Biological Variation in HbA1c Predicts Complication Risk

My A1c and average glucose level don’t really line up that well. There was a discussion recently on aiming for a time-in-range goal versus an A1c goal. I thought a time-in-range goal was better, but it got me thinking about which of these has been shown to be a better predictor of the development of complications.

I came across the study below and found it so interesting that I thought I would share. The study looks at mean glucose levels (not time in range), but I think it shows that people who are high glycosylators may need to pay more attention to their A1c. I think an A1c goal may be critical for this group of people. When setting goals based on a desired A1c, these people may need to aim for a tighter range than low or medium glycosylators.

Though after looking through the study some more, that may not do enough. “As our data show, however, reducing blood glucose levels alone may not be sufficient because even patients in the DCCT with relatively low blood MBG levels had elevated risk of retinopathy if they belonged to the high-HGI group.” That’s not very unhelpful.

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I don’t think the MBG was collected in a way that would show accurate mean throughout the day or that quarter. It only represented one day of 7 BGs, every 3 months. So comparing a one day average to A1C of same quarter doesn’t make sense to me.

Calculation of MBG
A 1-day, seven-sample glucose profile set and a blood sample for HbA1c were collected quarterly over the course of the DCCT from each participant (5,23). Each glucose profile set consisted of seven capillary blood samples drawn before and 90 min after main meals (breakfast, lunch, and dinner) and at bedtime. Profile set data were available for 95% of the scheduled pre- and postmeal time slots and for 92% of the bedtime slots. The protocol also called for 3:00 a.m. glucose measurements, but these were available for <1% of the profile sets. HbA1c levels and the glucose concentrations of the profile set blood samples were determined at a central laboratory (23). For the present study, MBG was calculated quarterly for each participant as the arithmetic mean of the glucose concentrations of the profile sets, excluding 3:00 a.m. measurements.

I have always abundantly monitored my BG and had my A1c check performed three to four times per year. When I looked at the “equivalent” average glucose that my A1c supposedly translated to, I found that my meter BG was always lower than the A1c suggested. My CGM data confirmed this situation. I’ve raised this issue with several doctors and was met with a shoulder shrug or less by way of explanation.

So, yes, I agree with this study’s authors, other factors beyond the background BG average drives the A1c. I don’t take comfort in this knowledge as it elevates my risk of diabetes complications. All I can do is try to keep my blood sugar as close to normal as possible.

This is a 2004 study; I wonder if more has been learned in the last 14 years.


Good point. I’ll check to see if I can find another study.

Yes, I agree that that a 1 day average does not paint a complete picture. It’s too bad that they couldn’t have done an average of a week or so each quarter. However, I’ve seen a decent number of reports of discrepancies between A1c and average blood sugar (predicted A1c). The study was conducted over 9 years so I think there may be some validity to it.

I’m going to see if there might be another study that was more thorough and more recent.

There are a lot of published studies showing that the complications of diabetes are very much genetically influenced or determined. For example, complications show a common familial pattern, so if your grandmother developed retinopathy after 12 years and renal failure after 20 years, this makes it likely you will have the same timing of complications, even though there is no connection between your degrees of blood sugar control. I have posted a sample of these studies on other threads on this site. Type 1 patients who survive for a long period frequently have a genetic modification which protects their DNA alterations, so this is now thought to shield them from damage from hyperglycemia. Other genetic influences may have either accelerating or retarding influences on the development of complications. Especially diabetic kidney disease seems to be heavily genetically dependent.

That said, the HbA1c value varies according to the degree of anemia patients have, so if the patient’s hemoglobin level is low, this will artificially cause their HbA1c to represent their actual blood sugar levels lower than it should.

By anemia, do you mean low iron levels? If not, what else could cause this?

I have healthy levels of iron, but consistently have a lower A1c than predicted by my average glucose levels. I’ve always wondered why. I don’t have problems with lows (this is often suggested as the reason).

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Iron deficiency anemia is just one of many kinds of anemia, which are caused by a variety of influences. For example, in some diabetics hemoglobin levels will be low because they are deficient in the hormone erythropoietin, which is one of the substances along with iron which is necessary for the production of red blood cells. Erythropoietin levels decline with declining renal function.

I get my kidneys tested regularly, and there are no problems there. I’ll look around for other forms of anemia that influence A1c levels. Iron deficiency anemia is the only form that has come up in my google searches so far.

This is interesting—I definitely can agree there’s individual difference in how well A1cs seem to map onto average blood sugars. I find my A1c to be spot on with my Dexcom, but seem to be in the minority with that. I’m also really lucky that after the better part of a decade of poor control (now much better), I only have some retinopathy and no other noticeable complications. After a while, before the retinopathy but well after I thought I should have problems, I had started to think I was kind of immune to the complications and it honestly didn’t help my motivation. So maybe the fact that my A1c and Dexcom do align unusually well is an indicator of a protective factor. I could buy it.

For what it’s worth, my red blood cell count is always on the high side for a woman.

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I’m feeling this a bit now. It’s helpful to read your experiences and how you perceive that reaction now.

My blood count always comes back normal. The only abnormal things I’ve had are low vitamin D, vitamin B12, and Alkaline Phosphatase /ALP (only slightly under normal). The vitamins deficiencies have been corrected, but I don’t know why they were low in the first place.

I think for, a lot of factors went into my slacking off for a while—I had other health problems that left me exhausted a lot of the time, I was in graduate school for many years for a really challenging degree, and I didn’t at that point have some of the tools that would eventually be essential for my getting back into control (CGM and metformin, and then coming to the realization via CGM that I needed to alter my diet). Without a CGM, I would have a few weeks here and there with tight control but then not be able to maintain energy/motivation to test that much etc, combined with the fact that it just didn’t seem to be hurting me even though I knew it probably eventually would. But it really wasn’t until I had a vitreous hemorrhage that my “I’ll get things in control once I’m done with [next step of training]” stopped and I started putting that all in motion. But yeah, I consider myself extremely lucky to have only that as a complication given everything, and likely evidence of low genetic risk for complications, whether A1c/mean blood glucose concordance is part of that or not.

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Given the unlikelihood of people genetically related necessarily controlling their blood sugar to the same degree, the similar natural history of the development of diabetic complications within families suggests that genetic factors may be playing a large role in who gets which complications and when. For example, in my family, no type 1 diabetic ever develops diabetic kidney disease, even generations ago, and yet they all have early development of diabetic retinopathy. The following study is interesting in this context:

Diabetes. 2008 Aug;57(8):2176-80. doi: 10.2337/db07-1495. Epub 2008 Apr 28.
Heritability of proliferative diabetic retinopathy.
Hietala K1, Forsblom C, Summanen P, Groop PH; FinnDiane Study Group.
Diabetic nephropathy clusters in families, suggesting that genetic factors play a role in its pathogenesis. We investigated whether similar clustering exists for proliferative retinopathy in families with two or more siblings with type 1 diabetes.
The FinnDiane Study has characterized 20% (4,800 patients) of adults with type 1 diabetes in Finland. In 188 families, there were at least two siblings with type 1 diabetes. Ophthalmic records were obtained for 369 of 396 (93%) and fundus photographs for 251 of 369 (68%) patients. Retinopathy was graded based on photographs and/or repeated ophthalmic examinations using the Early Treatment of Diabetic Retinopathy grading scale.
Mean age at onset of diabetes was 14.3 +/- 10.2 years, and mean duration was 25.9 +/- 11.8 years. Proliferative retinopathy was found in 115 of 369 patients (31%). The familial risk of proliferative retinopathy was estimated in 168 of 188 sibships, adjusted for A1C, duration, and mean blood pressure. Proliferative retinopathy in the probands (48 of 168) was associated with an increased risk (odds ratio 2.76 [95% CI 1.25- 6.11], P = 0.01) of proliferative retinopathy in the siblings of probands (61 of 182). The heritability of proliferative retinopathy was h(2) = 0.52 +/- 0.31 (P < 0.05).
We found a familial clustering of proliferative retinopathy in patients with type 1 diabetes. The observation cannot be accounted for by conventional risk factors, suggesting a genetic component in the pathogenesis of proliferative retinopathy in type 1 diabetes.

I have no real history of T1 diabetes in my family except, perhaps, a great uncle that died suddenly at a very young age for reasons unknown. Otherwise, my rather exceptionally large family had no occurrences of type 1 diabetes until me and my younger sister (by 10 years).

While I wouldn’t wish diabetes on any of my family members, it’d be nice to know what to expect.

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