Is Insulin Resistance the Main Cause of Heart Disease?


A recent study found that evacetrapib, a drug in trials by Eli Lilly, and which raises HDL cholesterol and lowers LDL cholesterol, did not reduce the incidence of heart attacks or any other cardiovascular event.

The doctors are baffled.

“Here we’ve got an agent that more than doubles the levels of good cholesterol and lowers bad cholesterol and yet has no effect on clinical events,” said Stephen Nicholls, M.B.B.S, Ph.D., a professor at Australia’s University of Adelaide, cardiologist at Royal Adelaide Hospital and the study’s lead author. “We were disappointed and surprised by the results.”

Another doctor said:

“As we close out the trial, we’re trying to understand how a drug that seems to do all the right things in terms of blood cholesterol levels doesn’t then translate into reducing clinical events.”

Perhaps HDL and LDL cholesterol are only markers for what really causes heart disease: insulin resistance and inflammation.

The “characteristic dyslipidemia seen in insulin-resistant subjects”, that is, high triglycerides and low HDL, “is at least as powerful a predictor of ischemic heart disease” as LDL.(1) This suggests that insulin resistance itself is at least as powerful a predictor of heart disease.

There’s an independent relationship between insulin resistance and HDL and triglyceride concentrations.(2) Whereas there was no relationship between body mass index, waist/hip ratio, or physical endurance and HDL and triglycerides.

The best predictor — by far — of coronary heart disease is the ratio of triglycerides to HDL cholesterol. Check out the following graph, courtesy of Dr. Ronald Krauss, one of world’s foremost experts on heart disease.




The highest quartile (upper fourth) of people in triglyceride/HDL ratio had a 16-fold higher risk of heart disease than the lowest. (Reference.)

You have to wonder, given that by definition 25% of people have that high a ratio, and that their risk was 16-fold higher than baseline, whether these unfortunate people may account for nearly all the cases of heart disease. Certainly a very high fraction.

A triglyceride/HDL ratio of greater than 3.0 is a reliable marker of insulin resistance.(3)

As for LDL, Ivor Cummins quotes Dr. Thomas Dayspring, a renowned cholesterol expert, as saying that unless LDL is greater than 200, it’s worthless as a marker for anything. (And by the way, that’s a terrific video on the root cause of heart disease, well worth watching in full.)

The waist-hip ratio is also a strong indicator of heart disease risk.(4)

Hemoglobin A1c, a measure of blood sugar control, is also strongly associated with risk of heart disease.(5)


In the lowest tertile of insulin resistance, no one got sick.

The above chart, taken from a paper by the renowned Gerald Reaven, shows the incidence of disease by tertiles (thirds) of insulin resistance. (I wrote about that here.) The diseases included heart disease, stroke, type 2 diabetes, cancer, and hypertension. Note that those in the lowest tertile of insulin resistance had zero disease incidence, and that the incidence of disease rose monotonically with increased insulin resistance.

So, it appears that the best way to avoid heart disease is to avoid insulin resistance.

Low-carbohydrate diets, fat loss, and exercise — especially strength training to build muscle — are the best ways to do this.

PS: Check out my Supplements Buying Guide for Men.

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  1. Excellent post – you’ve made a very clear path through a complicated forest of data.

  2. Allan Folz says:

    ““As we close out the trial, we’re trying to understand how a drug that seems to do all the right things in terms of blood cholesterol levels doesn’t then translate into reducing clinical events.””

    Heh. That writing’s been on the wall for going on 10 years now. These guys would be drummed out of any engineering dept even moderately worth its salt. Your working assumptions are making an ass out of you and me.

    Or, as Mark Twain put it, “It ain’t what you don’t know that gets you into trouble. It’s what you know for sure that just ain’t so.”

    • Allan Folz says:

      Haha. Just went to the Ivor link and saw that he is an engineer. There you go.

    • Geoff says:

      ““As we close out the trial, we’re trying to understand how a drug that seems to do all the right things in terms of blood cholesterol levels doesn’t then translate into reducing clinical events.””

      “-Because we’re unwilling to consider any dietary or behavioral changes that might reduce insulin resistance, as there is zero profitability to my pharmaceutical company associated with those options.”

      • P. D. Mangan says:


      • Uncle Maffoo says:

        “B-b-but…muh statins!”

      • Allan Folz says:


        That was a later thought that occurred to me with regard to Ivor Cummins’ video. He wants heart calcium accumulation to be the standard diagnostic instead of cholesterol. No argument here.

        However, lousy diagnostics are only half the problem. Treatment, nay prevention, is the other, and more important, half. Assume it is 20 years ago and everyone over 40 and blood cholesterol over 200 was given a calcium test. Treatment would still be take a statin.

        Thinking about it can also you can see the real reason calcium testing was ignored. We know there are a great many folks taking statins that don’t need to be. Ignoring the dubious efficacy for a moment, the real risk to the cash cow is that the tens of thousands of people taking them prophylactically decide they don’t need to.

        I suspect a calcium test is not going to find anybody in poor health with great cholesterol scores and great waist-hip ration. However, I do suspect it is going to find lots of people with 220+ cholesterol in otherwise fine heart health.

  3. Allan Folz says:

    BTW, this is a timely post as my wife got her lab results back today.

    Recall last time I was wondering what to make of the really low Ferritin. It was a 13 two days after giving blood. Well, now, about 4 weeks after giving blood, it’s down to a 6. Normal range for women is 15-150.

    Her other blood markers: white BC, red BC, hemoglobin, and hematocrit were all within normal range. Absent any other indicators of health problems, I’m assuming (no, the irony is not lost on me ;)) her very low ferritin is nothing to be concerned about.

    As to the lipid hypothesis, not that I put much weight in it, her results were great. Total chol 164, HDL 74, LDL-calc 75. Trigs 73, . Total chol/HDL: 2.2. (1/2 Avg cardio event risk is < 3.3, Avg event risk is 4.4, 2x event risk is 7.1).

    Her Insulin was 5.8 uIU/mL, listed normal range is 2.6-24.9. HA1c was 5.2, which was a touch higher than I expected and the one thing that actually caught my eye… methinks needs moar power cleans.

    Life Extentions also includes a "LP-IR Score" and risk level. Hers was <25. The 25th quartile is <27. Here's what they included about it:
    The LP-IR score is a laboratory developed index that has been
    associated with insulin resistance and diabetes risk and should be
    used as one component of a physician's clinical assessment. The
    LP-IR score listed above has not been cleared by the US Food and
    Drug Administration.

    I think I mentioned both her grandmothers lived to 90+? Well, there you go.

    Finally, for those wondering about the 1/2 off sale Life Extensions is running. From what I understand it's an annual thing they do every year from March to June 6. Since you have 6 months to use a lab test after ordering it, I'd say it's a pretty handy deal. Cheers!

  4. Jay says:

    Thank you for the article!
    I’ve been reading about autophagy induced by multi-day fasts. Since during autophagy body eats up anything that is useless and harmful, I wonder if autophagy could “eat” cholesterol plaques in arteries that have formed, or already healed and calcified. Found this paper and slides:

    I do not understand much of the paper, could you have a look? Does it state that autophagy clears plaques from the arteries? If so, multi-day fasts could be a good idea
    Thanks for your great work,

    • P. D. Mangan says:

      Hi Jay, the article mainly says that autophagy is necessary in prevention of atherosclerosis, that defective or declining autophagy may lead to it, and holds out the possibility that autophagy could treat it. Dr Joel Fuhrman has written about fasting and atherosclerosis and contends that fasting, which increases autophagy, can get rid of plaques. I’ll take a closer look at that article and see what I can find.

  5. Allan Folz says:

    Hello Denis,

    Not sure whether you follow Peter at Hyperlipid. I find his writing, shall we say obtuse, and nonetheless irresistible the way he connects dots. I saw a post of his on arteriosclerosis and immediately thought of this one from you, and Ivor Cummins’ work.

    Here’s the money paragraph:

    There are several things which spring to mind about DIT [diffuse intima thickening], insulin and oxygenation. If, as I think likely, a general thickening occurs under the effect of chronic hyperinsulinaemia acting on the ILGF-1 receptors which are on the lookout for platelets, we have a reason why insulin, not glucose, drives CVD. Anything which hastens thickening of the tunica intima hastens CVD. Insulin.


    • P. D. Mangan says:

      Thanks, Allan. I used to try to read Hyperlipid closely, but have in recent years found a lot of it very hard to follow. The quote, though, makes a lot of sense.

      • Allan Folz says:

        “Find it hard to follow”Yeah, I know what you mean. That Peter published that post almost a month ago should tell you how often I swing by his blog anymore.

        Also, I sat down this evening to wade into the comment thread (32!?!) and whom did I see… Ivor Cummins. Too funny. It was a good comment thread. Had Ivor and a few posts on K2 even. I go back and forth on whether I am living in an echo chamber, or do all roads lead to Rome, ie. all contemporary chronic health problems are entirely driven by at most a 1/2 dozen easily mitigated short-comings of the modern diet & lifestyle.

        I think it is the latter, but the Devil Advocate in me still challenges myself whether it is the former.

        • P. D. Mangan says:

          Good that you challenge the possible echo chamber, but in this case I believe that the causes of health problems are few: lack of exercise, excessive carbs and sugar, non-optimal (non-nutritious) food; throw in sleep, light exposure, adequate protein… there you have it.

          And by the way, seeing Ivor Cummins in the comments: it’s amazing how much internet content is created by a few people. In the English-speaking world, there’s about ~450 million (?) people, yet I recognize names of writers all the time, and not just in health journalism. Seems like I know many of them.

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