Invokana for type 2 diabetes mellitus

chemical structure of canagliflozin (tradename Invokana), a new drug for type 2 diabetes mellitus

2016 update


They cause diabetic ketoacidosis

I spent 2 days in the ICU after less than a month on Jardiance, a drug similar to Invokana. I had extremely acidic blood, was passing ketones though not on a ketogenic diet, was severly dehydrated, and was low on ALL electrolytes, sodium, potassium, chloride, magnesium, phosphate.

Lowering your bG is not worth dying over!

Last time I was at the endocrinologist, Deb, my nurse practitioner, recommended I do a trial of the hot new drug, Invokana. Because it's new, and thus patented, it's expensive and doctors have to call insurance companies to get it approved. To encourage this process along, Johnson and Johnson is giving away coupons for a month for free.

When Deb suggested this to me, honestly, I was less than enthusiastic. I'm not fond of ANY new drug. Let it be on the market for 20 years and see how many people it kills or three-headed babies are born and THEN I'll try it. I have a bad attitude. ;)

Nevertheless, I took 100 mg Invokana this morning, as I have for a while now, and I'm sharing my thoughts here about this drug and who I think should or should not give it a try.

how the kidneys work

Deb said it worked by causing you to urinate out glucose, which sounded bad. I have 25 years experience thinking of glucose in the urine as a bad thing; it only occurs when bG is SERIOUSLY uncontrolled, like over 300 mg/dL (normal is 70-90 or so for fasting, 100-120 or so after meals). So we had that prejudice to begin with, that I'm just used to thinking of glucose in urine as a BAD THING.

I asked if it didn't cause kidney damage, and as we spoke, realized I had no freaking idea how the kidneys work. It's not something I ever studied in school. I knew kidneys were for filtering the blood, and therefore thought of them as simple membranes.

I had this vague notion that they were a simple filter that mostly let things through based on size. Oh, I knew there were things like the hormone aldosterone, that causes the kidneys to retain sodium. But I thought the primary mechanism was about size. We pee out urea cause it's a small molecule; we don't pee out amino acids cause they're larger. I thought that glucose was too big to fit. I had the vague notion that bG being elevated caused pressure on the kidneys, what is called a concentration gradient, and the glucose was forcing itself through pores that were to small and had the notion this was why elevated bG caused kidney damage.

It turns out the kidneys don't handle glucose like that at all. The kidneys in their natural state are quite fine letting glucose through, just as they're fine letting sodium through unless aldosterone signals them not to. There is this biochemical called sodium-glucose linked transporter 2 (SGLT2) which causes glucose to be reabsorbed rather than lost in urine.

When bG is elevated, SGLT2 is all used up and thus the excess glucose leaks out into the urine. Similarly, the chemical canagliflozin inhibits SGLT2, thus increasing the urinary output of glucose.

So I came home with this coupon for a free month's trial, but I had a lot to think about before I considered using it. Honestly, I am immediately prejudiced against all new drugs; they are guilty until proven innocent.

In general, for T2 diabetes, the only treatments I approve of are greatly limiting carbohydrate intake (down to about 100 gram per day), the drug metformin which acts to improve the insulin sensitivity of the liver, and the various insulins. I wasn't entirely sure I'd approve of Invokana until I looked into it.

What does Jenny think?

My first step was checking Blood Sugar 101.

I've known Jenny forever, back in the Usenet days on a low-carb newsgroup as well as a diabetes one, over many years in many web forums. She is bright and well-educated on the topic of both low-carb dieting generally and diabetes specifically. I was working on a diabetes website when she came out with her utterly awesome site and said 99% of what I wanted to say (I disagree with her about 1% of the time). Since then, I've bought her book many times as a gift for diabetics I know. If you or anyone you know has diabetes mellitus type 2, I can't recommend this book highly enough - available in both paperback and Kindle versions. If you need a copy, use my link to get me a few Amazon cents with your purchase.

Since Jenny keeps up with the research and updates her main site and blog regularly, I can keep up with it to a large degree just by following her. That's why my first stop to find out about Invokana was her.

Not too surprisingly, I discovered that Jenny doesn't like Invokana. And honestly, I agree with most of her reasons.

The first step in controlling adult onset diabetes is diet - limiting carbohydrate. Exercise, if tolerated, both lowers bG and reduces the insulin resistance characteristic of this disease. Metformin, especially the extended release version, is a well-understood drug that improves insulin resistance. These should absolutely be the first steps in diabetes care.

These worked for me for decades before I had to go on insulin. And when I lead how to dose insulin to keep my bG tightly controlled, I figured that was the end of that.

Except over time, insulin caused edema, to a crippling degree. I've needed large doses of potassium to counteract the edema. Since potassium given all at once is fatal (it's how they kill people on death row after all), it comes in a GINORMOUS pill. When it got to the point that I needed 10-12 of these a day, the whole thing became untenable and I just quit insulin entirely for a time. This is actually why I wound up back at an endocrinologist again, as I was stuck between being literally unable to walk or allowing the same elevated bG that caused my first myocardial infarction.

What we had accomplished was a basic ramping up of insulin, with minimal use of potassium pills (and loads of magnesium oil and Epsom salts). We got me to a point where my bG was not well controlled, but at least wasn't ENTIRELY out-of-control. Problem is, this not-so-great control is requiring 3 times the total daily dose (TDD) of insulin as I took when well-controlled before.

And super-large doses of insulin cause weight gain; I've gained 50 lbs in the past six months while eating much less than normal due to fatigue and being just flat-out unable to prepare much food. I'm way past the point of wanting to look hot, but the weight gain is interfering with my life in all sorts of small annoying ways.

So while I agree with Jenny that almost all of those with adult onset diabetes should start with diet, exercise, metformin and if needed, insulin before considering outrageously expensive new drugs (Invokana costs $300/month!), I've already maxed out on those things. Thus I don't think those arguments apply to me.

does Invokana cause heart attacks?

Jenny also pointed out that Invokana barely got FDA approval at all; two thirds of the scientists who reviewed all the experimental data in the application voted for it. That's 67%, a failing grade on nearly every test I ever took!

The reason for the reluctant approval is that there was a higher rate of cardiovascular events (heart attack and stroke) in the treatment group versus the control group in a small study, but that difference was not statistically significant.

What does that mean? Well, say I flip a coin 10 times and get 6 heads; you will likely not accuse me of cheating as that's pretty close to the expected odds. But if I flip a coin 10 times and get 9 heads, you still don't really know if I was cheating or not, as it's not impossible to get 90%. But what if I flip the coin a thousand times? If I get 900 heads, you're pretty darned sure I'm cheating even though it's still 90%. And if I get 9,000 out of ten thousand I am CERTAINLY cheating.

This is what statisticians call statistical significance, a way of measuring whether the outcome is due to chance or not. The mathematical equations involved sometimes can't answer that question if there aren't enough data points, just as you can't really tell if I'm cheating if I only flip the coin 10 times but pretty much can if I flip it 10,000 times, even with the same 90% result.

The study in which they noticed more heart attacks in the treatment group didn't have very many participants, so we can't really tell if it's coincidence or due to the drug.

I would not take this drug unless already maxed out on dietary changes, exercise, metformin and insulin anyway, but with heart disease, it's a trickier equation. This is what I know for sure:

  1. High serum levels of insulin are inflammatory and cause heart disease. I am taking ridiculous amounts of insulin now.
  2. Elevated bG is inflammatory and cause heart disease. In spite of my high insulin doses, my bG remains quite elevated.
  3. Invokana MIGHT or MIGHT NOT cause heart disease; we probably won't know for many years. But it will allow me to reduce my insulin use and lower my bG, thus reducing two known risk factors.

So for me, this question is a wash.

the pharmaceutical insert

A summary of the studies done by the company seeking FDA approval is included in the pharmaceutical insert. Doctors SHOULD be completely familiar with this before prescribing, but aren't always.

common Invokana side effects

The most common unhappy side effects are about what you'd expecting from adding a bunch of sugar to your urine; it makes bugs happy. Thus urinary tract infections and genital yeast infections increase on Invokana. Most of us who've had type 2 diabetes mellitus for any length of time have had these issues anyways; bugs are sweet on us cause we're sweet. :(

Invokana also can change the amount and/or frequency of urination and thus also can lead to dehydration. For me, there's a definite frequency change to an annoying degree, but no increase in output. However, this would not be a negative for me even if it did occur given my edema issues.

Using Invokana as part of diabetes care results in elevated serum potassium and magnesium, a flat-out GOOD side effect.

And since it both increase fluid output and raises serum potassium, it also lowers bp. For many, this is a bonus, but in those already on the low side, you can get dizziness and such.

Increased fluid loss can also lead to increased thirst and constipation.

It has a BIG effect on bG so can cause hypoglycemia if you don't adjust insulin usage to compensate.

People who already had kidney issues (based on serum creatine levels) saw them worsen on Invokana, and it also didn't lower their bG very well, so it is not recommended. People with mild liver impairment didn't seem worsened and it did work fine.

Invokana also raises LDL, the so-called "bad" cholesterol, though the mechanism by which it does so is unclear. The difference is about 2-4%, depending on whether taking the 100mg or 300mg dose, so it's a small effect. HDL doesn't seem to be effected one way or the other.

the elephant in the room

Nothing I read online by any of the critics addressed what struck me as worst in the pharmaceutical insert, the rodent reproduction studies: babies born to moms on Invokana have deformed kidneys.

This would scare me pretty bad if I weren't past menopause.

Like all drugs, this one says it hasn't been tested in pregnant or breastfeeding humans, but that statement is on everything and has thus become meaningless. I rather wish it had big black-box warning: PREMENOPAUSAL WOMEN SHOULD NOT TAKE THIS DRUG.

Seriously, elevated bG is a long-term issue and may take decades to harm you; having a child on dialysis is a WAY more immediate problem.

preliminary experience

Thus far, my free month of Invokana is getting me lower bG readings on less insulin.

I am going to finish up my 100 mg prescription and then ask Deb to prescribe the 300 mg stuff and fight with my insurance company for it.

There will likely be further adjustment necessary as I continue with the 100 mg stuff and even more when I go to 300 mg.

I'll report back when I have more data.


sodium-glucose transport proteins from Wikipedia

U.S. FDA approves Johnson & Johnson diabetes drug, canagliflozin from Reuters

Invokana pharmaceutical insert (PDF)

Invokana prescription assistance for those who don't have insurance companies for their doctors to fight with

Disclosure: Affiliate
If you've ever tried Invokana, please share your experience below. There's little patient experience on the web yet; let's get it out there.