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. 2016 Nov 29;2016(11):CD012436. doi: 10.1002/14651858.CD012436
Trial 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
 (%)
Atabek 2008 I: metformin + diet and physical activity advice 90 1. Diarrhoea and mild abdominal pain
2. Mild discomfort from the abdomen		 1. 1
2. 1		 1. 1.1
2. 1.1
C: placebo + diet and physical activity advice 30 ‐ ‐ ‐
Berkowitz 2003 I: behavioural programme + sibutramine 42 1. High blood pressure and pulse rate
2. High blood pressure only
3. High pulse rate only
4. Knee surgery
5. Ventricular premature beats
6. Cholelithiasis/cholecystectomy
7. Rash, viral		 1. 3
2. 1
3. 1
4. 1
5. 1
6. 1
7. 1		 1. 7.1
2. 2.4
3. 2.4
4. 2.4
5. 2.4
6. 2.4
7. 2.4
C: behavioural programme + placebo 39 1. Elevated blood pressure and pulse rate*
2. Elevated pulse rate only*
3. Atrial premature beats
4. Tonsillectomy
5. Ventricular premature beats*
6. Ecchymoses*		 1. 1
2. 1
3. 1
4. 2
5. 1
6. 2		 1. 2.6
2. 2.6
3. 2.6
4. 5.1
5. 2.6
6. 5.1
Berkowitz 2006 I: behavioural therapy programme + sibutramine 368 1. Infection
2. Headache
3. Pharyngitis
4. Tachycardia
5. Accidental injury
6. Dry mouth
7. Pain
8. Hypertension
9. Rhinitis
10. Abdominal pain
11. Dysmenorrhoea
12. Vomiting
13. Cough increased
14. Nausea
15. Dizziness
16. Rash
17. Sinusitis
18. Constipation
19. Flu syndrome
20. Insomnia
21. Viral infection
22. Allergic reaction
23. Suicide attempt
24. Depression
25. Syncope
26. Chest pain
27. Arrhythmia
28. Extra systoles		 1. 167
2. 113
3. 49
4. 46
5. 41
6. 41
7. 42
8. 39
9. 41
10. 37
11. 21
12. 32
13. 28
14. 31
15. 28
16. 25
17. 24
18. 24
19. 23
20. 23
21. 20
22. 18
23. 1
24. 5
25. ‐
26. ‐
27. ‐
28. ‐		 1. 45.3
2. 30.7
3. 13.3
4. 12.5
5.11.1
6.11.1
7. 11.4
8. 10.6
9. 11.1
10. 10.1
11. 5.7
12. 8.7
13. 7.6
14. 8.4
15. 7.6
16. 6.8
17. 6.5
18. 6.5
19. 6.3
20. 6.3
21. 5.4
22. 4.9
23. 0.3
24. 1.4
25. ≤ 1.5
26. ≤ 1.5
27. ≤ 1.5
28. ≤ 1.5
C: behavioural therapy programme + placebo 130 1. Infection
2. Headache
3. Pharyngitis
4. Tachycardia
5. Accidental injury
6. Dry mouth
7. Pain
8. Hypertension
9. Rhinitis
10. Abdominal pain
11. Dysmenorrhoea
12. Vomiting
13. Cough increased
14. Nausea
15. Dizziness
16. Rash
17. Sinusitis
18. Constipation
19. Flu syndrome
20. Insomnia
21. Viral infection
22. Allergic reaction
23. Suicide attempt
24. Depression
25. Syncope
26. Chest pain
27. Arrhythmia
28. Extra systoles		 1. 53
2. 39
3. 23
4. 8
5. 8
6. 8
7. 12
8. 11
9. 17
10. 12
11. 13
12. 7
13. 12
14. 12
15. 5
16. 7
17. 6
18. 3
19. 7
20. 4
21. 2
22. 7
23. 1
24. 1
25. ‐
26. ‐
27. ‐
28. ‐		 1. 41
2. 30
3. 18
4. 6.2
5. 6.2
6. 6.2
7. 9.2
8. 8.5
9. 13.1
10. 9.2
11. 10
12. 5.4
13. 9.2
14. 9.2
15. 3.8
16. 5.4
17. 4.6
18. 2.3
19. 5.4
20. 3.1
21. 1.5
22. 5.4
23. 0.8
24. 0.8
25. ≤ 1.5
26. ≤ 1.5
27. ≤ 1.5
28. ≤ 1.5
Chanoine 2005 I: orlistat + diet + exercise + behavioural therapy 352 1. Fatty/oily stool
2. Oily spotting
3. Oily evacuation
4. Abdominal pain
5. Fecal urgency
6. Flatus with discharge
7. Soft stool
8. Nausea
9. Increased defecation
10. Flatulence
11. Fecal incontinence
12. Headache
13. Upper respiratory tract infection
14. Nasopharyngitis
15. Sore throat
16. Sinusitis
17. Joint sprain
18. Nasal congestion
19. Back pain
20. Gastroenteritis
21. Seasonal rhinitis
22. Limb injury
23. Asymptomatic gallstones
24. Pilonidal abscess
25. Depression
26. Asthma attack
27. Seizure
28. Admission for repair of deviated nasal septum
29. Appendicitis
30. Cholelithiasis
31. Gallbladder disorder followed by cholecystectomy
32. Adenoidal hypertrophy
33. Aseptic meningitis
34. Electrocardiogram abnormalities		 1. 177
2. 102
3. 82
4. 77
5. 73
6. 70
7. 53
8. 52
9. 48
10. 32
11. 31
12. 134
13. 114
14. 99
15. 59
16. 40
17. 35
18. 31
19. 28
20. 23
21. 21
22. 18
23. 6
24. 1
25. 2
26. 1
27. 1
28. 1
29. 1
30. 1
31. 1
32. 1
33. 1
34. 10		 1. 50.3
2. 29.0
3. 23.3
4. 21.9
5. 20.7
6. 19.9
7. 15.1
8. 14.8
9. 13.6
10. 9.1
11. 8.8
12. 38.1
13. 32.4
14. 28.1
15. 16.8
16. 11.4
17. 9.9
18. 8.8
19. 8.0
20. 6.5
21. 6.0
22. 5.1
23. 1.7
24. 0.3
25. 0.6
26. 0.3
27. 0.3
28. 0.3
29. 0.3
30. 0.3
31. 0.3
32. 0.3
33. 0.3
34. 2.8
C: placebo + diet + exercise + behavioural therapy 181 1. Fatty/oily stool
2. Oily spotting
3. Oily evacuation
4. Abdominal pain
5. Fecal urgency
6. Flatus with discharge
7. Soft stool
8. Nausea
9. Increased defecation
10. Flatulence
11. Fecal incontinence
12. Headache
13. Upper respiratory tract infection
14. Nasopharyngitis
15. Sore throat
16. Sinusitis
17. Joint sprain
18. Nasal congestion
19. Back pain
20. Gastroenteritis
21. Seasonal rhinitis
22. Limb injury
23. Acute demyelinating encephalomyelitis
24. Facial palsy
25. Pneumonia
26. Worsening of asthma
27. Pain in the right side
28. Electrocardiogram abnormalities		 1.15
2. 7
3. 3
4. 20
5. 20
6. 5
7. 19
8. 23
9. 16
10. 8
11. 1
12. 56
13. 48
14. 46
15. 29
16. 19
17. 17
18. 11
19. 11
20. 8
21. 9
22. 5
23. 1
24. 1
25. 1
26. 1
27. 1
28. 1		 1. 8.3
2. 3.9
3. 1.7
4. 11.0
5. 11.0
6. 2.8
7. 10.5
8. 12.7
9. 8.8
10. 4.4
11. 0.6
12. 30.9
13. 26.5
14. 25.4
15. 16.0
16. 10.5
17. 9.4
18. 6.1
19. 6.1
20. 4.4
21. 5.0
22. 2.8
23. 0.6
24. 0.6
25. 0.6
26. 0.6
27. 0.6
28. 0.6
Clarson 2009 I: metformin + lifestyle intervention 14 ‐ ‐ ‐
C: lifestyle intervention only 17 ‐ ‐ ‐
Franco 2014 I: sibutramine + dietary guidance 63 1. Anorexia
2. Dry mouth
3. Headache
4. Constipation
5. Changing the mood
6. Dyspnoea
7. Epigastralgia
8. Hypertension
9. Insomnia
10. Nausea
11. Tachycardia
12. Dizziness
13. Tremors
14. Vomiting		 ‐ 1. 0.9
2. 1.7
3. 6.8
4. 3.8
5. 1.3
6. 0.4
7. 0.9
8. 0.9
9. 1.3
10. 2.1
11. 1.3
12. 3.4
13. 0.4
14. 0.4
C: placebo + dietary guidance 63 1. Change in taste
2. Headache
3. Diarrhoea
4. Hypertension
5. Irritability
6. Tachycardia
7. Dizziness		 ‐ 1. 0.9
2. 3.3
3. 2.8
4. 0.5
5. 1.4
6. 0.5
7. 0.9
Freemark 2001 I: metformin 15 1. Transient abdominal discomfort or diarrhoea
2. Intermittent nausea		 1. 3
2. 1		 1. 20
2. 6.7
C: placebo 17 1. Transient abdominal discomfort or diarrhoea 1. 1 1. 5.9
Garcia‐Morales 2006 I: sibutramine + diet + exercise 23 1. Headache
2. Dry mouth
3. Headache with nausea
4. Headache with weakness
5. High DBP
6. High heart rate
7. High blood pressure (baseline)
8. High blood pressure (end of trial)		 1. 1
2. 1
3. 1
4. 1
5. 1
6. 3
7. 2
8. 2		 1. 4.3
2. 4.3
3. 4.3
4. 4.3
5. 4.3
6. 13.0
7. 8.7
8. 8.7
C: placebo + diet + exercise 23 1. Headache
2. Headache with somnolence
3. Headache with dry mouth
4. High DBP
5. High heart rate
6. High blood pressure (baseline)
7. High blood pressure (end of trial)		 1. 2
2. 1
3. 1
4. 2
5. 2
6. 7
7. 2		 1. 8.7
2. 4.3
3. 4.3
4. 8.7
5. 8.7
6. 30.4
7. 8.7
Godoy‐Matos 2005 I: sibutramine + hypocaloric diet + exercise 30 1. Dry mouth
2. Headache
3. Constipation
4. Abdominal pain
5. Cold
6. Dizzy
7. Tonsillitis
8. Menstrual cramp
9. Nausea
10. Toothache
11. Otitis
12. Hair loss
13. Rhinitis
14. Sinusitis
15. Sleepiness
16. Dry cough
17. Myalgia
18. Viral infection
19. Lumbago		 1. 7
2. 13
3. 12
4. 3
5. 9
6. 3
7. 2
8. 8
9. 3
10. 3
11. 3
12. 2
13. 1
14. 1
15. 1
16. 1
17. 1
18. 2
19. 2		 1. 23.3
2. 43.3
3. 40.0
4. 10.0
5. 30.0
6. 10.0
7. 6.7
8. 26.7
9. 10.0
10. 10.0
11. 10.0
12. 6.7
13. 3.3
14. 3.3
15. 3.3
16. 3.3
17. 3.3
18. 6.7
19. 6.7
C: placebo + hypocaloric diet + exercise 30 1. Dry mouth
2. Headache
3. Constipation
4. Abdominal pain
5. Cold
6. Dizzy
7. Tonsillitis
8. Menstrual cramp
9. Nausea
10. Toothache
11. Otitis
12. Hair loss
13. Rhinitis
14. Sinusitis
15. Sleepiness
16. Dry cough
17. Myalgia
18. Bronchitis
19. Inguinal dermatitis
20. Fever		 1. 3
2. 21
3. 4
4. 4
5. 11
6. 2
7. 2
8. 6
9. 1
10. 1
11. 1
12. 1
13. 2
14. 2
15. 2
16. 2
17. 2
18. 2
19. 2
20. 2		 1. 10.0
2. 70.0
3. 13.3
4. 13.3
5. 36.7
6. 6.7
7. 6.7
8. 20.0
9. 3.3
10. 3.3
11. 3.3
12. 3.3
13. 6.7
14. 6.7
15. 6.7
16. 6.7
17. 6.7
18. 6.7
19. 6.7
20. 6.7
Kendall 2013 I: metformin + healthy lifestyle advice 74 ‐ ‐ ‐
C: control + healthy lifestyle advice 77 ‐ ‐ ‐
Maahs 2006 I: orlistat + diet and exercise therapy 20 ‐ ‐ ‐
C: placebo + diet and exercise therapy 20 ‐ ‐ ‐
All: 40 1. Soft stools
2. Oily spotting
3. Fatty or oily stools
4. Oily evacuation
5. Liquid stools
6. Cramping
7. Flatus with discharge
8. Fecal incontinence		 ‐ ‐
Mauras 2012 I: metformin + diet/exercise intervention 35 ‐ ‐ ‐
C: diet/exercise intervention 31 ‐ ‐ ‐
NCT00001723 I: orlistat + behavioural weight loss programme 100 1. Hypoglycaemia
2. Left lower quadrant pain and vomiting
3. Ear disorders (otitis, earache, ear pain)
4. Eye disorders (change in vision, conjunctivitis, styes)
5. Abdominal pain or cramping
6. Bloating or gas
7. Borborygmi
8. Constipation
9. Controlled discharge of oil without stool
10. Decreased frequency of bowel movements
11. Diarrhoea
12. Fatty‐appearing stools
13. Flatulence (passage of gas)
14. Flatus with discharge
15. Frequent urge for bowel movement
16. Hiccups
17. Increased frequency of bowel movements
18. Nausea
19. Oily spotting
20. Rectal bleeding ‐ haemorrhoids
21. Soft or deliquescent stools
22. Stomach pain or cramps
23. Stools almost all liquid with very few solid parts
24. Stools hard and in the shape of small pellets
25. Stools mixed with fat or with a separate oily layer
26. Uncontrolled passage of stool or oil
27. Urgent, but controlled, need to produce stools
28. Vomiting
29. Dizziness
30. Epistaxis
31. Feeling cold
32. Headache
33. Increased sweating
34. Increased thirst
35. Sinusitis, postnasal drip or nasal stuffiness
36. Unusual tiredness or weakness (fatigue)
37. Pharyngitis
38. Sinusitis, postnasal drip or nasal stuffiness
39. Decrease in appetite
40. Muscle pain, stiffness, cramps or ache
41. Migraine headaches
42. Mental depression
43. Dysuria or UTI
44. Nocturia
45. Asthma symptoms
46. Cough
47. Upper respiratory infection
48. Skin rash		 1. 0
2. 0
3. 7
4. 8
5.16
6. 18
7. 6
8. 1
9. 56
10. 25
11. 21
12. 61
13. 60
14. 43
15. 19
16. 1
17. 68
18. 10
19. 6
20. 4
21. 68
22. 8
23. 64
24. 11
25. 83
26. 60
27. 44
28. 7
29. 4
30. 5
31. 5
32. 14
33. 3
34. 5
35. 2
36. 1
37. 6
38. 1
39. 11
40. 16
41. 3
42. 1
43. 1
44. 0
45. 5
46. 0
47. 14
48. 5		 1. 0
2. 0
3. 7
4. 8
5.16
6. 18
7. 6
8. 1
9. 56
10. 25
11. 21
12. 61
13. 60
14. 43
15. 19
16. 1
17. 68
18. 10
19. 6
20. 4
21. 68
22. 8
23. 64
24. 11
25. 83
26. 60
27. 44
28. 7
29. 4
30. 5
31. 5
32. 14
33. 3
34. 5
35. 2
36. 1
37. 6
38. 1
39. 11
40. 16
41. 3
42. 1
43. 1
44. 0
45. 5
46. 0
47. 14
48. 5
C: placebo + behavioural weight loss programme 100 1. Hypoglycaemia
2. Left lower quadrant pain and vomiting
3. Ear disorders (otitis, earache, ear pain)
4. Eye disorders (change in vision, conjunctivitis, styes)
5. Abdominal pain or cramping
6. Bloating or gas
7. Borborygmi
8. Constipation
9. Controlled discharge of oil without stool
10. Decreased frequency of bowel movements
11. Diarrhoea
12. Fatty‐appearing stools
13. Flatulence (passage of gas)
14. Flatus with discharge
15. Frequent urge for bowel movement
16. Hiccups
17. Increased frequency of bowel movements
18. Nausea
19. Oily spotting
20. Rectal bleeding ‐ haemorrhoids
21. Soft or deliquescent stools
22. Stomach pain or cramps
23. Stools almost all liquid with very few solid parts
24. Stools hard and in the shape of small pellets
25. Stools mixed with fat or with a separate oily layer
26. Uncontrolled passage of stool or oil
27. Urgent, but controlled, need to produce stools
28. Vomiting
29. Dizziness
30. Epistaxis
31. Feeling cold
32. Headache
33. Increased sweating
34. Increased thirst
35. Sinusitis, postnasal drip or nasal stuffiness
36. Unusual tiredness or weakness (fatigue)
37. Pharyngitis
38. Sinusitis, postnasal drip or nasal stuffiness
39. Decrease in appetite
40. Muscle pain, stiffness, cramps, or ache
41. Migraine headaches
42. Mental depression
43. Dysuria or UTI
44. Nocturia
45. Asthma symptoms
46. Cough
47. Upper respiratory infection
48. Skin rash		 1. 1
2. 1
3. 7
4. 9
5. 21
6. 5
7. 2
8. 7
9. 11
10. 22
11. 8
12. 6
13. 47
14. 11
15. 3
16. 3
17. 45
18. 9
19. 0
20. 2
21. 42
22. 9
23. 34
24. 10
25. 18
26. 11
27. 18
28. 7
29. 4
30. 2
31.2
32. 17
33. 4
34. 4
35. 5
36. 5
37. 12
38. 3
39. 9
40. 12
41. 0
42. 3
43. 5
44. 3
45. 3
46. 7
47. 17
48. 2		 1. 1
2. 1
3. 7
4. 9
5. 21
6. 5
7. 2
8. 7
9. 11
10. 22
11. 8
12. 6
13. 47
14. 11
15. 3
16. 3
17. 45
18. 9
19. 0
20. 2
21. 42
22. 9
23. 34
24. 10
25. 18
26. 11
27. 18
28. 7
29. 4
30. 2
31.2
32. 17
33. 4
34. 4
35. 5
36. 5
37. 12
38. 3
39. 9
40. 12
41. 0
42. 3
43. 5
44. 3
45. 3
46. 7
47. 17
48. 2
Ozkan 2004 I: conventional treatment + orlistat 22 1. Frequent stools
2. Soiling, frequent defecation
3. Mild hair loss
4. Reported muscle cramps		 1. 22
2. 5
3. 1
4. 1		 1. 100
2. 22.7
3. 4.5
4. 4.5
C: conventional treatment 20 ‐ ‐ ‐
Prado 2012 I: metformin + nutritional guide and exercise programme 10 1. Increase levels of ALT
2. Increase levels of AST
3. Reduction in haemoglobin		 ‐ ‐
C: placebo + nutritional guide and exercise programme 9 1. Increase levels of ALT
2. Increase levels of AST
3. Reduction in haemoglobin		 ‐ ‐
Rezvanian 2010 I1: metformin + healthy eating and physical activity advice 45 1. Headache
2. Abdominal pain
3. Loose stool		 1. 2
2. 2
3. 3		 1. 4.4
2. 4.4
3. 6.6
I2: fluoxetine + healthy eating and physical activity advice 45 1. Dry mouth
2. Loose stool		 1. 3
2. 2		 1. 6.6
2. 4.4
I3: metformin and fluoxetine + healthy eating and physical activity advice 45 ‐ ‐ ‐
C: placebo + healthy eating and physical activity advice 45 ‐ ‐ ‐
Srinivasan 2006 I: metformin first then placebo + "standardised information on healthy eating and exercise" 13 ‐ ‐ ‐
C: placebo first then metformin + "standardised information on healthy eating and exercise" 15 ‐ ‐ ‐
Van Mil 2007 I: sibutramine + energy‐restricted diet and exercise plan 12 1. Clinical depression
2. Flu syndrome
3. Headache
4. Abdominal complaints
5. Agitation
6. Increased appetite
7. Rash
8. Dizziness
9. Dysmenorrhoea
10. Joint problem
11. Heart rate > 100 bpm on 2 occasions
12. DBP > 85 mmHg on 2 occasions		 1. 1
2. 6
3. 2
4. 7
5. 3
6. 4
7. 2
8. 3
9. 3
10. 2
11. 4
12. 1		 1. 8.3
2. 50
3. 16.6
4. 58.3
5. 25
6. 33.3
7. 16.6
8. 25
9. 25
10. 16.6
11. 33.3
12. 8.3
C: placebo + energy‐restricted diet and exercise plan 12 1. Flu syndrome
2. Headache
3. Agitation
4. Increased appetite
5. Dizziness
6. Joint problem
7. DBP > 85 mmHg on 2 occasions		 1. 6
2. 3
3. 1
4. 2
5. 1
6. 2
7. 1		 1. 50
2. 25
3. 8.3
4. 16.6
5. 8.3
6. 16.6
7. 8.3
Wiegand 2010 I: metformin + multiprofessional lifestyle intervention 36 1. Gastrointestinal symptoms
2. Unspecific (e.g. weakness or fatigue)		 1. 5
2. 3		 1. 13.9
2. 8.3
C: placebo + multiprofessional lifestyle intervention 34 1. Gastrointestinal symptoms
2. Unspecific (e.g. weakness or fatigue)		 1. 9
2. 4		 1. 26.5
2. 11.8
Wilson 2010 I: metformin + lifestyle intervention 38 1. Headache
2. Nausea
3. Vomiting
4. Upper respiratory tract infection
5. Musculoskeletal complaints
6. Elevated ALT levels
7. Appendectomy
8. Leg vein thrombosis		 1. 18
2. 9
3. 6
4. 18
5. 5
6. 2
7. 1
8. 1		 1. 47
2. 24
3. 16
4. 47
5. 13
6. 5
7. 3
8. 3
C: placebo + lifestyle intervention 38 1. Headache
2. Nausea
3. Vomiting
4. Upper respiratory tract infection
5. Musculoskeletal complaints
6. Elevated ALT levels		 1. 13
2. 3
3. 1
4. 23
5. 7
6. 1		 1. 34
2. 8
3. 3
4. 61
5. 18
6. 3
Yanovski 2011 I: metformin + dietitian‐administered weight‐reduction programme 53 1. Liquid or loose stools
2. Vomiting
3. Fatigue
4. Lost interest in usual pleasurable activities		 1. 22
2. 22
3. 20
4. 1		 1. 41.5
2. 41.5
3. 37.7
4. 1.9
C: placebo + dietitian‐administered weight‐reduction programme 47 1. Liquid or loose stools
2. Vomiting
3. Fatigue		 1. 8
2. 10
3. 7		 1. 17
2. 21.3
3. 14.9
*Berkowitz 2003: these adverse events occurred during the open‐label phase where all participants received sibutramine
ALT: alanine transaminase; AST: aspartate transaminase; bpm: beats per minute; DBP: diastolic blood pressure; n: number of participants; UTI: urinary tract infection