Summary:
- We look at a couple of large recent studies that show excessive carbohydrate consumption, particularly of simple sugars, is associated with increased cardiovascular disease risk. Consumption of fats instead reduces cardiovascular risk.
- Next we take a look at the large recent study of the ideal cholesterol modifying drug — it reduced levels of LDL and increased HDL. Yet this drug had no effect on cardiovascular disease risk.
- Finally we observe that only exceedingly high or low levels of cholesterol have an influence on cardiovascular disease.
This is the 2nd installment of a two-part series. The first part is here:
KosAbility: A Tale Of Two Studies Leads To A Deeper Understanding Of Cardiovascular Disease
The PURE study:
The charts above are from a study published in 2017 in the Lancet entitled: Associations of fats and carbohydrate intake with cardiovascular disease and mortality in 18 countries from five continents (PURE): a prospective cohort study. It was
a large, epidemiological cohort study of individuals aged 35–70 years ... in 18 countries with a median followup of 7·4 years ... Dietary intake of 135,335 individuals was recorded using validated food frequency questionnaires. The primary outcomes were total mortality and major cardiovascular events (fatal cardiovascular disease, non-fatal myocardial infarction, stroke, and heart failure).
Top journal, big study. Not all of the trends shown in the above charts reached statistical significance but many did:
Higher carbohydrate intake was associated with an increased risk of total mortality (highest ... vs lowest quintile ... category, HR 1·28 ptrend=0·0001.... Intake of total fat and each type of fat was associated with lower risk of total mortality (quintile 5 vs quintile 1, total fat: HR 0·77 , ptrend<0·0001; saturated fat, HR 0·86 , ptrend=0·0088; monounsaturated fat: HR 0·81 , ptrend<0·0001; and polyunsaturated fat: HR 0·80 , ptrend<0·0001). Higher saturated fat intake was associated with lower risk of stroke (quintile 5 vs quintile 1, HR 0·79 , ptrend=0·0498)." [Emphases added. Confidence intervals removed to improve readability]
Even consumption of saturated fat instead of carbohydrates resulted in lower mortality. Most P values were much less than .05 indicating a high degree of significance. Authors' commentary:
A high carbohydrate diet is usually accompanied by a low fat intake. Our findings show a higher risk of total mortality, non-cardiovascular disease mortality, and stroke by lower fat consumption. The health benefit of replacing total fat with carbohydrate has been debated. Previous studies showed that replacement of fat with carbohydrate was not associated with lower risk of coronary heart disease and a pooled analysis of two large cohort studies (the Health Professionals Follow up and the Nurses’ Health Study) showed an inverse association between total fat and total mortality.
... In conclusion, we found that a high carbohydrate intake was associated with an adverse impact on total mortality, whereas fats including saturated and unsaturated fatty acids were associated with lower risk of total mortality and stroke. We did not observe any detrimental effect of fat intakes on cardiovascular disease events.
Sugar Intake vs. Cardiovascular Disease Study
One limitation of the foregoing study is that they did not distinguish between simple sugars and complex carbohydrates. Let us take a look at a study that examined sugar consumption - Added Sugar Intake and Cardiovascular Diseases Mortality Among US Adults, published in JAMA Internal Medicine. To obtain the data in this chart they tracked 11,733 participants for a total of 163,939 person-years:
According to this result - after adjusting for confounding factors, the hazard of death from cardiovascular disease for those in the highest 20% of the population by sugar consumption was double that of the lowest 20%.
These studies are telling us consumption of fat is good and consumption of sugar is bad when it comes to cardiovascular disease. How did we come to believe otherwise? We now turn to another study recently published in the Journal of the American Medical Association entitled: Sugar Industry and Coronary Heart Disease Research A Historical Analysis of Internal Industry Documents. This study documents at great length how the sugar industry paid for misleading studies to be put into medical journals exonerating sugar and casting doubt on legitimate studies that demonstrated otherwise:
We examined Sugar Research Foundation (SRF) internal documents, historical reports, and statements relevant to early debates about the dietary causes of CHD [coronary heart disease] and assembled findings chronologically into a narrative case study. The SRF sponsored its first CHD research project in 1965, a literature review published in the New England Journal of Medicine, which singled out fat and cholesterol as the dietary causes of CHD and downplayed evidence that sucrose consumption was also a risk factor. The SRF set the review’s objective, contributed articles for inclusion, and received drafts. The SRF’s funding and role was not disclosed. Together with other recent analyses of sugar industry documents, our findings suggest the industry sponsored a research program in the 1960s and 1970s that successfully cast doubt about the hazards of sucrose while promoting fat as the dietary culprit in CHD. [emphases added]
What about statins? Aren’t statins supposed to reduce cardiovascular risk by lowering cholesterol? Let us start with some well-informed commentary:
The global campaign to lower cholesterol by diet and drugs has failed to thwart the developing pandemic of coronary heart disease around the world. Some experts believe this failure is due to the explosive rise in obesity and diabetes, but it is equally plausible that the cholesterol hypothesis, which posits that lowering cholesterol prevents cardiovascular disease, is incorrect. The recently presented ACCELERATE trial dumbfounded many experts by failing to demonstrate any cardiovascular benefit of evacetrapib despite dramatically lowering low-density lipoprotein cholesterol and raising high density lipoprotein cholesterol in high-risk patients with coronary disease. This clinical trial adds to a growing volume of knowledge that challenges the validity of the cholesterol hypothesis and the utility of cholesterol as a surrogate end point. Inadvertently, the cholesterol hypothesis may have even contributed to this pandemic.
The Accelerate Trial
Now let us take a look at the Accelerate trial. There was more than one report on this trial but they all reached the same conclusion:
Evacetrapib and Cardiovascular Outcomes in High-Risk Vascular Disease
Background
The cholesteryl ester transfer protein inhibitor evacetrapib substantially raises the high-density lipoprotein (HDL) cholesterol level, reduces the low-density lipoprotein (LDL) cholesterol level...
Methods
In a multicenter, randomized, double-blind, placebo-controlled phase 3 trial, we enrolled 12,092 patients who had at least one of the following conditions: an acute coronary syndrome within the previous 30 to 365 days, cerebrovascular atherosclerotic disease, peripheral vascular arterial disease, or diabetes mellitus with coronary artery disease. Patients were randomly assigned to receive either evacetrapib at a dose of 130 mg or matching placebo, administered daily, in addition to standard medical therapy. The primary efficacy end point was the first occurrence of any component of the composite of death from cardiovascular causes, myocardial infarction, stroke, coronary revascularization [bypass or angioplasty], or hospitalization for unstable angina.
Results
At 3 months, a 31.1% decrease in the mean LDL cholesterol level was observed with evacetrapib versus a 6.0% increase with placebo, and a 133.2% increase in the mean HDL cholesterol level was seen with evacetrapib versus a 1.6% increase with placebo. After 1363 of the planned 1670 primary end-point events had occurred, the data and safety monitoring board recommended that the trial be terminated early because of a lack of efficacy. After a median of 26 months of evacetrapib or placebo, a primary end-point event occurred in 12.9% of the patients in the evacetrapib group and in 12.8% of those in the placebo group (hazard ratio, 1.01; 95% confidence interval, 0.91 to 1.11; P=0.91).
This result is fully consistent with the dietary studies referenced above.
Was the idea that cholesterol causes cardiovascular disease completely made up out of whole cloth by the sugar interests? Not entirely. Unusually high or unusually low-cholesterol can have an effect:
The cholesterol levels of Framingham participants who did and did not develop CHD [coronary heart disease] are remarkably similar except when the cholesterol level was extremely low (<150 mg/ dL) or extremely high (>380 mg/dL). For the vast majority of patients, cholesterol levels do not help us differentiate those who will and will not develop CHD.
Conclusions:
- Excess carbohydrate consumption, particularly of sugars, is a cause of cardiovascular disease.
- As long as one avoids extremely high cholesterol levels, consumption of naturally occurring fats is not a cause of cardiovascular disease.
For those interested in additional reading the following books may be of interest. Both are written by medical doctors and are thoroughly referenced to the medical literature:
The Great Cholesterol Myth ...
Eat Fat Get Thin
Reversing Type 2 diabetes: low carb, high fat
Open thread - Discussion of any health-related issue is welcome in the comments.