Thursday, July 13, 2006

Is It Time to Rethink the Traditional Risk Factors for Heart Disease?

This week's Archives of Internal Medicine had an interesting study published - An Assessment of Incremental Coronary Risk Prediction Using C-Reactive Protein and Other Novel Risk Markers: The Atherosclerosis Risk in Communities Study - in which researchers investigated the clinical utility of 19 "novel" risk markers for predicting cardiovascular disease compared with the traditional risk markers currently used by clinicans in practice today.

The cover graphic quickly provides a glimpse at the traditional risk markers and the "novel" markers currently making headlines as potentially important as part of the risk assessment with patients.

After reviewing these novel markers compared to the traditional risk markers, the researchers concluded that "Our findings suggest that routine measurement of these novel markers is not warranted for risk assessment. On the other hand, our findings reinforce the utility of major, modifiable risk factor assessment to identify individuals at risk for CHD for preventive action."

In an accompanying editorial, Predicting Cardiovascular Risk, Dr. Donald Llyod-Jones included a stunning comment followed by a critical question, "It is possible that, to date, we have examined the wrong novel risk markers. Should we seek as yet undiscovered markers that will improve risk prediction substantially when added to established risk factors?"

He continued with a caveat - "Such markers will need to be highly associated with CHD, uncorrelated with established risk factors, have a reasonable prevalence of risk-producing levels in the population, and not increase competing risks for other diseases. Where will we find such markers?"

But then, adds more questions, "Should we start again and create new CVD risk prediction models without guaranteeing inclusion of established risk factors? Would this be of clinical value? How would we know what to treat?"

And then asks an incredibly important question, "Do we perhaps need a different goal? Rather than identifying high-risk individuals for drug therapy, should we try to optimize identification of low-risk individuals and attempt to move the population profile toward this ideal through public health interventions?"

As I read through Dr. Llyod-Jones' editorial I was struck by the questions and the simplicity of exploring alternative risk prediction models. The literature is rich with data - much largely ignored when it comes to heart disease since we're entrenched in the belief that cholesterol and saturated fat are the culprits in heart disease.

But if we start with his last item - identifying low-risk individuals - we find something potentially ground-breaking, that's often not considered as we debate how to assess risk for heart disease - who can provide us with a good picture of long term health?

Centenarians - those who live to be 100 or older around the world. You don't live to be 100 without something important going on - and I contend, it's not just genetics.

We know those who live to be 100 or more are a very diverse group - their longevity isn't consistently based on moderate alcohol consumption, smoking habits, country of origin, or ethnicity. And we also know that cholesterol values, overall diet and levels of activity vary greatly. In fact, we know there are only three things that link centenarians around the world - relatively low blood glucose, strong insulin sensitivity and low triglycerides.

That's it - in study after study, these three things are the only three things that are shared "common denominators" in those 100 or older.

The question then begs - if strong insulin sensitivity, low triglycerides and low blood glucose are the common ties-that-bind centenarians together as a group, should these metabolic markers be our new starting point to understand and reduce the risk of heart disease?

A quick review of the literature suggests the answer is "yes."

An article in the May 16, 2006 issue of New Scientist had an interesting quote from Dr. Andrzej Bartke, a researcher at Southern Illinois University, "Insulin resistance is a risk factor for just about any problem you don't want to get: diabetes, atherosclerosis, cancer. It's sort of intuitive that the opposite situation would be beneficial."

The opposite, of course, is strong insulin sensitivity.

But we do have to ask - does strong insulin sensitivity confer any health benefit? In reverse, is there evidence that higher levels of insulin, and thus blood glucose and triglycerides, increase heath risks? Basically, does higher insulin, blood gluocse and triglycerides have a detrimental effect?

Interestingly, several studies show the atherogenic effects of high blood glucose and insulin:

2002 - American Journal of Hypertention; Correlates of aortic stiffness in elderly individuals: a subgroup of the Cardiovascular Health Study

"Mean aortic pulse wave velocity (850 cm/sec, range 365 to 1863) did not differ by ethnicity or sex. Increased aortic stiffness was positively associated with higher systolic blood pressure (SBP), age, fasting and 2-h postload glucose, fasting and 2-h insulin, triglycerides, waist circumference, body mass index, truncal fat, decreased physical activity, heart rate, and common carotid artery wall thickness (P < .05)...In these elderly participants, aortic stiffness was positively associated with risk factors associated with the insulin resistance syndrome, increased common carotid intima-media thickness, heart rate, and decreased physical activity measured several years earlier."

March 2001 - American Journal of Epidemiology; Metabolic syndrome and ischemic heart disease in elderly men and women

"In both men and women, three uncorrelated principal components were identified, representing a central metabolic factor (body mass index, fasting and 2-hour serum insulin, high serum triglycerides, and low HDL cholesterol), a glucose factor, and a blood pressure factor. In a multivariate model with age and sex, all three factors were significantly associated with IHD by electrocardiogram criteria; central metabolic factor, glucose factor, blood pressure factor, age (10 years), and female sex. Similar results were obtained in analyses using clinically manifest IHD as the outcome. These results support the thesis that the metabolic syndrome exerts effects through different risk factors by different mechanisms."

April 2000 - European Journal of Clinical Investigation; Effects of glucose ingestion on cardiac autonomic nervous system in healthy centenarians: differences with aged subjects

"In aged subject (AS), but not in healthy centenarians (HC), the baseline low frequency/high frequency ratio (LF/HF) correlated significantly with BMI, waist-hip-ratio (WHR), fasting plasma insulin, and norepinephrine concentration. Glucose ingestion was associated with a significant rise in LF/HF ratio in both groups studied but per cent changes in glucose mediated stimulation of LF/HF was lower in HC than in AS...Our study demonstrates that basal- and glucose-stimulated LF/HF, an indirect index of cardiac sympatho-vagal balance, are lower in HC than in AS."

January 2000 - European Journal of Clinical Investigation; Insulin resistance, lipid and fatty acid concentrations in 867 healthy Europeans. European Group for the Study of Insulin Resistance (EGIR)

"The associations of fasting triglycerides with the M-value and with nonesterified fatty acid (NEFA) at steady state were independent of each other. All these associations were independent of obesity and geographical location...The results in this large cohort of healthy European subjects suggest that triglyceride concentrations depend upon both insulin's gluco-regulation (estimated by glucose uptake) and antilipolytic insulin action (measured by NEFA levels) during an euglycaemic clamp."

April 1998 - Annals of Internal Medicine; Metabolic risk factors worsen continuously across the spectrum of nondiabetic glucose tolerance. The Framingham Offspring Study

"Multivariable-adjusted mean measures of risk factors and odds ratios for obesity, elevated waist-to-hip ratio, hypertension, low levels of high-density lipoprotein cholesterol, elevated triglyceride levels, and hyperinsulinemia showed continuous increases across the spectrum of nondiabetic glucose tolerance. Although a threshold effect near the upper range of nondiabetic glucose tolerance could not be ruled out for triglyceride levels in men and for insulin levels 2 hours after oral challenge in men and women, no other metabolic risk factors showed clear evidence of thresholds for increased risk...Metabolic risk factors for type 2 diabetes mellitus and for cardiovascular disease worsen continuously across the spectrum of glucose tolerance categories, beginning in the lowest quintiles of normal fasting glucose level."

February 1998 - Diabetes Care; U-shaped and J-shaped relationships between serum insulin and coronary heart disease in the general population. The Bruneck Study

"Results of the present study suggest that both hyperinsulinemia and "hypoinsulinemia" are independent indicators of CHD. Furthermore, it is proposed that the relationship between CHD and fasting insulin is U-shaped, whereas that between CHD and postglucose insulin may be J-shaped."

April 1998 - Metabolism; Insulin resistance and fat patterning with aging: relationship to metabolic risk factors for cardiovascular disease

"No index of overall obesity, fat patterning, glucose/insulin metabolism, and/or SI, was independently related to the plasma concentration of HDL-C after controlling for any one of the other two. Direct measurement of glucose/insulin metabolism and insulin sensitivity (SI), as well as fat patterning, provides information on their relative associations with CVD risk factors. The measures of glucose/insulin metabolism and SI were more consistently related to dyslipidemia and hypertension than were the overall obesity and fat patterning in this healthy population."

March 2006 - Journal of the American Geriatric Society; Impaired fasting glucose is associated with increased arterial stiffness in elderly people without diabetes mellitus: the Rotterdam Study

"In the total cohort, fasting glucose was strongly associated with carotid distensibility...IFG is related to arterial stiffness in elderly subjects. An advanced stage of arterial stiffness, comparable with that of subjects with DM, is only reached at the age of 75."

April 1994 - Arteriosclerosis and thrombosis; Hyperinsulinemia predicts multiple atherogenic changes in lipoproteins in elderly subjects

"Baseline insulin level was not significantly associated with the development of high LDL cholesterol or low HDL cholesterol levels. Baseline insulin was associated with the development of hypertriglyceridemia."

January 1991 - Arteriosclerosis and thrombosis; High fasting plasma insulin is an indicator of coronary heart disease in non-insulin-dependent diabetic patients and nondiabetic subjects

"The results suggest that hyperinsulinemia is an indicator of CHD in both NIDDM patients and nondiabetic subjects. Hyperinsulinemia may be directly atherogenic, but it is more probable that hyperinsulinemia reflects insulin resistance, which may be a factor enhancing atherogenesis by causing adverse changes in many CHD risk factors."

November 2002 - International Journal of Cardiology; Fasting insulin levels independently associated with coronary heart disease in non-diabetic Turkish men and women

"Hyperinsulinemia (i) may provide information on the coronary heart disease likelihood over and above that provided by the other risk factors, including HDL-cholesterol, and (ii) may contribute, within the frame of insulin resistance, to the coronary heart disease risk independently of the classical risk factors."

January 2006 - Diabetes Care; Relation Between Blood Glucose and Coronary Mortality Over 33 Years in the Whitehall Study

"A threshold model with linear slope best described the dose-response relationship between postload blood glucose and CHD mortality risk."

The above are just a dozen studies randomly selected that are available in the literature - many more exist and are easily accessible in To me, they highlight the pressing need to step back from our obession with dietary fats, which are, on their own, pretty much metabolically neutral, and re-evaluate the influcence our diet rich with carbohydrates, especially refined carbohydrates, is exerting on our long-term health.

This isn't rocket science - a very basic understanding of metabolism and metabolic pathways explains exactly how and why excessive carbohydrate consumption contributes to not only obesity, but insulin resistance, and thus heart disease.

Some of the most depressing studies available today are those investigating the cardiovascular health of children, already well on the road to diabetes, cardiovascular disease and a reduced life expectancy.

June 2003 - Obesity Research; Fasting plasma insulin modulates lipid levels and particle sizes in 2- to 3-year-old children

"Fasting insulin level was positively correlated with triglyceride levels and inversely correlated with HDL-cholesterol level in boys. Higher fasting insulin level was also correlated with smaller mean HDL particle size in both boys and girls and smaller mean LDL particle size in boys. The associations of fasting insulin level with triglyceride and HDL-cholesterol levels and HDL and LDL particle size remained significant after multivariate regression adjustment for age, sex, and BMI or ponderal index. Fasting insulin level is associated with relative dyslipidemia in healthy 2- and 3-year-old Hispanic children."

Two and three year old children, already experiencing the health damaging effects of high insulin and high triglycerides!

Yet, the "traditional" risk factors [see graphic above] do not include insulin levels, blood glucose or triglycerides in weighing an individuals risk for heart disease. It is only when an individual has progressed to diabetes that their metabolic condition is acknowledged to be the risk factor it is. The above studies clearly demonstrate the detrimental effects long before someone presents with diabetes!

While the study above explored the value of 19 additional potentially useful risk factors, noticiably absent are three that should have been considered - insulin, glucose and triglycerides.

I'd like to applaud Dr. Llyod-Jones for pointing out that our current thinking may be impeding our efforts to reduce the risk of cardiovascular disease.

Staring us in the face is the potent value of measuring insulin and insulin sensitivity, blood glucose and triglycerides - these, at low values, are the shared traits in centenarians around the world; and it is these same markers, at elevated levels, that are found again and again in studies where cardiovascular disease is an issue.

We've spent decades - and billions of dollars - convincing ourselves it is dietary fat that increases the risk of heart disease. I really have to wonder how much time we're going to continue to demonize dietary fat and cholesterol, while ignoring the data that insulin, blood glucose and triglycerides are strong predictors of cardiovascular disease and/or longevity.

How much longer can we afford to ignore the increased consumption of carbohydrates in the US? How much longer can we afford to ignore the lasting damage high insulin, blood sugar and triglycerides exact on our children and their long-term health?

How much longer until Americans wake up and demand the leading health organizations take the evidence seriously enough to step back and question the current paradigm, evaluate the role of excessive carbohydrate in disease, and base recommendations on science not dogma?


  1. It appears, to me, that you are advocating or at least moving toward an alternate hypothesis which states that carbohydrates, notwithstanding the antioxidants and vitamins found in some carbohydrate based foods such as fruits and vegetables, are the primary factor in the aging process due to an overstimulation of the pancreas leading to Type 2 Diabetes and the whole metabolic syndrome of obesity, heart disease, stroke and possibly cancer. When one looks at populations that consume little or no carbohydrates, the Masai and the Inuit come to mind, there does not appear to be exceptional longevity associated with these cultures. There are, certainly, other factors. the Inuit live in a harsh environment. The Masai are a warrior race and thus have a high rate of accidental and violent death. Neither group has access to modern medical care. Still, it seems that certain individuals would live to a very advanced age. In fact Vilhjalmur Stefansson, who live with the Inuit for several years, states in his article "Adventures in Diet" from Harper's Monthly Magazine, January 1936 that

    "So far as we can tell, the Eskimos, before the white men upset their physiological as well as their economic balance, lived on the average at least ten years less than we. Now their lives average still shorter; but that is partly from communicated diseases."

    In addition, the developed country with the longest with the longest average lifespan is Japan, which while not as high carb as most people assume, does have white rice as a staple food. Note that Japan owes it longevity at least in part, to a universal health care system and a strong family orientation and small families leading to a reduced infant mortality as well as having fewer processed foods in their diets.

    This is not meant as a dismissal of your column, but rather as a critical analysis of its implications. As always, thanks for the time and space to comment.

  2. It appears, to me, that you are advocating or at least moving toward an alternate hypothesis which states that carbohydrates, notwithstanding the antioxidants and vitamins found in some carbohydrate based foods such as fruits and vegetables, are the primary factor in the aging process due to an overstimulation of the pancreas leading to Type 2 Diabetes and the whole metabolic syndrome of obesity, heart disease, stroke and possibly cancer.

    Carbohydrates per se, excess (above what we need for essential nutrients) yes. I strongly believe that non-starchy vegetables, fruits in season and even some of the starchy roots have their place in our diet.

    We've lost sight of when and how much though.

    Years ago, Dr. John Yudkin pointed out that while it's common to point to cholesterol as the cause of heart disease (the abnormality easily measured), other abnormalities present with elevated cholesterol also - namely higher insulin, blood sugars, platelete stickiness and uric acid.

    So, the question then is - does the dyslipidemia cause these abnormalities too, or is the dyslipidemia a symptom with these other abnormalities?

    It's a good question - and if we take the time to go through the data, we find some very compelling data that insulin & blood glucose levels are truly important in the development of CHD, diabetes, stroke and some cancers. But, we're fixated on cholesterol levels and dietary fats and I believe missing the bigger picture.

    In addition, the developed country with the longest with the longest average lifespan is Japan, which while not as high carb as most people assume, does have white rice as a staple food. Note that Japan owes it longevity at least in part, to a universal health care system and a strong family orientation and small families leading to a reduced infant mortality as well as having fewer processed foods in their diets.

    True, rice is a staple in their diet. So is 33% of the world's fish, a higher intake of pork and pork fat, a much lower intake of vegetable oils, almost no trans-fats and a rich selection of non-starchy vegetables to compliment the entire diet.

    It's also easy to point to the Japanese and ignore the top 20 countries for longevity. (Incidentally, Japan is now #4, behind Andorra, San Marino and Macau) Following Japan is Singapore, Austalia, Guernsey, Switzerland, Sweden, Hong Kong, Canada, Iceland, Cayman Islands, Italy, France, Monaco, Liechtenstein, Spain and Norway.

    As I noted - dietary patterns in longevity are varied...some, like the French, consume very high intakes of saturated fats; others, like Japan consume fewer saturated fats. Those living the longest - centenarians - give us a unique opportunity to explore and understand what, in their varied dietary patterns, is similar to enhance health.

    At this point, I believe that no matter what their diet - what they ate - contributed to a strong insulin sensitivity, relatively low blood sugars and low TG's - it contributed to metabolic fitness rather than metabolic disorder.

    Will only one particular diet work to do that? I don't think so - I think the sum of the diet...calories, nutrients, EFA, EAA....along with some good genes is what is contributing to the centenarians longevity.

    At the root of that is a nutrient-dense diet - one that provides essential nutrients without excess from any macronutrient. It's a balance we've yet to define - but it's there...but I doubt we'll find it if we don't put aside the assumption we have about saturated fat and cholesterol in the diet.

  3. I think the answers are there for anyone who wants to see them. However with all the vested interests in keeping foundations & research groups funded & the fact that heart disease & cancer fund a huge job network, with enormous profit margins for some drug companies, they will never see them.
    Once again thanks for putting the evidence out there in such an easy to understand manner. One day the world might remember that nature created all things already in balance, especially our food & to place too much reliance on processed grains, & fat altered foods & sugar is what is making the planet's peoples' sick. I just hope it doesn't come too late for the future's children to ever get back good cellular health & thus good overall health. Once the damage is done at the, cell or DNA level can we ever reverse it???

  4. Anonymous8:54 PM

    Thank you for your interesting post!
    I thought perhaps you may also find this related post interesting to you:
    Body Size and Human Longevity