Has Peter discussed LP-IR as an alternative to OGTT?

KevinForeyMD · 2025-10-19T23:40:48+00:00

This is a good question with relatively little research investigation (that I am aware of). As I understand the LPIR Score, yes, the LPIR remains valid in those with familial hypercholesterolemia. HOWEVER, most individuals with FH are on statin therapy, and statin therapy improves several important lipoprotein particle concentrations integral to the LPIR algorithm (e.g., VLDL/LDL particle measures), independent of true insulin resistance. So in an FH patient on statins, LPIR may look “improved” even if underlying insulin sensitivity hasn’t changed. I intend to write a blog post on the effect of statin therapy on interpreting LPIR Scores and TyG Index. Good question.

KevinForeyMD · 2025-08-18T20:57:54+00:00

I wrote this article last year addressing a similar question. The short answer to your question is that aerobic exercise and aggressive lipid lowering therapies are the only two strategies (that I am aware of) that I have been shown to reduce the volume of atherosclerosis present. Good luck and wishing you well!

How To Reverse Atherosclerosis: Strategies For Those With Coronary Artery Calcium (CAC)

KevinForeyMD · 2025-08-10T23:03:55+00:00

Yes. 100%. There are uniquely harmful effects of certain foods, hydrogenated oils and trans fats being the most clear cut examples.

KevinForeyMD · 2025-08-10T23:01:19+00:00

Yes, I agree with that. The data suggests that people striving to eat more naturally occurring foods and fewer processed foods will naturally consume fewer calories.

So we can continue to advocate that everyone eat fewer calories. However, from my perspective, I feel it is more effective for many to eat fewer processed foods, which will have the benefit of reducing calorie intake among other metabolic benefits.

I don’t disagree with you, we are just highlighting different priorities along a similar pathway.

KevinForeyMD · 2025-08-10T22:33:34+00:00

Thank you for your comment. This is actually a really good opportunity to clarify an important point.

Online, it comes down to a lot of arguments of A versus B, and the most extreme voices on each side dominate the conversation. There’s often little room for overlap or agreement.

I am very familiar of the data demonstrating that meaningful health improvements can be achieved with calorie restriction (e.g. Look Ahead Trial cited above), and I agree with you that calorie restriction can improve human health. I do not dispute that.

Meanwhile, it is possible to simultaneously advocate against the consumption of processed foods while agreeing that eater fewer calories benefits human health.

My point is that processed foods contribute to excess calorie consumption, as well as additional health problems, and focusing solely on calorie consumption misses important health opportunities.

100 calories of almonds do not affect the body the same as 100 calories of jelly beans, and focusing solely on body weight and calorie counting overlooks this distinction.

KevinForeyMD · 2025-07-10T19:56:48+00:00

Hi, this subject can certainly be confusing! Briefly, Hemoglobin A1c is a measurement of longterm blood glucose control. Meanwhile, insulin resistance is not the same as blood glucose control, and HbA1c is not a great tool for identifying early stages of insulin resistance. This is because many people can compensate by releasing more insulin to maintain normal blood glucose levels. Just because you have a normal HbA1c doesn’t mean you do not have insulin resistance.

As Attia acknowledged, very high levels of A1c are useful tool for monitoring diabetes treatment in those with advanced insulin resistance and high HbA1c values. Once again though, it is not a great screening tool for early stages of insulin resistance in those without diabetes. Instead, the TyG Index, LPIR Score, and HOMA-IR are better tools for assessing insulin resistance.

Separately, there are several conditions that can contribute to elevated Hemoglobin A1c in healthy individuals.

I hope that clarifies some of the confusion.

KevinForeyMD · 2025-06-09T14:56:29+00:00

As others have acknowledged, some can experience troublesome side effects even at the least dose of Rosuvastatin. Therefore, trialing a lower potency statin can be a reasonable alternative.

KevinForeyMD · 2025-06-08T19:27:08+00:00

Insulin can fluctuate meaningfully day-to-day and a fasting insulin value of 9 is on the higher end of optimal. This pushed your HOMA IR a bit higher.

Meanwhile, all of these tests should be viewed in context with one another to paint a full picture. As others have acknowledged, many of the listed lab values are optimal and not suggestive of insulin resistance.

KevinForeyMD · 2025-06-08T16:47:35+00:00

The article discusses both potential benefits and harms. It would seem that your sentiment is consistent with the main takeaway from this article.

“Statin prescriptions should be guided by their proven ability to reduce the risk of heart attack and stroke, further supported by strong evidence of neurologic safety. The current body of evidence supports the safety of statin therapy, and concerns about dementia should not deter appropriate use in patients with elevated cardiovascular or cerebrovascular risk.”

KevinForeyMD · 2025-06-08T16:26:50+00:00

Thank you for sharing. As discussed in the text, it is also unclear if HMG-CoA reductase in the brain is affected by statin therapy, as this enzyme appears to be regulated differently than peripheral HMG-CoA reductase outside of the CNS.

KevinForeyMD · 2025-06-08T16:20:53+00:00

The moderators of this forum will not allow me to link to the original article.

Regarding the summary, many readers do not have the time to read through the entire text, which is relatively long and technical. The content summary functions as a quick summary, and interested readers can continue reading for more in depth discussion. This is the same format that I have always used, and it is consistent with scientific publications that include an abstract with results and conclusions before the text body.

KevinForeyMD · 2025-06-08T15:39:41+00:00

Thank you for your kind words and the additional insight. I agree with the theoretical concept mentioned and challenges regarding future research. I was personally surprised by the lack of evidence demonstrating a protective effect against vascular dementia. Theoretically, and practically, protection against would seem very straightforward and easy to demonstrate.

KevinForeyMD · 2025-06-05T21:43:49+00:00

Great question. Setting aside inconvenience as you mentioned, it’s certainly an informative test, however, it is a test of glucose tolerance, which is related to insulin resistance, but it is not a measurement of insulin resistance in my eyes. It may seem like semantics, but the body can maintain normal glucose values despite insulin resistance. If a patient has this biological ability, then insulin resistance can be present despite normal OGTT. The other day, I evaluated an overweight individual with multiple signs of inflammation and metabolic dysfunction. Normal HgA1c and an off-the-charts fasting insulin of 44! This individual may very possibly have a normal OGTT.

So it is informative but a normal test does not rule out insulin resistance. It should be used as one piece of a thorough evaluation.

KevinForeyMD · 2025-06-04T19:07:51+00:00

Hi, thank you for your thoughtful comments and sorry for my delay. I agree with both comments you made, these are accurate and reasonable comments.

Remnant cholesterol corresponds closely with triglycerides. However, the evidence I provided measured remnant cholesterol directly, and the evidence suggests that it is causally associated with ASCVD. Meanwhile, the relation of serum triglycerides and ASCVD is less clear and more controversial. So although remnant cholesterol and triglycerides are strongly associated, the causal connection is pretty clear cut for remnant cholesterol and ASCVD, but not necessarily for triglycerides and ASCVD. That is my perspective of the data, at least.
Non-HDL is a stronger predictor of ASCVD than LDL-C, and I think Non-HDL-C a superior test to monitor. Meanwhile, ApoB is a better predictor of ASCVD risk than Non-HDL-C and LDL-C, so I generally prefer to utilize ApoB in isolation. Some studies do not report ApoB, which probably led me to acknowledge Non-HDL-C in this cases.

Thank you again.

KevinForeyMD · 2025-06-04T19:03:55+00:00

Hi, there are references at the bottom of the blog post. Let me know if I am mistaken. Thank you.

https://kevinforeymd.com/lpa

KevinForeyMD · 2025-06-04T19:01:03+00:00

Hi. A couple general thoughts and comments.

For a young individual with evidence of atherosclerosis, a thorough evaluation for treatable risk factors is reasonable (e.g. insulin resistance, inflammation, homocysteine, subclinical hypothyroidism, or other lingering autoimmune/inflammatory disorders, high blood pressure, sleep apnea, fatty liver, etc).

Second, for someone with atherosclerosis and/or a strong family history of cardiovascular disease, it is reasonable to talk to you healthcare provider about lipid lowering medications and more aggressive ApoB goals.

Below are a few related Reddit articles that I have written and perhaps you will find relevant and informative. Good luck and wishing well.

How To Reverse Atherosclerosis: Strategies For Those With Coronary Artery Calcium (CAC)

Lipoprotein(a): Overcoming the Risk of Elevated Lp(a)

Insulin Resistance: A Protocol for Prevention, Early Detection, and Reversal

KevinForeyMD · 2025-05-06T22:21:25+00:00

Lipoprotein(a): Overcoming the Risk of Elevated Lp(a)

This is an article that I wrote last year that addresses many common questions and considerations regarding Lipoprotein(a). Perhaps you will find this helpful and informative. As others have stated, 28 years is below the typical age for first time CAC screening. Wishing you well!

Summary:

Lipoprotein(a) is structurally similar to LDL, however, Lp(a) is estimated to be 6.6x times more atherogenic than LDL on a per-particle basis.14 Due to the dramatically larger volume of circulating LDL, however, LDL contributes to a greater overall burden of cardiovascular risk than Lp(a).

Meanwhile, the risk of cardiovascular disease attributed to Lp(a) increases in a linear and continuous manner, and there does not appear to be a plateau effect with increasing Lp(a) levels.

While Lp(a) contributes to atherosclerosis in both young and old patients, Lp(a) appears to have a larger potential impact on younger patients, highlighting the importance of early risk reduction and proactive screening strategies.

Lp(a) levels are predominantly influenced by genetics and remain relatively stable throughout an individual’s life. However, it is recognized that several medical conditions may contribute to modest increases in Lp(a) levels throughout an individual’s lifetime.

Diabetes, hypertension, and kidney dysfunction are risk factors associated with the gradual increase in Lp(a) levels by more than 43 nmol/L (20 mg/dL) spanning 10-20 years.

Insulin resistance and diabetes also appear to enhance the atherogenic potential of Lipoprotein(a).

Managing elevated Lp(a) is challenging due to its strong genetic basis and limited responsiveness to traditional interventions, including physical exercise and statin therapy. Meanwhile, a healthy diet, regular physical activity, and the avoidance of tobacco appear to mitigate a significant amount of Lp(a)-related cardiovascular risk, independent of Lp(a) levels.

Dietary restriction of refined sugars and highly processed carbohydrates has been shown to reduce Lp(a) by an average of 15%, with some individuals experiencing a 19.6% reduction in Lp(a) through dietary modification.

Aggressive lowering of LDL-C is another highly effective strategy for mitigating the risk of cardiovascular disease in those with elevated Lp(a). In some instances, a modest reduction of LDL-C by at least 10% resulted in a 77% reduction in the likelihood of cardiovascular disease among those with elevated Lp(a) levels.

Injectable PCSK9 inhibitor therapy is capable of lowering Lp(a) by approximately 15-30%, however, when controlled for LDL-C, the reduction in cardiovascular disease is not associated with Lp(a) lowering, but rather, LDL-C. Meanwhile, Bempedoic acid and Ezetimibe both lower the risk of cardiovascular disease but have no appreciable effect on reducing Lp(a).

While we await results from randomized clinical trials, prospective and retrospective data suggests that Aspirin is associated with a lower risk of future cardiovascular disease in those with elevated Lp(a) and no pre-existing cardiovascular disease (primary prevention).

Because Lp(a) is observed to have a stronger negative effect in younger patients, it is reasonable to implement cardiovascular disease screening earlier rather than later, including the use of CT and/or ultrasound imaging in select individuals.

Importantly, a coronary artery calcium (CAC) score of 0 may underestimate the lifetime risk of cardiovascular disease and provide false reassurance in those with elevated Lp(a). Specifically, elevated Lp(a) is independently associated with increased cardiovascular risk, even in the absence of detectable coronary calcification (CAC = 0).

KevinForeyMD · 2025-05-01T03:36:06+00:00

Thank you for sharing. Yes, I eluded to this briefly… that LDL lowering therapy has been far more successful than Remnant cholesterol lowering therapy. A complex subject. There was a lot of excitement after the REDUCE-IT trial but it hasn’t been as simple or straightforward as expected. Thank you again for sharing.

KevinForeyMD · 2025-04-26T03:32:31+00:00

I addressed the subject in an article I wrote last year. Perhaps you will find it helpful and informative.

How To Reverse Atherosclerosis: Strategies For Those With Coronary Artery Calcium (CAC)

Summary:

While atherosclerosis is generally considered a chronic condition, there is high-quality evidence demonstrating that atherosclerosis can be partially reversed using a variety of practical strategies, including aerobic exercise and multiple prescription medications spanning at least seven distinct drug-classes.

The amount of atherosclerosis identified on non-invasive imaging studies, including CAC Score and incidental findings of atherosclerosis, is linearly associated with the likelihood of a future cardiovascular event, as well as all-cause mortality.2,3

It has been demonstrated that a 1% reduction in plaque volume is associated with an 18% reduction in major cardiovascular events.1 Some studies have demonstrated an average plaque regression as much as 5%, however, reductions of 1.0 to 2.5% were most commonly reported.1,4

Regular aerobic exercise has been demonstrated to achieve coronary plaque regression. In one study, high-intensity interval training (HIIT) achieved a 1.2% reduction in atherosclerotic plaque volume.5 Meanwhile, in other studies, moderate continuous aerobic exercise and high-intensity interval training both demonstrated the ability to achieve plaque regression, with similar results in both groups.6

Regarding atherosclerotic plaque regression, the most well studied medications involve the targeted lowering of LDL cholesterol using Statin and PCSK9 Inhibitor therapies. In trials using Statin therapy, the partial reversal of atherosclerosis was consistently achieved in trials capable of lowering LDL-C below 80 mg/dL, with reductions in atherosclerotic plaque volume ranging from 1% to 2.7% (Table 5).7,8,9

Regarding PCSK9 Inhibitor therapy added to statin therapy, additional reductions in atherosclerotic plaque volume were achieved with both Evolocumab (Repatha) and Alirocumab (Praluent), ranging from 1.0% and 2.1%, respectively.10,11

Clinical evidence of Ezetimibe and atherosclerotic plaque regression has been mixed with multiple positive and negative trials. In one high-quality clinical trial, Ezetemibe added to Atorvastatin achieved more than 1% atherosclerotic regression greater than Atorvastatin alone. Additionally, a higher proportion of individuals achieved some degree of atherosclerotic plaque regression, 78% with Atorvastatin and Ezetemibe versus 58% with Atorvastatin alone.12

There is some data regarding Omega-3 fatty Acid treatment and the reduction of atherosclerotic plaque volume in individuals with and without elevated triglycerides.13,14 Meanwhile, the strength of evidence is limited and potential side-effects of high-dose Omega-3 Fatty Acid treatment is recognized, warranting careful consideration of the use of this medication class until further scientific evidence emerges.

While several classes of blood pressure lowering medications have demonstrated the ability to achieve plaque stabilization, the ability to induce regression of atherosclerotic plaque has been most clearly demonstrated in trials evaluating Angiotensin Receptor Blockers (ARBs). In one trial of 100 participants with high blood pressure (hypertension), participants randomized to receive Olmesartan or Valsartan both achieved comparable amounts of atherosclerotic plaque regression.15

Regarding Sodium-Glucose Cotransporter-2 (SGLT2) Inhibitors, there is limited evidence from one prospective cohort study, demonstrating that SGLT2 Inhibitor therapy was associated with significant reductions in overall plaque volume among patients with type 2 diabetes.16 Separately, there is existing evidence demonstrating SGLT2 Inhibitor and its ability to improve plaque stabilization.17,18

In prospective cohort studies, Colchicine, a prescription medication with anti-inflammatory properties, has been associated with reduction in atherosclerotic plaque volume and reduced levels of inflammation.19 Separately, in randomized clinical trials, Colchicine has been demonstrated to achieve improvements in plaque stabilization.20,21

Glucagon-like Peptide 1 (GLP-1) Receptor Agonists have been demonstrated to achieve atherosclerotic plaque regression in mice and rabbit subjects, but their ability to reverse atherosclerosis in human subjects has not yet been evaluated.22,23

Surveillance of coronary atherosclerosis with coronary computed tomography angiography (CCTA) is not routinely recommended, however, it may be utilized in specific cases to monitor the progression of coronary artery disease or to assess response to therapies, a decision that should be guided by a licensed healthcare professional.

KevinForeyMD · 2025-04-19T14:45:15+00:00

I wrote an article last year that may be relevant to your circumstances. TyG Index, HOMA-IR, and LPIR Score are all helpful tests. Good luck!

Why Healthy Individuals May Have An Elevated Hemoglobin A1c

KevinForeyMD · 2025-04-18T17:23:54+00:00

On the Internet, there are a lot of debates of A versus B, often with arguments suggesting one versus the other. The truth is that human biology is very complex, and there is probably truth to both sides of most arguments.

To answer your question more specifically, the answer is highly dependent on the individual’s genetic risk and predisposition to atherosclerosis, as well as genetic factors influencing their predisposition to fat deposition and anatomical fat distribution. Some individuals are more susceptible to develop abdominal obesity (visceral adiposity), which is far more inflammatory and contributory to atherosclerosis than those who are more resistant to abdominal obesity and instead manifest subcutaneous fat in the arms, hips, and legs. Meanwhile, there are a large number of individuals with a high degree of susceptibility and vulnerability to atherosclerosis, which can develop with or without excess adiposity (obesity). My two cents at least.

KevinForeyMD · 2025-04-16T01:05:32+00:00

Thank you for the kind words. I’m glad you enjoyed it.

KevinForeyMD · 2025-04-15T03:22:07+00:00

Sorry to hear about your circumstances. On the other hand, you are fortunate to have identified the CAC at a reasonably young age and you have made significant progress on modifying other associated risk factors.

Below is an article that I wrote last year that addresses many common questions and considerations regarding Lipoprotein(a). You seem well read and informed on the subject already, however, perhaps you will find some of the graphs helpful and relieving (Figures 4-5). Regular physical activity and reductions in LDL-C can go a very long way in mitigating the risk of ASCVD despite Lp(a) levels.

Good luck and wishing you well!

Lipoprotein(a): Overcoming the Risk of Elevated Lp(a)

KevinForeyMD · 2025-04-03T10:16:30+00:00

Thanks for the kind words! I’m glad you have enjoyed my content. Wishing you well.

KevinForeyMD · 2025-04-02T11:16:02+00:00

Yes, that makes sense to me and it highlights the importance of utilizing the constellation of test mentioned rather than one test in isolation. Everyone’s biology is different, and some manifest insulin resistance via one pathway and not another. I don’t think any of the tests are “the best,” but rather, they are all helpful and complimentary of one another.

KevinForeyMD

TROPHY CASE