Lyon Diet Heart Study is still considered as the ultimate evidence for the health benefits of Mediterranean diet. Unfortunately its' results have never been re-produced since then. However, PREDIMED trial may change this situation.

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Lyon Diet Heart Study
Mediterranean diet vs “traditional” western diet
Published as two separate papers:
de Lorgeril et al. Mediterranean diet, traditional risk factors, and the rate of
cardiovascular complications after myocardial infarction: final report of the
Lyon Diet Heart Study. Circulation. 1999; 99(6):779-85
de Lorgeril et al. Mediterranean alpha-linolenic acid-rich diet in
secondary prevention of coronary heart disease. Lancet 1994;
343(8911):1454-9
1 Original paper: 27 months of randomization
2 Follow up of 46 months’s

2. Page 2
Pronutritionist’s background
• In recent prospective cohorts based meta-analyses, saturated fat intake
was not linked to coronary heart disease (CHD) incidence (
Siri-Tarino et al. 2010, Skeaff & Miller J. 2009 and Mente et al. 2009)
• Another meta-analysis based on 48 randomized outcome trials,
demonstrated a lower incidence of CHD if saturated fat was replaced by
unsaturated fat or reduced (Hooper et al. 2011)
• However, a majority of the studiesare done during 1960s and 1970s,
used either soy, corn or safflower oil. All of these cooking oils have
been largely replaced by olive or canola (or turnip rapeseed) oil in
recent years, at least in many Nordic and Western European countries
• No hard outcome data exists for either canola or olive oil in clinical trials
scrutinizing the sole effect of displacement of saturated fat with canola
oil
• In Lyon Diet Heart Study (LDHS) canola oil was used as an integrative
part of Mediterranean diet model
• How do the results of LDHS stand the test of the time?
de Lorgeril et al.. Lancet 1994; 343(8911):1454-9

3. Methods (schematic)
Page 3
Randomization
Experimental diet
Mediterranean diet including free canola oil based margarine
Control diet
normal French Diet
27 months
randomized
period
y. 1988
19 months open
follow up (delay in
stopping)
Premature
discontinuation (!)
de Lorgeril et al.. Lancet 1994; 343(8911):1454-9

4. Methods (patients)
• Parallel randomized trial, Single blinded
• Secondary prevention of CHD among myocardial infarction (MI) survivors
• Primary outcomes: Reinfarctions and cardiac death
• Secondary outcomes: Coronary bypass surgery, angioplasty, and their
complications, stroke, angina, heart failure, pulmonary/venous embolism,
thrombophlebitis
• N=605, circa 90 % were males, median age 53,5 years
• Slightly more than 60 % of the patients received beta-blockers and ASA.
Statins were not prescribed
• Recruitment: during the hospitalization due to MI
• LDL cholesterol levels at baseline in both groups circa 4,5 mmol/L (175 mg/dl)
• Subjects were free living
• Length: 5 years per arm (!) but was discontinued prematurely at 27 months
due to excessive morbidity/mortality rate in control group (”Because of a
statistically significant result, the decision was made to stop the trial.” deLoergeril et al.
1999)
• Era: 1988 →
Page 4 de Lorgeril et al.. Lancet 1994; 343(8911):1454-9

5. Methods (diet)
• Experimental Diet = Cretan style Mediterranean diet
• Patients in the experimental group were advised by the research cardiologist
and dietitian (a one-hour-long session)
• Mediterranean-type diet:
– more bread
– more root vegetables and green vegetables
– more fish, less meat (beef, lamb, and pork to be replaced with poultry)
– No day without fruit
– Butter and cream to be replaced with margarine supplied by the study. ”This margarine had a
composition comparable to olive oil with 15 % saturated fatty acids, 48% oleic acid but 5-4%
18:1 trans. However, it was slightly higher in linoleic (16-4 vs 8-6%) and more so in alpha-
linolenic acid (4-8 vs 0-6%)”
– The oils recommended for salads and food preparation were rapeseed and olive oils
exclusively.
– Moderate alcohol consumption in the form of wine was allowed at meals.
• At each subsequent visit of the experimental patients, a dietary survey and
further counselling were done by the research dietitian. Diet evaluations
comprised a 24-hour recall and frequency questionnaire.
Page 5 de Lorgeril et al.. Lancet 1994; 343(8911):1454-9

6. Results 1/5 (27 months randomization)
• Totally 584 subjects were analyzed
• Drop out rate was low, ie. 7-8 % (patients who did not
attend two consecutive appointments)
• Dietary intake and biochemical parameters was analyzed
in 411 patients (70 % of all)
• There were no differences in baseline characteristics of
patients
• There was no difference in the degree of attention or care
given to the study groups (verified by separate survey)
• At the end of the study, number of smokers was higher in
Mediterranean group
• Study was discontinued prematurely due to excessive
morbidity/mortality rate in control group
Page de Lorgeril et al.. Lancet 1994; 343(8911):1454-9

7. Results 2/5 (27 months randomization)
Page 7
Mediterranean diet Control French Diet Δ significance
Energy 1928 kcal 2140 kcal p< 0.001
SFA 8.3 E % 11.7 E % p< 0.001
Oleic acid 12.9 E % 10.3 E % p< 0.001
Linoleic acid 3.6 E % 5.3 E % p< 0.001
α –linolenic acid 0.81 E % 0.27 E % p< 0.001
Cholesterol 217 mg 318 mg p< 0.001
Carbohydrates* 52.3 E % 50.8 E % N/A
Protein 17.2 E % 16.5 E % P=0.12
Fat 30.5 E % 32.7 E % P=0.008
Fiber N/A N/A N/A
Trans fat** N/A N/A N/A
Dietary changes (at 1-4 years)
*) Not given, calculated **) Trans fat content of serum lipids did not differ between groups
de Lorgeril et al.. Lancet 1994; 343(8911):1454-9

8. Results 3/5 (27 months randomization)
Page 8
Mediterranean
diet
Control
French Diet
Baseline value
(MedDiet/Ctrl)
Weight +1 kg +3 kg 74/73
Systolic blood pressure + 7 mmHg + 9 mmHg 120/119
Diastolic blood pressure + 4 mmHg + 5 mmHg 74/74
Triglycerides -0.15 mmol/L -0.23 mmol/L 2.0/2.15
LDL -0,36 mmol/L -0.43 mmol/L 4.52/4.54
HDL + 0.16 mmol/L + 0.11 mmol/L 1.16/1.17
Changes in cardiovascular risk factors vs baseline (at 104 weeks)
Note!
• There were no significant differences between groups
• Serum antioxidant levels were higher in Med Diet group
de Lorgeril et al.. Lancet 1994; 343(8911):1454-9

9. Results 4/5 (27 months randomization)
Page 9
Deaths and cardiovascular end points (number of events)
P=0.02
Δ - 73 % (adjusted)
P=0.02
P=0.001
Δ - 76 % (adjusted)
Δ - 70 % (adjusted)
de Lorgeril et al.. Lancet 1994; 343(8911):1454-9

10. Results 5/5
(follow up results up 4 years)
Page 10 de Lorgeril et al.. Circulation 1999;
99(6):779-85
preceding plus minor events
requiring hospital admission,
including recurrent stable
angina, restenosis etc. -47 %
(CO 3)
Myocardial infarction
plus cardiovascular death plus major
secondary events -67 %
(CO 2).
Myocardfial infarction plus
cardiovascular death -72 %
(CO 1)
Note! Addtionally
reported in this paper:
- Fiber intake:
18,6 g/ 15,5 g/day
-Lipid Lowering Drugs
26,5 % vs 34 %
(Med Diet vs Controls)

11. Pronutritionist’s discussion (1/5)
• In my knowledge, LDHS delivered best-ever results in reducing
cardiovascular events in randomized dietary trial
• Remarkably, the results are not explained by any difference in LDL
cholesterol between the groups (4,2 vs 4.3 mmol/L)
• Authors interestingly point out that the high linoleic acid intake (such as in
classic outcome RCTs) is associated with platelet-induced aggregation
and lipid peroxidation.
• The magnitude of the displacement of SFA with margarine was circa 5 %
of daily energy intake (15 grams of butter was replaced with margarine)
and was associated with null difference in LDL cholesterol
• In a recent meta-analysis by Mozaffarian (2010), 5 E % replacement of
SFA with PUFA was 10 % reduction CHD events. However, in Lyon Heart
Study the outcomes were not driven by any changes in cholesterol, and
even more interestingly, the intake of PUFA was lower in Mediterranean
Diet group than in control group (4.6 E % vs 6.1 E %, p=0,0001, 4 year
results)
• Most striking dietary difference was α –linolenic acid intake (0.81 E % in
MedDiet vs 0.27 E % in controls)
Page 11 de Lorgeril et al. 1994; de Lorgeril et al. 1999

12. Pronutritionist’s discussion (2/5)
Strengths of Lyon Diet Heart Study
Page 12
• Randomized trial with free supplementation of margarine. Feeding of any
food item is likely to improve compliance to diet (which is notoriously poor
in long term trials)
• Diets were relatively well reported, even if fiber intake was reported only at
4 years (15.5 g/day in controla and 18.6g/day in Mediterranean group p=
0.004)
• Medical attention is likely to have been quite similar in between the groups
• Drop out is very low at 27 months (≤ 8 %)
• Well documented end points
• Well documented medications
de Lorgeril et al. 1994; de Lorgeril et al. 1999

13. Pronutritionist’s discussion (3/5)
Weaknesses of Lyon Diet Heart Study
Page 13
• Glucose levels of patients were neither monitored nor reported. It is not
known if incidence of diabetes or IGT was equally distributed among
groups
• A small difference in weight gain between the groups favoring active group
• The changes is dietary intakes were modest or even subtle, and underlining
the importance of free supplementation
• The mechanistic model behind the observed effects is vague (platelet-
induced aggregation and lipid peroxidation) and inadequately proven in
later trials. For example, latest meta-analyses on omega-3 fatty acid
supplementation have demonstrated modest or disappointing results (Chen
et al. 2011 )
• Currently, statins are routinely prescribed to MI survivors. It is not known if
Lyon Diet would yield good results on top of widely prescribed statin
treatment. In omega- 3 trials, the effect of omega-3 supplementation is only
seen among those who do not use statins and other modern MI drugs (
Chen et al. 2011 )
• The results have not been re-produced in any other long-term outcome trial
de Lorgeril et al. 1994; de Lorgeril et al. 1999

14. Pronutritionist’s discussion (4/5)
Contrasting Lyon and Oslo Diet Heart
Lyon Heart Study
ACTIVE TREATMENT
Oslo Diet Heart
ACTIVE TREATMENT
Linoleic acid intake (omega-6
FA intake)
↓ (rather low circa 4 E %) ↑ (very high, circa 15 E %)
α –linolenic acid ↑ ( circa 0,8 E %) ↑ ( circa 2,7 E %, Ramsden et al. 2010)
Trans fat ↑
(as margarine, circa 1 g/d)
↓
(Hard margarine was prohibited)
Marine omega-3 fatty acids ↑ (due to promotion of fish) ↑↑ (due to supplementation of sardines)
Fiber ↑ ↑ *
SFA ↓ ↓
Vitamin D No change ↑**
Total PUFA ↓ ↑
Antioxidants/(Polyphenols) ↑ ↑
Page 14 http://www.facebook.com/pron
utritionist
*) not reported but likely as brown bread, vegetables and fruit were promoted), **) free sardines in cod liver oil, intake of
vitamin estimated to be circa 15 mcg/day (Ramsden et al. 2010)
de Lorgeril et al. 1994; de Lorgeril et al. 1999

15. Pronutritionist’s discussion (5/5)
Conclusion
• LHS delivered robust results without any difference in LDL, HDL or
triglycerides
• LHS and Oslo Diet-Heart are very alike:
– Both were multi-factorial meal pattern trials where subjects were given
food items for free
– Both trials had emphasis on increasing omega-3 fatty acids, fish
instead of meat, fruit/vegetables, whole grains, and oils in cooking.
– But these trials also demonstrate that not one bad single dietary
change can dilute positive effects of comprehensive dietary
modification (very high linoleic acid intake in Oslo Diet-Heart, trans fat
intake in Lyon heart study)
• Background diet in LHS is much closer to current one than in any other
large fat displacement trials
• The LHS is still considered as the ultimate evidence for the health benefits
of Mediterranean diet. The results have not been reproduced since Lyon
Heart Study. PREDIMED trial will soon show if the effects of Mediterranean
diet can be re-produced
Page 15 http://www.facebook.com/pron
utritionist
de Lorgeril et al. 1994; de Lorgeril et al. 1999

16. Read also about
Oslo Diet-Heart Study
&
Predimes Study
www.pronutritionist.net16

17. Welcome aboard
25/06/1417
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Reijo Laatikainen, Registered dietitian, MSc MBA