21
	Pooled exenatide QW (n=1,934)	Pooled exenatide BID (n=606)	Pooled non-GLP-1RA comparators (n=1,338)
With one or more TEAEs	1,383 (71.5) (69.50–73.52)	457 (75.4) (71.98–78.84)	880 (65.8) (63.23–68.31)
Serious AEs	61 (3.2) (2.38–3.93)	18 (3.0) (1.62–4.32)	60 (4.5) (3.38–5.59)
Deaths	2 (0.1) (0.00–0.25)	1 (0.2) (0.00–0.49)	2 (0.1) (0.00–0.36)
Discontinued due to AEs	85 (4.4) (3.48–5.31)	47 (7.8) (5.63–9.89)	32 (2.4) (1.57–3.21)
Serious AEs	15 (0.8) (0.38–1.17)	3 (0.5) (0.00–1.05)	9 (0.7) (0.23–1.11)
GI-related AEs	28 (1.4) (0.92–1.98)	35 (5.8) (3.92–7.63)	15 (1.1) (0.56–1.69)
Injection site-related AEs	16 (0.8) (0.42–1.23)	0 (0.0)	0 (0.0)

Note: Values are n (%) (95% CI).

Abbreviations: AEs, adverse events; BID, twice daily; CI, confidence interval; GI, gastrointestinal; GLP-1RA, glucagon-like peptide-1 receptor agonist; QW, once weekly; TEAEs, treatment-emergent adverse events; DURATION, Diabetes Therapy Utilization: Researching Changes in A1C, Weight, and Other Factors Through Intervention With Exenatide Once Weekly.

Table 3 Summary of serious AEs, discontinuations, and deaths for the DURATION-6 study

	DURATION-6^Citation19
	Exenatide QW (n=461)	Liraglutide QD (n=450)	Difference (95% CI)a
With one or more TEAEs	283 (61.4) (56.94–65.83)	306 (68.0) (63.69–72.31)	−6.6 (−12.8, −0.4)
Serious AEs	13 (2.8) (1.31–4.33)	7 (1.6) (0.41–2.70)	1.3 (−0.6, 3.2)
Deaths	0 (0.0)	1 (0.2) (0.00–0.66)	−0.2 (−0.7, 0.2)
Discontinued due to AEs	12 (2.6) (1.15–4.06)	23 (5.1) (3.08–7.15)	−2.5 (−5.0, −0.0)
Serious AEs	3 (0.7) (0.00–1.38)	2 (0.4) (0.00–1.06)	0.2 (−0.8, 1.2)
GI-related AEs	6 (1.3) (0.27–2.34)	18 (4.0) (2.19–5.81)	−2.7 (−4.8, −0.6)
Injection site-related AEs	1 (0.2) (0.00–0.64)	0 (0.0)	0.2 (−0.2, 0.6)

Notes: Values are n (%) (95% CI) unless otherwise indicated.

a Difference = exenatide QW incidence (%) minus liraglutide QD incidence (%).

Abbreviations: AEs, adverse events; CI, confidence interval; GI, gastrointestinal; QD, once daily; QW, once weekly; TEAEs, treatment-emergent adverse events; DURATION, Diabetes Therapy Utilization: Researching Changes in A1C, Weight, and Other Factors Through Intervention With Exenatide Once Weekly.

Table 4 Summary of frequent (≥5%) treatment-emergent adverse events for DURATION-1–6 and Asian studies

Preferred term	DURATION-1–6 and Asian studies^Citation14^–^Citation21
	Pooled exenatide QW (n=1,934)	Pooled exenatide BID (n=606)	Pooled non-GLP-1RA comparators (n=1,338)
Nausea	279 (14.4) (12.86–15.99)	181 (29.9) (26.22–33.51)	66 (4.9) (3.77–6.09)
Diarrhea	203 (10.5) (9.13–11.86)	51 (8.4) (6.21–10.63)	99 (7.4) (6.00–8.80)
Nasopharyngitis	183 (9.5) (8.16–10.77)	24 (4.0) (2.41–5.51)	152 (11.4) (9.66–13.06)
Vomiting	130 (6.7) (5.61–7.84)	79 (13.0) (10.36–15.72)	33 (2.5) (1.64–3.30)
Injection site induration	126 (6.5) (5.42–7.61)	2 (0.3) (0.00–0.79)	12 (0.9) (0.39–1.40)
Constipation	124 (6.4) (5.32–7.50)	38 (6.3) (4.34–8.20)	33 (2.5) (1.64–3.30)
Headache	123 (6.4) (5.27–7.45)	28 (4.6) (2.95–6.29)	116 (8.7) (7.16–10.18)
Injection site nodule	119 (6.2) (5.08–7.22)	0 (0.0)	48 (3.6) (2.59–4.58)
Injection site pruritus	106 (5.5) (4.47–6.50)	12 (2.0) (0.87–3.09)	19 (1.4) (0.79–2.05)
Decreased appetite	75 (3.9) (3.02–4.74)	38 (6.3) (4.34–8.20)	7 (0.5) (0.14–0.91)
Upper respiratory tract infection	73 (3.8) (2.93–4.62)	44 (7.3) (5.19–9.33)	52 (3.9) (2.85–4.92)
Dyspepsia	65 (3.4) (2.56–4.16)	13 (2.1) (0.99–3.30)	33 (2.5) (1.64–3.30)
Dyslipidemia	59 (3.1) (2.28–3.82)	34 (5.6) (3.78–7.44)	31 (2.3) (1.51–3.12)
Dizziness	52 (2.7) (1.97–3.41)	30 (5.0) (3.22–6.68)	42 (3.1) (2.20–4.07)

Note: Values are n (%) (95% CI).

Abbreviations: BID, twice daily; CI, confidence interval; GLP-1RA, glucagon-like peptide-1 receptor agonist; QW, once weekly; DURATION, Diabetes Therapy Utilization: Researching Changes in A1C, Weight, and Other Factors Through Intervention With Exenatide Once Weekly.

Table 5 Summary of frequent (≥5%) treatment-emergent adverse events for the DURATION-6 study

Preferred term	DURATION-6
	Exenatide QW (n=461)	Liraglutide QD (n=450)	Difference (95% CI)a
Nausea	43 (9.3) (6.67–11.98)	93 (20.7) (16.93–24.41)	−11.3 (−15.9, −6.8)
Diarrhea	28 (6.1) (3.89–8.25)	59 (13.1) (9.99–16.23)	−7.0 (−10.8, −3.2)
Nasopharyngitis	31 (6.7) (4.44–9.01)	32 (7.1) (4.74–9.49)	−0.4 (−3.7, 2.9)
Vomiting	17 (3.7) (1.97–5.41)	48 (10.7) (7.81–13.52)	−7.0 (−10.3, −3.6)
Injection site induration	NR	NR	NR
Constipation	21 (4.6) (2.65–6.46)	22 (4.9) (2.90–6.88)	−0.3 (−3.1, 2.4)
Headache	27 (5.9) (3.71–8.00)	38 (8.4) (5.88–11.01)	−2.6 (−5.9, 0.8)
Injection site nodule	48 (10.4) (7.62–13.20)	5 (1.1) (0.14–2.08)	9.3 (6.3, 12.3)
Injection site pruritus	15 (3.3) (1.63–4.87)	1 (0.2) (0.00–0.66)	3.0 (1.4, 4.7)
Decreased appetite	17 (3.7) (1.97–5.41)	29 (6.4) (4.18–8.71)	−2.8 (−5.6, 0.1)
Upper respiratory tract infection	12 (2.6) (1.15–4.06)	12 (2.7) (1.18–4.16)	−0.1 (−2.1, 2.0)
Dyspepsia	11 (2.4) (0.99–3.78)	27 (6.0) (3.81–8.19)	−3.6 (−6.2, −1.0)
Dyslipidemia	NR	NR	NR
Dizziness	13 (2.8) (1.31–4.33)	15 (3.3) (1.67–4.99)	−0.5 (−2.8, 1.7)

Notes: Values are n (%) (95% CI) unless otherwise indicated.

a Difference = exenatide QW incidence (%) minus liraglutide QD incidence (%) in DURATION-6. From Lancet, Volume 381(9861), Buse JB, Nauck M, Forst T, et al, Exenatide once weekly versus lira glutide once daily in patients with type 2 diabetes (DURATION-6): a randomised, open-label study, 117–124, Copyright 2013, with permission from Elsevier.¹⁹

Abbreviations: CI, confidence interval; NR, not reported using this term; QD, once daily; QW, once weekly; DURATION, Diabetes Therapy Utilization: Researching Changes in A1C, Weight, and Other Factors Through Intervention With Exenatide Once Weekly.

Figure 2 Incidence and duration of gastrointestinal-related adverse events over time. Incidence (left panel) and duration (right panel) for (A, B) nausea, (C, D) vomiting, and (E, F) diarrhea in each treatment group. Duration of the nausea/vomiting event is calculated as the resolution date (or the last participation date if event is ongoing at the time of study termination) minus the event onset date plus 1. ^aEvents lasting longer than 7 days in duration included reports of both continuous and intermittent nausea/vomiting. 95% confidence interval for the difference (exenatide QW incidence [%] minus liraglutide QD incidence [%] in DURATION-6).

Abbreviations: BID, twice daily; QD, once daily; QW, once weekly; DURATION, Diabetes Therapy Utilization: Researching Changes in A1C, Weight, and Other Factors Through Intervention With Exenatide Once Weekly.

Figure 3 Occurrence of gastrointestinal-related adverse events over time with exenatide QW treatment. Incidences of nausea, vomiting, and diarrhea in patients treated with exenatide QW are combined for weeks 0–12 in 2-week increments.^14–21

Abbreviation: QW, once weekly.

Figure 4 Incidence of hypoglycemia by treatment and use of SFU. Percentage of patients who experienced minor hypoglycemia. 95% confidence interval of the difference (exenatide QW incidence [%] minus liraglutide QD incidence [%] in DURATION-6).

Abbreviations: BID, twice daily; QD, once daily; QW, once weekly; SFU, sulfonylurea; DURATION, Diabetes Therapy Utilization: Researching Changes in A1C, Weight, and Other Factors Through Intervention With Exenatide Once Weekly.

Figure 5 Adverse events of interest. Exposure-adjusted incidence per 100 patient-years and difference in thyroid neoplasm, pancreatitis, renal failure, and gallbladder disease. Pancreatitis includes acute pancreatitis and chronic pancreatitis. Thyroid neoplasm includes benign neoplasm of the thyroid gland and malignant thyroid neoplasm. 95% confidence interval for the difference (exenatide QW incidence [%] minus liraglutide QD incidence [%] in DURATION-6).

Abbreviations: BID, twice daily; QD, once daily; QW, once weekly; DURATION, Diabetes Therapy Utilization: Researching Changes in A1C, Weight, and Other Factors Through Intervention With Exenatide Once Weekly.

Table 6 Treatment-emergent serious adverse events by body system (>1% in any group) for 24-week to 30-week randomized comparator-controlled trials^14–21

System	Incidence, n (%) (preferred terms)
	Pooled exenatide QW (n=1,934)	Pooled exenatide BID (n=606)	Pooled non-GLP-1RA comparators (n=1,338)	Exenatide QW (n=461)	Liraglutide QD (n=450)
Cardiac disorders	8 (0.4%)	4 (0.7%)	9 (0.7%)	1 (0.2%)	2 (0.4%)
Gastrointestinal disorders	9 (0.5%)	2 (0.3%)	8 (0.6%)	3 (0.7%)	2 (0.4%)
General disorders and administration site conditions	1 (<0.1%)	2 (0.3%)	7 (0.5%)	0 (0.0%)	1 (0.2%)
Hepatobiliary disorders	5 (0.3%)	2 (0.3%)	6 (0.4%)	2 (0.4%)	0 (0.0%)
Infections and infestations	12 (0.6%)	2 (0.3%)	12 (0.9%)	2 (0.4%)	0 (0.0%)
Neoplasms benign, malignant, and unspecified (including cysts and polyps)	5 (0.3%)	0 (0.0%)	4 (0.3%)	2 (0.4%)	0 (0.0%)
Nervous system disorders	6 (0.3%)	1 (0.2%)	6 (0.4%)	0 (0.0%)	1 (0.2%)

Abbreviations: BID, twice daily; GLP-1RA, glucagon-like peptide-1 receptor agonist; QD, once daily; QW, once weekly.

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