New insights into the role of HDL in heart disease risk of T1D

Really fascinating.


That was a great read with a striking conclusion:

in the diabetes group the proportion of active HDL-apolipoprotein A1 was significantly and inversely correlated with HbA1c. The reduction in the sequestering function of lipids by HDL was apparent soon after the onset of type 1 diabetes and persisted over time.

It thus appears that type 1 diabetes leads to a reduction in the cardioprotective function of HDL. It is likely that this ongoing deficit in the breakdown of lipoproteins by HDL contributes to the increased risk of cardiovascular disease known to occur in patients with type 1 diabetes.

I am still puzzled by the stock photo they posted :slight_smile:

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So is it T1D that reduces the cardio protective HDL, or is it high A1c? If the latter, would T1Ds who achieve near-normal blood glucose and and A1c within the non-diabetic range regain the benefits of HDL?

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in general A1C doesn’t seem to be correlated with heart disease risk in T1Ds, if I remember correctly. So my guess is that some cellular programming leads to a conformational change in HDL very early in the diagnostic period and lowering A1C later on doesn’t do much to reduce that risk. Probably diagnosing kids really early and getting them into tight control really early could do something to prevent this change, but who knows.

The article says this:

"The proportion of active HDL-apolipoprotein A1 was significantly lower in the diabetes group compared with the control group7 and remained relatively consistent from baseline to 5 years.

Furthermore, in the diabetes group the proportion of active HDL-apolipoprotein A1 was significantly and inversely correlated with HbA1c. The reduction in the sequestering function of lipids by HDL was apparent soon after the onset of type 1 diabetes and persisted over time."

I think this is saying that A1c does have an impact :slight_smile:

but the article seems to be saying the A1C was fairly stable for individual people over the 5-year period, so which comes first – the lower A1C early on and the better HDL function, or does lowering A1C 10 years into diagnosis have the same effect? This study can’t say, but the fact that A1C doesn’t seem to correlate with heart disease risk very well in large epidemiological studies suggests otherwise.

They may be saying that those with lower, stable A1cs were less likely to have a lower proportion of active HDL-apolipoprotein A1 whereas those with higher, stable A1cs were more likely to have a lower proportion of active HDL-apolipoprotein A1c.

I’m not sure that they say that the A1c was stable throughout the whole study though. They definitely don’t indicate if improvement in A1c causes a higher proportion of active HDL-apolipoprotein A1 (reversal of the effects of a high A1c). Wish they clarified that a bit better. We can conclude only that those with lower A1cs were less likely to have problems, but we don’t know if the effects of having a higher A1c (and consequently low HDL-apolipoprotein A1) can be reversed.

What a mouthful :stuck_out_tongue_winking_eye:

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Yes, this is the sentence that got me wondering. I don’t see anywhere in the article saying that A1c level was stable or not.

I’m wondering about T1s who achieve near-normal BGs and a non-diabetic level A1c (i.e., <=6.0% or so). To my knowledge, most large studies looking at diabetes don’t look at people who have really tight control as a subgroup. They just include people who have varying degrees of average control, such as comparing 7% to 9%. Sure, 7% is better than 9%, bot both are still actually high compared to someone without diabetes.

If heart disease is just inherently part of Type 1 and something that can’t be mitigated (which has been the message so far), that’s kind of depressing. But if heart disease is something that can be mitigated by seeking very tight control, that’s a much more empowering outcome.


Well, in both T2s and T1s heart disease risk and BG control are thought to be mediated by inflammation, so my guess is that whatever you do to reduce that inflammation is good. hyperglycemia does fuel inflammation but other processes are also going on independent of that BG level-mediated inflammation, so probably tight A1C from the get-go has some moderating influence but is nowhere near as impressive as we’d hope in terms of eliminating all increased risk. But I don’t know.

You’re right though; until now the only people in studies who had an A1C of, say, 5.8 or 5.9 were people who were constantly going persistently low. There was no such thing as a person with an A1C of 5.8 and an SD of 30 in the DCCT – those people were probably often fluctuating up to the 200s or 300s; they were just also spending tons of time in the 30s and 40s (mg/DL).

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I think just the process of autoimmunity plays a role in inflammation, especially because so many people with T1 have multiple autoimmune conditions. I’m sure my immune system is always ramped up between attacking my pancreas, thyroid, esophagus, two dozen allergens, plus all the normal bacteria and viruses it has to fight off. I’ve had the CRP test (which measures nonspecific inflammation) done twice and it was high both times (2.8 and 3.1). I’m sure that indicates that my body is in a constant state of low-grade inflammation.

See, all that stuff I just wrote is depressing. It would be nice if it were something that was under our control.


I was unhappy to see the third paragraph of the article state “Patients who are not able to produce any insulin are said to have type 1 diabetes, which usually presents in childhood,” because both clauses are wrong. I treat any scientific paper as dubious when it states falsehoods as facts, because where there’s one roach there probably are many. What else did they get wrong? Are they also careless in the technical work and in the formation of conclusions?


Sure, but this is science journalism, which is often full of mistakes and sensationalized. If you want the real story, you need to read the actual peer-reviewed research article, which is here (and doesn’t include any statements like that as best I can tell from my very quick skim): Reduced HDL function in children and young adults with type 1 diabetes | Cardiovascular Diabetology | Full Text

It’s open access, so everyone can download it.


My blunder. Thanks for the clarification.

On the contrary, the original paper (not the article) says that “correlations between HbA1c and HAE in the diabetes patients of this study were quite modest, and the association did not remain significant at follow-up when controlling for confounding variables.” So there was some correlation, but to the extent that HAE is responsible for increased risk of heart disease, controlling HbA1c would not significantly affect that risk. Which is consistent with TiaG’s point that A1c doesn’t correlate with heart disease in other studies.

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I didn’t read the real peer-reviewed study, just the science journalism article. This reiterates Cardamom’s point.

Actually, now that I look at it, i don’t think a correlation between HbA1c and HAE is as important as a correlation with HAE-apoA-I ratio. “The HAE-apoA-I ratio, reflecting the HDL function per concentration unit apoA-I, was significantly lower in the diabetes group both at baseline…The HAE-apoA-I ratio was significantly and inversely correlated with HbA1c, except in the control group at baseline, as shown in Table 2.”

“HAE calculated per unit HDL, as the HAE-apoA-I ratio, yields a measure of HDL function analogous to enzymatic specific activity and is more discriminating of CVD status than HAE alone [21].”


But the patients being studied had a mean A1c of 8.4% (baseline) and 9.0% (follow-up). The control group had a mean A1c of 5.3% at baseline and follow-up. So to me, the fact that this study didn’t show a statistically-significant correlation doesn’t mean much, because it’s likely comparing a high A1c to a higher A1c… What would the results be if you had a group of patients who had a mean A1c of 5.5% compared to controls with a mean A1c of 5.3%?


Can someone point me to these other studies? What I’ve seen on this topic points to very strong correlation between HbA1c and the risk of coronary events. For example, you may take a look at the recent Glycaemic control and excess risk of major coronary events in persons with type 1 diabetes (Heart, British Cardiovascular Society, Nov.2017). Here is a portion of their Figure 2, which shows relative risk (HR) for acute myocardial infarction (AMI) or coronary heart disease (CHD) death as a function of HbA1c.
Looks like an extremely clear and strong correlation.

What seems to be unknown: (a) mechanisms behind the correlation, and (b) does the relative risk go down to 1 for PWD’s with consistently non-diabetic HbA1c (probably because it is still impossible to find a statistically relevant sample to check this).


Yes, this is an excellent point—correlations only mean something if you’ve got good representation across the full range that you want to extrapolate to. Restriction of range (i.e., all of the patients having elevated A1cs, vs including more with tighter and very tight control) can result in smaller correlations when in fact there would really be a larger one if a broader sample were included. However, most studies probably don’t include many if any of those patients because they are not representative of typical diabetics, or leave much room for improvement in control if it is a clinical trial, leaving it unclear what the picture really looks like for those with very tight control. It would probably take a study specifically seeking the answer to the question “does having achieved very tight control negate long term health risks associated with diabetes” to answer the question. I don’t know if anyone is doing that. The best way to find out what large studies are in the works though is via NIH’s reporter tool: RePORT ⟩ RePORTER


That isn’t what they did; they segmented each group (control or diabetic) into subgroups based on A1c and looked for differences between the subgroups. They did not say what the range of A1c’s was within each group (though they did give the st dev) - but it would presumably be whatever range would be expected in a group of about 300 T1 subjects; based on st dev, it was about 34% 7.1-8.4; 34% 8.4-9.7; 16% 7.0 or less; 16% 9.8 or more.

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I’m just reporting what I’m reading, not what I believe to be the case. I don’t think any one paper should be believed to the exclusion of others, either the OP’s paper or the one you cited. My take on it, based on a quick review of pubmed, is that there is a range of opinions on this issue, and papers to support both points of view. And therefore no consensus yet, though I think I do see more papers, and papers done on larger populations, supporting that there is an increased risk from poor control. This one is also hopeful: “If currently recommended HbA1c targets (< 7.0) can be reached, renal complications and smoking avoided in persons with type 1 diabetes, the excess risk of mortality will likely converge substantially to that of the general population.”

Given that, my belief is that it is good to err on the side of getting the best control you can, since that has many other benefits even if it turns out that the heart disease risk benefits may not be as great as other risks.