Clinical review of the efficacy and safety of oral semaglutide in patients with type 2 diabetes compared with other oral antihyperglycemic agents and placebo

Figures & data

Figure 1. Overview of study designs of PIONEER trials 1, 2, 3, and 7 [20–23]. Text in italics indicates permitted background medication. All trials shown here included a 2-week screening period and 5-week follow-up period (for those not continuing into an extension phase [not shown] in PIONEER 7). Changes in other parameters of efficacy, safety and tolerability were evaluated in all trials. DPP-4i, dipeptidyl peptidase-4 inhibitor; HbA_1c, glycated hemoglobin; SGLT2i, sodium-glucose co-transporter-2 inhibitor; SU, sulfonylurea; TZD, thiazolidinedione

Table 1. Selected secondary efficacy endpoints for PIONEER trials 1, 2, 3, and 7

				% of patients attaining
Trial (N randomized)	Background regimen/trial duration/time of primary end point	Mean baseline characteristics	Treatment arms	HbA1c <7.0%	HbA1c ≤6.5%	Body weight loss ≥5%	HbA1c <7.0% without hypoglycemia^† and without weight gain	HbA1c reduction ≥1% and body weight loss ≥3%
PIONEER 1 (N = 703) [20]	Diet and exercise/ 26 weeks/week 26	Age: 55 years HbA1c: 8.0% Diabetes duration: 3.5 years Body weight: 88.1 kg BMI: 31.8 kg/m^2 eGFR: 98 mL/min/1.73 m^2	Oral semaglutide 3 mg (n = 175)	55*	36*	20	37*	18
			Oral semaglutide 7 mg (n = 175)	69*	48*	27*	57*	37*
			Oral semaglutide 14 mg (n = 175)	77*	64*	41*	69*	51*
			Placebo (n = 178)	31	18	15	23	11
PIONEER 2(N = 822)^‡ [21]	MET/52 weeks/week 26	Age: 58 years HbA1c: 8.1% Diabetes duration: 7.4 years Body weight: 91.6 kg BMI: 32.8 kg/m^2 eGFR: 95 mL/min/1.73 m^2	Oral semaglutide 14 mg (n = 411)	67*	47	41	61*	45*
			Empagliflozin 25 mg (n = 410)	40	17	36	36	28
PIONEER 3 (N = 1,864) [23]	MET ± SU/78 weeks/week 26	Age: 58 years HbA1c: 8.3% Diabetes duration: 8.6 years Body weight: 91.2 kg BMI: 32.5 kg/m^2 eGFR: 95–96 mL/min/1.73 m^2§	Oral semaglutide 3 mg (n = 466)	27	13	13	20	13
			Oral semaglutide 7 mg (n = 465)	42*	26*	19*	34*	26*
			Oral semaglutide 14 mg (n = 465)	55*	36*	30*	46*	37*
			Sitagliptin 100 mg (n = 467)	32	14	10	20	9
PIONEER 7 (N = 504) [22]	1–2 of: MET, SU, TZD, SGLT2 inhibitor/52 weeks/week 52	Age: 57 years HbA1c: 8.3% Diabetes duration: 8.8 years Body weight: 88.6 kg BMI: 31.5 kg/m^2 eGFR: 95–97 mL/min/1.73 m^2§	Oral semaglutide(flexible 3, 7, or 14 mg) (n = 253)	58*	33*	27*	45*	35*
			Sitagliptin 100 mg (n = 251)	25	12	12	15	11

Note: efficacy outcomes are shown at the time of the primary endpoint for the treatment policy estimand, which evaluated the treatment effect for all randomized patients regardless of trial product discontinuation or the use of rescue medication (estimated by a pattern mixture model using multiple imputation to handle missing data).

*p < 0.05 for the estimated odds ratios favoring oral semaglutide over placebo or active comparator; ^†severe or blood glucose-confirmed symptomatic hypoglycemia; ^‡data from one patient was excluded due to duplication (already enrolled in the trial at another site); ^§stated range is the range of mean values reported across the treatment groups.

BMI, body mass index; eGFR, estimated glomerular filtration rate; HbA_1c, glycated hemoglobin; MET, metformin; SGLT2, sodium-glucose co-transporter-2; SU, sulfonylurea; TZD, thiazolidinedione.

Figure 2. Mean change in HbA_1c from baseline in PIONEER 1, 2, 3, and 7 [20–23]. *p < 0.05 for ETD for oral semaglutide versus comparator; ^†p < 0.05 for ETD for sitagliptin versus oral semaglutide 3 mg. ETD, estimated treatment difference; HbA_1c, glycated hemoglobin

Figure 3. Mean change in body weight from baseline in PIONEER 1, 2, 3, and 7 [20–23]. *p < 0.05 for estimated treatment difference for oral semaglutide versus comparator

Table 2. Selected safety data for PIONEER trials 1, 2, 3, and 7

					GI AEs				Hypoglycemia
Trial (N randomized)	Treatment arm	AEs, n (%)	SAEs, n (%)	AEs leading to premature trial product discontinuation, n (%)	Nausea, n (%)	Vomiting, n (%)	Diarrhea, n (%)	GI AEs leading to premature trial product discontinuation, n (%)	Severe orBG-confirmed symptomatic hypoglycemic events,*^†‡ n (%)	Severe hypoglycemic episodes,*^† n (%)
PIONEER 1 (N = 703) [20]	Oral semaglutide 3 mg (n = 175)	101 (58)	5 (3)	4 (2)	14 (8)	5 (3)	15 (9)	3 (2)	5 (3)	0
	Oral semaglutide 7 mg (n = 175)	93 (53)	3 (2)	7 (4)	9 (5)	8 (5)	9 (5)	4 (2)	2 (1)	1 (1)
	Oral semaglutide 14 mg (n = 175)	99 (57)	2 (1)	13 (7)	28 (16)	12 (7)	9 (5)	9 (5)	1 (1)	0
	Placebo (n = 178)	99 (56)	8 (4)	4 (2)	10 (6)	4 (2)	4 (2)	1 (1)	1 (1)	0
PIONEER 2 (N = 822)# [21]	Oral semaglutide 14 mg (n = 410)	289 (70)	27 (7)	44 (11)	81 (20)	30 (7)	38 (9)	33 (8)	7 (2)	1 (<1)
	Empagliflozin 25 mg (n = 409)	283 (70)	37 (9)	18 (4)	10 (2)	7 (2)	13 (3)	3 (1)	8 (2)	1 (<1)
PIONEER 3 (N = 1,864) [23]	Oral semaglutide 3 mg (n = 466)	370 (80)	64 (14)	26 (6)	34 (7)	13 (3)	45 (10)	11 (2)	23 (5)	0
	Oral semaglutide 7 mg (n = 464)	363 (78)	47 (10)	27 (6)	62 (13)	28 (6)	53 (11)	16 (3)	24 (5)	0
	Oral semaglutide 14 mg (n = 465)	370 (80)	44 (9)	54 (12)	70 (15)	42 (9)	57 (12)	32 (7)	36 (8)	1 (<1)
	Sitagliptin 100 mg (n = 466)	388 (83)	58 (12)	24 (5)	32 (7)	19 (4)	37 (8)	12 (3)	39 (8)	4 (1)
PIONEER 7 (N = 504) [22]	Oral semaglutide (flexible 3, 7, or 14 mg) (n = 253)	197 (78)	24 (9)	22 (9)	53 (21)	14 (6)	22 (9)	14 (6)	14 (6)	0
	Sitagliptin 100 mg (n = 250)	172 (69)	24 (10)	8 (3)	6 (2)	2 (1)	8 (3)	2 (1)	14 (6)	0

*Hypoglycemic episodes were reported on a separate form to AEs; ^†requiring assistance of another person to actively administer carbohydrate or glucagon, or take other corrective actions; ^‡based on a BG value (<56 mg/dL) with symptoms consistent with hypoglycemia; ^#data from one patient was excluded due to duplication (already enrolled in the trial at another site).

AE, adverse event; BG, blood glucose; GI, gastrointestinal; SAE, serious adverse event.

Table 3. AEs related to diabetic retinopathy for PIONEER trials 1, 2, 3, and 7

Trial (N randomized)	Treatment arm	Patients experiencing AEs related to diabetic retinopathy, n (%)
PIONEER 1 (N = 703) [20]	Oral semaglutide 3 mg (n = 175)	1 (1)
	Oral semaglutide 7 mg (n = 175)	6 (3)
	Oral semaglutide 14 mg (n = 175)	2 (1)
	Placebo (n = 178)	3 (2)
PIONEER 2 (N = 822) [21]	Oral semaglutide 14 mg (n = 410)	14 (3)
	Empagliflozin 25 mg (n = 409)	5 (1)
PIONEER 3 (N = 1,864) [23]	Oral semaglutide 3 mg (n = 466)	31 (7)
	Oral semaglutide 7 mg (n = 464)	28 (6)
	Oral semaglutide 14 mg (n = 465)	26 (6)
	Sitagliptin 100 mg (n = 466)	36 (8)
PIONEER 7 (N = 504) [22]	Oral semaglutide (flexible 3, 7, or 14 mg) (n = 253)	6 (2)
	Sitagliptin 100 mg (n = 250)	6 (2)

AE, adverse event.

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