Safety and tolerability of exenatide twice daily in patients with type 2 diabetes: integrated analysis of 5594 patients from 19 placebo-controlled and comparator-controlled clinical trials

Figures & data

Figure 1 Selection of trials for pooled analysis. Of the 61 clinical trials with available data, 19 placebo-controlled or comparator-controlled studies met the criteria for inclusion in the pooled analysis.

Abbreviations: BID, twice daily; GAA-I, α-glucosidase inhibitor; INS, insulin; ITT, intent-to-treat; Met, metformin; SFU, sulfonylurea; TZD, thiazolidinedione; w/wout, with/without.

Figure 2 Mean treatment exposure. Cumulative duration of exposure (proportion of patients within each duration shown) and mean treatment exposure for the exenatide (166 days) and pooled comparator (171 days) groups.

Abbreviation: BID, twice daily.

Table 1 Summary of treatment-emergent adverse events and discontinuations

Patients with treatment-emergent AEs	Exenatide BID (N = 3261)	Pooled comparator (N = 2333)	Risk difference
	n (%)	n (%)	(95% CI)b
With one or more AEs	2653 (81.4)	1613 (69.1)	12.3 (9.9, 14.5)
With study drug-related AEsa	1569 (48.1)	372 (15.9)	32.2 (29.9, 34.4)
With GI-related AEs	1677 (51.4)	495 (21.2)	30.2 (27.8, 32.6)
With serious AEs	119 (3.6)	90 (3.9)	−0.3 (−1.2, 0.8)
With serious drug-related AEsa	14 (0.4)	5 (0.2)	0.2 (−0.1, 0.5)
Deaths	2 (<0.1)	3 (<0.1)	0 (−0.2, 0.1)
Discontinued due to AEs	255 (7.8)	43 (1.8)	6.0 (4.9, 7.0)
Discontinued due to drug-related AEsa	207 (6.3)	18 (0.8)	5.5 (4.7, 6.5)
Discontinued due to serious AEs	25 (0.8)	17 (0.7)	0.1 (−0.4, 0.5)
Discontinued due to serious drug-related AEsa	5 (0.2)	2 (0.1)	0.1 (−0.1, 0.2)
Discontinued due to GI-related AEs	173 (5.3)	7 (0.3)	5.0 (4.2, 5.8)

Notes:

a Determined by the investigator to be possibly, probably, or definitely drug-related;

b RD = Exenatide IR (%) minus pooled comparator IR (%).

Abbreviations: AEs, adverse events; BID, twice daily; CI, confidence interval; GI, gastrointestinal.

Table 2 Summary of treatment-emergent adverse events by system organ class

System organ classa	Exenatide BID (N = 3261) n (%)	Pooled comparator (N = 2333) n (%)	Risk difference (95% CI)b
Blood and lymphatic system disorders	34 (1.0)	17 (0.7)	0.3 (−0.2, 0.8)
Cardiac disorders	68 (2.1)	53 (2.3)	−0.2 (−1.0, 0.6)
Congenital, familial, and genetic disorders	2 (<0.1)	1 (0.0)	<0.1 (−0.1, 0.1)
Ear and labyrinth disorders	49 (1.5)	52 (2.2)	−0.7 (−1.5, 0.0)
Endocrine disorders	10 (0.3)	2 (<0.1)	0.2 (−0.0, 0.4)
Eye disorders	90 (2.8)	65 (2.8)	0 (−0.9, 0.8)
Gastrointestinal disorders	1677 (51.4)	495 (21.2)	30.2 (27.8, 32.6)
General disorders and administration site conditions	586 (18.0)	283 (12.1)	5.9 (4.0, 7.7)
Hepatobiliary disorders	24 (0.7)	15 (0.6)	0.1 (−0.3, 0.5)
Immune system disorders	50 (1.5)	29 (1.2)	0.3 (−0.3, 0.9)
Infections and infestations	971 (29.8)	731 (31.3)	−1.5 (−4.0, 0.9)
Injury, poisoning, and procedural complications	234 (7.2)	153 (6.6)	0.6 (−0.7, 2.0)
Investigations	231 (7.1)	94 (4.0)	3.1 (1.9, 4.2)
Metabolism and nutrition disorders	1128 (34.6)	719 (30.8)	3.8 (1.3, 6.3)
Musculoskeletal and connective tissue disorders	471 (14.4)	356 (15.3)	−0.9 (−2.7, 1.1)
Neoplasms, benign, malignant, and unspecified	36 (1.1)	18 (0.8)	0.3 (−0.2, 0.8)
Nervous system disorders	602 (18.5)	332 (14.2)	4.3 (2.3, 6.2)
Pregnancy, puerperium, and perinatal conditions	1 (0.0)	0 (0.0)	0 (−0.0, 0.1)
Psychiatric disorders	153 (4.7)	77 (3.3)	1.4 (0.4, 2.4)
Renal and urinary disorders	69 (2.1)	53 (2.3)	−0.2 (−0.9, 0.6)
Reproductive system and breast disorders	64 (2.0)	34 (1.5)	0.5 (−0.2, 1.2)
Respiratory, thoracic, and mediastinal disorders	313 (9.6)	220 (9.4)	0.2 (−1.4, 1.7)
Skin and subcutaneous tissue disorders	260 (8.0)	163 (7.0)	1.0 (−0.4,2.4)
Social circumstances	5 (0.2)	1 (0.0)	0.2 (−0.0, 0.3)
Surgical and medical procedures	86 (2.6)	47 (2.0)	0.6 (−0.2, 1.4)
Vascular disorders	107 (3.3)	78 (3.3)	0 (−1.0, 0.9)

Notes:

a Events listed by system organ class are indicated by number (n) of patients who experienced an adverse event;

b RD = Exenatide IR (%) minus pooled comparator IR (%).

Abbreviations: BID, twice daily; CI, confidence interval.

Table 3 Frequent (≥5%) treatment-emergent adverse events

Preferred term^a	Exenatide BID (N = 3261) n (%)	Pooled comparator (N = 2333) n (%)	Risk difference (95% CI)
Nausea	1202 (36.9)	193 (8.3)	28.6 (26.6, 30.6)
Vomiting	442 (13.6)	67 (2.9)	10.7 (9.3, 12.0)
Diarrhea	346 (10.6)	127 (5.4)	5.2 (3.8, 6.6)
Dizziness	173 (5.3)	78 (3.3)	2.0 (0.9, 3.0)
Headache	275 (8.4)	173 (7.4)	1.0 (−0.4, 2.4)
Nasopharyngitis	288 (8.8)	219 (9.4)	−0.6 (−2.1, 1.0)
Upper respiratory tract infection	193 (5.9)	137 (5.9)	0 (−1.2, 1.3)

Notes: Events listed by preferred term (MedDRA v 13.0 terms) are indicated by number (n) of patients who experienced an adverse event.

Abbreviations: BID, twice daily; CI, confidence interval.

Table 4 Study drug-relateda serious adverse events by preferred term

Preferred termb	Study	Intensity	Outcome	Discontinued study due to this adverse event
Exenatide BID
Hypertension	Heine et al^Citation5	Moderate	Recovered	No
Vomiting	Heine et al^Citation5	Severe	Recovered	No
Injection-site cellulitis	Nauck et al^Citation9	Severe	Unknown	Yes
Nausea	Nauck et al^Citation9	Severe	Unknown	Yes
Anorexia	Nauck et al^Citation9	Severe	Unknown	No
Weight loss	Nauck et al^Citation9	Severe	Unknown	No
Hyperglycemia	Davis et al^Citation8	Severe	Recovered	Yes
Allergic alveolitis	Zinman et al^Citation6	Severe	Recovered	No
Gastroesophageal reflux disease	DeFronzo et al^Citation14	Severe	Not resolved	No
Gastroenteritis	DeFronzo et al^Citation14	Severe	Recovered	No
Hemorrhoidal hemorrhage	DeFronzo et al^Citation14	Severe	Recovered	No
Allergic dermatitis	Gallwitz et al^Citation19	Severe	Not resolved	Yes
Accidental overdose	Buse et al^Citation20,Citation66	Mild	Recovered	No
Gastritis	DeFronzo et al^Citation3	Severe	Recovered	Yes
Presyncope	Kendall et al^Citation4	Severe	Recovered	No
Acute pancreatitis	Kadowaki et al^Citation17	Moderate	Recovered	Yes
Hypoglycemia	Gao et al^Citation10	Severe	Recovered	No
Acute myocardial infarction	Davies et al^Citation13	Severe	Recovered	No
Supraventricular tachycardia	Davies et al^Citation13	Severe	Recovered	No
Insulin glargine
Ureteric calculus	Heine et al^Citation5	Severe	Recovered	No
Angiodema	Heine et al^Citation5	Severe	Recovered	No

Notes:

a Determined by the investigator to be possibly, probably, or definitely related to study drug;

b events listed by preferred term (MedDRA v 13.0 terms) are the individual events observed.

Abbreviation: BID, twice daily.

Figure 3 Incidence, recurrence, and duration of nausea and vomiting over time. Nausea and vomiting with exenatide twice daily 10 μg (4-week lead-in period with 5 μg exenatide twice daily, followed by dose increase to 10 μg twice daily for the duration of the trial; n = 2558), placebo (n = 1325), and insulin (n = 1008). (A) Occurrence and recurrence of nausea over time (grouped into 4-week intervals). (B) Occurrence and recurrence of vomiting over time. Each event is attributed to a defined period according to the event onset date, and recurrence of nausea/vomiting is defined as an event with onset during the defined period and any of the previous periods. Percentages are based on number of subjects who remained in the trial during the defined period. (C) Duration of nausea. (D) Duration of vomiting. The 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.

Figure 4 Incidence of hypoglycemia by treatment. Percentage of patients who experienced hypoglycemia (minor or major).

Note:^a95% confidence interval for the risk difference (exenatide incidence rate [%] minus pooled comparator incidence rate [%]).
Abbreviations: RD, risk difference; Ex, exenatide; BID, twice daily; Ins, insulin; PBO, placebo; SFU, sulfonylurea. PBO + SFU or Ins refers to placebo with SFU or with background insulin.

Figure 5 Adverse events of interest. Exposure-adjusted incidence rate and risk difference of thyroid neoplasm, pancreatitis, and renal impairment (exenatide twice daily n = 3261, pooled comparator n = 2333) and major adverse cardiac events analysis (n = 2316, n = 1629, respectively). Thyroid neoplasm includes benign neoplasm of thyroid gland and malignant thyroid neoplasm. Pancreatitis includes acute pancreatitis and chronic pancreatitis. Renal impairment includes renal failure. Major adverse cardiac events include stroke, myocardial infarction, cardiac mortality, acute coronary syndrome, and revascularization procedures.

Notes:^a95% confidence interval for the risk difference (exenatide incidence rate [%] minus pooled comparator incidence rate [%]); ^bmajor adverse cardiac events analysis: risk ratio and 95% confidence interval for the risk ratio.
Abbreviations: EAIR, exposure-adjusted incidence rate; BID, twice daily, MACE, major adverse cardiac events; PY, patient years.

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