Semaglutide 2.4 Mg for the Management of Overweight and Obesity: Systematic Literature Review and Meta-Analysis

Figures & data

Table 1 Eligibility Criteria for the Systematic Literature Review

Criteria	Include
Population	Adults with:  ● BMI ≥27 kg/m^2 and one weight-related co-morbidity  ● BMI ≥30 kg/m^2 (with weight-related co-morbidities)  ● BMI ≥30 kg/m^2 (without weight-related co-morbidities) Populations of interest for the meta-analysis included:  ● Full population (full population in terms of BMI categories) (principal population of interest)  ● Normal glucose tolerance (full population in terms of BMI categories)  ● Non-T2DM (full population in terms of BMI categories)  ● High CVD risk^† (full population in terms of BMI categories)  ● Pre-diabetic (full population in terms of BMI categories)  ● Pre-diabetic and high CVD risk (full population in terms of BMI categories)  ● Pre-diabetic and BMI ≥35 kg/m^2  ● Pre-diabetic and BMI ≥35 kg/m^2 and high CVD risk  ● T2DM (full population in terms of BMI categories)  ● Subjects eligible for bariatric surgery in the following subpopulations [only population to consider bariatric surgery as a comparator]   o BMI ≥35 kg/m^2 (with weight-related co-morbidities)   o BMI ≥40 kg/m^2 (with or without weight-related co-morbidities)
Intervention & comparators	Intervention of interest: semaglutide 2.4 mg Comparators of interest to include:  ● No treatment (placebo)  ● Diet and exercise (to include behavioural therapy components)  ● Liraglutide, 3.0 mg  ● Orlistat (any dose)  ● Naltrexone/bupropion (any dose)  ● Phentermine/topiramate (Qsymia) (any dose)  ● Phentermine (Adipex P, Suprenza), 15–37.5 mg/daily  ● Bariatric surgery (no restriction on surgery type and for eligible subpopulation only)
Outcomes	Efficacy outcomes  ● Proportion of subjects losing at least 5, 10 and 15% of baseline fasting body weight  ● CFB weight change in kg  ● CFB weight change in %  ● CFB SBP in mmHg  ● CFB total cholesterol in mg/dL (log-transformed scale as per the STEP trials)  ● CFB HDL in mg/dL (log-transformed scale as per the STEP trials)  ● CFB HbA1c in %  ● Incidence of patients reverting from prediabetes to normal glucose tolerance  ● Incidence of patients reducing antihypertensive treatment  ● Incidence of patients reducing glucose lowering drugs  ● CFB waist circumference in cm Safety outcomes  ● Incidence of hypoglycaemia  ● Incidence of SAEs  ● Discontinuations due to AEs
Study design	● Randomised controlled trials  ● SLR and meta-analysis publications
Geography	No restriction
Date of publication	No restriction
Language	No restriction. The primary focus will be English language publications or non-English language publications with an English abstract.

Notes: ^†High risk of CVD defined as: (i) total cholesterol >5 mmol/L, or (ii) SBP >140 mmHg, or (iii) HDL <1.0 mmol/L for men and <1.3 mmol/L for women, or (iv) any other definition applied in the publication.

Abbreviations: AE, adverse event; BMI, body mass index; CFB, change from baseline; CVD, cardiovascular disease; HbA1c, hemoglobin A1cl; HDL, high density lipoprotein; SAE, serious adverse event; SBP, systolic blood pressure; SLR, systematic literature review; STEP, Semaglutide Treatment Effect in People with obesity; T2DM, type 2 diabetes mellitus.

Table 2 Summary of Eligible Studies Investigating Pharmacological Agents Identified in Systematic Literature Review

Study Details				Baseline Characteristics					Total Treatment Duration (Weeks)	Total Follow-Up Duration (Weeks)
Study Name, Design, Country	Population (Key Inclusion Criteria)	Intervention	N (Rand.)	Mean (SD) Age, Years	Males, n (%)	Mean (SD) Weight, Kg	Mean BMI (SD), Kg/m^2	Comorbidities (eg T2DM, %)
Liraglutide
Astrup 2009^Citation55 NCT00422058 Phase 2, double-blind Europe	Age 18-65 years BMI 30–40 kg/m^2 Stable body weight FPG <7 mmol/L at run in	Liraglutide 3.0 mg/day (initiated at 0.6 mg/day and escalated by 0.6 mg per week)	93	45.9 (10.7)	25 (75)	97.6 (13.7)	34.8 (2.8)	Pre-diabetes: 29.0% T2DM: 4.3% NGT: 65.6%	20	20
		Orlistat 120 mg three times daily	95	45.9 (9.1)	23 (77)	96.0 (11.7)	34.1 (2.6)	Pre-diabetes: 28.4% T2DM: 3.2% NGT: 67.4%
		Placebo	98	45.9 (10.3)	25 (75)	97.3 (12.3)	34.9 (2.8)	Pre-diabetes: 32.7% T2DM: 4.1% NGT: 62.2%
O’Neill 2018^Citation56 NCT02453711 Phase 2, double-blind International	Age ≥18 years BMI ≥30 kg/m^2 not of endocrine aetiology, without diabetes ≥1 previous unsuccessful nonsurgical weight loss attempt Free from major depressive symptoms	Liraglutide 3.0 mg/day (initiated at 0.6 mg/day and escalated by 0.6 mg per week)	103	49 (11)	36 (35)	108.7 (21.9)	38.6 (6.6)	None	52	52
		Placebo	136	46 (13)	48 (35)	114.2 (25.4)	40.1 (7.2)
Wadden 2019^Citation38 NCT02911818 Open-label (phase unclear) US	Aged 21–70 years BMI 30–55 kg/m^2 Prior lifetime weight loss effort with diet and exercise	IBT	50	49.5 (11)	NR (22)	105.8 (14.7)	38 (4.3)	T2DM: 0%	52	56
		IBT/liraglutide 3.0 mg/day (initiated at 0.6 mg/day and escalated by 0.6 mg per week)	50	45.2 (12.3)	NR 16)	107.8 (17.9)	38.5 (5.4)
		Multi-component (IBT/liraglutide 3.0 mg/day [initiated at 0.6 mg/day and escalated by 0.6 mg per week] + 12 week diet intervention)	50	48 (11.9)	NR (24)	111.7 (19.4)	38.8 (5)
Davies 2015^Citation30 SCALE Diabetes trial (NCT01272232) Double-blind (phase unclear) International	Age >18 years BMI >27.0 Stable body weight T2DM treated with diet and exercise alone or in combination with 1–3 oral hypoglycaemic agents	Liraglutide 3 mg/day	423	55 (10.8)	NR (52)	105.7 (21.9)	37.1 (6.5)	T2DM: 100% Dyslipidaemia: 69.7% Hypertension: 69.3%	56	68
		Liraglutide 1.8 mg/day	211	54.9 (10.7)	NR (51.2)	105.8 (21)	37 (6.9)	T2DM: 100% Dyslipidaemia: 67.8% Hypertension: 70.1%
		Placebo	212	54.7 (9.8)	NR (45.8)	106.5 (21.3)	37.4 (7.1)	T2DM: 100% Dyslipidaemia: 59.4% Hypertension: 68.4%
Wadden 2020^Citation39 SCALE IBT trial (NCT02963935) Phase 3, double-blind US	Age ≥18 years Stable body weight BMI ≥30 kg/m^2	Liraglutide 3.0 mg/day	142	45.4 (11.6)	NR (16.2)	108.5 (22.1)	39.3 (6.8)	None	52	56
		Placebo	140	49 (11.2)	NR (17.1)	106.7 (22)	38.7 (7.2)
Garvey 2020^Citation31 SCALE Insulin trial (NCT02963922) Phase 3, double-blind International	Age ≥18 years BMI ≥27 kg/m^2 Stable body weight T2DM with HbA1c ≥6.0 to ≤10% (42–86 mmol/mol) at screening Receiving stable treatment with any basal insulin and ≤2 OADs	Liraglutide 3.0 mg/day	198	55.9 (11.3)	90 (45.5)	100.6 (20.8)	35.9 (6.5)	T2DM: 100%	52	56
		Placebo	198	57.6 (10.4)	99 (50)	98.9 (19.9)	35.3 (5.8)	T2DM: 100%
Pi-Sunyer 2015^Citation57 SCALE Obesity and Prediabetes trial (NCT01272219) Double-blind (phase unclear) International	Age ≥18 years BMI ≥30 kg/m2 or ≥27 kg/m2 if the patient had treated or untreated dyslipidaemia or hypertension	Liraglutide 3.0 mg/day (initiated at 0.6 mg/day and escalated by 0.6 mg per week)	2487	45.2 (12.1)	530 (21.3)	106.2 (21.2)	38.3 (6.4)	Pre-diabetes: 61.4% Dyslipidaemia: 29.6% Hypertension: 34.2%	52	56
		Placebo	1244	45 (12)	273 (21.9)	106.2 (21.7)	38.3 (6.3)	Pre-diabetes: 60.9% Dyslipidaemia: 28.9% Hypertension: 35.9%
Orlistat
Bakris 2002^Citation58 Double-blind (phase unclear) US	Age ≥40 years BMI 28–43 kg/m^2 Taking ≥1 antihypertensive medication Sitting DBP 96–109 mmHg on two consecutive visits Individuals with easily controlled and stable diabetes were allowed to participate	Orlistat 120 mg three times daily	278	53.2 (0.5)	98 (35.3)	101.2 (1)	35.8 (3.9)	Hypertension: 100% T2DM: 8%	52	52
		Placebo	276	52.5 (0.5)	109 (39.5)	101.5 (1)	35.4 (4)
Berne 2005^Citation23 Double-blind (phase unclear) Sweden	Age 30–75 years BMI 28–40 kg/m^2 HbA1c 6.5–10%	Orlistat 120 mg three times daily	111	58.9 (9.1)	NR (55)	95.3 (12.6)	32.6 (3.1)	T2DM: 100%	54	54
		Placebo	109	59.3 (8.5)	NR (54)	95.7 (12.5)	32.9 (3)
Broom 2002^Citation59 Double-blind (phase unclear) UK	Age 18–80 years BMI ≥28 kg/m^2 at screening and baseline visits ≥1 obesity-associated CV risk factor	Orlistat 120 mg three times daily	265	46.7 (11.4)	57 (22.0)	100.9 (20.5)	37.1 (604)	Dyslipidemia: 43% Hypertension: 5.6% Obesity-associated CV risk factor: 100%	52	54
		Placebo	266	45.3 (11.5)	56 (21.3)	101.8 (19.8)	37.0 (6.2)	Dyslipidemia: 45.1% Hypertension: 4.2% Obesity-associated CV risk factor: 100%
Davidson 1999^Citation60 Double-blind (phase unclear) US	Age ≥18 years BMI 30–43 kg/m^2 Absence of weight loss (>4 kg) in previous 3 months	Orlistat 120 mg three times daily	668	43.3 (0.6)	113 (17.2)	100.7 (0.6)	36.2 (0.1)	Pre-diabetes: 6.1% T2DM: 4% Dyslipidaemia: 32.1% Hypertension: 5.5% Hypertriglyceridemia: 10.5%	52	56
		Placebo	224	44 (0.7)	26 (11.7)	100.6 (0.9)	36.5 (0.1)	Pre-diabetes: 5.8% T2DM: 4.5% Dyslipidaemia: 35.9% Hypertension: 7.2% Hypertriglyceridemia: 5.4%
Derosa 2003^Citation61 Double-blind (phase unclear) Italy	BMI >30 kg/m^2 Age >40 years Severe hypercholesterolemia (TC >240 mg/dL) Normotensive (SBP <140 mmHg and DBP <90 mmHg)	Orlistat 120 mg three times daily	27	51.6 (8.3)	13 (48.1)	94.2 (9.8)	32 (1.3)	Hypercholesterolemia: 100%	52	52
		Fluvastatin 80 mg/d	24	50.6 (9.4)	11 (45.8)	95.4 (10)	32.1 (1.2)
		Orlistat 120 mg three times daily plus fluvastatin 80 mg daily	25	53.1 (10)	13 (52)	96.1 (9.7)	32.5 (1.4)
		Placebo	23	52.4 (10.2)	11 (47.8)	95.3 (10.2)	31.7 (1)
Derosa 2010^Citation25 Double-blind (phase unclear) Italy	Age ≥18 years BMI ≥30 kg/m^2 Uncontrolled T2DM in therapy with different OAD ages or insulin	Orlistat 120 mg three times daily	126	53 (6)	62 (53.9)	94.5 (9.6)	33.1 (2.9)	T2DM: 100% Dyslipidaemia: 21.3% Hypertension: 86.1% Hypercholesterolemia: 39.8% Hypertriglyceridemia: 4.6%	9 months	9 months
		Placebo	128	52 (5)	66 (54.1)	91.7 (8.7)	32.5 (2.3)	T2DM: 100% Dyslipidaemia: 18.9% Hypertension: 80.2% Hypercholesterolemia: 41.4% Hypertriglyceridemia: 2.7%
Finer 2000^Citation62	Age ≥18 years BMI 30–43 kg/m^2	Orlistat 120 mg three times daily	114	41.5 (10.5)	12 (10.9)	97.9 (12.9)	36.8 (3.6)	None	52	52
		Placebo	114	41.4 (10)	13 (12)	98.4 (15)	36.8 (3.7)
Hanefeld 2002^Citation26 Double-blind (phase unclear) Germany	Age 18–70 years BMI ≥28 kg/m^2 HbA1c of 6.5–11% T2DM treated with sulphonylureas for ≥2 months before screening or diagnosed with T2DM but not yet treated with antidiabetic medication	Orlistat 120 mg three times daily	195	56.6 (8.6)	91 (48)	99.4 (17.5)	34.5 (5.6)	T2DM: 100%	48	52
		Placebo	188	55.8 (8.9)	90 (50)	98.4 (18.5)	33.7 (5.2)
Hauptman 2000^Citation63 Double-blind (phase unclear) US	Age >18 years BMI of 30–44 kg/m^2	Orlistat 120 mg three times daily	210	43.2 (NR)	44 (21.0)	100.5 (NR)	36 (NR)	None	52	56
		Orlistat 60 mg three times daily	213	42.6 (NR)	47 (22.1)	100.4 (NR)	35.8 (NR)
		Placebo	212	41.6 (NR)	47 (22.2)	101.8 (NR)	36.1
Hollander 1998^Citation27 Double-blind (phase unclear) US	Age >18 years BMI 28–40 kg/m^2 were on an oral hypoglycaemic drug therapy for ≥6 months before the study Stable plasma glucose level on a second-generation sulfonylurea agent (glyburide or glypizide) as the only hypoglycaemic agent at trial entry	Orlistat 120 mg three times daily	163	55.4 (8.8)	79 (48.8)	99.6 (14.5)	34.5 (3.2)	T2DM: 100%	52	52
		Placebo	159	54.7 (9.7)	85 (53.5)	99.7 (15.4)	34 (3.4)
Karhunen 2000^Citation44 Double-blind (phase unclear) Finland	Age ≥18 years BMI 30.0–43.0 kg/m^2	Orlistat 120 mg three times daily	36	42.9 (6.4)	NR	98.1 (12.2)	35.7 (3.4)	None	52	52
		Placebo	36	44.4 (6.4)	NR	97.3 (14.8)	36.1 (4.4)
Krempf 2003^Citation64 Double-blind (phase unclear) France	Age 18–65 years BMI ≥28 kg/m^2	Orlistat 120 mg three times daily	346	40 (NR)	44 (12.7)	97 (NR)	36 (0.3)	None	52	52
		Placebo	350	42 (NR)	51 (14.6)	97.5 (NR)	36.2 (0.3)
Lindgarde 2000^Citation32 The Swedish Multimorbidity Study Double-blind (phase unclear) Sweden	Age 18–75 years BMI 28–38 kg/m^2 One of the following obesity-associated CHD risk factors: fasting serum glucose ≥6.7 mmol/l or confirmed T2DM treated with sulphonylurea or metformin but not insulin; total serum cholesterol ≥6.5 mmol/l and/or LDL cholesterol ≥4.2 mmol/l on at least two occasions or prescribed lipid-lowering medication; DBP ≥90 mmHg on at least two occasions or confirmed hypertension treated with antihypertensive medication	Orlistat 120 mg three times daily	190	53.7 (9.4)	66 (34.7)	96.1 (13.7)	33.2 (3)	T2DM: 28% Hypertension: 82% Hypercholesterolemia: 39%	52	54
		Placebo	186	53.2 (9.9)	71 (38.2)	95.9 (13.5)	33.2 (3.1)	T2DM: 24% Hypertension: 74% Hypercholesterolemia: 40%
Lucas 2003^Citation42 Double-blind (phase unclear) US	Age >18 years BMI 30–43 kg/m^2 Hypercholesterolemia Absence of weight loss in previous 3 months	Orlistat 120 mg three times daily	256	48 (10)	NR (22.3)	98.6 (15.3)	35.7 (3.7)	Hypercholesterolemia: 100%	52	52
		Placebo	188	48 (10)	NR (16.0)	99.2 (13.6)	36.2 (3.8)
Mathus-Vliegen 2006^Citation43 Double-blind (phase unclear) Netherlands	Age ≥18 years BMI 28–43 kg/m^2	Orlistat 120 mg three times daily	14	42 (11.7)	3 (10.7)	102.6 (12.3)	35.7 (3.8)	None	52	52
		Placebo	14	45.5 (8.71)		109.3 (16.4)	37.6 (3.9)
Miles 2002^Citation28 Double-blind (phase unclear) US and Canada	Age 40–65 years BMI of 28–43 kg/m^2 Stable weight for ≥3 months T2DM HbA1c between 7.5–12.0% Metformin treatment at 1000–2550 mg/day for at least 6 weeks	Orlistat 120 mg three times daily	255	52.5 (0.4)	NR (52)	102.1 (NR)	35.6 (NR)	T2DM: 100%	52	52
		Placebo	261	53.7 (0.4)	NR (52)	101.1 (NR)	35.2 (NR)
Poston 2003^Citation40 Open-label (phase unclear) US	Female Mexican origin Age 21–65 years BMI ≥27 kg/m^2	Orlistat 120 mg three times daily and lifestyle modification	56	42.4 (9.2)	0	96.4 (17.3)	37.8 (6.2)	T2DM: 12.7% Hypertension: 12.5%	52	52
		Wait-list control	52	43.7 (9.2)		92.2 (15.4)	36 (5.2)	T2DM: 9.6% Hypertension: 15.4%
Poston 2006^Citation41 NR (phase unclear) US	Age 25–55 years BMI ≥27 and <40 kg/m^2 SBP <140 mmHg DBP <90 mmHg Fasting blood glucose level <126 mg dL	Orlistat 120 mg three times daily	83	41.6 (8.1)	NR (6)	97.9 (11.5)	36.2 (2.9)	None	52	52
		Brief counselling	85	40.8 (8.3)	NR (5.9)	95.1 (11.5)	36 (3.2)
		Orlistat 120 mg three times daily/brief counselling	82	40.5 (9.2)	NR (11)	94.8 (12.1)	36 (3.3)
Rossner 2000^Citation65 Phase 3, double-blind Europe	Age ≥18 years BMI 28–43 kg/m^2	Orlistat 120 mg three times daily	244	43.6 (11.4)	40 (16.5)	96.7 (13.8)	34.7 (3.7)	None	104	104
		Orlistat 60 mg three times daily	243	44.7 (10.7)	56 (23.4)	99.1 (14.3)	35.2 (3.9)
		Placebo	243	44.3 (10.8)	31 (13.1)	97.7 (14.6)	35.3 (4.1)
Sjostrom 1998^Citation66 Double-blind (phase unclear) Europe	Age ≥18 years BMI 28–47 kg/m^2	Orlistat 120 mg three times daily	345	45.2 (NR)	59 (17.2)	99.1 (NR)	36 (NR)	None	52	56
		Placebo	343	44.3 (NR)	57 (16.8)	99.8 (NR)	36.1 (NR)
Swinburn 2005^Citation67 Double-blind (phase unclear) Australia and New Zealand	Age 40–70 years BMI 30–50 kg/m^2 ≥1 of the following: hypercholesterolemia; hypertension; T2DM treated with dietary modification or any oral hypoglycaemic agent for ≥6 months and clinically stable (glycated haemoglobin: 6.5–10%)	Orlistat 120 mg three times daily	170	52 (7.5)	66 (38.8)	103.3 (17.8)	37.6 (5.1)	T2DM: 8.2% Hypertension: 15.3% Hypercholesterolemia: 30%	52	52
		Placebo	169	52.5 (7.4)	80 (47.3)	106.9 (17.8)	38 (4.9)	T2DM: 8.3% Hypertension: 15.3% Hypercholesterolemia: 30%
Torgerson 2004^Citation68 XENDOS Double-blind (phase unclear) Sweden	Age 30-60 years BMI ≥30 kg/m^2 Normal or IGT	Orlistat 120 mg three times daily	1650	43.7 (8)	735 (44.8)	110.4 (16.3)	37.3 (4.2)	Pre-diabetes: 21.3%	52	52
		Placebo	1655	43.7 (8)	732 (44.7)	110.6 (16.5)	37.4 (4.5)	Pre-diabetes: 21%
Naltrexone/bupropion
Wadden 2011^Citation37 COR-BMOD Double-blind (phase unclear) US	Age 18–65 years BMI 30–45 kg/m^2 or BMI 27–45 kg/m^2 Controlled hypertension and/or dyslipidaemia	Naltrexone 32 mg/day and bupropion 360 mg/day	591	45.9 (10.4)	NR (10.7)	100.2 (15.4)	36.3 (4.2)	None	52	56
		Placebo	202	45.6 (11.4)	NR (8.4)	101.9 (15)	37 (4.2)
Hollander 2013^Citation24 COR-diabetes (NCD00474630) Phase 3, double-blind US	Age 18–70 years BMI 27–45 kg/m^2 T2DM (either not taking a diabetes medication or on stable doses of OADs for ≥3 months prior to randomization) SBP <145 mHg DBP <95 mmHg	Naltrexone 32 mg/day and bupropion 360 mg/day	335	53.9 (9.2)	NR (45.7)	106.3 (19.1)	36.7 (4.8)	T2DM: 100% Dyslipidaemia 82.6%	52	56
		Placebo	170	53.8 (9.7)	NR (47.2)	105 (17.1)	36.3 (4.3)	T2DM: 100% Dyslipidaemia: 85.5%
Greenway 2010^Citation69 COR-I (NCT00532779) Phase 3, double-blind US	Age 18–65 years BMI 30–45 kg/m^2 and uncomplicated obesity or BMI 27–45 kg/m^2 and controlled hypertension or dyslipidaemia, or both	Naltrexone 32 mg/day and bupropion 360 mg/day	471	44.4 (11.1)	NR (15)	99.7 (15.9)	6.1 (4.4)	Dyslipidaemia: 50% Hypertension: 20%	52	56
		Naltrexone 16 mg/day and bupropion 360 mg/day	578	44.4 (11.3)	NR (15)	99.5 (14.8)	36.2 (4.3)	Dyslipidaemia: 49% Hypertension: 22%
		Placebo	581	43.7 (11.1)	NR (15)	99.5 (14.3)	36.2 (4)	Dyslipidaemia: 50% Hypertension: 19%
Apovian 2013^Citation70 COR-II Phase 3, double-blind US	Age 18–65 years BMI 30–45 kg/m^2 or BMI 27–45 kg/m^2 and controlled hypertension and/or dyslipidaemia	Naltrexone 32 mg/day and bupropion 360 mg/day	1001	44.3 (11.2)	NR (15.4)	100.3 (16.6)	36.2 (4.5)	Dyslipidaemia: 55.9% Hypertension: 21.2%	52	56
		Placebo	495	44.4 (11.4)	NR (15.2)	99.2 (15.9)	36.1 (4.3)	Dyslipidaemia: 53.1% Hypertension: 21.4%
Nissen 2016^Citation33 The Light study (NCT01601704) Phase 3, double-blind US	Age ≥50 years (women) or ≥45 years (men) BMI 27–50 kg/m^2 Waist circumference ≥88 cm (women) or ≥102 cm (men) Increased risk of adverse CV outcomes (including existing CVD) T2DM permitted if patients also had ≥2 of the following: hypertension, dyslipidaemia requiring pharmacotherapy, low HDL (<50 mg/dL [1.30 mmol/L] in women or <40 mg/dL [1.04 mmol/L] in men), or current tobacco smoking	Naltrexone 32 mg/day and bupropion 360 mg/day	4456	61.1 (7.27)	NR (45.3)	105.6 (19.1)	Median (IQR): 36.6 (33.1–40.8)	T2DM: 84.9% Dyslipidaemia: 92% Hypertension: 93.4%	NR	NR
		Placebo	4454	60.9 (7.38)	NR (45.6)	106.3 (19.2)	Median (IQR): 36.7 (33.1–41.1)	T2DM: 85.5% Dyslipidaemia: 91.5% Hypertension: 92.5%
Phentermine/topiramate
Gadde 2011^Citation34 CONQUER (NCT00553787) Phase 3, double-blind US	Age 18–70 years BMI 27–45 kg/m^2 (no lower limit for patients with T2DM) ≥2 comorbidities (hypertension, dyslipidaemia, T2DM [managed with lifestyle changes or metformin] or prediabetes, or abdominal obesity) Waist circumference ≥102 cm (men) or ≥88 cm (women)	Phentermine 15 mg/day and topiramate 92 mg/day	995	51.0 (10.65)	NR (30)	103 (17.6)	36.6 (4.5)	T2DM or IGT: 67% Hypertension: 52% Hypertriglyceridemia: 36%	52	56
		Phentermine 7.5 mg/day and topiramate 46 mg/day	498	51.1 (10.43)	NR (30)	102.6 (18.2)	36.2 (4.4)	T2DM or IGT: 69% Hypertension: 52% Hypertriglyceridemia: 36%
		Placebo	994	51.2 (10.25)	NR (30)	103.3 (18.1)	36.7 (4.6)	T2DM or IGT: 68% Hypertension: 53% Hypertriglyceridemia: 36%
Allison 2012^Citation71 EQUIP Double-blind (phase unclear) US	Age 18–70 years BMI ≥35 kg/m^2 Triglycerides ≤200 mg/dL with max. 1 lipid-lowering medication BP ≤140/90 mm Hg with treatment of 0–2 antihypertensive medications FSG ≤110 mg/dL	Phentermine 15 mg/day and topiramate 92 mg/day	512	41.9 (12.21)	88 (17.2)	115.2 (20.66)	41.9 (6.04)	No weight-related comorbidity	52	56
		Phentermine 3.75 mg/day and topiramate 23 mg/day	241	43 (10.96)	40 (16.6)	118.5 (21.85)	42.6 (6.5)
		Placebo	514	43 (11.76)	89 (17.3)	115.8 (21.46)	42 (6.15)
Garvey 2014^Citation29 OB-202/DM-230 (NCT00600067) Phase 2, double-blind US	Age 18–70 years T2DM controlled by diet or OAD medications BMI 27–45 kg/m^2 HbA1c 7.0–12.0% (53–108 mmol/mol)	Phentermine 15 mg/day /topiramate 92 mg/day	75	49.7 (7.5)	NR (23)	94.9 (17.9)	35.5 (4.7)	T2DM: 100 Dyslipidaemia: 52 Hypertension: 47	52	56
		Placebo	55	49.5 (8.6)	NR (42)	98.1 (17)	35.3 (5)	T2DM: 100 Dyslipidaemia: 55 Hypertension: 42
Semaglutide
Wilding 2021^Citation12 STEP 1 (NCT03548935) Phase 3, double-blind International	Age ≥18 years BMI ≥30.0 kg/m^2 or ≥27.0 kg/m^2 ≥1 of the following weight-related comorbidities (treated or untreated): hypertension, dyslipidaemia, obstructive sleep apnoea or CVD History of ≥1 self-reported unsuccessful dietary effort to lose body weight	Semaglutide 2.4 mg once weekly	1306	46 (13)	351 (26.9)	105.4 (22.1)	37.8 (6.7)	Dyslipidaemia: 38.2% Hypertension: 36.1%	52	68
		Placebo	655	47 (12)	157 (24)	105.2 (21.5)	38 (6.5)	Dyslipidaemia: 34.5% Hypertension: 35.7%
Davies 2021^Citation15 STEP 2 (NCT03552757) Phase 3, double-blind International	Age ≥18 years BMI ≥27.0 kg/m^2 Diagnosed with T2DM ≥180 days prior to screening and treated with either diet and exercise alone or stable treatment with metformin, SU, SGLT2i, glitazone as single agent therapy OR stable treatment with ≤3 OADs (metformin, SU, SGLT2i or glitazone) HbA1c 7–10% (53–86 mmol/mol)	Semaglutide 2.4 mg once weekly	404	NR	181 (44.8)	99.9 (22.5)	35.9 (6.4)	T2DM: 100%	52	68
		Semaglutide 1.0 mg once weekly	403	NR	200 (49.6)	99 (21.1)	35.3 (5.9)
		Placebo	403	NR	213 (52.9)	100.5 (20.9)	35.9 (6.5)
Wadden 2021^Citation36 STEP 3 (NCT03611582) Phase 3, double-blind US	Age ≥18 years BMI ≥30.0 kg/m^2 or ≥27.0 kg/m^2 with ≥1 weight-related comorbidities (treated or untreated): hypertension, dyslipidaemia, obstructive sleep apnoea or CVD History of at least one self-reported unsuccessful dietary effort to lose body weight	Semaglutide 2.4 mg once weekly	407	46 (13)	92 (22.6)	106.9 (22.8)	38.1 (6.7)	Dyslipidaemia: 35.6% Hypertension: 35.6%	52	68
		Placebo	204	46 (13)	24 (11.8)	103.7 (22.9)	37.8 (6.9)	Dyslipidaemia: 32.8% Hypertension: 32.8%

Abbreviations: BMI, body mass index; CHD, coronary heart disease; CV, cardiovascular; CVD, cardiovascular disease; DBP, diastolic blood pressure; FPG, fasting plasma glucose; IBT, intensive behavioral therapy; IGT, impaired glucose tolerance; LDL, low density lipoprotein; NGT, normal glucose tolerance; NR, not reported; OAD, oral antidiabetic drug; SBP, systolic blood pressure; SD, standard deviation; SGLTi, sodium glucose cotransporter inhibitor; SU, sulphonylurea; T2DM, type 2 diabetes mellitus.

Table 3 Comparators for Which Data are Available Across the Populations of Interest

Outcome	Total	NGT	Non-T2DM	Pre-Diabetic	T2DM
Percent weight CFB to 52 weeks	Liraglutide Orlistat Phentermine/topiramate Naltrexone/bupropion	Liraglutide	Liraglutide Orlistat Phentermine/topiramate Naltrexone/bupropion	Liraglutide Phentermine/topiramate	Liraglutide Orlistat Phentermine/topiramate Naltrexone/bupropion
Proportion of participants losing ≥5% baseline fasting body weight at 12 weeks (full therapeutic dose)	Liraglutide Orlistat	Liraglutide	Liraglutide Orlistat	Liraglutide	Liraglutide

Abbreviations: CFB, change from baseline; NGT, normal glucose tolerance; T2DM, type 2 diabetes mellitus.

Table 4 NMA Results: Estimates of Difference in Percent Weight CFB (Semaglutide versus Comparators, Excluding Trials That Included IBT)

Population (model)	Comparator
	Placebo/Control	Liraglutide 3.0 Mg	Naltrexone 16 Mg/ Bupropion	Naltrexone 32 Mg/ Bupropion	Orlistat 120 Mg TID	Orlistat 60 Mg TID	Phentermine 15 Mg/ Topiramate 92 Mg	Phentermine 3.75 Mg/ Topiramate 23 Mg	Phentermine 7.5 Mg/ Topiramate 46 Mg
Total (RE)	−9.36 (−12.06, −6.62)	−4.48 (−8.04, −0.87)	−6.01 (−10.43, −1.58)	−5.25 (−8.65, −1.89)	−7.39 (−10.42, −4.36)	−7.94 (−12.32, −3.52)	−0.40 (−4.22, 3.46)	−6.03 (−11.36, −0.68)	−2.58 (−7.07, 1.93)
T2DM (RE)	−6.22 (−11.29, −1.19)	−2.33 (−9.45, 4.69)	NA	−3.29 (−9.44, 2.92)	−4.87 (−10.70, 0.60)	NA	0.67 (−6.65, 7.86)	NA	−1.32 (−8.82, 5.97)
Non-T2DM (RE)	−12.43 (−14.51, −10.38)	−7.02 (−9.61, −4.41)	−8.64 (−11.45, −5.85)	−7.45 (−9.97, −4.94)	−9.80 (−12.37, −7.59)	−10.70 (−13.64, −7.92)	−3.35 (−5.85, −0.80)	−8.99 (−12.81, −5.08)	−5.43 (−8.21, −2.61)
Pre-diabetes (FE)	−11.26 (−12.52, −10.01)	−5.83 (−7.20, −4.49)	NA	NA	NA	NA	−3.06 (−4.55, −1.59)	NA	−5.26 (−6.83, −3.72)
NGT (FE)	−13.42 (−14.56, −12.28)	−8.13 (−9.47, −6.80)	NA	NA	NA	NA	NA	NA	NA

Notes: Results that exclude the null value of 0 indicated in bold. Note that results for the comparators were based on the last observation carried forward approaches to missing data.

Abbreviations: CFB, change from baseline; CrI, credible interval; FE, FE, fixed-effect; IBT, intensive behavioral therapy; NA, not available; NGT, normal glucose tolerance; NMA, network meta-analysis; RE, random-effect; T2DM, type 2 diabetes mellitus; TID, three times daily.

Table 5 NMA Results: OR (95% CrI) for Proportion of Participants Losing ≥5% of Baseline Fasting Body Weight at 12 Weeks Full Therapeutic Dose (Semaglutide versus Comparators, Excluding Trials That Included IBT)

Population	Comparator
	Placebo/Control	Liraglutide 3.0 Mg	Orlistat 120 Mg TID
Total (RE)	11.68 (6.97, 18.44)	1.58 (0.81, 2.80)	6.09 (2.86, 11.95)
T2DM (FE)	8.62 (6.24, 12.00)	1.29 (0.70, 2.31)	NA
Non-T2DM (FE)	14.36 (11.46, 18.15)	1.94 (1.47, 2.59)	7.75 (5.29, 11.37)
Pre-diabetes (FE)	14.23 (10.10, 20.44)	1.90 (1.26, 2.90)	NA
NGT (FE)	14.81 (11.02, 20.17)	2.17 (1.44, 3.27)	NA

Note: Results that exclude the null value of 1 indicated in bold.

Abbreviations: CrI, credible interval; FE, fixed-effect; IBT, intensive behavioral therapy; NA, not applicable; NGT, normal glucose tolerance; NMA, network meta-analysis; OR, odds ratio; RE, random-effect; T2DM, type 2 diabetes mellitus; TID, three times daily.

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