September 13, 2010

Diabetes Drug Interactions Can Harm You

One of the most disturbing things about now doctors practice medicine today is that they very often don't know about the way that the different drugs they prescribe interact with each other, and some of these interactions can be quite dangerous.

I learned this the hard way over the past few months.

I had long known that Dr. Andrew Hattersley, who is the world expert on the form of MODY diabetes I appear to have, believes that long term people with MODY do better on insulin stimulating drugs like Sulfonylureas.

For years I ignored this, as the tiniest dose of a Sulf drug caused me to hypo dramatically. Then I ran into some new data which suggested why this might be true: it turns out that a substance, C-peptide, which is a by-product of insulin secretion, by the beta cell may play a protective function for nerves. When we inject insulin, we don't get that C-peptide.

So last winter, after years of doing very well on low dose fast acting insulin at meal time, I decided to switch to the one, much milder, insulin stimulating drug that I'd learned in the past I could take without hypoing, Prandin.

Prandin is marketed with the information that it is very short acting--and is out of the body in about 3 hours. I had tried it a few years ago and this seemed to be the case.

What I didn't know--and learned the very hard way--is that this is only true if you take Prandin alone--without Metformin. If you combine the two, it turns out that the Metformin blocks the mechanism in the liver that eliminates Prandin and the drug ends up being much, much more potent.

Very oddly, this interaction is not listed in the "drug interaction" section of the Prandin Prescribing Information insert. You learn it only by paying attention to a chart displayed in the clinical trial section of the Prescribing Information.

It is there that we learn that, over a 4-5 month period, people taking Prandin alone saw their blood fasting blood sugar rise by an of 8 mg/dl, and people taking Metformin alone saw an average drop in their fasting blood sugar of 4.5 mg/dl, but people taking both drugs simultaneously experienced an average decline in fasting blood sugar of 39.2 mg/dl--almost ten times as much as with Metformin alone!

A1c dropped dramatically in the combination group compared to the groups taking each drug alone, too.

Since the combination of the two drugs was giving me extremely normal blood sugars (fasting in the 80s rather than the high 90s I get with insulin and post meal numbers never higher than 140 mg/dl ) I was happy. I loved not having to fuss with injections or having to worry about my insulin losing its potency in heat or cold.

Until recently, when after taking Prandin for about 8 months I started to experience severe hypos. How severe? In the very low 40 mg/dl range. And the only tipoff I had that something was going on was seeing some oddities in my visual field. No shakes, no pounding heartbeat. In short, no hypo awareness.

To make it worse these hypos turned out to be resistant to glucose. After seeing a 43 mg/dl reading on my meter I immediately downed 15 grams of glucose which should have raised my blood sugar to the 110s but when I tested 15 minutes later my blood sugars were still in the 40s. At that I glugged down a can of sugary soda and after that my blood sugars finally rose to the low 90s.

What made these hypos all the more confusing is that in the past when I was injecting insulin I could not get my blood sugar to drop any lower than the mid-60s no matter what. Any time my blood sugar went lower than the low 80s I'd get a fierce counterregulatory response that would give me shakes, a high pulse, and all the classic hypo (or false hypo) symptoms. Suddenly my hypo awareness was gone.

I'm not entirely sure what changed--these hypos happened a full eight months after I started using the Prandin/Metformin combination and I had not been seeing hypos before that. It is possible I was having milder hypos but not catching them because of the lack of symptoms, but who knows?

It is also possible that another drug I was prescribed--the blood pressure medication hydrocholorothiazide (HCTZ), a diuretic, played a part in the loss of hypo awareness.

Any drug that causes my beta cells to secrete insulin on their own at meal times seems to cause my body to hold on to salt and that, in turn, raises my blood pressure. Only HCTZ which flushes out extra salt lowered it. So I was taking one low dose HCTZ pill every 3 days which was keeping my blood pressure stable.

A Google Search came up with one site that wrote, without attribution, that HCTZ affects the autonomic nervous system which I know is involved in the counterregulatory response. So it is possible that the HCTZ was what turned off the hypo awareness. And indeed, it looked as if my hypos were happening on the day when I took my HCTZ.

But outside of that one line posted somewhere on the Internet I could find no other warning that HCTZ could turn off hypo awareness. In fact, everything I read suggested it should raise blood sugar, not lower it, though it did not raise mine.

After my 3rd hypo--which happened after I had stopped taking Metformin long enough that it should have washed out of my system, I stopped taking Prandin. And here's where things got interesting.

For the next week--even with the Metformin completely washed out of my body--I was seeing completely normal blood sugars after eating significant amounts of carbs. As in a "high" of 105 mg/dl which I saw after eating 3 ounces of muffin.

It was only after a week that my blood sugar started creeping back up to 143 after that dose of muffin--a dose that in the past would have shot my blood sugar up to at least the 250s.

Did the Prandin "heal" me? I doubt it. Instead, my guess is that it somehow built up in my body and is taking a very long time to wash out. Since my 1 hour readings are going up slowly and my fasting blood sugar is back to where it usually is without Metformin I assume my beta cells will go back to behaving as poorly as usual.

It is possibly I was experiencing yet another of the many weird MODY things that no one knows about except other people with MODY. I have received reports of "scary hypos" with Prandin from one other person with MODY.

But given the results of the Prandin/Metformin trial reported in the Prandin Prescribing Information, maybe this effect is also happening to people with more common forms of Type 2 who take this drug combination. If it has happened to you, please post about it in the comment section of this post.

But here's what's certain: No doctor, including the endocrinologist I see, had any knowledge that Metformin and Prandin interact to dramatically lower blood sugar. Had I not been the research wonk I am I would have had no clue why I was suffering the scary hypos, and if I didn't test my blood sugar religiously, I might not even have known I was having dangerous hypos--until I ended up in an ambulance.

And nowhere on the web is there any hint that the impact of this particular drug combination can be cumulative and take many months to kick in and cause the dangerous hypos.

It took months before I started to hypo on the dose that had been giving me normal blood sugars. And eight months is twice as long as the 4 to 5 months over which the Prandin/Metformin combination was tested.

Bottom Line: Drug combinations can be very dangerous, especially as doses build up in your system. Your response to a drug or drug combination may change over time if the drug is building up in your system. With blood sugar lowering drugs this can cause very dangerous hypos. But when they do, don't expect doctors to have a clue.


Andreboco said...

Jenny glad you figured this and are ok. Please turn us insulin users on the new data about needing C-Peptide when we inject insulin. Is there any availability of C-Peptide. Is it something we can get our hands on? Wiil you go back to insulin.

Does the story that Dr. Bernstein tell of Type 2s on the machine that clamped their blood sugar at 90 for 2 weeks then it took 2 years for their A1c to go back up to the previous levels apply to you? Andre

He attributes this to resting the betas, but you are stimulating the betas with Prandid. I am confused yet glad you are out of the woods.

Jenny said...


Insulin stimulating drugs bypass the gene that is broken in MODY-1 and MODY-3. In MODY the betas aren't "exhausted." They just don't get the signal that tells them that blood sugar is rising.

However, Dr. Bernstein's contention that insulin stimulating drugs "burn out beta cells" is not borne out by long term studies of people taking these drugs whose insulin response remains the same as those of people taking Metformin.

C-peptide is not available. There are people in the Type 1 community who would like it to be.

I'll go back to insulin once my blood sugar response goes back to what it used to be. I wouldn't be safe to use insulin right now since I still am getting insulin secretion. I'm very insulin sensitive (also part of MODY) so I couldn't use it safely until that happens. For now I'm eating mostly low carb with occasional carby meals to test insulin response.

Unfortunately, when I eat LC without insulin or Prandin, my fasting bg goes up into the 110 range, but I can't use Lantus or Levemir because they push me too low at night. I've tried them numerous times.

Helen said...

Yikes! That is really scary. It also shows once again how important it is to monitor your blood glucose closely. Thank you for passing this information along. Let me pass some other drug information on.

A few months ago I started getting leg cramps while on Metformin. Because I'd read good things about grapefruit and diabetes, I'd started eating a bit of grapefruit each day. I Googled the two and got this:

I called my pharmacist, who said the combination was safe. My general practitioner, however, said it is not safe. There was nothing about this in the package insert or in online information on Metformin.

Otherwise, I do think Metformin is a beneficial drug to insulin-resistant diabetics. But I think this interaction should be more widely known.

As you know, I am *still* waiting to see if I have MODY 2 diabetes. Nothing seems to be bringing my blood sugars down consistently. Metformin, I recently discovered, may not only be useless but also counterproductive, if I'm not particularly insulin-resistant, because it lowers glucokinase activity. I've stopped taking it for the second time and I'll see if things get better, worse, or the same.

Jenny said...


Thanks for the link. But tat studies are so often misleading for humans with diabetes, so I would not worry about this too much.

The incidence of lactic acidosis among people taking metformin is extremely low--no different from that in the general population. Were grapefruits that toxic, you'd see a lot more lactic acidosis.

What grapefruit mostly does is raise the concentration of some drugs in the bloodstream. Extremely high doses of Metformin might make you feel like crap, but they aren't fatal. People have survived huge (intentional) overdoses.

nonegiven said...

I have a prejudice, If it works for you, don't f with it.

Steve Parker, M.D. said...

I don't doubt what you are saying, Jenny, but...

I looked for an interaction between metformin and prandin in's drug interaction software program (Lexi-Interact, by Lexi-Comp), and it reports no interaction.

I don't blame your endocrinologist for not knowing about this potential interaction.

Jenny said...

Dr. Parker,

Click on the link to the Prandin Prescribing Information insert and scroll down to "clinical trials" then look at the charts and you'll see what I mean.

Why isn't a combination that makes two drugs 10 times more potent than each one taken alone not considered an "interaction?"

Terry Hilsberg said...


Perhaps reflecting the sentiment of Steve Parker's contribution, I have pondered your case study.

My partner, an MD by trade, is one of the researchers mounting an Australian research project (which is NIH equivalent funded). This project combines direct testing of the usefulness of diagnosis and/or prescribing software packages, with an attempt at trying to analyze the objective data, regarding use of diagnostic and prescribing resources at the primary care practitioner level.

I have suggested they look at the particular issue you have raised as one of the many case studies being examined.

I will let you know whether they take up this potential case study.

Drs. Cynthia and David said...

This type of reaction is well known as "synergistic". Usually, when something is found that synergizes the action of a another drug, it becomes the subject of a patent application with method of treatment claims specifically to that effect. The company tries to use the synergism as a marketing angle if they think it is useful for patients (makes the drug safer, more effective, improves compliance, etc.), and it ends up listed on the FDA label. Perhaps they missed this effect somehow, or wanted to sweep it under the rug because of the potential hypos.


nodders said...

Hello Jenny. I wouldn't want to comment on your theory about the drug interactions. If it's true that often doctors don't have a clue, I can assure you that researchers do want to find out (and research) interactions prior to releasing the drug.

What your story reminded me of, on the other hand, is that people react to drugs quite differently, and that this is due to our genes. I attended a lecture by a researcher from Boston on pharmagenetics in type 2 and he showed how metformin and sulfonylureas can and do work differently on people that have certain genetic variants. And it's quite more common in MODY which is a monogenetic disorder. He almost illustrated your own case, and implied that different reactions to drugs are almost always explainable from genotype rather than phenotype effects.
Thus often traditional protocol will fail people who carry rare genetic profiles (nothing new here).

Said that, his presentation had only mono-drug trials. Trials that look at combination therapy are few and far between, just as much there is a reluctance to correlate genotype to pharmakinetics and even side effects.

Jenny said...

Note to commenters, if you have a personal message for me, email me. Comments are for everyone to read.

George said...

My dotor recently increased my metformin intake from 1000milograms to 2000 a day. This, along with the 8 milograms of prandin , has so far worked well. I occasionly do go hypo extreme. The last time my blood sugar lowered to 46. This does not happen often though, for wich i am glad because im a tad hypo-insensitive as well! 6

Jenny said...


Cut down on your Prandin dose because you don't want to risk any more of those hypos. Another 20 mg/dl and you could become unconsious.

Metformin makes Prandin MUCH more long lasting than the label says it is.