The Risks of Hypoglycemia

Given how long the glycemic variability thread has become, and given that we’re sort of skirting around a topic that keeps coming up, I thought it would be good to create a new thread on the risks of hypoglycemia. I’m going to look through the literature later on today and pull what I’ve read about how to balance those risks with the risks of hyperglycemia. I’ve been mulling this one for a while actually, ever since I got back from diabetes camp and listened to a talk from one of the leading researchers in the field, who seemed pretty nonchalant about the risks of even severe hypoglycemia.

Others involved in the thread (@oni @Eric @Michel @ClaudnDaye @katers87), I’d love it if you could contribute here as well!


I’d much rather read about the specific medical reasons that can cause it, instead of cohort studies. There are so many other factors that can affect a cohort study.


there are a ton of proposed mechanism studies as well. I can dig around tonight. There are always going to be limitations with these studies. But realistically speaking, a cohort study is going to be stronger evidence than a petri dish or mouse study that can elucidate the underlying mechanisms with more granularity. The latter are certainly useful for generating hypotheses but it’s really tough to get those mechanistic studies in humans that are also long-term. Just too $$$. But I’ll try to do some digging.


@TiaG, sorry for not splitting threads earlier, I was on phone only all day… Will work on it tonight.

We have several strong discussions from about 9 months ago. Several studies we quoted and discussed concluded that no brain damage was accruing even in severe hypoglycemic episodes. After reading these studies and following these discussions, I have discounted the importance of hypoglycemia with regards to later medical consequences.

So, for me, the two issues are (a) hypoinsensituvity following to many ling hypoglycemic episodes, and, if course (b) death due to severe hypoglycemia. But I am not really worried about (b) while my boy lives at home. Thank God for CGMs :slight_smile:

I won’t be able to look up any study for several days but I will try next week if nobody puts any up.

Btw, I notice 30 other threads tagged with hypoglycemia

I’ve seen several early studies tying hypos to both microvascular complications and cardiac autonomic neuropathy. These studies are pretty preliminary though, so I don’t put a lot of weight to them. Nevertheless, I wouldn’t discount them altogether.
I’m not as worried about the cognitive effects; the researcher I was discussing also basically said that even people who have severe hypoglycemic seizures several times over the course of their childhood have only very mild cognitive impairments.
But my guess is that the brain is probably the organ that is most robust to the effects of glucose starvation. I’ll dig around tonight.

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Here is my post about that from a while ago:


And here is one showing hypoglycemia is a much greater concern than glucose variability:

[PASTED from separate post for the purpose of splitting thread: Should diabetes treatment optimize glycemic variability?]

There’s also this one, which is just a review but it does summarize quite a few studies. (I actually kind of hate this finding as my son does spend too much time low, and one of biggest worries is cardiac autonomic neuropathy, neuropathy in general and vascular function)


Study authors:

Markolf Hanefeld
Eva Duetting
Peter Bramlage

Competing interest:

Markolf Hanefeld and Peter Bramlage declare to have received research funding and honoraria from a number of companies producing antidiabetic drugs including Novartis. Eva Duetting is an employee of Novartis.


The preparation of this article was funded by Novartis,

Novartis is the maker of diabetes drugs Eucreas/Galvus Met (vildagliptin/metformin) and Starlix (nateglinide)

In April 2013, federal prosecutors filed two lawsuits against Novartis under the False Claims Act for off-label marketing and kickbacks


Eric, are you suggesting that this is an invalid study, even though it is summarizing MANY other studies? So is it just the summary that is invalid, or the studies that are being summarized? Do you really believe that there are NO risks from hypoglycemia? Give me the word, and I will be happy to gather studies that show there are risks from hypoglycemia, and - full disclosure - I am not getting any money from Novartis.

I don’t know if that study is invalid. I am sorry I was snarky about it.

But I do not like when companies with a profit motive for a particular study outcome are the ones who are doing the study.

I know that there are risks to hypoglycemia, but I have not seen any conclusive proof that low A1C’s cause cardiovascular disease. For every study that shows it, there is another study that shows the opposite. We could exchange links to conflicting studies all day.

I also do not like the cohort studies.

There are people on some diabetic sites who post about their low A1C’s, and how they have only 15 grams of carbs a day, but have 80% of their caloric intake from fat.

If someone like that gets cardiovascular disease, is it because of their low A1C, or because of the large amount of fat they consume in their diet?

You can find a cohort studies that will try to correlate the low A1C with the risk, and I don’t think that is a good way of proving it. There are always multiple factors at work.


what’s the profit motive for Novartis to show risks associated with insulin (i.e. hypoglycemia)? I don’t mean tthat sarcastically at all I am just genuinely curious about what you think is the perceived conflict here. Are they peddling a drug that prevents hypoglycemia? (I’m guessing probably; I just don’t know…)

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I think the risks might be different for people with T1 and T2.

When I search this topic on PMC, I get a whole bunch of studies saying opposite things.

My personal opinion is that severe hypoglycemia is hard on your body- especially prolonged severe hypoglycemia. I don’t know exactly how/why it’s bad for you, but I know that when it has occurred (thankfully not for years), it took my young body at least 1-2 days to fully recover. My brain was slow and my body ached. I think avoiding these instances is the number one benefit of a cgm (among many others).

I’m not convinced that mild hypoglycemia has any lasting effect though.

I think severe hypoglycemia actually occurs more often in those with poorer control, and it seems like it’d be hard to isolate the exact cause of CVD in those instances.


Having lived in both the “hard” science realm, as well as spending most of my career in the medical space working for large companies, finding physicians that are doing research without accepting some form of funding from the companies is rare. Why? Because the NIH doesn’t fund enough medical studies, so the only way to get funding in many cases is to accept it from the companies.

They don’t outwardly influence the results, however whenever you see very difficult studies with complicated statistics you can bet the company statistician did the analysis for the physician, very few of whom are able to perform this level of analysis.

With that said, I don’t think any doctor would outwardly perjure themselves for the company money, at most the influence to not publish a negative study would be the biggest sin in my experience.


I just spent a good bit of time carefully reading @TiaG’s excellent meta-study.

In my opinion, this meta-study does an excellent job at summarizing the present research. The present research, however, is quite inconclusive:

  • The meta-study identifies all the recent high-quality clinic trials: DCCT/EDIC, UKPDS, ACCORD, ADVANCE, VADT, ORIGIN. While many of them show increased hypoglycemia with intensive treatment, only one of them, ADVANCE, showed a possible link between hypoglycemia and increased risk of CVD:

In contrast, the ADVANCE study, which analysed 11,140 T2D patients, did not observe increased mortality. However, intensive therapy again led to hypoglycaemia, which was linked to vascular events and CV-related death.

That sole example was also exclusive to T2D patients.

  • The meta-study identifies many mechanistic studies (close to 100) that link hypoglycemia to factors of CV risk. Of all of them, the association that seemed strongest to me was the link between hypoglycemia and inflammation. But, again, these are highly tentative studies at this stage: there is no direct link or causal relationship established, and certainly no statistical correlation.

So, at this stage, it seems to me that it is good to remain alert to the issue, but that no further action is necessary, beyond what we all already do to minimize hypoglycemia whenever possible.

I am particularly interested in the issue because we run into several episodes of hypoglycemia every day, in the course of treating daily peaks.


Seems like there should have been a control group of normoglycemic children in this trial as well.

It is not completely clear in the linked write-up, but I think they did have 50 gluco-normal patients as the control.

[quote=“Michel, post:15, topic:5221”]
While many of them show increased hypoglycemia with intensive treatment, only one of them, ADVANCE, showed a possible link between hypoglycemia and increased risk of CVD:

I think it’s worth remembering that there are risks from hypoglycemia beyond cardiovascular. These include coma and death in rare circumstances, but also increased harm from falls and automobile or other machinery accidents due to small or moderate differences in reaction time, balance, etc, and an increased risk of brain effects from BG low enough to cause seizure but not low enough for coma. I thought this article was interesting in that regard:


Sorry, but I hadn’t actually read this that carefully, just noticed it was talking about hypo seizures from diabetes and written by someone respected in online diabetes community, so posted it because I thought it was relevant. I abolutely agree with you that the DCCT, who he is apparently referencing , didn’t suggest it was best to aim for an a1c of 9, in fact far from it. This concluding sentence from their first report is the best summation of the DCCT in my view: “The recommendation of the DCCT remains that intensive therapy with the goal of achieving near-normal glycemia should be implemented as early as possible in as many IDDM patients as is safely possible.”

So I suspect we agree that the important caveat in that statement with regards to brain safety is the statement “as is safely possible”. And although he missed the point of the DCCT, he does cite two links that seem relevant to the discussion. The first suggests there are clearly risks from running BG low enough to get seizure - . The second re-used the DCCT results to suggest the risks were low or at least undetectable using the psychological tests they used:

The thing is, personally I do believe that there is probably some nervous system damage from running BG low enough to get seizures or coma - starving brain cells of the food they need to live. It just makes too much sense. Hopefully the damage is small enough to be negligible. But I also do believe that it makes it important not to trivialize the risks of severe low BG, and I think there is sometimes a tendency to do that in dforums where it can seem like “the lower the better”.

And in case it sounds like I’m preaching, please know that this isn’t my intent and I care about this issue because it is highly relevant to me. In the 40 plus years I’ve had t1 I have not gone into coma, but I have had a fair number of seizures (uncontrollable violent shaking) that have all been resolved by treating with glucose or whatever candy I had available. We all have to walk the same tightrope between high and low blood sugar.


I also think seizures or a coma are very scary. I have not yet experienced either, finger crossed that continues! I have experienced severe lows that lasted awhile while sleeping though (before a cgm). I felt terrible afterwards for at least a full day.

I think there’s a big difference between a severe low and a minor low. I would consider a value in the 60s to be minor.

I think the biggest risks of lows can be better managed with a cgm. Without a cgm, I think it’s much harder to lower your target range safely.

I think we both agree that the target range should be customized to the individual. If I were prone to seizures, I would prioritize reducing lows more than I currently do. With a cgm in hand, I prioritize limiting severe lows but feel that higher bgs are more damaging to me long term than minor lows.