Pharmacological profile of once-weekly injectable semaglutide for chronic weight management

Figures & data

Figure 1. Pharmacokinetic properties of once-weekly subcutaneous semaglutide 2.4 mg treatment in patients with overweight and obesity.

Table 1. Study design overviews for the phase 3 STEP trials

Trial	Trial status	Reference	Study design^a	Treatments
STEP 1 (NCT03548935)	Completed; results published	Wilding et al. 2021 [41]	Multicenter, randomized, double-blind, placebo-controlled trial Investigated the efficacy and safety of OW semaglutide in adults with overweight or obesity, in combination with diet and physical activity, over 68 weeks of treatment	1961 Adults were randomized 2:1 to OW injectable semaglutide (dose-escalated to 2.4 mg) or placebo, for a 68-week treatment period Followed by a 7-week follow-up period without medication
STEP 2 (NCT03552757)	Completed; results published	Davies et al. 2021 [42]	Multicenter, randomized, double-blind, double-dummy superiority trial Investigated the efficacy and safety of OW semaglutide in adults with T2D^b with overweight or obesity, in combination with diet and physical activity, over 68 weeks of treatment	1210 Adults were randomized 1:1:1 to OW semaglutide (dose-escalated to 2.4 mg or 1.0 mg) or placebo for a 68-week treatment period Followed by a 7-week follow-up period
STEP 3 (NCT03611582)	Completed; results published	Wadden et al. 2021 [43]	Multicenter, randomized, double-blind, placebo-controlled, parallel-group trial Investigated the efficacy and safety of OW semaglutide in adults with overweight or obesity, in combination with intensive behavioral therapy, diet, and physical activity, over 68 weeks of treatment	611 Adults were randomized 2:1 to OW semaglutide (dose-escalated to 2.4 mg) or placebo for a 68-week treatment period Followed by a 7-week follow-up period without medication
STEP 4 (NCT03548987)	Completed; results published	Rubino et al. 2021 [44]	Multicenter, randomized, double-blind, placebo-controlled, withdrawal trial Investigated the efficacy and safety of OW semaglutide in adults with overweight or obesity, in combination with diet and physical activity, over a 48-week randomization treatment period, following a 20-week run-in	For a 20-week open-label, run-in period, all 902 patients received OW semaglutide (dose-escalated to 2.4 mg) Following run-in, patients were randomized 2:1 to either continue receiving OW semaglutide (2.4 mg) or switch to placebo for a 48-week randomization treatment period Followed by a 7-week follow-up period
STEP 5 (NCT03693430)	Completed; results not fully published	Congress presentation reference: Garvey et al. 2021 [47]	Multicenter, randomized, double-blind, placebo-controlled trial Investigated the efficacy and safety of OW semaglutide in adults with overweight or obesity, in combination with diet and physical activity over 104 weeks of treatment	304 Adults were randomized 1:1 to OW injectable semaglutide (dose-escalated to 2.4 mg) or placebo for a 104-week treatment period Followed by a 7-week follow-up period without medication
STEP 6 (NCT03811574)	Completed; results published	Kadowaki et al. 2022 [45]	Randomized trial investigating the efficacy and safety of OW semaglutide in East Asian adults with overweight or obesity, in combination with diet and physical activity, over 68 weeks of treatment	401 Adults randomized to OW injectable semaglutide (dose-escalated to 1.7 mg or 2.4 mg) or placebo for 68 weeks
STEP 7 (NCT04251156)	Estimated study completion: 26 August 2022	Not yet available	Randomized, parallel-group trial Investigating the efficacy and safety of OW semaglutide in Chinese adults with overweight or obesity, in combination with diet and physical activity, over 44 weeks of treatment	375 Adults were randomized 1:1 to OW injectable semaglutide (dose-escalated to 2.4 mg) or placebo for 44 weeks
STEP 8 (NCT04074161)	Completed; results published	Rubino et al. 2022 [46]	Randomized, open-label, parallel-group trial Assessed the efficacy and safety of OW semaglutide vs OD liraglutide in adults with overweight or obesity, both in combination with diet and physical activity, over 68 weeks of treatment	338 Adults were randomized (3:1:3:1) to OW subcutaneous semaglutide (16-week dose-escalation to 2.4 mg), or matching placebo, or OD subcutaneous liraglutide (4-week dose-escalation to 3.0 mg), or matching placebo for 68 weeks
STEP 9 (NCT05064735)	Recruiting; estimated study completion: September 2023	Not yet available	Randomized, parallel-group, triple-blind, placebo-controlled trial Investigating the efficacy and safety of OW semaglutide, in combination with diet and physical activity, in adults with obesity and knee OA,^c over 68 weeks of treatment	An estimated 375 adults will be randomized 1:1 to OW injectable semaglutide (dose-escalated to 2.4 mg) or placebo for 68 weeks
STEP 10 (NCT05040971)	Recruiting; estimated study completion: July 2023	Not yet available	Randomized, quadruple-blind, placebo-controlled trial Investigating the efficacy and safety of OW semaglutide, in combination with diet and physical activity, in adults with obesity and prediabetes,^d over 52 weeks of treatment	An estimated 201 adults will be randomized to OW injectable semaglutide (dose-escalated to 2.4 mg) or placebo for 52 weeks
STEP 11 (NCT04998136)	Not yet recruiting; study completion: May 2023	Not yet available	Randomized, quadruple-blind, parallel-group trial Investigating the efficacy and safety of OW semaglutide in adults from Thailand and South Korea with overweight or obesity for 44 weeks of treatment	An estimated 150 adults will be randomized to receive OW injectable semaglutide (dose-escalated to 2.4 mg) or placebo for 44 weeks
STEP TEENS (NCT04102189)	Estimated study completion: March 2022	Not yet available	Randomized, double-blind, parallel-group trial Investigating the efficacy and safety of OW semaglutide in adolescents^e with overweight or obesity, in combination with diet and physical activity, over 68 weeks of treatment	An estimated 163 adolescents will be randomized 1:1 to OW injectable semaglutide (dose-escalated to 2.4 mg) or placebo for 68 weeks
SELECT (NCT03574597)	Estimated study completion: September 2023	Not yet available	Randomized, parallel-group, placebo-controlled trial Investigating the effects of OW semaglutide on cardiovascular outcomes^f in adults with overweight or obesity, as an adjunct to standard of care	An estimated 17,500 adults will be randomized 1:1 to OW injectable semaglutide (dose-escalated to 2.4 mg) or placebo as an adjunct to standard of care for 31–59 months
STEP HFpEF (NCT04788511)	Recruiting; estimated study completion: April 2023	Not yet available	Randomized, parallel-group, placebo-controlled, double-blind trial Investigating the effects of OW semaglutide, as an adjunct to SOC, on function and symptoms in adults with obesity-related heart failure with preserved ejection fraction	An estimated 516 adults will be randomized to OW injectable semaglutide (dose-escalated to 2.4 mg) or placebo for 59 weeks
STEP HFpEF DM (NCT04916470)	Recruiting; estimated study completion: August 2023	Not yet available	Randomized, parallel-group, placebo-controlled, quadruple-blind trial Investigating the effects of OW semaglutide, as an adjunct to SOC, on function and symptoms in adults with obesity-related heart failure with preserved ejection fraction, and T2D	An estimated 610 adults will be randomized to OW injectable semaglutide (dose-escalated to 2.4 mg) or placebo for 52 weeks

All studies presented in the table are phase 3 clinical trials. ^aFor inclusion in the STEP trials, overweight was defined as a BMI ≥27.0 kg/m²; obesity was defined as a BMI ≥ 30.0 kg/m²; adults were required to be ≥18 years of age. ^bIn STEP 2, patients with T2D were included who had an HbA_1c between 7% and 10% and were managed on diet and exercise alone or were stable on up to three oral antidiabetic drugs. ^cIn STEP 9, OA was defined as a clinical diagnosis of knee OA (based on the ACR criteria) with moderate radiographic changes (Kellgren–Lawrence grades 2 or 3) in the target knee. ^dIn STEP 10, prediabetes was defined as a HbA_1c between 6.0% and 6.4% (42.0–47.0 mmol/mol) and/or an FPG between 5.5 and 6.9 mmol/L (99.0–125.0 mg/dL). ^eIn STEP TEENS, adolescents were required to be between 12 and 17 years of age. ^fIn SELECT, cardiovascular outcomes include composite endpoint, consisting of cardiovascular death, nonfatal myocardial infarction nonfatal stroke, and additional endpoints, such as time to cardiovascular death, heart failure, first occurrence of nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, unstable angina requiring hospitalization, and heart failure hospitalization.

ACR, American College of Rheumatology; BMI, body mass index; FPG, fasting plasma glucose; HbA_1c, glycated hemoglobin; OA, osteoarthritis; OD, once daily; OW, once weekly; SOC, standard of care; T2D, type 2 diabetes.

Table 2. Summary of patients’ baseline characteristics for STEP 1–6 and STEP 8 [41–47]

Parameter	Sema for WM, 68 weeks	Sema for WM in T2D, 68 weeks	Sema + IBT for WM, 68 weeks	Sema for sustained WM, 20-week run-in + 48 weeks of treatment	Sema for long-term WM, 104 weeks	Sema for WM in East Asian adults, 68 weeks	Sema vs lira for WM, 68 weeks
	STEP 1 (N = 1961)	STEP 2 (N = 1210)	STEP 3 (N = 611)	STEP 4 (N = 803)	STEP 5 (N = 304)	STEP 6(N = 401)	STEP 8 (N = 338)
Female, %	74.1	50.9	81.0	79.0	78.0	37.0	78.4
Age, years	47	55	46	46	47	51	49
Race, % White Black/African American Asian Other^a	75.1 5.7 13.3 6.0	62.1 8.3 26.2 3.5	76.1 19.0 1.8 3.1	83.7 13.0 2.4 1.0	93.1 3.9 0.7 2.3	0 0 100 0	73.7 18.9 3.8 3.6
HbA1c, %	5.7	8.1	5.7 (sema); 5.8 (placebo)	5.7	5.7	6.4	5.5 (sema and lira); 5.6 (placebo)
BMI, kg/m^2	37.9	35.7	38.0	38.4	38.5	31.9	37.5
Waistcircumference, cm	114.7	114.6	113.0	115.3	115.7	103.2	113.3

Data presented in the table represent mean values. ^aNative American, Alaska Native, Native Hawaiian or other Pacific Islander, or other.

BMI, body mass index; HbA_1c, glycated hemoglobin; IBT, intensive behavioral therapy; lira, liraglutide; sema, semaglutide; T2D, type 2 diabetes; WM, weight management.

Figure 2. Effects of once-weekly subcutaneous semaglutide 2.4 mg on body weight from STEP 1–6 and STEP 8 [41–47].

Table 3. Summary of primary and secondary efficacy endpoints for STEP 1–6 and STEP 8 [41–47]

Efficacy parameters	Sema for WM, 68 weeks		Sema for WM in T2D, 68 weeks			Sema + IBT for WM, 68 weeks		Sema for sustained WM, 20-week run-in + 48 weeks of treatment		Sema for long-term WM, 104 weeks		Sema for WM in East Asian adults, 68 weeks			Sema vs lira for WM, 68 weeks
	STEP 1		STEP 2			STEP 3		STEP 4^a		STEP 5		STEP 6			STEP 8
	Sema 2.4 mg (n = 1306)	PBO (n = 655)	Sema 2.4 mg (n = 404)	Sema 1.0 mg (n = 403)	PBO (n= 403)	Sema 2.4 mg (n = 407)	PBO (n = 204)	Sema 2.4 mg (n = 535)	PBO (n = 268)	Sema 2.4 mg (n = 152)	PBO (n = 152)	Sema 2.4 mg (n = 199)	Sema 1.7 mg (n = 101)	PBO (n = 101)	Sema 2.4 mg (n = 126)	Lira 3.0 mg (n = 127)
Primary endpoints/co-primary endpoints
Change from BL to EOT in BW, % change	–14.9	–2.4	–9.6	–7.0	–3.4	–16.0	–5.7	–7.9	6.9	–15.2	–2.6	–13.2	–9.6	–2.1	–15.8	–6.4
Weight reduction of ≥5%, %	86.4	31.5	68.8	57.1	28.5	86.6	47.6	88.7	47.6	77.1	34.4	82.9	72.4	21.0	87.2^b	58.1^b
Secondary endpoints
Weight reduction of ≥10% (%)	69.1	12.0	45.6	28.7	8.2	75.3	27.0	79.0	20.4	61.8	13.3	60.6	41.8	5.0	70.9	25.6
Weight reduction of ≥15% (%)	50.5	4.9	25.8	13.7	3.2	55.8	13.2	63.7	9.2	52.1	7.0	40.9	24.5	3.0	55.6	12.0
Weight reduction of ≥20% (%)	32.0	1.7	13.1	4.7	1.6	35.7	3.7	39.6	4.8	36.1	2.3	19.7	11.2	2.0	38.5	6.0
Secondary endpoints: change from baseline to EOT in the following:
WC (cm)	–13.54	–4.13	–9.4	–6.7	–4.5	–14.6	–6.3	–6.4	3.3	–14.4	–5.2	–11.2	–7.8	–1.8	–13.2	–6.6
BW (kg)	–15.3	–2.6	–9.7	–6.9	–3.5	–16.8	–6.2	–7.1	6.1	NA	NA	–11.3	–8.3	–1.7	–15.3	–6.8
SBP (mmHg)	–6.16	–1.06	–3.9	–2.9	–0.5	–5.6	–1.6	0.5	4.4	–5.7	–1.6	–11.0	–12.0	–5.0	–5.7	–2.9
DBP (mmHg)	–2.83	–0.42	–1.6	–0.6	–0.9	–3.0	–0.8	0.3	0.9	–4.5	–0.8	–5	–5	–3	–5.0	–0.5
SF-36	2.21	0.41	2.5	2.4	1.0	2.4	1.6	1.0	−1.5	NA	NA	1.0	0.0	–0.5	NA	NA
IWQOL-Lite	14.67	5.25	10.1	8.7	5.3	NA	NA	NA	NA	NA	NA	–4.3	–3.1	–0.6	NA	NA
BMI (kg/m^2)	–5.54	–0.92	–3.5	–2.5	–1.3	–6.0	–2.2	–2.6	2.2	NA	NA	–4.3	–3.1	–0.6	NA	NA
HbA1c (%-points)	–0.45	–0.15	–1.6	–1.5	–0.4	–0.51	–0.27	–0.1	0.1	–0.43	–0.10	–1.0	–0.9	0.0	–0.2	–0.1
FPG (mg/dL)	–8.35	–0.48	–2.1	–1.8	–0.1	–6.73	–0.65	–0.8	6.7	–7.6	1.6	–19.3	–18.3	1.7	–8.3	–4.3
Total cholesterol^c HDL^c LDL^c VLDL^c FFAs^c TGs^c	0.97 1.05 0.97 0.78 0.83 0.78	1.00 1.01 1.01 0.93 0.93 0.93	0.99 1.07 1.00 0.79 0.84 0.78	0.98 1.05 0.99 0.83 0.86 0.83	0.99 1.04 1.00 0.90 0.99 0.91	–3.8 6.5 –4.7 –22.5 –11.9 –22.5	2.1 5.0 2.6 –6.6 4.0 –6.5	5 18 1 –6 –18 –6	11 18 8 15 –14 15	NA NA NA NA NA –19.0	NA NA NA NA NA 3.7	0.91 1.08 0.86 0.79 0.96 0.79	0.93 1.06 0.90 0.79 1.04 0.78	1.00 1.06 0.95 1.05 1.28 1.05	–7.1 –0.3 –6.5 –20.7 –12.6 –20.7	–0.1 1.9 0.9 –10.9 –8.8 –11.0
CRP (mg/dL)	0.47	0.85	0.51	0.58	0.83	NA	NA	NA	NA	NA	NA	0.39	0.64	0.92	NA	NA
CRP (% change)	NA	NA	NA	NA	NA	–59.6	–22.9	NA	NA	–56.7	–7.8	NA	NA	NA	–52.6	–24.5

^aFor STEP 4, change from BL to EOT represents the change from week 20 (after the run-in period) to week 68. ^bFor STEP 8, the percentage of individuals achieving a weight loss from baseline to EOT of ≥5% was an exploratory secondary endpoint rather than a co-primary endpoint. ^cFor STEP 1, STEP 2, and STEP 6, these data were presented as ratios of baseline values; for STEP 3–5, these data were expressed as changes from baseline.

BL, baseline; BMI, body mass index; BW, body weight; CRP, C-reactive protein; DBP, diastolic blood pressure; EOT, end of treatment; FFA, free fatty acid; FPG, fasting plasma glucose; HbA_1c, glycated hemoglobin; HDL, high-density lipoprotein; IBT, intensive behavioral therapy; IQWQOL-Lite, Impact of Weight on Quality of Life-Lite; LDL, low-density lipoprotein; lira, liraglutide; NA, not available; PBO, placebo; SBP, systolic blood pressure; sema, semaglutide; SF-36, 36-Item Short Form Health Survey; T2D, type 2 diabetes; TG, triglyceride; VLDL, very low-density lipoprotein; WC, waist circumference; WM, weight management; VLDL, very low-density lipoprotein.

Table 4. Adverse events and tolerability profiles for STEP 1–6 and STEP 8 [41–47]

AEs, n (%)	Sema for WM, 68 weeks		Sema for WM in T2D, 68 weeks			Sema + IBT for WM, 68 weeks		Sema for sustained WM, 20-week run-in + 48 weeks of treatment		Sema for long-term WM, 104 weeks		Sema for WM in East Asian adults, 68 weeks			Sema vs lira for WM, 68 weeks
	STEP 1		STEP 2			STEP 3		STEP 4^a		STEP 5		STEP 6			STEP 8
	Sema 2.4 mg (n = 1306)	PBO (n = 655)	Sema 2.4 mg (n = 403)	Sema 1.0 mg (n = 402)	PBO (n = 402)	Sema 2.4 mg (n = 407)	PBO (n = 204)	Sema 2.4 mg (n = 535)	PBO (n = 268)	Sema 2.4 mg (n = 152)	PBO (n = 152)	Sema 2.4 (n = 199)	Sema 1.7 (n = 100)	PBO (n = 101)	Sema 2.4 mg (n = 126)	Lira 3.0 mg (n = 127)	PBO (n = 85)
Serious AEs	128 (9.8)	42 (6.4)	40 (9.9)	31 (7.7)	37 (9.2)	37 (9.1)	6 (2.9)	41 (7.7)	15 (5.6)	NA (7.9)	NA (11.8)	10 (5.0)	7 (7.0)	1 (1.0)	10 (7.9)	14 (11.0)	6 (7.1)
AEs leading to product discontinuation	92 (7.0)	20 (3.1)	25 (6.2)	20 (5.0)	14 (3.5)	24 (5.9)	6 (2.9)	13 (2.4)	6 (2.2)	NA (5.9)	NA (4.6)	5 (3)	3 (3)	1 (1)	4 (3.2)	16 (12.6)	3 (3.5)
Any AEs	1171 (89.7)	566 (86.4)	353 (87.6)	329 (81.8)	309 (76.9)	390 (95.8)	196 (96.1)	435 (81.3)	201 (75.0)	NA (96.1)	NA (89.5)	171 (86)	82 (82)	80 (79)	120 (95.2)	122 (96.1)	81 (95.3)
AEs in ≥10% of participants in any treatment group by MeDRA-preferred term
Nausea	577 (44.2)	114 (17.4)	136 (33.7)	129 (32.1)	37 (9.2)	237 (58.2)	45 (22.1)	75 (14.0)	13 (4.9)	NA	NA	35 (18)	18 (18)	4 (4)	77 (61.1)	75 (59.1)	19 (22.4)
Constipation	305 (23.4)	62 (9.5)	70 (17.4)	51 (12.7)	22 (5.5)	150 (36.9)	50 (24.5)	62 (11.6)	17 (6.3)	NA	NA	52 (26)	19 (19)	3 (3)	49 (38.9)	40 (31.5)	20 (23.5)
Diarrhea	412 (31.5)	104 (15.9)	86 (21.3)	89 (22.1)	48 (11.9)	147 (36.1)	45 (22.1)	77 (14.4)	19 (7.1)	NA	NA	32 (16)	22 (22)	6 (6)	35 (27.8)	23 (18.1)	22 (25.9)
Vomiting	324 (24.8)	43 (6.6)	88 (21.8)	54 (13.4)	11 (2.7)	111 (27.3)	22 (10.8)	55 (10.3)	8 (3.0)	NA	NA	17 (9)	10 (10)	2 (2)	32 (25.4)	26 (20.5)	5 (5.9)

Currently, STEP 5 data are only published in abstract form, so not all safety data are available for this study.

AE, adverse event; IBT, intensive behavioral therapy; GI, gastrointestinal; lira, liraglutide; NA, not available; sema, semaglutide; T2D, type 2 diabetes; WM, weight management.

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