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Insulin Resistance is the Strongest Risk Factor for Coronary Heart Disease
Study Insight (January 2021)

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Quick Summary tl;dr

A study of 28,024 followed for over 20 years showed the diabetes and insulin resistance are far stronger risk factors for coronary heart disease than LDL cholesterol.

Diabetes was associated with a 10.71-fold increased risk of coronary heart disease in women <55, and a 10.92 increased risk of coronary heart disease in women <65.

The risk associated with diabetes and insulin resistance even without diabetes was 4 – 8 times greater than the risk associated with LDL cholesterol.

When the researchers looked more closely at LDL-associated risk, they noticed no risk was associated with having more large fluffy LDL. The risk was due to small LDL. Those with insulin resistance have less large fluffy and more small LDL.

Just a few months ago, in January 2021, an important study was published in the journal JAMA Cardiology that demonstrated insulin resistance is the strongest risk factor for coronary heart disease (CHD). (Sagar B. Dugani, 2021)

Study Design

This study followed 28,024 women for a median time period of 21.4 years. During this time, 1,548 (5.5%) of the women developed CHD. The researcher collected data on over 50 clinical factors and biomarkers, so were able to determine what the strongest risk factors were for heart disease. The risk associated with each variable was reported as a Hazards Ratio (HR), which is the fold increase in risk associated with the presence of that variable as compared to when it is absent. For example, if women with high triglycerides were twice as likely to have CHD as women with lower triglycerides, the HR would be 2.

Diabetes and Insulin Resistance

Of the clinical parameters, diabetes was associated with the highest risk of CHD by far. For women <55, the HR of diabetes was 10.71. For women 55 - 65, the HR of diabetes was 10.92. In other words, having diabetes increased coronary heart disease risk by over 1000%!

Unsurprisingly, metabolic syndrome had the second strongest association with CHD. Metabolic syndrome is defined by the presence of at least three of the following: low HDL, high triglycerides, high blood pressure, large waist circumference, high fasting glucose or insulin. I said “unsurprisingly” because metabolic syndrome is a disease that itself is associated with insulin resistance and diabetes. For women <55, the HR of metabolic syndrome was 6.09.

Consistent with the clinical associations, a blood marker of insulin resistance - lipoprotein insulin resistance (LIPR) - was the strongest risk factor among the biomarkers for CHD. The HR associated with LIPR was 6.4 among women <55. And the associated remained even when the researchers adjusted for diabetes.

These data show that if you want to reduce your risk of heart disease, focus on improving insulin resistance. Probably the best way to do this is to eat a clean low-carb diet. Sleep and exercise as also important lifestyle factors.

Having diabetes increases coronary heart disease risk by over 1000%!

Cholesterol

Also unsurprisingly, HDL was negatively associated with CHD and triglycerides were positively associated with CHD. Simply put, you want high HDL and low triglycerides. Importantly, HDL and triglycerides were both stronger risk factors than LDL cholesterol, the so called “bad cholesterol.”

Here is a list of just some clinical variables and markers that were associated with a greater risk of heart disease than LDL: Being overweight or obese, smoking, diabetes, metabolic syndrome, high blood pressure, sedentary lifestyle, high triglycerides, low HDL, and any of four markers of inflammation (CRP, fibrinogen, ICAM-1, GlycA). In fact, the HR associated LDL cholesterol was just 1.38, about 1/8th the risk associated with diabetes.

What’s more, when the researchers examined the risk associated with the different LDL particle sizes, there was no association between big fluffy LDL particles and CHD. By contrast, small LDL particles were associated with CHD risk, HR = 2.25. This is an extremely important detail because when low-carb diets increase LDL, they do so specifically by increasing large LDL ( Norwitz et al, 2020), while often decreasing small LDL. Thus, even if overall LDL goes up on a low-carb diet you risk may not increase.

Having diabetes increases your risk of heart disease 8-times more than having high LDL.

Conclusion

There is a lot of debate about what “causes” heart disease and what we should treat to reduce cardiovascular risk. Conventional care for heart health focuses on lowering LDL cholesterol, while largely turning a blind eye towards insulin resistance. In America, a primary care physician is far more likely to order and LDL than a fasting insulin, not to mention a Kraft test, 2-hour insulin, HOMA-IR, or LIPR (other measures of insulin resistance).

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But these data show us insulin resistance is a far stronger risk factor for heart disease than LDL. What’s more, statins, the most common drug used to lower LDL cholesterol, can increase insulin resistance and diabetes risk. Take a moment for that to sink in... And, while a low-carb diet can increase LDL, it tends to specifically increase large LDL, which is not associated with increased risk.

These data, collected in 28,024 women over the course of decades, suggest the way we go about preventing coronary heart disease in this country is wrong. The medical algorithm is if LDL is greater than 190 mg/dL, go on a statin. Is that 190 mg/dL of big LDL? Small LDL? The question is rarely asked and the most effective means to improve insulin resistance, a low-carb diet, is often cast aside because as few as 20-30% of people who choose that lifestyle experience a rise in large LDL, increasing their total LDL.

It’s a radical idea, but what if we were to focus on the 10.71-fold increased risk associated with diabetes, rather than on the 1.38-fold increased risk associated with LDL (which is misguided anyway because it lacks the nuance of distinguishing among LDL particle sizes)? Just a thought.

Insulin Resistance is the Strongest Risk Factor for Coronary Heart Disease - Study Insight (January 2021)

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Dr. Nicholas Norwitz
PhD in Ketogenics and Metabolism, Oxford University

Nicholas Notwitz

Dr. Nicholas Norwitz is a new shining star in nutrition science. This 25-year-old Ivy League Valedictorian obtained his PhD at Oxford University in just two years and is now pursing his MD at Harvard Medical School. His research expertise is ketosis and brain aging; however, he has published scientific papers on topics ranging from neuroscience to heart disease to gastrointestinal health to genetics to bone health to diabetes.

You can find Nick on Twitter at @nicknorwitz.

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Comments (5)

I wish my dr would understand this. He diagnoses from his laptop and spreadsheets algorithms from drug companies.

If only our Primary Healthcare providers would get their heads out of the sand! There is enough research now to warrant new thinking about the real causes of just about any disease! Everything relates back to what you put in your mouth! I'm not so worried about my high LDL given that my HDL is high & Triglycerides are low & I am in ketosis & feeling fabulous at 66. This has been my way of life for the past 10 years & will be so always.
Thanks for confirming my thoughts.

Good for you Anne! I happen to know an Ann who is a Harvard MD PhD and 56 with high HDL and low Trigs and LDL 400. She refuses to take a statin  because there is no evidence LDL lowering is beneficial for primary prevention in individuals with high HDL and low Trigs, to the best fo my knowledge. And if someone can provide such data I will eat my hat, along with a mountain of WonderBread. And Dave Feldman will give them $3000 (seen him tandem drop expt?). To be clear, I’m confirming nothing and recommending nothing. I’m only pointing out the fact that standard practice is such that a sub-population of likely healthy individuals is being encouraged to take medications that have serious potential downsides despite a complete lack of evidence of benefit in said sub-population. Now, if someone eats a standard American diet and is metabolically unhealthy and lifestyle change isn’t an option for whatever reason, statins are reasonable.

Hello Martina,
I think there are a few errors in this blog. The study was not the Womens Health Initiative but was an extension of The Womens Health Study - these studies are quite distinct. I think the heading of the diagram with HR’s needs correction. I am not sure how Nick can say that having T2D increases your chance of CVD by 1000% when the HR was 10.71 - or thereabouts. Otherwise I think it is an excellent summary of the paper and also where it fits in the literature.

Hi Debbie, thank you for your careful reading of Nick's post. Nick didn't use the term "Women's Health Initiative" in the text, only in the graph. But the graph, as it shown in the bottom left, was produced by the Noakes Foundation. He chose to use this graph - rather than the one in the manuscript itself - because we thought it would be easier for lay readers to understand. The study is linked so you are free to look at the graphs yourself, which show data that's based on different age groups (<55, 55-65, etc.). For simplicity the <55 are shown in the Noakes Foundation graph, otherwise the data become harder for lay readers to comprehend. As for the 1000% increase, given an aHR of 10.71 for women <55 and 10.92 for women <65, technically it would be a 971-992% increase over a 100% baseline. That's true. Given this is a blog (and the confidence interval easily covers 1000%), it isn't misleading to round 992% to 1000%. On balance, we feel the choice to use the Noakes foundation graph, despite the substitution of word "study" with "initiative" and the rounding of 971-992% to 1000% were fair choices that did not mislead or distract from the blog's message. Fair enough?