Clinical review of the efficacy and safety of oral semaglutide in patients with type 2 diabetes considered for injectable GLP-1 receptor agonist therapy or currently on insulin therapy

Figures & data

Table 1. Summary of key clinical considerations for injectable therapies for T2D [1,2]

Clinical consideration	GLP-1RAs	Insulins
Effect on HbA1c levels	↓↓	↓↓
Effect on body weight	↓	↑
Hypoglycemia risk	Neutral	↑
Cardiovascular effects	Benefit in patients with, or at high risk of ASCVD (select GLP-1RAs*)	Neutral for ASCVD and heart failure
	Neutral for heart failure
Renal effects	Beneficial effect on diabetic kidney disease seen with select agents^†	Neutral effect on diabetic kidney disease
	No renal dose adjustments or limitations with dulaglutide, liraglutide, oral semaglutide or subcutaneous semaglutide; specific considerations for other GLP-1RAs^‡	Lower insulin dose required with impaired renal function; dose should be adjusted based on clinical response
	Monitor renal function in patients with renal impairment reporting severe adverse gastrointestinal reactions
Other considerations	Gastrointestinal side effects common (nausea, vomiting and diarrhea)	Injection site reactions
	Injection site reactions (with subcutaneous GLP-1RAs)
	Boxed warning of thyroid C-cell tumors in rodents with exenatide ER, dulaglutide, liraglutide, subcutaneous semaglutide and oral semaglutide; human relevance has not been determined. These agents are contraindicated in patients with a personal or family history of MTC or MEN 2

*Dulaglutide, liraglutide and once-weekly subcutaneous semaglutide have a label indication for reducing CVD events [9,22,23]; ^†improvements in renal outcomes versus placebo have been reported for dulaglutide, liraglutide and once-weekly subcutaneous semaglutide in cardiovascular outcomes trials [19,24,25]; ^‡exenatide is not recommended in patients with eGFR <30 mL/min/1.73 m² or ESRD [26]; exenatide ER is not recommended in patients with eGFR <45 mL/min/1.73 m² or ESRD [27]; lixisenatide is not recommended in patients with ESRD [28].

ASCVD, atherosclerotic cardiovascular disease; eGFR, estimated glomerular filtration rate; ER, extended-release; ESRD, end-stage renal disease; GLP-1RA, glucagon-like peptide-1 receptor agonist; HbA_1c, glycated hemoglobin; MEN 2, multiple endocrine neoplasia syndrome type 2; MTC, medullary thyroid carcinoma; T2D, type 2 diabetes.

Table 2. Summary of selected efficacy outcomes from SUSTAIN 1–7 studies with subcutaneous semaglutide [14]

Studies shaded blue evaluated once-weekly subcutaneous semaglutide vs other injectable therapies or as add-on to basal insulin. Efficacy analyses for SUSTAIN 1–5 and 7 were based on all randomized and exposed patients using on-treatment data collected prior to onset of rescue medication.

*p < 0.05 versus (dose-matched) comparator (SUSTAIN 7: semaglutide 0.5 mg versus dulaglutide 0.75 mg and semaglutide 1.0 mg versus dulaglutide 1.5 mg); ^†percentage of patients achieving the outcome of HbA_1c <7.0% (<53 mmol/mol), no weight gain and no severe or blood glucose-confirmed hypoglycemia.

CVOT, cardiovascular outcomes trial; Dula, dulaglutide; ER, extended-release; Exe, exenatide extended-release; HbA_1c, glycated hemoglobin; IGlar, insulin glargine;NR, not reported; Pbo, placebo; Sema, semaglutide; Sita, sitagliptin.

Reproduced from Aroda et al. Comparative efficacy, safety, and cardiovascular outcomes with once-weekly subcutaneous semaglutide in the treatment of type 2 diabetes: insights from the SUSTAIN 1–7 trials. Diabetes Metab. 2019;45(5):409–418. Copyright © 2020, Elsevier Masson SAS. All rights reserved.

Table 3. Overview of the design of the PIONEER 4 and PIONEER 8 trials [32,33]

HbA_1c, glycated hemoglobin; SGLT2, sodium-glucose co-transporter-2; T2D, type 2 diabetes.

Table 4. Overview of the efficacy outcomes of the PIONEER 4 and PIONEER 8 trials [32,33]

	PIONEER 4 (add-on to metformin ± an SGLT2 inhibitor)			PIONEER 8 (add-on to insulin ± metformin)
	Oral semaglutide 14 mg (n = 285)	Liraglutide 1.8 mg (n = 284)	Placebo (n = 142)	Oral semaglutide 7 mg (n = 182)	Oral semaglutide 14 mg (n = 181)	Placebo (n = 184)
Mean change in HbA1c from baseline, %
Week 26	–1.2*	–1.1	–0.2	–0.9*	–1.3*	–0.1
Week 52	–1.2*^†	–0.9	–0.2	–0.8*	–1.2*	–0.2
Mean change in body weight from baseline, kg
Week 26	–4.4*^†	–3.1	–0.5	–2.4*	–3.7*	–0.4
Week 52	–4.3*^†	–3.0	–1.0	–2.0*	–3.7*	0.5
HbA1c <7.0% (<53 mmol/mol), % of patients
Week 26	67.6*	61.8	14.2	42.5*	58.4*	6.8
Week 52	60.7*	55.0	15.0	39.6*	54.2*	9.3
Body weight reduction ≥5%, % of patients
Week 26	43.5*^†	27.7	7.5	30.5*	38.7*	2.8
Week 52	44.7*^†	24.5	12.0	28.1*	39.4*	5.2
HbA1c <7.0% (<53 mmol/mol) without weight gain, and without severe^‡ or blood glucose-confirmed symptomatic hypoglycemia, % of patients
Week 26	60.8*	53.5	11.2	27.0*	43.9*	2.3
Week 52	56.4*	48.3	11.3	25.4*	36.3*	4.7

Data are for the treatment policy estimand, including all patients regardless of premature discontinuation of trial product or use of rescue medication. PIONEER 8 includes results for the recommended maintenance doses of oral semaglutide 7 and 14 mg only.

*p < 0.05 versus placebo for the estimated treatment differences (continuous endpoints) or estimated odds ratio (binary endpoints); ^†p < 0.05 versus liraglutide for the estimated treatment differences (continuous endpoints) or estimated odds ratio (binary endpoints); ^‡severe hypoglycemia was defined according to the ADA classification (requires assistance of another person to actively administer carbohydrate, glucagon, or take other corrective actions). Blood glucose confirmation of symptomatic hypoglycemia was based on a blood glucose value <56 mg/dL (<3.1 mmol/L) with symptoms consistent with hypoglycemia.

ADA, American Diabetes Association; HbA_1c, glycated hemoglobin; SGLT2, sodium-glucose co-transporter-2.

Table 5. Overview of key on-treatment adverse events from the PIONEER 4 and PIONEER 8 trials [32,33]

	PIONEER 4 (add-on to metformin ± an SGLT2 inhibitor)			PIONEER 8 (add-on to insulin ± metformin)
Number of patients (%)	Oral semaglutide 14 mg (n = 285)	Liraglutide 1.8 mg (n = 284)	Placebo (n = 142)	Oral semaglutide 7 mg (n = 181)	Oral semaglutide 14 mg (n = 181)	Placebo (n = 184)
≥1 AE	229 (80)	211 (74)	95 (67)	142 (78)	151 (83)	139 (76)
Serious AEs	31 (11)	22 (8)	15 (11)	19 (10)	12 (7)	17 (9)
AEs leading to premature trial product discontinuation	31 (11)	26 (9)	5 (4)	16 (9)	24 (13)	5 (3)
Deaths*	3 (1)	4 (1)	1 (1)	0	3 (2)	0
Most common AEs (occurring in ≥10% of patients in any treatment group in either study)
Nausea	56 (20)	51 (18)	5 (4)	30 (17)	42 (23)	13 (7)
Diarrhea	43 (15)	31 (11)	11 (8)	22 (12)	27 (15)	11 (6)
Nasopharyngitis	41 (14)	37 (13)	15 (11)	21 (12)	18 (10)	27 (15)
Decreased appetite	16 (6)	20 (7)	0	18 (10)	23 (13)	2 (1)
Severe or blood glucose-confirmed symptomatic hypoglycemic episodes^†	2 (1)	7 (2)	3 (2)	47 (26)	48 (27)	54 (29)
Severe or blood glucose-confirmed symptomatic hypoglycemic episodes^† by background insulin regimen
Basal insulin	-	-	-	12 (16)	10 (13)	16 (20)
Basal-bolus insulin	-	-	-	29 (40)	31 (44)	27 (38)
Premixed insulin	-	-	-	6 (19)	7 (20)	11 (34)
AEs of special interest (in-trial events)
Diabetic retinopathy	8 (3)	3 (1)	2 (1)	8 (4)	9 (5)	8 (4)
Acute pancreatitis^‡	0	1 (0.4)	1 (1)	0	0	0
Cardiovascular events^‡	4 (1)	3 (1)	2 (1)	5 (3)	5 (3)	5 (3)
Malignant neoplasm^‡#	3 (1)	3 (1)	0	2 (1)	2 (1)	0
Papillary malignant thyroid neoplasm^‡	1 (0.4)	1 (0.4)	0	NR	NR	NR

PIONEER 8 includes results for the recommended maintenance doses of oral semaglutide 7 and 14 mg only.

*All deaths in PIONEER 4 were judged as not treatment-related by the investigator. EAC-reported cause of death was malignancy (n = 3), acute myocardial infarction (n = 1), sudden cardiac death (n = 1), cardiovascular procedure (n = 1), non-prescription drug reaction or overdose (n = 1), and undetermined (n = 1). In PIONEER 8, of the 3 deaths reported, none reported severe or blood glucose-confirmed symptomatic hypoglycemic episodes during the study; EAC-reported cause of death was infection (n = 1) and undetermined as medical records were unavailable (n = 2); ^†severe hypoglycemia was defined according to the ADA classification (requires assistance of another person to actively administer carbohydrate, glucagon, or take other corrective actions). Blood glucose confirmation of symptomatic hypoglycemia was based on a blood glucose value <56 mg/dL (<3.1 mmol/L) with symptoms consistent with hypoglycemia; ^‡External Event Adjudication Committee-confirmed event; ^#excludes malignant thyroid neoplasms.

ADA, American Diabetes Association; AE, adverse event; EAC, Event Adjudication Committee; NR, not reported; SGLT2, sodium-glucose co-transporter-2.

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