Trial ID	Intervention(s) and comparator(s)	Participants included in analysis (N)	Participants with a specific adverse event (description)	Participants with at least one specific adverse events (N)	Participants with at least one specific adverse event (%)
Bilezikian 2013	I: metformin	111	Peripheral oedema Weight increased Dyspepsia Back pain Fatigue Headache Overweight Diarrhoea Nausea	0 1 6 1 1 0 0 12 2	0.0 0.9 5.4 0.9 0.9 0.0 0.0 1.8 1.8
	C1: rosiglitazone	114	Peripheral oedema Weight increased Dyspepsia Back pain Fatigue Headache Overweight Diarrhoea Nausea	12 9 2 2 2 2 2 1 1	10.5 7.9 1.8 1.8 1.8 1.8 1.8 0.9 0.9
Campbell 1994	I: metformin	24	—	—	—
	C1: glipizide	24	—	—	—
Derosa 2003	I: metformin	56	Mild hypoglycaemia Severe hypoglycaemia Nausea and diarrhoea	0 0 2	0 0 3.6
	C1: repaglinide	56	Mild hypoglycaemia Severe hypoglycaemia Nausea and diarrhoea	0 0 0	0 0 0
Derosa 2004	I: metformin	83	Diarrhoea Nausea	2 2	2.4 2.4
	C1: glimepiride	81	Diarrhoea Nausea	0 0	0 0
Derosa 2009	I: metformin	67	Excessive body weight increase Nausea Gastroinstentinal events Hypoglycemia	0 1 4 0	0 1.5 6.0 0
	C1: rosiglitazone	69	Excessive body weight increase Nausea Gastrointestinal events Hypoglycemia	3 0 0 0	4.3 0 0 0
Erem 2014	I: metformin	19	—	—	—
	C1: gliclazide	19	—	—	—
	C2: pioglitazone	19	—	—	—
Kahn 2006	I: metformin	1454	Cardiovascular disease Fatal myocardial infarction Nonfatal myocardial infarction Congestive heart failure Stroke Peripheral vascular disease Gastrointestinal events 8 Nausea Vomiting Diarrhoea Abdominal discomfort Hypoglycaemia Weight gain Oedema	46 (12)a 2 (0) 18 (3) 12 (7) 17 (2) 6 (21) 7 (550) 0 (170) 1 (83) 1 (344) 6 (218) 1 (167) 0 (18) 0 (104)	3.2 (0.8)a 0.1 (0) 1.2 (0.2) 0.8 (0.5) 1.2 (0.1) 0.4 (1.4) 0.5 (37.8) 0.0 (11.7) 0.1 (5.7) 0.1 (23.7) 0.4 (15.0) 0.1 (11.5) 0 (1.2) 0 (7.2)
	C1: rosiglitazone	1456	Cardiovascular disease Fatal myocardial infarction Nonfatal myocardial infarction Congestive heart failure Stroke Peripheral vascular disease Gastrointestinal events Nausea Vomiting Diarrhoea Abdominal discomfort Hypoglycaemia Weight gain Oedema	49 (13)a 2 (0) 22 (3) 12 (10) 13 (3) 7 (29) 8 (327) 2 (110) 0 (58) 1 (128) 5 (156) 1 (141) 3 (97) 2 (203)	3.4 (0.9)a 0.1 (0) 1.5 (0.2) 0.8 (0.7) 0.9 (0.2) 0.5 (2.0) 0.5 (22.5) 0.1 (7.6) 0 (4.0) 0.1 (8.8) 0.3 (10.7) 0.1 (9.7) 0.2 (6.7) 0.1 (13.9)
	C2: glibenclamide	1441	Cardiovascular disease Fatal myocardial infarction Nonfatal myocardial infarction Congestive heart failure Stroke Peripheral vascular disease Gastrointestinal events Nausea Vomiting Diarrhoea Abdominal discomfort Hypoglycaemia Weight gain Oedema	26 (15)a 3 (0) 11 (4) 3 (6) 12 (5) 4 (27) 3 (313) 0 (99) 0 (45) 0 (142) 3 (160) 8 (549) 0 (47) 2 (121)	1.8 (1.0)a 0.2 (0) 0.8 (0.3) 0.2 (0.4) 0.8 (0.3) 0.3 (1.9) 0.2 (21.7) 0.0 (6.9) 0.0 (3.1) 0.0 (9.9) 0.2 (11.1) 0.6 (38.1) 0.0 (3.3) 0.1 (8.4)
Kiyici 2009	I: metformin	16	—	—	—
	C1: rosiglitazone	19	—	—	—
	C2: no intervention	15	—	—	—
Onuchin 2010	I: metformin	46	Hypoglycaemia	—	—
	C1: insulin	45
Pfützner 2011	I: metformin	328	Nasopharyngitis Urinary tract infection Influenza Upper respiratory tract infection Diarrhoea Headache Back pain Hypertension Reported hypoglycaemia Confirmed hypoglycaemia Sudden death Cardiac arrest Cardiac failure Coronary artery arteriosclerosis Ischaemic stroke Acute myocardial infarction, Cerebrovascular accident Pancreatic neoplasm/sepsis Gastrointestinal AEs Skin‐related AEs Lymphopenia	19 25 19 10 30 18 11 17 20 2 0 1 1 0 0 1 1 1 76 16 1	5.8 7.6 5.8 3.0 9.1 5.5 3.4 5.2 6.1 0.6 0.0 0.3 0.3 0.0 0.0 0.3 0.3 0.3 23.2 4.9 0.3
	C1: saxagliptin	335	Nasopharyngitis Urinary tract infection Influenza Upper respiratory tract infection Diarrhoea Headache Back pain Hypertension Reported hypoglycaemia Confirmed hypoglycaemia Sudden death Cardiac arrest Coronary artery arteriosclerosis Ischaemic stroke Acute myocardial infarction, Cerebrovascular accident Pancreatic neoplasm/sepsis Gastrointestinal AEs Skin‐related AEs Lymphopenia	24 23 17 14 12 31 12 19 7 0 0 0 1 1 0 0 0 5 2 7	7.2 6.9 5.1 4.2 3.6 9.3 3.6 5.7 2.1 0.0 0.0 0.0 0.3 0.3 0.0 0.0 0.0 16.7 6.9 2.1
Rahman 2011	I: metformin	102	—	—	—
	C1: glimepiride	102	—	—	—
Schernthaner 2004	I: metformin	597	Diarrhoea NOS Nausea Oedema peripheral Oedema NOS Fatigue Bronchitis NOS Influenza Nasopharyngitis Arthralgia Back pain Dizziness Headache NOS Pharyngitis Hypertension NOS Liver function tests Weight gain	66 25 10 1 12 14 22 19 12 17 11 14 9 17 9 0	11.1 4.2 1.7 0.2 2.0 2.3 3.7 3.2 2.0 2.8 1.8 2.3 1.5 2.8 1.5 0
	C1: pioglitazone	597	Diarrhoea NOS Nausea Edema peripheral Edema NOS Fatigue Bronchitis NOS Influenza Nasopharyngitis Arthralgia Back pain Dizziness Headache NOS Pharyngitis Hypertension NOS Liver function tests Weight gain	19 14 27 13 8 11 14 25 9 14 14 26 15 15 0 6	3.2 2.3 4.5 2.2 1.3 1.8 2.4 4.2 1.5 2.3 2.3 4.4 2.5 2.5 0 1.0
Schweizer 2007b	I: metformin	252	Headache Nasopharyngitis Diarrhoea Back pain Upper respiratory tract infection Dizziness Nausea Abdominal pain Any GI event Constipation Dyspepsia Flatulence Vomiting	18 24 66 9 15 15 26 18 110 5 12 10 11	7.1 9.5 26.2 3.6 6.0 6.0 10.3 7.1 43.7 2.0 4.8 4.0 4.4
	C1: vildagliptin	529	Headache Nasopharyngitis Diarrhoea Back pain Upper respiratory tract infection Dizziness Nausea Abdominal pain Any GI event Constipation Dyspepsia Flatulence Vomiting	52 50 31 27 27 25 17 12 113 25 6 5 11	10.0 9.6 6.0 5.2 5.2 4.8 3.3 2.3 21.8 4.8 1.2 1.0 2.1
Teupe 1991	I: metformin	50	Diarrhoea	—	—
	C1: no intervention	50
UKPDS 34 1998	I: metformin	342	—	—	—
	C1: glibenclamide	277	—	—	—
	C2: insulin	409	—	—	—
Umpierrez 2014	I: metformin	268	Nausea Diarrhoea Vomiting Decreased appetite Constipation Nasopharyngitis URTI Headache	43 37 13 12 3 28 8 20	16.0 13.8 4.9 4.5 1.1 10.4 3.0 7.5
	C1: dulaglutide (1.5 mg/week)	269	Nausea Diarrhoea Vomiting Decreased appetite Constipation Nasopharyngitis URTI Headache	53 30 26 18 18 14 16 10	19.7 11.2 9.7 6.7 6.7 5.2 5.9 3.7
	C2: dulaglutide (0.75 mg/week)	270	Nausea Diarrhoea Vomiting Decreased appetite Constipation Nasopharyngitis URTI Headache	31 21 20 12 13 8 15 14	11.5 7.8 7.4 4.4 4.8 3.0 5.6 5.2
Williams‐Herman 2010c	I: metformin (1000 mg/day)	182	Hypoglycaemia All gastrointestinal AEs Diarrhoea Nausea Abdominal pain Vomiting	3 38 14 6 7 0	1.6 20.9 7.7 3.3 3.8 0
	I2: metformin (2000 mg/day)	182	Hypoglycaemia All gastrointestinal AEs Diarrhoea Nausea Abdominal pain Vomiting	4 60 23 19 12 8	2.2 33.0 12.6 10.4 6.6 4.4
	C1: sitagliptin	179	Hypoglycaemia All gastrointestinal AEs Diarrhoea Nausea Abdominal pain Vomiting	2 37 8 2 9 1	1.1 20.7 4.5 1.1 5.0 0.6
Yamanouchi 2005	I: metformin	39	Peripheral oedema Transient hypoglycaemia	0 0	0 0
	C1: pioglitazone	38	Peripheral oedema Transient hypoglycaemia	4 0	10.5 0
	C2: glimepiride	37	Peripheral oedema Transient hypoglycaemia	0 1	0 2.7
—: denotes not reported aResults reported as: serious adverse events (adverse events) bAll results are from the initial 52 week intervention period cResults after 104 weeks of intervention AEs: adverse events; C: comparator; GI: gastrointestinal; I: intervention, N: number of participants; NOS: not otherwise specified; UKPDS: United Kingdom Prospective Diabetes Study; URTI: upper respiratory tract infections.