Practical guidance for use of oral semaglutide in primary care: a narrative review

Figures & data

Figure 1. The ADA and AACE/ACE 2020 recommendations for GLP-1RA therapy in the treatment of T2D

*Thresholds defining initial treatment strategy; recommendations also apply to patients, not at goal (HbA_1c ≤ 6.5%, unless with concurrent serious illness or at risk for hypoglycemia) on monotherapy/dual therapy; ^†≥ 24 hours’ duration; ^‡proven CVD benefit means the medication has a label indication of reducing CVD events. AACE/ACE, American Association of Clinical Endocrinologists/American College of Endocrinology; ADA, American Diabetes Association; ASCVD, atherosclerotic cardiovascular disease; CKD, chronic kidney disease; CVD, cardiovascular disease; eGFR, estimated glomerular filtration rate; GLP-1RA, glucagon-like peptide-1 receptor agonist; HbA_1c, glycated hemoglobin; HF, heart failure; HFrEF, heart failure with reduced ejection fraction; SGLT2i, sodium-glucose co-transporter-2 inhibitor; T2D, type 2 diabetes.

Table 1. Key efficacy endpoints for PIONEER trials 1–5, 7, and 8

Trial	Background regimen	Treatment duration	Treatment arm (number of randomized patients)	ETD, change in HbA1c (%) ^##	ETD, change in body weight (kg) ****	% of patients attaining: ^††††			Frequency of on-treatment AEs (%)		Frequency of select on‑treatment GI AEs (%)
						HbA1c < 7.0%	HbA1c < 7.0% without hypoglycemia/weight gain^‡‡‡‡	Body weight loss ≥ 5%	Any AE	SAE	Nausea	Diarrhea	Vomiting
Placebo-controlled trials
PIONEER 1 (N = 703) [52]	Diet and exercise	26 weeks	Efficacy analysis timepoint: week 26^###						Safety analysis timepoint: on-treatment period
			Oral semaglutide 3 mg (n = 175)	–0.6***	–0.1	55.1^§§§	37.1^§§	19.6	57.7	2.9	8.0	8.6	2.9
			Oral semaglutide 7 mg (n = 175)	– 0.9***	–0.9	68.8^§§§	56.9^§§§	26.9^§	53.1	1.7	5.1	5.1	4.6
			Oral semaglutide 14 mg (n = 175)	–1.1***	–2.3***	76.9^§§§	68.8^§§§	41.3^§§§	56.6	1.1	16.0	5.1	6.9
			Placebo (n = 178)	-	-	31.0	23.2	14.9	55.6	4.5	5.6	2.2	2.2
PIONEER 5 (N = 324) (moderate renal impairment) [56]	MET, SU, or both; or basal insulin ± MET	26 weeks	Efficacy analysis timepoint: week 26^###						Safety analysis timepoint: on-treatment period
			Oral semaglutide 14 mg (n = 163)	–0.8***	–2.5***	58^§§§	51^§§§	36^§§§	74	10	19	10	12
			Placebo (n = 161)	-	-	23	17	10	65	11	7	4	1
PIONEER 8 (N = 731) [57]	Any basal, basal-bolus, or premixed insulin ± MET	52 weeks	Efficacy analysis timepoint: week 26^###						Safety analysis timepoint: on-treatment period
			Oral semaglutide 3 mg (n = 184)	–0.5***	–0.9*	28.4^§§§	18.2^§§§	13.0^§§	74.5	13.6	11.4	8.7	6.0
			Oral semaglutide 7 mg (n = 182)	–0.9***	–2.0***	42.5^§§§	27.0^§§§	30.5^§§§	78.5	10.5	16.6	12.2	7.7
			Oral semaglutide 14 mg (n = 181)	–1.2***	–3.3***	58.4^§§§	43.9^§§§	38.7^§§§	83.4	6.6	23.2	14.9	9.9
			Placebo (n = 184)	-	-	6.8	2.3	2.8	75.5	9.2	7.1	6.0	3.8
Active-controlled trials
PIONEER 2 (N = 822) [53]	MET	52 weeks/week 26	Efficacy analysis timepoint: week 26^###						Safety analysis timepoint: on-treatment period
			Oral semaglutide 14 mg (n = 412)	–0.4^†††	–0.1	66.8^¶¶¶	60.5^¶¶¶	41.2	70.5	6.6	19.8	9.3	7.3
			Empagliflozin 25 mg (n = 410)	-	-	40.0	35.7	36.1	69.2	9.0	2.4	3.2	1.7
PIONEER 3 (N = 1,864) [54]	MET ± SU	78 weeks	Efficacy analysis timepoint: week 26^###						Safety analysis timepoint: on-treatment period
			Oral semaglutide 3 mg (n = 466)	0.2^‡‡	–0.6^#,†	27^§§§§	20^§§§§	13^§§§§	79.4	13.7	7.3	9.7	2.8
			Oral semaglutide 7 mg (n = 466)	–0.3^†††	–1.6^†††	42^¶¶¶,§§§§	34^¶¶¶,§§§§	19^¶¶¶,§§§§	78.2	10.1	13.4	11.4	6.0
			Oral semaglutide 14 mg (n = 465)	–0.5^†††	–2.5^†††	55^¶¶¶,§§§§	46^¶¶¶,§§§§	30^¶¶¶,§§§§	79.6	9.5	15.1	12.3	9.0
			Sitagliptin 100 mg (n = 467)	-	-	32^§§§§	20^§§§§	10^§§§§	83.3	12.4	6.9	7.9	4.1
PIONEER 4 (N = 711) [55]	MET ± SGLT2i	52 weeks	Efficacy analysis timepoint: week 26^###						Safety analysis timepoint: on-treatment period
			Oral semaglutide 14 mg (n = 285)	–0.1 vs liraglutide –1.1 vs placebo***	–1.2 vs liraglutide^††† –3.8 vs placebo***	67.6^§§§	60.8^§§§	43.5^§§§,¶¶¶	80	11	20	15	9
			Liraglutide 1.8 mg (n = 284)	-	-	61.8	53.5	27.7	74	8	18	11	5
			Placebo (n = 142)	-	-	14.2	11.2	7.5	67	11	4	8	2
PIONEER 7 (N = 504) [49]	1–2 OADs of: MET, SU, TZD, SGLT2i	52 weeks	Efficacy analysis timepoint: week 52^###						Safety analysis timepoint: on-treatment period
			Oral semaglutide (flexible 3, 7, or 14 mg) (n = 253)	–0.5^†††	–1.9^†††	58^¶¶¶	45.2^¶¶¶	27.0^¶¶¶	78	9	21	9	6
			Sitagliptin 100 mg (n = 251)	-	-	25	14.7	12.1	69	10	2	3	1

*p < 0.05; ***p < 0.001 in favor of oral semaglutide vs placebo;

^†p < 0.05, ^†††p < 0.001 in favor of oral semaglutide vs active comparator;

^‡‡p < 0.01 in favor of comparator vs oral semaglutide;

^§p < 0.05, ^§§p < 0.01, ^§§§p < 0.001 for odds ratio in favor of oral semaglutide vs placebo;

^¶p < 0.05, ^¶¶¶p < 0.001 for odds ratio in favor of oral semaglutide vs active comparator;

^#As noninferiority with respect to HbA_1c was not demonstrated for oral semaglutide 3 mg vs sitagliptin, superiority with respect to body weight was not tested;

^##Primary endpoint at week 26 for all trials except PIONEER 7, for which the primary endpoint was proportion of patients who achieved HbA_1c < 7.0% at week 52;

^###Efficacy outcomes shown at the time of the primary endpoint (week 52 for PIONEER 7 and week 26 for all other trials) for the treatment policy estimand, which evaluated the treatment effect for all randomized patients regardless of trial product discontinuation and the use of rescue medication (estimated by a pattern mixture model using multiple imputation to handle missing data);

****Key secondary endpoint at week 26 (PIONEER 1–5 and 8) or week 52 (PIONEER 7);

^††††Observed proportions unless otherwise specified;

^‡‡‡‡Symptomatic hypoglycemic events defined as severe according to the ADA classification, or confirmed by blood glucose concentration (3.1 mmol/L [< 56 mg/dL]);

^§§§§Estimated by analysis of covariance for continuous endpoints and generalized linear model, with binomial distribution and identity link for binary endpoints.

ADA, American Diabetes Association; AE, adverse event; ETD, estimated treatment difference; GI, gastrointestinal; HbA_1c, glycated hemoglobin; MET, metformin; OAD, oral antidiabetic drug; SAE, serious adverse event; SGLT2i, sodium-glucose co-transporter-2 inhibitor; SU, sulfonylurea; TZD, thiazolidinedione; -, data not applicable.

Figure 2. Summary of practical guidance for initiating patients on oral semaglutide [12]

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