Scolaris Content Display Scolaris Content Display

Reduction in saturated fat intake for cardiovascular disease

This is not the most recent version

Appendices

Appendix 1. Search strategies March 2014

CENTRAL

#1 lipid near (low* or reduc* or modifi*)

#2 cholesterol* near (low* or modifi* or reduc*)

#3 (#1 or #2)

#4 MeSH descriptor: [Nutrition Therapy] explode all trees

#5 diet* or food* or nutrition*

#6 (#4 or #5)

#7 (#3 and #6)

#8 fat* near (low* or reduc* or modifi* or animal* or saturat* or unsaturat*)

#9 MeSH descriptor: [Diet, Atherogenic] explode all trees

#10 MeSH descriptor: [Diet Therapy] explode all trees

#11 (#7 or #8 or #9 or #10)

#12 MeSH descriptor: [Cardiovascular Diseases] this term only

#13 MeSH descriptor: [Heart Diseases] explode all trees

#14 MeSH descriptor: [Vascular Diseases] explode all trees

#15 MeSH descriptor: [Cerebrovascular Disorders] this term only

#16 MeSH descriptor: [Brain Ischemia] explode all trees

#17 MeSH descriptor: [Carotid Artery Diseases] explode all trees

#18 MeSH descriptor: [Dementia, Vascular] explode all trees

#19 MeSH descriptor: [Intracranial Arterial Diseases] explode all trees

#20 MeSH descriptor: [Intracranial Embolism and Thrombosis] explode all trees

#21 MeSH descriptor: [Intracranial Hemorrhages] explode all trees

#22 MeSH descriptor: [Stroke] explode all trees

#23 coronar* near (bypas* or graft* or disease* or event*)

#24 cerebrovasc* or cardiovasc* or mortal* or angina* or stroke or strokes or tia or ischaem* or ischem*

#25 myocardi* near (infarct* or revascular* or ischaem* or ischem*)

#26 morbid* near (heart* or coronar* or ischaem* or ischem* or myocard*)

#27 vascular* near (peripheral* or disease* or complication*)

#28 heart* near (disease* or attack* or bypas*)

#29 (#12 or #13 or #14 or #15 or #16 or #17 or #18 or #19 or #20 or #21 or #22 or #23 or #24 or #25 or #26 or #27 or #28)

#30 (#11 and #29)

MEDLINE OVID

1. (lipid$ adj5 (low$ or reduc$ or modifi$)).mp.

2. (cholesterol$ adj5 (low$ or modific$ or reduc$)).mp.

3. 1 or 2

4. exp Nutrition Therapy/

5. (diet$ or food$ or nutrition$).mp.

6. 4 or 5

7. 3 and 6

8. (fat adj5 (low$ or reduc$ or modifi$ or animal$ or saturat$ or unsatur$)).mp.

9. exp Diet, Atherogenic/

10. exp Diet Therapy/

11. 7 or 8 or 9 or 10

12. cardiovascular diseases/ or exp heart diseases/ or exp vascular diseases/

13. cerebrovascular disorders/ or exp brain ischemia/ or exp carotid artery diseases/ or exp dementia, vascular/ or exp intracranial arterial diseases/ or exp "intracranial embolism and thrombosis"/ or exp intracranial hemorrhages/ or exp stroke/

14. (coronar$ adj5 (bypas$ or graft$ or disease$ or event$)).mp.

15. (cerebrovasc$ or cardiovasc$ or mortal$ or angina$ or stroke or strokes).mp.

16. (myocardi$ adj5 (infarct$ or revascular$ or ischaemi$ or ischemi$)).mp.

17. (morbid$ adj5 (heart$ or coronar$ or ischaem$ or ischem$ or myocard$)).mp.

18. (vascular$ adj5 (peripheral$ or disease$ or complication$)).mp.

19. (heart$ adj5 (disease$ or attack$ or bypass$)).mp.

20. 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19

21. 11 and 20

22. randomized controlled trial.pt.

23. controlled clinical trial.pt.

24. randomized.ab.

25. placebo.ab.

26. drug therapy.fs.

27. randomly.ab.

28. trial.ab.

29. groups.ab.

30. 22 or 23 or 24 or 25 or 26 or 27 or 28 or 29

31. exp animals/ not humans.sh.

32. 30 not 31

33. 21 and 32

34. 33

35. limit 34 to yr="2010 ‐Current"

36. limit 35 to "core clinical journals (aim)"

EMBASE OVID

1. cardiovascular diseases/ or exp heart diseases/ or exp vascular diseases/

2. cerebrovascular disorders/ or exp brain ischemia/ or exp carotid artery diseases/ or exp dementia, vascular/ or exp intracranial arterial diseases/ or exp "intracranial embolism and thrombosis"/ or exp intracranial hemorrhages/ or exp stroke/

3. (coronar$ adj5 (bypas$ or graft$ or disease$ or event$)).mp.

4. (cerebrovasc$ or cardiovasc$ or mortal$ or angina$ or stroke or strokes).mp.

5. (myocardi$ adj5 (infarct$ or revascular$ or ischaemi$ or ischemi$)).mp.

6. (morbid$ adj5 (heart$ or coronar$ or ischaem$ or ischem$ or myocard$)).mp.

7. (vascular$ adj5 (peripheral$ or disease$ or complication$)).mp.

8. (heart$ adj5 (disease$ or attack$ or bypass$)).mp.

9. or/1‐8

10. (lipid$ adj5 (low$ or reduc$ or modifi$)).mp.

11. (cholesterol$ adj5 (low$ or modific$ or reduc$)).mp.

12. 10 or 11

13. (diet$ or food$ or eat$ or nutrition$).mp.

14. exp nutrition/

15. 13 or 14

16. 12 and 15

17. (fat adj5 (low$ or reduc$ or modifi$ or animal$ or saturat$ or unsatur$)).mp.

18. exp lipid diet/ or exp fat intake/ or exp low fat diet/

19. 16 or 17 or 18

20. 9 and 19

21. random$.tw.

22. factorial$.tw.

23. crossover$.tw.

24. cross over$.tw.

25. cross‐over$.tw.

26. placebo$.tw.

27. (doubl$ adj blind$).tw.

28. (singl$ adj blind$).tw.

29. assign$.tw.

30. allocat$.tw.

31. volunteer$.tw.

32. crossover procedure/

33. double blind procedure/

34. randomized controlled trial/

35. single blind procedure/

36. 21 or 22 or 23 or 24 or 25 or 26 or 27 or 28 or 29 or 30 or 31 or 32 or 33 or 34 or 35

37. (animal/ or nonhuman/) not human/

38. 36 not 37

39. 20 and 38

40. (2010* or 2011* or 2012* or 2013* or 2014*).em.

41. 39 and 40

42. limit 41 to priority journals

Flow diagram for review
Figures and Tables -
Figure 1

Flow diagram for review

Methodological quality summary: review authors' judgements about each methodological quality item for each included study. Please note that while Rose 1965 (Rose corn oil 1965; Rose olive 1965) and WHI 2006 (WHI with CVD 2006; WHI without CVD 2006) each appear twice in this summary, they are each a single trial. Rose 1965 was a 3‐arm trial and we have used the two intervention arms separately in the review, while WHI 2006 provided some data separately for people with or without CVD at baseline.
Figures and Tables -
Figure 2

Methodological quality summary: review authors' judgements about each methodological quality item for each included study. Please note that while Rose 1965 (Rose corn oil 1965; Rose olive 1965) and WHI 2006 (WHI with CVD 2006; WHI without CVD 2006) each appear twice in this summary, they are each a single trial. Rose 1965 was a 3‐arm trial and we have used the two intervention arms separately in the review, while WHI 2006 provided some data separately for people with or without CVD at baseline.

Forest plot of comparison: 1 SFA reduction vs usual diet ‐ health events, outcome: 1.1 All‐cause mortality.
Figures and Tables -
Figure 3

Forest plot of comparison: 1 SFA reduction vs usual diet ‐ health events, outcome: 1.1 All‐cause mortality.

Funnel plot of comparison: fat modification or reduction vs usual diet ‐ total mortality.
Figures and Tables -
Figure 4

Funnel plot of comparison: fat modification or reduction vs usual diet ‐ total mortality.

Forest plot of comparison: 1 SFA reduction vs usual diet ‐ Primary outcomes, outcome: 1.2 Cardiovascular mortality.
Figures and Tables -
Figure 5

Forest plot of comparison: 1 SFA reduction vs usual diet ‐ Primary outcomes, outcome: 1.2 Cardiovascular mortality.

Forest plot of comparison: 1 SFA reduction vs usual diet ‐ Primary outcomes, outcome: 1.3 Combined cardiovascular events.
Figures and Tables -
Figure 6

Forest plot of comparison: 1 SFA reduction vs usual diet ‐ Primary outcomes, outcome: 1.3 Combined cardiovascular events.

Funnel plot of comparison: fat modification or reduction vs usual diet ‐ combined cardiovascular events.
Figures and Tables -
Figure 7

Funnel plot of comparison: fat modification or reduction vs usual diet ‐ combined cardiovascular events.

Exploring saturated fat cut‐offs.
Figures and Tables -
Figure 8

Exploring saturated fat cut‐offs.

Comparison 1 SFA reduction vs usual diet ‐ Primary outcomes, Outcome 1 All‐cause mortality.
Figures and Tables -
Analysis 1.1

Comparison 1 SFA reduction vs usual diet ‐ Primary outcomes, Outcome 1 All‐cause mortality.

Comparison 1 SFA reduction vs usual diet ‐ Primary outcomes, Outcome 2 Cardiovascular mortality.
Figures and Tables -
Analysis 1.2

Comparison 1 SFA reduction vs usual diet ‐ Primary outcomes, Outcome 2 Cardiovascular mortality.

Comparison 1 SFA reduction vs usual diet ‐ Primary outcomes, Outcome 3 Combined cardiovascular events.
Figures and Tables -
Analysis 1.3

Comparison 1 SFA reduction vs usual diet ‐ Primary outcomes, Outcome 3 Combined cardiovascular events.

Comparison 2 SFA reduction vs usual diet ‐ secondary health events, Outcome 1 Myocardial infarctions.
Figures and Tables -
Analysis 2.1

Comparison 2 SFA reduction vs usual diet ‐ secondary health events, Outcome 1 Myocardial infarctions.

Comparison 2 SFA reduction vs usual diet ‐ secondary health events, Outcome 2 Non‐fatal MI.
Figures and Tables -
Analysis 2.2

Comparison 2 SFA reduction vs usual diet ‐ secondary health events, Outcome 2 Non‐fatal MI.

Comparison 2 SFA reduction vs usual diet ‐ secondary health events, Outcome 3 Stroke.
Figures and Tables -
Analysis 2.3

Comparison 2 SFA reduction vs usual diet ‐ secondary health events, Outcome 3 Stroke.

Comparison 2 SFA reduction vs usual diet ‐ secondary health events, Outcome 4 CHD mortality.
Figures and Tables -
Analysis 2.4

Comparison 2 SFA reduction vs usual diet ‐ secondary health events, Outcome 4 CHD mortality.

Comparison 2 SFA reduction vs usual diet ‐ secondary health events, Outcome 5 CHD events.
Figures and Tables -
Analysis 2.5

Comparison 2 SFA reduction vs usual diet ‐ secondary health events, Outcome 5 CHD events.

Comparison 2 SFA reduction vs usual diet ‐ secondary health events, Outcome 6 Diabetes diagnoses.
Figures and Tables -
Analysis 2.6

Comparison 2 SFA reduction vs usual diet ‐ secondary health events, Outcome 6 Diabetes diagnoses.

Comparison 3 SFA reduction vs usual diet ‐ other secondary outcomes, Outcome 1 Total cholesterol, mmol/L.
Figures and Tables -
Analysis 3.1

Comparison 3 SFA reduction vs usual diet ‐ other secondary outcomes, Outcome 1 Total cholesterol, mmol/L.

Comparison 3 SFA reduction vs usual diet ‐ other secondary outcomes, Outcome 2 LDL cholesterol, mmol/L.
Figures and Tables -
Analysis 3.2

Comparison 3 SFA reduction vs usual diet ‐ other secondary outcomes, Outcome 2 LDL cholesterol, mmol/L.

Comparison 3 SFA reduction vs usual diet ‐ other secondary outcomes, Outcome 3 HDL cholesterol, mmol/L.
Figures and Tables -
Analysis 3.3

Comparison 3 SFA reduction vs usual diet ‐ other secondary outcomes, Outcome 3 HDL cholesterol, mmol/L.

Comparison 3 SFA reduction vs usual diet ‐ other secondary outcomes, Outcome 4 Triglycerides, mmol/L.
Figures and Tables -
Analysis 3.4

Comparison 3 SFA reduction vs usual diet ‐ other secondary outcomes, Outcome 4 Triglycerides, mmol/L.

Comparison 3 SFA reduction vs usual diet ‐ other secondary outcomes, Outcome 5 total cholesterol /HDL ratio.
Figures and Tables -
Analysis 3.5

Comparison 3 SFA reduction vs usual diet ‐ other secondary outcomes, Outcome 5 total cholesterol /HDL ratio.

Comparison 3 SFA reduction vs usual diet ‐ other secondary outcomes, Outcome 6 LDL /HDL ratio.
Figures and Tables -
Analysis 3.6

Comparison 3 SFA reduction vs usual diet ‐ other secondary outcomes, Outcome 6 LDL /HDL ratio.

Comparison 3 SFA reduction vs usual diet ‐ other secondary outcomes, Outcome 7 Lp(a), mmol/L.
Figures and Tables -
Analysis 3.7

Comparison 3 SFA reduction vs usual diet ‐ other secondary outcomes, Outcome 7 Lp(a), mmol/L.

Comparison 3 SFA reduction vs usual diet ‐ other secondary outcomes, Outcome 8 Insulin sensitivity.
Figures and Tables -
Analysis 3.8

Comparison 3 SFA reduction vs usual diet ‐ other secondary outcomes, Outcome 8 Insulin sensitivity.

Summary of findings for the main comparison. Summary of findings: What is the effect of reducing saturated fat compared to usual saturated fat on CVD risk in adults? (Note: for the full set of GRADE tables see additional tables 24 to 28)

Low saturated fat compared with usual saturated fat for CVD risk

Patient or population: people at any baseline risk of CVD

Intervention: reduction of saturated fat intake

Comparison: usual saturated fat intake

Outcomes

Relative effect
(95% CI)

Absolute effects

(per 10,000)

No of Participants
(studies)

Quality of the evidence
(GRADE)

Comments

All‐cause mortality

follow‐up mean duration 56 months1

RR 0.97 (0.90 to 1.05)

17 fewer

(from 57 fewer to 29 more)

55,858
(12)

⊕⊕⊕⊝
moderate2,3,4,5,6

Critical importance

Cardiovascular mortality

follow‐up mean duration 53 months1

RR 0.95 (0.80 to 1.12)

10 fewer
(from 39 fewer to 23 more)

53,421
(12)

⊕⊕⊕⊝
moderate2,3,4,5,6

Critical importance

Combined cardiovascular events

follow‐up mean duration 52 months1

RR 0.83 (0.72 to 0.96)

138 fewer

(from 33 fewer to 228 fewer)

53,300
(13)

⊕⊕⊕⊝
moderate2,4,6,7,8

Critical importance

Myocardial infarctions

follow‐up mean duration 55 months

RR 0.90 (0.80 to 1.01)

32 fewer

(from 63 fewer to 3 more)

53,167
(11)

⊕⊕⊕⊝
moderate2,3,4,5,6

Critical importance

Non‐fatal MI

follow‐up mean duration 55 months1

RR 0.95 (0.80 to 1.13)

13 fewer

(from 51 fewer to 33 more)

52,834
(9)

⊕⊕⊕⊝
moderate2,3,4,5,9

Critical importance

Stroke

follow‐up mean duration 59 months1

RR 1.00 (0.89 to 1.12)

0 fewer

(from 25 fewer to 25 more)

50,952
(8)

⊕⊕⊕⊝
moderate2,3,4,5,9

Critical importance

CHD mortality

follow‐up mean duration 65 months1

RR 0.98 (0.84 to 1.15)

3 fewer

(from 25 fewer to 23 more)

53,159
(10)

⊕⊕⊕⊝
moderate2,3,4,5,6

Critical importance

CHD events

follow‐up mean duration 59 months1

RR 0.87 (0.74 to 1.03)

80 fewer

(from 160 fewer to 19 more)

53,199
(12)

⊕⊕⊝⊝
low2,4,5,6,10

Critical importance

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk Ratio; CHD: coronary heart disease.

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

1Minimum study duration was 24 months

2These large RCTs of relatively long duration were well randomised but fewer than half had good allocation concealment (the rest were unclear). Blinding was only well‐conducted in 1 RCT, however blinding is very difficult in trials of dietary fat intake. Incomplete outcome data were variable, and most included studies had systematic differences in care (i.e. intervention group had more time or attention than the control group). We noted no other biases. We downgraded each study once for a combination of these issues around validity and issues around precision. The level of compliance with interventions involving long‐term behaviour change, such as those used in these studies, can vary widely. This is likely to attenuate the pooled effect and bias it towards the null.

3No important heterogeneity; I² ≤ 30%

4These RCTs directly assessed the effect of lower vs usual saturated fat intake on health outcomes of interest. Participants included men and women with and without CVD at baseline (also some participants with CVD risk factors like diabetes, or at risk of cancers).

5The 95% CI crosses 1.0 and does not exclude important benefit or harm.

6The funnel plot did not suggest any small‐study (publication) bias.

7Potentially important heterogeneity was identified; I² = 65%. However, the heterogeneity was partly explained by the degree of saturated fat reduction, and the degree of cholesterol lowering achieved (in subgrouping and in meta‐regression). For this reason we did not downgrade the study for inconsistency.

8The 95% CI does not cross 1.0 or a threshold of important harm.

9Too few studies to reliably assess small‐study bias (< 10 RCTs)

10Important heterogeneity; I² = 66%.

Figures and Tables -
Summary of findings for the main comparison. Summary of findings: What is the effect of reducing saturated fat compared to usual saturated fat on CVD risk in adults? (Note: for the full set of GRADE tables see additional tables 24 to 28)
Table 1. Comparison of study interventions for included RCTs

Reference

Population

CVD risk category

Is intervention delivered to Individual or group?

intervention given by?

Face‐to‐face or other?

Number of visits

Is intervention advice only or other intervention?

Black 1994

People with non‐melanoma skin cancer

Low

Unclear

Dietitian

Face‐to‐face

8 x weekly classes then monthly follow‐up sessions

Advice (behaviour techniques learning)

DART 1989

Men recovering from a MI

High

Individual

Dietitian

Face‐to‐face

9

Advice (diet advice, recipes and encouragement)

Houtsmuller 1979

Adults with newly‐diagnosed diabetes

Moderate

Unclear

Dietitian

Unclear

Unclear

Advice?

Ley 2004

People with impaired glucose intolerance or high normal blood glucose

Moderate

Small group

Unclear

Face‐to‐face

Monthly meetings

Advice (education, personal goal setting, self‐monitoring)

Moy 2001

Middle‐aged siblings of people with early CHD, with at least 1 CVD risk factor

Moderate

Individual

Trained nurse

Face‐to‐face

6 ‐ 8 weekly for 2 years

Advice (individualised counselling sessions)

MRC 1968

Free‐living men who have survived a 1st MI

High

Individual

Dietitian

Face‐to‐face

Unclear

Advice and supplement (soy oil)

Oslo Diet‐Heart 1966

Men with previous MI

High

Individual

Dietitian

Face‐to‐face and other

Unclear

Advice and supplement (food)

Oxford Retinopathy 1978

Newly‐diagnosed non‐insulin‐dependent diabetics

Moderate

Individual

Diabetes dietitian

Face‐to‐face

After 1 month then at 3‐month intervals

Advice

Rose corn oil 1965

Men (?) with angina or following MI

High

Unclear

Unclear

Unclear

Follow‐up clinic monthly, then every 2 months

Advice and supplement (oil)

Rose olive 1965

Men (?) with angina or following MI

High

Unclear

Unclear

Unclear

Follow‐up clinic monthly, then every 2 months

Advice and supplement (oil)

Simon 1997

Women with a high risk of breast cancer

Low

Individual followed by individual or group

Dietitian

Face‐to‐face

Bi‐weekly over 3 months followed by monthly

Advice (individualised eating plan and counselling sessions)

STARS 1992

Men with angina referred for angiography

High

individual

Dietitian

Face‐to‐face

Clinic visits at 3‐months intervals

Advice

Sydney Diet‐Heart 1978

Men with angina referred for angiography

High

Individual

Unclear

Face‐to‐face

3 times in 1st year and twice annually thereafter

Advice

Veterans Admin 1969

Men living at the Veterans Administration Center

Low

Individual

Unclear (whole diet provided)

N/A

N/A

Diet provided

WHI with CVD 2006

Post‐menopausal women aged 50 ‐ 79 with CVD at baseline

High

Group

Nutritionists

Face‐to‐face

18 sessions/ 1st yr and quarterly maintenance sessions after

Advice

WHI without CVD 2006

Post‐menopausal women aged 50 ‐ 79 without CVD at baseline

Low

Group

Nutritionists

Face‐to‐face

18 sessions/ 1st yr and quarterly maintenance sessions after

Advice

WINS 2006

Women with localised resected breast cancer

Low

Individual followed by group

Dietitian

Face‐to‐face

8 bi‐weekly sessions, then 3‐monthly contact and optional monthly sessions

Advice

N/A: not applicable

Figures and Tables -
Table 1. Comparison of study interventions for included RCTs
Table 2. Number of participants and number of outcomes for dichotomous variables (by intervention arm)

Participants

All‐cause mortality

CV mortality

CVD events

MI

Non‐fatal MI

Stroke

CHD mortality

CHD events

Diabetes Diagnoses

Black 1994

133

133

133

133

0

0

0

0

0

0

DART 1989

2033

2033

2033

2033

2033

2033

0

2033

2033

0

Houtsmuller 1979

102

0

0

102

102

0

0

102

102

0

Ley 2004

176

176

176

176

176

0

176

0

176

0

Moy 2001

267

0

0

235

235

235

235

0

267

0

MRC 1968

393

393

393

393

393

393

393

393

393

0

Oslo Diet‐Heart 1966

412

412

412

412

412

412

412

412

412

0

Oxford Retinopathy 1978

249 (data not provided by arm)

0

0

0

0

0

0

0

0

0

Rose corn oil 1965

41

41

41

41

41

41

0

41

41

0

Rose olive 1965

39

39

39

39

39

39

0

39

39

0

Simon 1997

194 (data not provided by arm)

0

0

0

0

0

0

0

0

0

STARS 1992

60

55

55

55

55

0

55

0

55

0

Sydney Diet‐Heart 1978

458

458

458

0

0

0

0

458

0

0

Veterans Admin 1969

846

846

846

846

846

846

846

846

846

0

WHI with CVD 2006

2277

0

2277

2277

0

2277

2277

2277

2277

0

WHI without CVD 2006

48835

48835

46558

46558

48835

46558

46558

46558

46558

48835

WINS 2006

2437

2437

0

0

0

0

0

0

0

0

Total Participants

58509

55858

53421

53300

53167

52834

50952

53159

53204

48835

Percent of participants for this outcome

100%

95%

91%

91%

91%

90%

87%

91%

91%

83%

These numbers are the numbers of participants in each study who were available for assessment of outcomes within meta‐analysis (not necessarily the number of participants randomised within the trial).

Figures and Tables -
Table 2. Number of participants and number of outcomes for dichotomous variables (by intervention arm)
Table 3. Number of participants and number of participants with data for continuous outcomes (by intervention arm)

Participants

Total cholesterol

LDL cholesterol

HDL cholesterol

Triglycerides

TG/HDL ratio

Total cholesterol/HDL ratio

LDL/HDL ratio

LP (a)

Insulin sensitivity

Black 1994

133

0

0

0

0

0

0

0

0

0

DART 1989

2033

1855

0

1855

0

0

0

0

0

0

Houtsmuller 1979

102

96

0

0

96

0

0

0

0

96

Ley 2004

176

103

103

103

103

0

103

0

0

103

Moy 2001

267

0

235

235

235

0

0

0

0

0

MRC 1968

393

177

0

0

0

0

0

0

0

0

Oslo Diet‐Heart 1966

412

329

0

0

0

0

0

0

0

0

Oxford Retinopathy 1978

249

58

0

0

0

0

0

0

0

0

Rose corn oil 1965

41

22

0

0

0

0

0

0

0

0

Rose olive 1965

39

24

0

0

0

0

0

0

0

0

Simon 1997

194

72

71

72

71

0

0

0

0

0

STARS 1992

55

50

50

50

50

0

50

50

50

50

Sydney Diet‐Heart 1978

458

458

0

0

458

0

0

0

0

0

Veterans Admin 1969

846

843

0

0

0

0

0

0

0

0

WHI with CVD 2006

2277

0

0

0

0

0

0

0

0

0

WHI without CVD 2006

48835

2832

2832

2832

2832

0

2832

0

2832

2832

WINS 2006

2437

196

0

0

0

0

0

0

0

0

Total Participants

58952

7115

3291

5147

3845

0

2985

50

2882

3081

Percent of participants for this outcome

100%

12%

6%

9%

7%

0%

5%

0.1%

5%

5%

These numbers are the numbers of participants in each study who were available for assessment of outcomes within meta‐analysis (not necessarily the number of participants randomised within the trial).

Figures and Tables -
Table 3. Number of participants and number of participants with data for continuous outcomes (by intervention arm)
Table 4. All‐cause mortality, sensitivity analyses

Analysis

RR (95% CI) of all‐cause mortality

No. of events

No. of participants

Main analysis

0.97 (0.90 to 1.05)

3%

3276

> 55,000

Sensitivity analyses

Stated aim to reduce SFA

0.97 (0.89 to 1.06)

11%

3231

> 53,000

SFA significantly reduced

0.99 (0.92 to 1.06)

0%

3095

> 54,000

TC significantly reduced

0.96 (0.83 to 1.11)

33%

2871

> 52,000

Minus WHI

0.96 (0.84 to 1.11)

12%

872

> 7000

Mantel‐Haenszel fixed‐effect

0.98 (0.91 to 1.04)

3%

3276

> 55,000

Peto fixed‐effect

0.97 (0.90 to 1.05)

16%

3276

> 55,000

SFA: saturated fatty acids
TC: total cholesterol

Figures and Tables -
Table 4. All‐cause mortality, sensitivity analyses
Table 5. All‐cause mortality, subgroup data

Analysis, P value for subgroup differences

RR (95% CI) of all‐cause mortality

No. of events

No. of participants

Subgroup by replacement

P = 0.79

PUFA replacement

0.96 (0.82 to 1.13)

26%

824

> 4000

MUFA replacement

3.00 (0.33 to 26.99)

N/A

4

52

CHO replacement

0.98 (0.91 to 1.05)

0%

2677

> 53,000

Protein replacement

0.98 (0.91 to 1.06)

0%

2673

> 53,000

Subgroup by duration, P = 0.60

Up to 24 months

0.99 (0.78 to 1.26)

0%

236

> 2000

> 24 to 48 months

0.96 (0.83 to 1.12)

0%

414

> 1000

> 48 months

1.00 (0.79 to 1.27)

55%

2618

> 52,000

Unclear duration

0.33 (0.07 to 1.61)

N/A

8

> 100

Subgroup by baseline SFA, P = 0.48

Up to 12%E SFA

1.18 (0.60 to 2.32)

N/A

34

> 2400

> 12 to 15%E SFA

1.01 (0.86 to 1.19)

26%

2706

> 51,000

> 15 to 18%E SFA

0.35 (0.04 to 3.12)

N/A

4

55

> 18%E SFA

0.98 (0.83 to 1.15)

N/A

351

846

Subgroup by SFA change, P = 0.31

Up to 4%E SFA difference

1.02 (0.88 to 1.19)

26%

2737

> 53,000

> 4 to 8%E SFA difference

0.41 (0.08 to 2.07)

0%

7

> 100

> 8%E SFA difference

0.98 (0.83 to 1.15)

N/A

351

> 800

Subgroup by sex, P = 0.40

Men

0.96 (0.83 to 1.11)

13%

830

> 4000

Women

0.98 (0.91 to 1.06)

0%

2438

> 51,000

Mixed, men and women

0.33 (0.07 to 1.61)

N/A

8

176

Subgroup by CVD risk, P = 0.40

Low CVD risk

0.98 (0.91 to 1.05)

0%

2792

> 52,000

Moderate CVD risk

0.33 (0.07 to 1.61)

N/A

8

176

Existing CVD

0.97 (0.90 to 1.05)

33%

476

> 3000

Subgroup by serum TC reduction,

P = 0.85

TC reduced by ≥ 0.2 mmol/L

0.96 (0.81 to 1.14)

32%

823

> 4000

TC reduced by < 0.2 mmol/L

0.98 (0.91 to 1.06)

0%

2450

> 51,000

Unclear TC change

0.51 (0.05 to 5.46)

N/A

3

> 100

Subgroup by decade of publication, P = 0.28

1960s

0.92 (0.80 to 1.07)

2%

532

> 1700

1970s

1.49 (0.95 to 2.34)

N/A

67

458

1980s

0.98 (0.76 to 1.25)

N/A

224

2033

1990s

0.41 (0.08 to 2.07)

0%

7

188

2000s

0.98 (0.83 to 1.15)

5%

2446

> 51,000

CHO: carbohydrate
CVD: cardiovascular disease
MUFA: mon‐unsaturated fatty acid
N/A: not applicable
PUFA: polyunsaturated fatty caid
SFA: saturated fatty acid
TC: total cholesterol

Figures and Tables -
Table 5. All‐cause mortality, subgroup data
Table 6. CVD mortality, sensitivity analyses

Analysis

RR (95% CI) of CVD mortality

No. of events

No. of participants

Main analysis

0.95 (0.80 to 1.12)

30%

1096

>53000

Sensitivity analyses

Stated aim to reduce SFA

0.96 (0.81 to 1.13)

32%

1089

> 53,000

SFA significantly reduced

0.96 (0.79 to 1.18)

42%

945

> 52,000

TC significantly reduced

1.00 (0.86 to 1.16)

19%

942

> 52,000

Minus WHI

0.92 (0.72 to 1.18)

40%

563

> 4000

Mantel‐Haenszel fixed‐effect

0.95 (0.85 to 1.07)

30%

1096

> 53,000

Peto fixed‐effect

0.95 (0.84 to 1.08)

41%

1096

> 53,000

SFA: saturated fatty acid
TC: total cholesterol

Figures and Tables -
Table 6. CVD mortality, sensitivity analyses
Table 7. CVD mortality, subgroup data

Analysis, P value for subgroup differences

RR (95% CI) of CVD mortality

No. of events

No. of participants

Subgroup by replacement

P = 0.79

PUFA replacement

0.95 (0.73 to 1.25)

55%

553

> 4000

MUFA replacement

3.00 (0.33 to 26.99)

N/A

4

52

CHO replacement

0.99 (0.86 to 1.14)

0%

745

> 51,000

Protein replacement

0.99 (0.86 to 1.14)

0%

741

> 51,000

Subgroup by duration, P = 0.33

Up to 24 months

1.26 (0.54 to 2.94)

26%

213

> 2000

> 24 to 48 months

0.79 (0.57 to 1.08)

14%

194

> 1000

> 48 months

1.01 (0.79 to 1.30)

54%

685

> 49,000

Unclear duration

0.25 (0.03 to 2.19)

N/A

5

> 100

Subgroup by baseline SFA, P = 0.13

Up to 12%E SFA

N/A

> 12 to 15%E SFA

1.04 (0.88 to 1.24)

19%

803

> 51,000

> 15 to 18%E SFA

0.35 (0.04 to 3.12)

N/A

4

55

> 18%E SFA

0.70 (0.51 to 0.96)

N/A

138

846

Subgroup by SFA change, P = 0.08

Up to 4%E SFA difference

1.05 (0.89 to 1.24)

21%

801

>51000

> 4 to 8%E SFA difference

0.29 (0.05 to 1.70)

0%

6

> 100

> 8%E SFA difference

0.70 (0.51 to 0.96)

N/A

152

> 900

Subgroup by sex, P = 0.45

Men

0.96 (0.73 to 1.25)

48%

559

> 4000

Women

1.00 (0.84 to 1.19)

0%

533

> 48,000

Mixed, men and women

0.25 (0.03 to 2.19)

NA

5

176

Subgroup by CVD risk, p=0.26

Low CVD risk

0.84 (0.60 to 1.16)

54%

568

> 47,000

Moderate CVD risk

0.25 (0.03 to 2.19)

NA

5

176

Existing CVD

1.04 (0.83 to 1.31)

33%

524

> 5000

Subgroup by serum TC reduction,

P = 0.57

TC reduced by ≥ 0.2 mmol/L

0.95 (0.73 to 1.25)

55%

553

> 4000

TC reduced by < 0.2 mmol/L

1.00 (0.84 to 1.18)

0%

542

> 49,000

Unclear TC change

0.20 (0.01 to 4.15)

N/A

2

> 100

Subgroup by decade of publication, P = 0.04

1960s

0.78 (0.63 to 0.97)

2%

289

> 1700

1970s

1.59 (0.99 to 2.55)

N/A

62

458

1980s

1.01 (0.77 to 1.31)

N/A

201

> 2000

1990s

0.29 (0.05 to 1.70)

0%

6

188

2000s

0.99 (0.83 to 1.18)

0%

538

> 49,000

CHO: carbohydrate
CVD: cardiovascular disease
MUFA: mon‐unsaturated fatty acid
N/A: not applicable
PUFA: polyunsaturated fatty caid
SFA: saturated fatty acid
TC: total cholesterol

Figures and Tables -
Table 7. CVD mortality, subgroup data
Table 8. CVD events, sensitivity analyses

Analysis

RR (95% CI) of CVD events

No. of events

No. of participants

Main analysis

0.83 (0.72 to 0.96)

65%

4377

> 53,000

Sensitivity analyses

Stated aim to reduce SFA

0.84 (0.72 to 0.97)

69%

4354

> 52,000

SFA significantly reduced

0.91 (0.79 to 1.04)

53%

4012

> 52,000

TC significantly reduced

0.81 (0.68 to 0.98)

77%

4092

> 52,000

Minus WHI

0.75 (0.61 to 0.91)

51%

932

> 4000

Mantel‐Haenszel fixed‐effect

0.93 (0.88 to 0.98)

65%

4377

> 53,000

Peto fixed‐effect

0.92 (0.86 to 0.98)

72%

4377

> 53,000

SFA: saturated fatty ac5d
TC: total cholesterol

Figures and Tables -
Table 8. CVD events, sensitivity analyses
Table 9. CVD events, subgroup data

Analysis, P value for subgroup differences

RR (95% CI) of CVD events

No. of events

No. of participants

Subgroup by replacement

P = 0.14

PUFA replacement

0.73 (0.58 to 0.92)

69%

884

> 3000

MUFA replacement

1.00 (0.53 to 1.89)

NA

22

52

CHO replacement

0.93 (0.79 to 1.08)

57%

3785

> 51,000

Protein replacement

0.98 (0.90 to 1.06)

15%

3757

> 51,000

Subgroup by duration, P = 0.15

Up to 24 months

0.96 (0.78 to 1.16)

0%

330

> 2000

> 24 to 48 months

0.73 (0.56 to 0.95)

50%

383

> 1000

> 48 months

0.93 (0.79 to 1.11)

75%

3599

> 49,000

Unclear duration

0.43 (0.17 to 1.08)

NA

65

> 200

Subgroup by baseline SFA, P = 0.13

Up to 12%E SFA

NA

> 12 to 15%E SFA

0.98 (0.91 to 1.05)

6%

3765

> 51,000

> 15 to 18%E SFA

0.41 (0.22 to 0.78)

NA

28

55

> 18%E SFA

0.79 (0.63 to 1.00)

NA

219

846

Subgroup by SFA change, P = 0.005

Up to 4%E SFA difference

0.98 (0.91 to 1.05)

6%

3763

> 51,000

> 4 to 8%E SFA difference

0.40 (0.22 to 0.74)

0%

30

> 100

> 8%E SFA difference

0.79 (0.63 to 1.00)

NA

219

> 800

Subgroup by sex, P = 0.05

Men

0.80 (0.69 to 0.93)

24%

859

> 3000

Women

1.00 (0.88 to 1.14)

60%

3445

> 48,000

Mixed, men and women

0.59 (0.23 to 1.49)

71%

73

> 500

Subgroup by CVD risk, P = 0.67

Low CVD risk

0.89 (0.75 to 1.06)

40%

3130

> 47,000

Moderate CVD risk

0.59 (0.23 to 1.49)

71%

73

> 500

Existing CVD

0.86 (0.71 to 1.05)

63%

1174

> 5000

Subgroup by serum TC reduction,

P = 0.03

TC reduced by ≥ 0.2 mmol/L

0.74 (0.59 to 0.92)

63%

887

> 4000

TC reduced by < 0.2 mmol/L

0.99 (0.90 to 1.08)

15%

3488

> 49,00

Unclear TC change

0.20 (0.01 to 4.15)

NA

2

> 100

Subgroup by decade of publication, P , 0.0001

1960s

0.79 (0.69 to 0.91)

0%

546

> 1700

1970s

0.27 (0.14 to 0.52)

NA

38

102

1980s

0.92 (0.74 to 1.15)

NA

283

> 2000

1990s

0.40 (0.22 to 0.74)

0%

30

188

2000s

0.99 (0.89 to 1.11)

25%

3480

> 49,000

CHO: carbohydrate
CVD: cardiovascular disease
MUFA: mon‐unsaturated fatty acid
N/A: not applicable
PUFA: polyunsaturated fatty caid
SFA: saturated fatty acid
TC: total cholesterol

Figures and Tables -
Table 9. CVD events, subgroup data
Table 10. Metaregression of effects of SFA reduction on cardiovascular events

Regression factor

No. of studies

Constant

Coefficient (95% CI)

P value

Proportion of between study variation explained

Change in SFA as %E

8

0.01

0.05 (‐0.03 to 0.13)

0.16

89%

Change in SFA as % of control

8

0.26

0.01 (‐0.01 to 0.03)

0.14

89%

Baseline SFA as %E

8

0.68

‐0.06 (‐0.15 to 0.04)

0.19

81%

Change in TC, mmol/L

12

0.03

0.69 (0.05 to 1.33)

0.04

99%

Change in PUFA as %E

5

‐0.01

‐0.02 (‐0.08 to 0.03)

0.25

100%

Change in MUFA as %E

5

‐0.26

‐0.03 (‐0.14 to 0.09)

0.50

‐87%

Change in CHO as %E

7

‐0.11

‐0.00 (‐0.05 to 0.05)

0.92

‐273%

Change in total fat intake as %E

9

‐0.17

‐0.01 (‐0.03 to 0.01)

0.28

100%

Gender*

13

‐0.17

‐0.14 (‐0.63 to 0.35)

0.55

‐13%

Study duration

13

‐0.47

0.00 (‐0.01 to 0.02)

0.76

‐24.8

CVD risk at baseline**

13

‐0.44

0.03 (‐0.48 to 0.55)

0.89

‐39%

*0 = women, 1 = mixed, 2 = men
** 1 = Low CVD risk, 2 = Moderate CVD risk, 3 = existing CVD
CHO: carbohydrate
CVD: cardiovascular disease
MUFA: mon‐unsaturated fatty acid
PUFA: polyunsaturated fatty caid
SFA: saturated fatty acid

Figures and Tables -
Table 10. Metaregression of effects of SFA reduction on cardiovascular events
Table 11. Myocardial infarction (fatal and non‐fatal), sensitivity analyses

Analysis

RR (95% CI) of any MI

No. of events

No. of participants

Main analysis

0.90 (0.80 to 1.01)

10%

1714

> 53,000

Sensitivity analyses

Stated aim to reduce SFA

0.89 (0.78 to 1.02)

17%

1707

> 53,000

SFA significantly reduced

0.94 (0.85 to 1.04)

0%

1520

> 52,000

TC significantly reduced

0.89 (0.76 to 1.05)

26%

1561

> 52,000

Minus WHI

0.85 (0.73 to 0.98)

1%

608

> 4000

Mantel‐Haenszel fixed‐effect

0.92 (0.84 to 1.01)

10%

1714

> 53,000

Peto fixed‐effect

0.92 (0.83 to 1.01)

31%

1714

> 53,000

SFA: saturated fatty acid
TC: total cholesterol

Figures and Tables -
Table 11. Myocardial infarction (fatal and non‐fatal), sensitivity analyses
Table 12. Myocardial infarction (fatal and non‐fatal), subgroup data

Analysis, P value for subgroup differences

RR (95% CI) of any MI

No. of events

No. of participants

Subgroup by replacement

P = 0.48

PUFA replacement

0.83 (0.67 to 1.02)

29%

591

> 3000

MUFA replacement

1.40 (0.51 to 3.85)

N/A

12

52

CHO replacement

0.96 (0.86 to 1.06)

0%

1392

> 51,000

Protein replacement

0.96 (0.86 to 1.07)

0%

1389

> 51,000

Subgroup by duration, P = 0.78

Up to 24 months

0.95 (0.77 to 1.17)

0%

300

> 2000

> 24 to 48 months

0.83 (0.64 to 1.06)

0%

207

> 1000

> 48 months

0.81 (0.54 to 1.24)

78%

1194

> 49,000

Unclear duration

0.41 (0.02 to 7.73)

71%

13

> 200

Subgroup by baseline SFA, P = 0.50

Up to 12%E SFA

N/A

> 12 to 15%E SFA

0.96 (0.87 to 1.07)

0%

1392

> 51,000

> 15 to 18%E SFA

0.52 (0.05 to 5.39)

N/A

3

55

> 18%E SFA

0.76 (0.55 to 1.05)

N/A

125

846

Subgroup by SFA change, P = 0.50

Up to 4%E SFA difference

0.96 (0.87 to 1.07)

0%

1392

> 51,000

> 4 to 8%E SFA difference

0.52 (0.05 to 5.39)

N/A

3

55

> 8%E SFA difference

0.76 (0.55 to 1.05)

N/A

125

> 800

Subgroup by sex, P = 0.35

Men

0.85 (0.73 to 0.98)

0%

592

> 3000

Women

0.97 (0.86 to 1.09)

N/A

1106

> 48,000

Mixed, men and women

0.75 (0.13 to 4.47)

51%

16

> 500

Subgroup by CVD risk, P = 0.96

Low CVD risk

0.90 (0.72 to 1.13)

49%

1231

> 49,000

Moderate CVD risk

0.75 (0.13 to 4.47)

51%

16

> 500

Existing CVD

0.87 (0.74 to 1.03)

0%

467

> 2000

Subgroup by serum TC reduction,

P = 0.12

TC reduced by ≥ 0.2 mmol/L

0.83 (0.70 to 0.98)

9%

592

> 4000

TC reduced by < 0.2 mmol/L

0.98 (0.87 to 1.10)

0%

1122

> 49,000

Unclear TC change

Subgroup by decade of publication, P = 0.23

1960s

0.80 (0.64, 1.00)

10%

313

1731

1970s

0.08(0.0, 1.33)

N/A

6

102

1980s

0.91 (0.73, 1.14)

N/A

276

2033

1990s

0.52 (0.05, 5.39)

N/A

3

55

2000s

0.98 (0.87, 1.10)

0%

1116

> 49,000

CHO: carbohydrate
CVD: cardiovascular disease
MUFA: mon‐unsaturated fatty acid
N/A: not applicable
PUFA: polyunsaturated fatty caid
SFA: saturated fatty acid
TC: total cholesterol

Figures and Tables -
Table 12. Myocardial infarction (fatal and non‐fatal), subgroup data
Table 13. Non‐fatal myocardial infarction, sensitivity analyses

Analysis

RR (95% CI) of non‐fatal MI

No. of events

No. of participants

Main analysis

0.95 (0.80 to 1.13)

27%

1348

> 52,000

Sensitivity analyses

Stated aim to reduce SFA

0.95 (0.80 to 1.13)

27%

1348

> 52,000

SFA significantly reduced

0.91 (0.72 to 1.25)

60%

1225

> 51,000

TC significantly reduced

0.97 (0.79 to 1.19)

45%

1296

> 51,000

Minus WHI

0.81 (0.64 to 1.04)

0%

242

> 3000

Mantel‐Haenszel fixed‐effect

0.94 (0.85 to 1.05)

27%

1348

> 52,000

Peto fixed‐effect

0.94 (0.84 to 1.05)

27%

1348

> 52,000

SFA: saturated fatty acid
TC: total cholesterol

Figures and Tables -
Table 13. Non‐fatal myocardial infarction, sensitivity analyses
Table 14. Non‐fatal myocardial infarction, subgroup analyses

Analysis, P value for subgroup differences

RR (95% CI) of non‐fatal MI

No. of events

No. of participants

Subgroup by replacement

P = 0.62

PUFA replacement

0.80 (0.63 to 1.03)

0%

233

> 3000

MUFA replacement

1.20 (0.42 to 3.45)

N/A

11

52

CHO replacement

0.99 (0.73 to 1.35)

75%

1188

> 50,000

Protein replacement

0.99 (0.73 to 1.35)

75%

1188

> 50,000

Subgroup by duration, P = 0.64

Up to 24 months

0.83 (0.57 to 1.22)

0%

103

> 2000

> 24 to 48 months

0.82 (0.53 to 1.27)

10%

84

> 1000

> 48 months

1.01 (0.74 to 1.38)

73%

1161

> 49,000

Unclear duration

Subgroup by baseline SFA, P = 0.43

Up to 12%E SFA

N/A

> 12 to 15%E SFA

1.00 (0.75 to 1.35)

64%

1191

> 51,000

> 15 to 18%E SFA

> 18%E SFA

0.62 (0.31 to 1.21)

N/A

34

846

Subgroup by SFA change, P = 0.43

Up to 4%E SFA difference

1.00 (0.75 to 1.35)

64%

1191

> 51,000

> 4 to 8%E SFA difference

> 8%E SFA difference

0.62 (0.31 to 1.21)

N/A

34

> 800

Subgroup by sex, P = 0.35

Men

0.81 (0.63 to 1.03)

0%

239

> 3000

Women

1.10 (0.73 to 1.64)

85%

1106

> 48,000

Mixed, men and women

2.02 (0.19 to 21.94)

N/A

3

> 200

Subgroup by CVD risk, P = 0.61

Low CVD risk

0.87 (0.68 to 1.12)

19%

968

> 47,000

Moderate CVD risk

2.02 (0.19 to 21.94)

N/A

3

> 200

Existing CVD

1.00 (0.76 to 1.31)

N/A

377

> 5000

Subgroup by serum TC reduction,

P = 0.14

TC reduced by ≥ 0.2 mmol/L

0.80 (0.62 to 1.03)

0%

234

> 3000

TC reduced by < 0.2 mmol/L

1.11 (0.77 to 1.60)

71%

1114

> 48,000

Unclear TC change

Subgroup by decade of publication, P = 0.34

1960s

0.84 (0.62, 1.13)

0%

157

1743

1970s

1980s

0.74 (0.48, 1.14)

NA

82

2033

1990s

2000s

1.11 (0.76, 1.61)

71%

1109

> 49,000

CHO: carbohydrate
CVD: cardiovascular disease
MUFA: mon‐unsaturated fatty acid
N/A: not applicable
PUFA: polyunsaturated fatty caid
SFA: saturated fatty acid
TC: total cholesterol

Figures and Tables -
Table 14. Non‐fatal myocardial infarction, subgroup analyses
Table 15. Stroke (any type and outcome), sensitivity analyses

Analysis

RR (95% CI) of stroke

No. of events

No. of participants

Main analysis

1.00 (0.89 to 1.12)

0%

1125

> 50,000

Sensitivity analyses

Stated aim to reduce SFA

1.00 (0.90 to 1.12)

0%

1119

> 50,000

SFA significantly reduced

0.99 (0.88 to 1.12)

2%

1120

> 50,000

TC significantly reduced

1.02 (0.91 to 1.14)

0%

1084

> 49,000

Minus WHI

0.63 (0.35 to 1.14)

0%

49

> 2000

Mantel‐Haenszel fixed‐effect

0.99 (0.89 to 1.11)

0%

1125

> 50,000

Peto fixed‐effect

0.99 (0.88 to 1.13)

18%

1125

> 50,000

SFA: saturated fatty acid
TC: total cholesterol

Figures and Tables -
Table 15. Stroke (any type and outcome), sensitivity analyses
Table 16. Stroke (any time and outcome), subgroup analyses

Analysis, P value for subgroup differences

RR (95% CI) of stroke

No. of events

No. of participants

Subgroup by replacement

P = 0.69

PUFA replacement

0.68 (0.37 to 1.27)

0%

41

> 1700

MUFA replacement

CHO replacement

1.01 (0.90 to 1.13)

0%

1083

> 49,000

Protein replacement

1.01 (0.89 to 1.15)

11%

1082

> 49000

Subgroup by duration, P = 0.17

Up to 24 months

1.01 (0.06 to 15.93)

N/A

2

> 200

> 24 to 48 months

0.57 (0.30 to 1.11)

0%

36

> 900

> 48 months

1.02 (0.91 to 1.14)

0%

1079

> 49,000

Unclear duration

0.20 (0.02 to 1.68)

N/A

6

196

Subgroup by baseline SFA, P = 0.36

Up to 12%E SFA

N/A

> 12 to 15%E SFA

1.01 (0.90 to 1.13)

0%

1084

> 49,000

> 15 to 18%E SFA

0.35 (0.01 to 8.12)

N/A

1

55

> 18%E SFA

0.59 (0.30 to 1.15)

N/A

35

846

Subgroup by SFA change, P = 0.36

Up to 4%E SFA difference

1.01 (0.90 to 1.13)

0%

1084

> 49,000

> 4 to 8%E SFA difference

0.35 (0.01 to 8.12)

N/A

1

55

> 8%E SFA difference

0.59 (0.30 to 1.15)

N/A

35

> 800

Subgroup by sex, P = 0.35

Men

0.63 (0.33 to 1.18)

0%

39

> 1300

Women

1.02 (0.91 to 1.14)

0%

1076

> 48,000

Mixed, men and women

0.37 (0.07 to 1.97)

0%

8

> 400

Subgroup by CVD risk, P = 0.42

Low CVD risk

0.86 (0.52 to 1.42)

59%

597

> 47,000

Moderate CVD risk

0.37 (0.07 to 1.97)

0%

8

> 400

Existing CVD

1.01 (0.86 to 1.18)

0%

518

> 2000

Subgroup by serum TC reduction,

P = 0.24

TC reduced by ≥ 0.2 mmol/L

0.70 (0.38 to 1.28)

0%

43

> 1900

TC reduced by < 0.2 mmol/L

1.01 (0.89 to 1.15)

11%

1082

> 49,000

Unclear TC change

Subgroup by decade of publication, P=0.79

1960s

0.92 (0.31, 2.69)

23%

40

1651

1970s

1980s

1990s

0.35 (0.01, 8.12)

N/A

1

55

2000s

1.01 (0.90, 1.13)

0%

1084

> 49,000

CHO: carbohydrate
CVD: cardiovascular disease
MUFA: mon‐unsaturated fatty acid
N/A: not applicable
PUFA: polyunsaturated fatty caid
SFA: saturated fatty acid
TC: total cholesterol

Figures and Tables -
Table 16. Stroke (any time and outcome), subgroup analyses
Table 17. CHD mortality, sensitivity analyses

Analysis

RR (95% CI) of CHD mortality

No. of events

No. of participants

Main analysis

0.98 (0.84 to 1.15)

21%

886

> 53,000

Sensitivity analyses

Stated aim to reduce SFA

0.98 (0.84 to 1.15)

21%

886

> 53,000

SFA significantly reduced

1.02 (0.87 to 1.20)

17%

735

> 52,000

TC significantly reduced

1.00 (0.83 to 1.20)

33%

786

> 52,000

Minus WHI

0.97 (0.76 to 1.24)

37%

494

> 4000

Mantel‐Haenszel fixed‐effect

0.98 (0.86 to 1.12)

21%

886

> 53,000

Peto fixed‐effect

0.98 (0.85 to 1.13)

39%

886

> 53,000

SFA: saturated fatty acid
TC: total cholesterol

Figures and Tables -
Table 17. CHD mortality, sensitivity analyses
Table 18. CHD mortality, subgroup data

Analysis, P value for subgroup differences

RR (95% CI) of CHD mortality

No. of events

No. of participants

Subgroup by replacement

P = 0.80

PUFA replacement

0.98 (0.74 to 1.28)

49%

491

> 4000

MUFA replacement

3.00 (0.33 to 26.99)

N/A

4

52

CHO replacement

1.01 (0.86 to 1.18)

0%

586

> 50,000

Protein replacement

1.01 (0.86 to 1.18)

0%

586

> 50,000

Subgroup by duration, P = 0.33

Up to 24 months

1.02 (0.78 to 1.33)

0%

203

> 2000

> 24 to 48 months

0.87 (0.64 to 1.19)

N/A

141

> 1000

> 48 months

1.03 (0.79 to 1.34)

52%

537

> 49,000

Unclear duration

0.09 (0.01 to 1.60)

N/A

5

> 100

Subgroup by baseline SFA, P = 0.35

Up to 12%E SFA

N/A

> 12 to 15%E SFA

1.06 (0.90 to 1.25)

11%

644

> 51,000

> 15 to 18%E SFA

> 18%E SFA

0.82 (0.55 to 1.21)

N/A

91

> 800

Subgroup by SFA change, P = 0.35

Up to 4%E SFA difference

1.06 (0.90 to 1.25)

11%

644

> 51,000

> 4 to 8%E SFA difference

> 8%E SFA difference

0.82 (0.55 to 1.21)

N/A

91

> 800

Subgroup by sex, P = 0.26

Men

0.98 (0.79 to 1.23)

30%

489

> 4000

Women

1.01 (0.83 to 1.24)

0%

392

> 48,000

Mixed, men and women

0.09 (0.01 to 1.60)

N/A

5

> 100

Subgroup by CVD risk, P = 0.23

Low CVD risk

0.95 (0.78 to 1.16)

0%

400

> 47,000

Moderate CVD risk

0.09 (0.01 to 1.60)

N/A

5

> 100

Existing CVD

1.03 (0.83 to 1.27)

22%

481

> 5000

Subgroup by serum TC reduction,

P = 0.73

TC reduced by ≥ 0.2 mmol/L

0.96 (0.75 to 1.24)

42%

491

> 4000

TC reduced by < 0.2 mmol/L

1.02 (0.83 to 1.25)

0%

395

> 48,000

Unclear TC change

Subgroup by decade of publication, P = 0.62

1960s

0.84 (0.66, 1.06)

23%

40

1651

1970s

0.54 (0.03, 9.26)

75%

63

560

1980s

1.00 (0.76, 1.30)

N/A

194

2033

1990s

2000s

1.01 (0.83, 1.24)

0%

392

> 48,000

CHO: carbohydrate
CVD: cardiovascular disease
MUFA: mon‐unsaturated fatty acid
N/A: not applicable
PUFA: polyunsaturated fatty caid
SFA: saturated fatty acid
TC: total cholesterol

Figures and Tables -
Table 18. CHD mortality, subgroup data
Table 19. CHD events, sensitivity analyses

Analysis

RR (95% CI) of CHD events

No. of events

No. of participants

Main analysis

0.87 (0.74 to 1.03)

66%

3307

> 53,000

Sensitivity analyses

Stated aim to reduce SFA

0.87 (0.74 to 1.03)

66%

3307

> 53,000

SFA significantly reduced

1.95 (0.82 to 1.10)

49%

2988

> 52,000

TC significantly reduced

0.85 (0.70 to 1.03)

75%

3034

> 52,000

Minus WHI

0.80 (0.61 to 1.03)

59%

758

> 4000

Mantel‐Haenszel fixed‐effect

0.93 (0.87 to 0.99)

66%

3307

> 53,000

Peto fixed‐effect

0.92 (0.86 to 0.99)

72%

3307

> 53,000

SFA: saturated fatty acid
TC: total cholesterol

Figures and Tables -
Table 19. CHD events, sensitivity analyses
Table 20. CHD events, subgroup analyses

Analysis, P value for subgroup differences

RR (95% CI) of CHD events

No. of events

No. of participants

Subgroup by replacement

P = 0.28

PUFA replacement

0.76 (0.57 to 1.00)

71%

737

> 3000

MUFA replacement

1.50 (0.62 to 3.61)

N/A

15

52

CHO replacement

0.98 (0.83 to 1.14)

55%

2846

> 51,000

Protein replacement

0.99 (0.88 to 1.12)

41%

2833

> 51,000

Subgroup by duration, P = 0.72

Up to 24 months

1.01 (0.76 to 1.35)

5%

307

> 2000

> 24 to 48 months

0.79 (0.55 to 1.14)

50%

251

> 1000

> 48 months

0.93 (0.76 to 1.14)

79%

2703

> 49,000

Unclear duration

0.60 (0.10 to 3.58)

81%

46

> 200

Subgroup by baseline SFA, P = 0.09

Up to 12%E SFA

N/A

> 12 to 15%E SFA

0.99 (0.88 to 1.12)

34%

2837

> 51,000

> 15 to 18%E SFA

0.30 (0.09 to 0.98)

N/A

13

60

> 18%E SFA

0.77 (0.56 to 1.04)

N/A

138

> 800

Subgroup by SFA change, P = 0.09

Up to 4%E SFA difference

0.99 (0.88 to 1.12)

34%

2837

> 51,000

>4 to 8%E SFA difference

0.30 (0.09 to 0.98)

N/A

13

60

>8%E SFA difference

0.77 (0.56 to 1.04)

N/A

138

> 800

Subgroup by sex, P = 0.39

Men

0.84 (0.70 to 1.02)

35%

708

> 3000

Women

1.02 (0.84 to 1.23)

77%

2549

> 48,000

Mixed, men and women

0.88 (0.18 to 4.36)

76%

50

> 500

Subgroup by CVD risk, P = 0.95

Low CVD risk

0.90 (0.76 to 1.05)

33%

2236

> 47,000

Moderate CVD risk

0.88 (0.18 to 4.36)

76%

50

> 500

Existing CVD

0.94 (0.75 to 1.17)

61%

1021

> 5000

Subgroup by serum TC reduction,

P = 0.06

TC reduced by ≥ 0.2 mmol/L

0.75 (0.58 to 0.99)

65%

738

> 4000

TC reduced by < 0.2 mmol/L

1.03 (0.87 to 1.21)

44%

2569

> 49,000

Unclear TC change

Subgroup by decade of publication, P < 0.001

1960s

0.84 (0.68, 1.05)

30%

419

1731

1970s

0.27 (0.14, 0.52)

N/A

38

102

1980s

0.91 (0.73, 1.14)

N/A

276

2033

1990s

0.33 (0.10, 1.09)

N/A

13

57

2000s

1.03 (0.86, 1.23)

48%

2561

> 49,000

CHO: carbohydrate
CVD: cardiovascular disease
MUFA: mon‐unsaturated fatty acid
N/A: not applicable
PUFA: polyunsaturated fatty caid
SFA: saturated fatty acid
TC: total cholesterol

Figures and Tables -
Table 20. CHD events, subgroup analyses
Table 21. Process outcome data (secondary outcomes)

Outcome

Effect (95% CI)

No. of studies (participants)

Differential effect by replacement?

Summary

TC, mmol/L

‐0.24 (‐0.36 to ‐0.13)

60%

13 (7115)

No, P = 0.20

TC reduced

LDL, mmol/L

‐0.19 (‐0.33 to ‐0.05)

37%

5 (3291)

No, P = 0.16

LDL reduced

HDL, mmol/L

‐0.01 (‐0.02 to 0.01)

0%

7 (5183)

No, P = 0.99

No effect

TG, mmol/L

‐0.08 (‐0.21 to 0.04)

51%

7 (3845)

No, P = 0.12

No effect

TG/HDL ratio

N/A

N/A

N/A

N/A

No data

TC/HDL ratio

‐0.10 (‐0.33 to 0.13)

24%

3 (2985)

No, P = 0.45

No effect

LDL/HDL ratio

‐0.36 (‐0.92 to 0.20)

N/A

1 (50)

N/A

Unclear

Lipoprotein (a), mmol/L

0.00 (‐0.00 to 0.00)

0%

2 (2882)

No, P = 1.00

No effect

Diabetes diagnosis

RR 0.96 (0.90 to 1.02)

N/A

1 (> 48,000; 3342 diagnoses)

No, P = 1.00

No effect

HbA1c, %

N/A

N/A

N/A

N/A

No data

Glucose 2 hrs post GTT, mmol/L

‐1.69 (‐2.55 to ‐0.82)

45%

3 (249)

N/A

Reduced

HOMA

0.00 (‐0.04 to 0.04)

NA

1 (2832)

N/A

No effect

GTT: glucose tolerance test
HOMA: homeostatic model assessment
TC: total cholesterol
TG: triglyceride

Figures and Tables -
Table 21. Process outcome data (secondary outcomes)
Table 22. Potential harms (secondary outcomes)

Outcome

Effect (95% CI)

No. of studies (participants)

Differential effect by replacement?

Summary

Cancer diagnoses

RR 0.94 (0.83 to 1.07)

33%

4 (> 52,000; 5476 diagnoses)

No, P = 0.33

No effect

Cancer deaths

RR 1.00 (0.61 to 1.64)

49%

5 (> 52,000; 2472 deaths)

No, P = 0.94

No effect

Body weight, kg

MD ‐1.97 (‐3.67 to ‐0.27)

72%

6 (4541)

No, P = 1.00

Weight loss

BMI, kg/m²

MD ‐0.50 (‐0.82 to ‐0.19)

55%

6 (5553)

No, P = 0.41

BMI reduced

Systolic BP, mmHg

MD ‐0.19 (‐1.36 to 0.97)

0%

5 (3812)

No, P = 0.97

No effect

Diastolic BP, mmHg

MD ‐0.36 (‐1.03 to 0.32)

0%

5 (3812)

No, P = 1.00

No effect

BMI: body mass index
MD: mean difference
RR: risk ratio

Figures and Tables -
Table 22. Potential harms (secondary outcomes)
Table 23. SFA cut‐off data

Cut‐ off

RR of all‐cause mortality

RR of CVD mortality

RR of CVD events

RR of MI

RR of non‐fatal MI

RR of stroke

RR of CHD mortality

RR of CHD events

7%E

1.11 (0.58 to 2.12)

0.20 (0.01 to 4.15)

0.20 (0.01 to 4.15)

N/A

N/A

N/A

N/A

N/A

8%E

1.11 (0.58 to 2.12)

0.20 (0.01 to 4.15)

0.20 (0.01 to 4.15)

N/A

N/A

N/A

N/A

N/A

9%E

0.99 (0.84 to 1.15)

0.69 (0.51 to 0.94)

0.79 (0.62 to 0.99)

0.76 (0.55 to 1.05)

0.62 (0.31 to 1.21)

0.59 (0.30 to 1.15)

0.82 (0.55 to 1.21)

0.77 (0.56 to 1.04)

10%E

0.99 (0.90 to 1.09)

0.97 (0.74 to 1.26)

0.89 (0.74 to 1.07)

0.93 (0.80 to 1.08)

0.99 (0.69 to 1.41)

1.00 (0.89 to 1.12)

1.05 (0.83 to 1.32)

0.93 (0.75 to 1.14)

11%E

1.00 (0.88 to 1.12)

0.95 (0.73 to 1.24)

0.88 (0.74 to 1.05)

0.94 (0.84 to 1.06)

0.99 (0.69 to 1.41)

0.98 (0.83 to 1.14)

1.02 (0.87 to 1.20)

0.94 (0.77 to 1.15)

12%E

0.99 (0.91 to 1.07)

0.96 (0.79 to 1.18)

0.91 (0.79 to 1.04)

0.94 (0.85 to 1.04)

0.95 (0.72 to 1.25)

0.99 (0.88 to 1.12)

1.02 (0.87 to 1.20)

0.95 (0.82 to 1.10)

13%E

1.02 (0.83 to 1.25)

0.93 (0.63 to 1.38)

0.78 (0.61 to 1.00)

0.87 (0.73 to 1.04)

0.72 (0.50 to 1.03)

0.54 (0.29 to 1.00)

1.06 (0.76 to 1.48)

0.84 (0.63 to 1.12)

CHD coronary heart disease
CVD cardiovascular disease
MI myocardial infarction
N/A not applicable (no relevant studies)
RR: risk ratio
SFA saturated fat, as percentage of energy

Figures and Tables -
Table 23. SFA cut‐off data
Table 24. GRADE profile: What is the effect of replacing some saturated fat with other fats, protein or CHO in adults?

Quality assessment

No of participants

(study event rate%)

Effect

Quality

Importance

No of studies

Design 1

Risk of bias

Inconsistency

Indirectness

Imprecision

Other considerations

Reduced

saturated fat intake

Usual saturated fat intake

Relative effect
(95% CI)

Absolute effects

(per 10,000)

All‐cause mortality (follow‐up mean 56 months1)

12

RCTs

no serious risk of

bias2

no serious inconsistency3

no serious indirectness4

serious imprecision5

none6

1377/22819

(6%)

1899/33039

(5.7%)

RR 0.97

(0.9 to 1.05)

17 fewer

(from 57 fewer to 29 more)

♁♁♁O
MODERATE

CRITICAL

Cardiovascular mortality (follow‐up mean 53 months1)

12

RCTs

no serious risk of

bias2

no serious inconsistency3

no serious indirectness4

serious imprecision5

none6

483/21844
(2.2%)

613/31577
(1.9%)

RR 0.95
(0.8 to 1.12)

10 fewer
(from 39 fewer to 23 more)

♁♁♁O

MODERATE

CRITICAL

Cardiovascular events (follow‐up mean 52 months1)

13

RCTs

no serious risk of

bias2

serious inconsistency7

no serious indirectness4

no serious imprecision8

none6

1774/21791
(8.1%)

2603/31509
(8.3%)

RR 0.83
(0.72 to 0.96)

138 fewer

(from 33 fewer to 228 fewer)

♁♁♁O

MODERATE

CRITICAL

Fatal and non‐fatal myocardial infarction (follow‐up mean 55 months1)

11

RCTs

no serious risk of

bias2

no serious inconsistency3

no serious indirectness4

serious imprecision5

none6

717/21725
(3.3%)

997/31442
(3.2%)

RR 0.90
(0.8 to 1.01)

32 fewer

(from 63 fewer to 3 more)

♁♁♁O

MODERATE

CRITICAL

Non‐fatal myocardial infarction (follow‐up mean 55 months1)

9

RCTs

no serious risk of

bias2

no serious inconsistency3

no serious indirectness4

serious imprecision5

none9

547/21559
(2.5%)

801/31275
(2.6%)

RR 0.95
(0.8 to 1.13)

13 fewer

(from 51 fewer to 33 more)

♁♁♁O
MODERATE

CRITICAL

Stroke (follow‐up 59 mean months1)

8

RCTs

no serious risk of

bias2

no serious inconsistency3

no serious indirectness4

serious imprecision5

none9

453/20602
(2.2%)

672/30350
(2.2%)

RR 1.00
(0.89 to 1.12)

0 fewer

(from 25 fewer to 25 more)

♁♁♁O
MODERATE

CRITICAL

CHD mortality (follow‐up mean 65 months1)

10

RCTs

no serious risk of

bias2

no serious inconsistency3

no serious indirectness4

serious imprecision5

none 6

401/21714
(1.8%)

485/31445
(1.5%)

RR 0.98
(0.84 to 1.15)

30 fewer

(from 25 fewer to 23 more)

♁♁♁O
MODERATE

CRITICAL

CHD events (follow‐up mean 59 months1)

12

RCTs

no serious risk of

bias2

serious inconsistency10

no serious indirectness4

serious imprecision5

none 6

1346/21743
(6.2%)

1961/31456
(6.2%)

RR 0.87
(0.74 to 1.03)

80 fewer

(from 160 fewer to 19 more)

♁♁OO
LOW

CRITICAL

1Minimum study duration was 24 months.

2These large RCTs of relatively long duration were well randomised and almost half had good allocation concealment (the rest were unclear). Blinding was only well‐conducted in 1 RCT, however blinding is very difficult in trials of dietary fat intake. Incomplete outcome data were variable, and most included studies had systematic differences in care (i.e. intervention group had more time or attention than the control group). These risks to validity were combined with risks from imprecision, and outcomes were downgraded once for a combination of both issues. We noted no other biases. We noted that the level of compliance with interventions involving long‐term behaviour change, such as those used in these studies, can vary widely. This is likely to attenuate the pooled effect and bias it towards the null.

3No important heterogeneity; I² ≤ 30%

4These RCTs directly assessed the effect of lower vs usual saturated fat intake on health outcomes of interest. Participants included men and women with and without CVD at baseline (also some participants with CVD risk factors like diabetes, or at risk of cancers).

5 The 95% CI crosses 1.0 and does not exclude important benefit or harm

6The funnel plot did not suggest any small study (publication) bias

7Potentially important heterogeneity was identified; I² = 65%. However, the heterogeneity was partly explained by the degree of saturated fat reduction, and the degree of cholesterol lowering achieved (in subgrouping and in meta‐regression).

8The 95% CI does not cross 1.0 or a threshold of important harm.

9Too few studies to reliably assess publication bias (< 10 RCTs).

10Important heterogeneity; I² = 66%

Figures and Tables -
Table 24. GRADE profile: What is the effect of replacing some saturated fat with other fats, protein or CHO in adults?
Table 25. GRADE profile: What is the effect of replacing some saturated fat with PUFA* on risk of CVD in adults?

Quality assessment

No of participants

(study event rate %)

Effect

Quality

Importance

No of studies

Design

Risk of bias

Inconsistency

Indirectness

Imprecision

Other considerations

Reduced

saturated fat intake

Usual saturated fat intake

Relative effect
(95% CI)

Absolute effects

(per 10,000)

All‐cause mortality (follow‐up mean 56 months1)

7

RCTs

no serious risk of bias2

no serious inconsistency3

no serious indirectness4

serious imprecision5

none6

406/2123
(19.1%)

418/2115
(19.8%)

RR 0.96 (0.82 to 1.13)

79 fewer

(from 360 fewer to 256 more)

♁♁♁O
MODERATE

CRITICAL

Cardiovascular mortality (follow‐up mean 55 months1)

7

RCTs

no serious risk of bias2

serious inconsistency7

no serious indirectness4

serious imprecision5

none6

266/2123
(12.5%)

287/2128
(13.5%)

RR 0.95 (0.73 to 1.25)

67 fewer

(from 364 fewer to 337 more)

♁♁OO
LOW

CRITICAL

Cardiovascular events (follow‐up mean 53 months1)

7

RCTs

no serious risk of bias2

serious inconsistency8

no serious indirectness4

no serious imprecision9

none6

390/1953
(20%)

494/1942
(25.4%)

RR 0.73 (0.58 to 0.92)

687 fewer

(from 204 fewer to 1068 fewer)

♁♁♁O
MODERATE

CRITICAL

Fatal and non‐fatal myocardial infarction (follow‐up mean 53 months1)

7

RCTs

no serious risk of bias2

no serious inconsistency3

no serious indirectness4

serious imprecision5

none6

269/1953
(13.8%)

322/1942
(16.6%)

RR 0.83 (0.67 to 1.02)

282 fewer

(from 547 fewer to 33 more)

♁♁♁O
MODERATE

CRITICAL

Non‐fatal myocardial infarction (follow‐up mean 53 months1)

5

RCTs

no serious risk of bias2

no serious inconsistency3

no serious indirectness4

serious imprecision5

none6

104/1875
(5.5%)

129/1863
(6.9%)

RR 0.8 (0.63 to 1.03)

138 fewer

(from 256 fewer to 21 more)

♁♁♁O
MODERATE

CRITICAL

Stroke (follow‐up mean 63 months1)

4

RCTs

no serious risk of bias2

no serious inconsistency3

no serious indirectness4

very serious10

none6

17/856
(2%)

24/850
(2.8%)

RR 0.68 (0.37 to 1.27)

90 fewer

(from 178 fewer to 76 more)

♁OOO
VERY LOW

CRITICAL

CHD mortality (follow‐up mean 36 months1)

7

RCTs

no serious risk of bias2

no serious inconsistency3

no serious indirectness4

serious imprecision5

none6

240/2147
(11.2%)

251/2151
(11.7%)

RR 0.98 (0.74 to 1.28)

23 fewer

(from 303 fewer to 327 more)

♁♁♁O
MODERATE

CRITICAL

CHD events (follow‐up mean 53 months1)

7

RCTs

no serious risk of bias2

serious inconsistency11

no serious indirectness4

serious imprecision5

none6

329/1956
(16.8%)

408/1944
(21%)

RR 0.76 (0.57 to 1.0)

504 fewer

(from 902 fewer to 0 more)

♁♁OO
LOW

CRITICAL

* Polyunsaturated fatty acids replacing saturated fatty acids in individual studies were predominantly of plant origin.

1 Minimum study duration was 24 months.

2 These large RCTs of relatively long duration were well randomised but fewer than half had good allocation concealment (the rest were unclear). Blinding was only well‐conducted in 1 RCT, however blinding is very difficult in trials of dietary fat intake. In about half the included studies, it was unclear if outcome data were incomplete and most studies had systematic differences in care (i.e. intervention group had more time or attention than the control group). We noted no other biases. Not downgraded for bias, however we note that the level of compliance with interventions involving long‐term behaviour change, such as those used in many of these studies, can vary widely. This is likely to attenuate the pooled effect and bias it towards the null.

3 No important heterogeneity; I² < 50%
4 These RCTs directly assessed the effect of reducing saturated fat, and replacing it with other dietary sources of energy, compared to usual diet, on health outcomes of interest. Participants included men and women with and without CVD at baseline.
5 The 95% CI crosses 1.0 and does not exclude important benefit or harm.

6 Too few studies to reliably assess publication bias (< 10 RCTs).

7 Important heterogeneity; I² = 55%

8 Important heterogeneity; I² = 69%.Subgrouping suggested greater effects on cardiovascular events with greater reduction in SFA intake, higher baseline SFA intake and greater serum total cholesterol reduction (meta‐regression not carried out).

9 95% CI does not cross threshold of important benefit or harm.

Figures and Tables -
Table 25. GRADE profile: What is the effect of replacing some saturated fat with PUFA* on risk of CVD in adults?
Table 26. GRADE profile: What is the effect of replacing some saturated fat with MUFA on risk of CVD in adults?

Quality assessment

No of participants

(study event rate%)

Effect

Quality

Importance

No of studies

Design

Risk of bias

Inconsistency

Indirectness

Imprecision

Other considerations

Reduced

saturated fat intake

Usual saturated fat intake

Relative effect
(95% CI)

Absolute effects

(per 10,000)

All‐cause mortality (follow‐up mean 24 months)

1

RCTs

serious risk of bias1

no serious inconsistency2

no serious indirectness3

very serious imprecision4

none5

3/26
(11.5%)

1/26
(3.8%)

RR 3.0

(0.33 to 26.99)

769 more

(from 258 fewer to 9996 more)

♁OOO
VERY LOW

CRITICAL

Cardiovascular mortality (follow‐up mean 24 months)

1

RCTs

serious risk of bias1

no serious inconsistency2

no serious indirectness3

very serious imprecision4

none5

3/26
(11.5%)

1/26
(3.8%)

RR 3.0

(0.33 to 26.99)

769 more

(from 258 fewer to 9996 more)

♁OOO
VERY LOW

CRITICAL

Cardiovascular events (follow‐up mean 24 months)

1

RCTs

serious risk of bias1

no serious inconsistency2

no serious indirectness3

very serious imprecision4

none5

11/26
(42.3%)

11/26
(42.3%)

RR 1.0

(0.53 to 1.89)

0 fewer

(from 1988 fewer to 3765 more)

♁OOO
VERY LOW

CRITICAL

Fatal and non‐fatal myocardial infarction (follow‐up mean 24 months)

1

RCTs

serious risk of bias1

no serious inconsistency2

no serious indirectness3

very serious imprecision4

none5

7/26
(26.9%)

5/26
(19.2%)

RR 1.4 (0.51 to 3.85)

769 more

(from 942 fewer to 5481 more)

♁OOO
VERY LOW

IMPORTANT

Non‐fatal myocardial infarction (follow‐up mean 24 months)

1

RCTs

serious risk of bias1

no serious inconsistency2

no serious indirectness3

very serious

imprecision4

none5

6/26
(23.1%)

5/26
(19.2%)

RR 1.2 (0.42 to 3.45)

385 more

(from 1115 fewer to 4711 more)

♁OOO
VERY LOW

IMPORTANT

Stroke

0

No studies identified reporting this outcome

CHD mortality (follow‐up mean 24 months)

1

RCTs

serious risk of bias1

no serious inconsistency2

no serious indirectness3

very serious imprecision4

none5

3/26
(11.5%)

1/26
(3.8%)

RR 3

(0.33 to 26.99)

769 more

(from 258 fewer to 9996 more)

♁OOO
VERY LOW

IMPORTANT

CHD events (follow‐up mean 24 months)

1

RCTs

serious risk of bias1

no serious inconsistency2

no serious indirectness3

very serious imprecision4

none5

9/26
(34.6%)

6/26
(23.1%)

RR 1.5 (0.62 to 3.61)

1154 more

(from 877 fewer to 6023 more)

♁OOO
VERY LOW

IMPORTANT

1This single, very small RCT of relatively long duration was well randomised, but had an unclear risk of bias in terms of allocation concealment and incomplete outcome data, and lacked participant blinding; however blinding is very difficult in trials of dietary fat intake. We downgraded it for serious risk of bias.
2Only one trial

3This RCT directly assessed the effect of reducing saturated fat, and replacing it with other dietary sources of energy, compared to usual diet, on health outcomes of interest. Participants included men with CVD at baseline.

4The 52 participants in the relevant arms of this trial experienced relatively few events. As a result, there were wide to very wide confidence intervals. In addition, the 95% CI crosses 1.0 and does not exclude important benefit or harm.

5Too few studies to reliably assess publication bias (< 10 RCTs).

Figures and Tables -
Table 26. GRADE profile: What is the effect of replacing some saturated fat with MUFA on risk of CVD in adults?
Table 27. GRADE profile: What is the effect of replacing some saturated fat with CHO on risk of CVD in adults?

Quality assessment

No of participants

(study event rate %)

Effect

Quality

Importance

No of studies

Design1

Risk of bias

Inconsistency

Indirectness

Imprecision

Other considerations

Reduced

saturated fat intake

Usual saturated fat intake

Relative effect
(95% CI)

Absolute effects

(per 10,000)

All‐cause mortality (follow‐up mean 48 months2)

6

RCTs

no serious risk of bias3

no serious inconsistency4

no serious indirectness5

serious imprecision6

none7

1080/21715
(5%)

1597/31954
(5%)

RR 0.98 (0.91 to 1.05)

10 fewer

(from 45 fewer to 25 more)

♁♁♁O
MODERATE

CRITICAL

Cardiovascular mortality (follow‐up mean 46 months2)

6

RCTs

no serious risk of bias3

no serious inconsistency4

no serious indirectness5

serious imprecision6

none7

316/20740
(1.5%)

429/30492
(1.4%)

RR 0.99 (0.86 to 1.14)

1 fewer

(from 20 fewer to 20 more)

♁♁♁O
MODERATE

CRITICAL

Cardiovascular events (follow‐up mean 46 months2)

6

RCTs

no serious risk of bias3

serious inconsistency9

no serious indirectness5

serious imprecision6

none7

1512/20740
(7.3%)

2273/30492
(7.5%)

RR 0.93 (0.79 to 1.08)

52 fewer

(from 157 fewer to 60 more)

♁♁OO
LOW

CRITICAL

Fatal and non‐fatal myocardial infarction (follow‐up mean 51 months2)

4

RCTs

no serious risk of bias3

no serious inconsistency4

no serious indirectness5

serious imprecision6

none7

572/20674
(2.8%)

820/30425
(2.7%)

RR 0.96 (0.86 to 1.06)

11 fewer

(from 38 fewer to 16 more)

♁♁♁O
MODERATE

IMPORTANT

Non‐fatal myocardial infarction (follow‐up mean 60 months2)

3

RCTs

no serious risk of bias3

serious inconsistency9

no serious indirectness5

serious imprecision6

none7

470/20559
(2.3%)

718/30309
(2.4%)

RR 0.99 (0.73 to 1.35)

2 fewer

(from 64 fewer to 83 more)

♁♁OO
LOW

IMPORTANT

Stroke (follow‐up mean 60 months2)

4

RCTs

no serious risk of bias3

no serious inconsistency4

no serious indirectness5

serious imprecision6

none7

435/19656
(2.2%)

648/29410
(2.2%)

RR 1.01 (0.9 to 1.13)

2 more

(from 22 fewer to 29 more)

♁♁♁O
MODERATE

IMPORTANT

CHD mortality (follow‐up mean 60 months2)

3

RCTs

no serious risk of bias3

no serious inconsistency4

no serious indirectness5

serious imprecision6

none7

255/20559
(1.2%)

331/30309
(1.1%)

RR 1.01 (0.86 to 1.18)

1 more

(from 15 fewer to 20 more)

♁♁♁O
MODERATE

IMPORTANT

CHD events (follow‐up mean 51 months2)

5

RCTs

no serious risk of bias3

serious inconsistency8

no serious indirectness5

serious imprecision6

none7

1140/20677
(5.5%)

1706/30427
(5.6%)

RR 0.98 (0.83 to 1.14)

11 fewer

(from 95 fewer to 79 more)

♁♁OO
LOW

IMPORTANT

1There was insufficient information across all studies to make any determination about the type of carbohydrate used as replacement.

2Minimum study duration was 24 months.
3These large RCTs of relatively long duration were well randomised, most had good allocation concealment (the rest were unclear) and most were not at risk for bias in terms of incomplete outcome data. In no studies was blinding well‐conducted; however blinding is very difficult in trials of dietary fat intake. All studies had systematic differences in care (i.e. intervention group had more time or attention than the control group). No other biases noted. Not downgraded for bias, however we note that the level of compliance with interventions involving long‐term behaviour change, such as those used in these studies, can vary widely. This is likely to attenuate the pooled effect and bias it towards the null.

4No important heterogeneity; I² = 0%.
5These RCTs directly assessed the effect of reducing saturated fat, and replacing it with other dietary sources of energy, compared to usual diet, on health outcomes of interest. Participants included men and women with and without CVD at baseline.

6The 95% CI crosses 1.0 and does not exclude important benefit or harm.

7Too few studies to reliably assess publication bias (< 10 RCTs).

8Important heterogeneity; I² = 55%.

Figures and Tables -
Table 27. GRADE profile: What is the effect of replacing some saturated fat with CHO on risk of CVD in adults?
Table 28. GRADE profile: What is the effect of replacing some saturated fat with protein on the risk of CVD in adults?

Quality assessment

No of participants

(study event rate%)

Effect

Quality

Importance

No of studies

Design

Risk of bias

Inconsistency

Indirectness

Imprecision

Other considerations

Reduced

saturated fat intake

Usual saturated fat intake

Relative effect
(95% CI)

Absolute effects

(per 10,000)

All‐cause mortality (follow‐up mean 50 months1)

5

RCTs

no serious risk of bias2

no serious inconsistency3

no serious indirectness4

serious imprecision5

none6

1079/21688
(5%)

1594/31926
(5%)

RR 0.98 (0.91 to 1.06)

10 fewer

(from 45 fewer to 30 more)

♁♁♁O
MODERATE

CRITICAL

Cardiovascular mortality (follow‐up mean 48 months1)

5

RCTs

no serious risk of bias2

no serious inconsistency3

no serious indirectness4

serious imprecision5

none6

315/20713
(1.5%)

426/30464
(1.4%)

RR 0.99 (0.86 to 1.14)

1 fewer

(from 20 fewer to 20 more)

♁♁♁O
MODERATE

CRITICAL

Cardiovascular events (follow‐up mean 48 months1)

5

RCTs

no serious risk of bias2

no serious inconsistency3

no serious indirectness4

serious imprecision5

none6

1504/20713
(7.3%)

2253/30464
(7.4%)

RR 0.98 (0.9 to 1.06)

15 fewer

(from 74 fewer to 44 more)

♁♁♁O
MODERATE

CRITICAL

Fatal and non‐fatal myocardial infarction (follow‐up mean 56 months1)

3

RCTs

no serious risk of bias2

no serious inconsistency3

no serious indirectness4

serious imprecision5

none6

571/20647
(2.8%)

818/30397
(2.7%)

RR 0.96 (0.86 to 1.07)

11 fewer

(from 38 fewer to 19 more)

♁♁♁O
MODERATE

IMPORTANT

Non‐fatal myocardial infarction (follow‐up mean 60 months1)

3

RCTs

no serious risk of bias2

serious inconsistency7

no serious indirectness4

serious imprecision5

none6

470/20559
(2.3%)

718/30309
(2.4%)

RR 0.99 (0.73 to 1.35)

2 fewer

(from 64 fewer to 83 more)

♁♁OO
LOW

IMPORTANT

Stroke (follow‐up mean 72 months1)

3

RCTs

no serious risk of bias2

no serious inconsistency3

no serious indirectness4

serious imprecision5

none6

435/19629
(2.2%)

647/29382
(2.2%)

RR 1.01 (0.89 to 1.15)

2 more

(from 24 fewer to 33 more)

♁♁♁O
MODERATE

IMPORTANT

CHD mortality (follow‐up mean 60 months1)

3

randomised trials

no serious risk of bias2

no serious inconsistency3

no serious indirectness4

serious imprecision5

none6

255/20559
(1.2%)

331/30309
(1.1%)

RR 1.01 (0.86 to 1.18)

1 more

(from 15 fewer to 20 more)

♁♁♁O
MODERATE

IMPORTANT

CHD events (follow‐up mean 56 months1)

4

randomised trials

no serious risk of bias2

no serious inconsistency3

no serious indirectness4

serious imprecision5

none6

1137/20647
(5.5%)

1696/30397
(5.6%)

RR 0.99 (0.88 to 1.12)

6 fewer

(from 67 fewer to 67 more)

♁♁♁O
MODERATE

IMPORTANT

1Minimum study duration was 24 months.
2These large RCTs of relatively long duration were well randomised, most had good allocation concealment (the rest were unclear) and most were not at risk for bias in terms of incomplete outcome data. In no studies was blinding well‐conducted, however blinding is very difficult in trials of dietary fat intake. All studies had systematic differences in care (i.e. intervention group had more time or attention than the control group). We noted no other biases. Not downgraded for bias; however we note that the level of compliance with interventions involving long‐term behaviour change, such as those used in these studies, can vary widely. This is likely to attenuate the pooled effect and bias it towards the null.
3No important heterogeneity; I2 <50%.
4These RCTs directly assessed the effect of reducing saturated fat, and replacing it with other dietary sources of energy, compared to usual diet, on health outcomes of interest. Participants included men and women with and without CVD at baseline.

5The 95% CI crosses 1.0 and does not exclude important benefit or harm.

6Too few studies to reliably assess publication bias (< 10 RCTs).

7Important heterogeneity; I² = 75%.

Figures and Tables -
Table 28. GRADE profile: What is the effect of replacing some saturated fat with protein on the risk of CVD in adults?
Comparison 1. SFA reduction vs usual diet ‐ Primary outcomes

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 All‐cause mortality Show forest plot

12

55858

Risk Ratio (M‐H, Random, 95% CI)

0.97 [0.90, 1.05]

2 Cardiovascular mortality Show forest plot

12

53421

Risk Ratio (M‐H, Random, 95% CI)

0.95 [0.80, 1.12]

3 Combined cardiovascular events Show forest plot

13

53300

Risk Ratio (M‐H, Random, 95% CI)

0.83 [0.72, 0.96]

Figures and Tables -
Comparison 1. SFA reduction vs usual diet ‐ Primary outcomes
Comparison 2. SFA reduction vs usual diet ‐ secondary health events

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Myocardial infarctions Show forest plot

11

53167

Risk Ratio (M‐H, Random, 95% CI)

0.90 [0.80, 1.01]

2 Non‐fatal MI Show forest plot

9

52834

Risk Ratio (M‐H, Random, 95% CI)

0.95 [0.80, 1.13]

3 Stroke Show forest plot

8

50952

Risk Ratio (M‐H, Random, 95% CI)

1.00 [0.89, 1.12]

4 CHD mortality Show forest plot

10

53159

Risk Ratio (M‐H, Random, 95% CI)

0.98 [0.84, 1.15]

5 CHD events Show forest plot

12

53199

Risk Ratio (M‐H, Random, 95% CI)

0.87 [0.74, 1.03]

6 Diabetes diagnoses Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Figures and Tables -
Comparison 2. SFA reduction vs usual diet ‐ secondary health events
Comparison 3. SFA reduction vs usual diet ‐ other secondary outcomes

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Total cholesterol, mmol/L Show forest plot

14

7115

Mean Difference (IV, Random, 95% CI)

‐0.24 [‐0.36, ‐0.13]

2 LDL cholesterol, mmol/L Show forest plot

5

3291

Mean Difference (IV, Random, 95% CI)

‐0.19 [‐0.33, ‐0.05]

3 HDL cholesterol, mmol/L Show forest plot

6

5147

Mean Difference (IV, Random, 95% CI)

‐0.01 [‐0.02, 0.01]

4 Triglycerides, mmol/L Show forest plot

7

3845

Mean Difference (IV, Random, 95% CI)

‐0.08 [‐0.21, 0.04]

5 total cholesterol /HDL ratio Show forest plot

3

2985

Mean Difference (IV, Random, 95% CI)

‐0.10 [‐0.33, 0.13]

6 LDL /HDL ratio Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Subtotals only

7 Lp(a), mmol/L Show forest plot

2

2882

Mean Difference (IV, Random, 95% CI)

0.0 [‐0.00, 0.00]

8 Insulin sensitivity Show forest plot

4

Mean Difference (IV, Random, 95% CI)

Subtotals only

8.1 HbA1c (glycosylated haemoglobin), %

0

0

Mean Difference (IV, Random, 95% CI)

0.0 [0.0, 0.0]

8.2 GTT (glucose tolerance test), glucose at 2 hours, mmol/L

3

249

Mean Difference (IV, Random, 95% CI)

‐1.69 [‐2.55, ‐0.82]

8.3 HOMA

1

2832

Mean Difference (IV, Random, 95% CI)

0.0 [‐0.04, 0.04]

Figures and Tables -
Comparison 3. SFA reduction vs usual diet ‐ other secondary outcomes