Adventures with Invokana

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1

I had my endo appointment in September and we again discussed Invokana. Invokana is a relatively new drug (along with Farxiga) which is also a new class of drugs called SGLT-2 inhibitors. They act by making you excrete more glucose in your urine. I had brought this up before at a previous appointment and she initially took the position that it wouldn't help me. She still waffles about my diabetes type and said it isn't for type 1s. I always have to remind her that she has no evidence I am type 1, I'm just on insulin and am not overweight nor have the "hallmarks" of type 2 (whatever that means). Since Invokana was still a tier 3 drug for my insurance I put off the question. But before my last appointment I checked with my insurance and it is now covered as a tier 2 drug at $40 for a 90 day supply (Farxiga is still tier 3 and expensive). And there has been a lot more discussion about the use of Invokana for type 1s. So I decided to bring the topic up again thinking that it would be more acceptable.

And surprisingly my endo was more positive about it. I had initially been worried that it would be of little help to me. I thought the drug worked primarily by reducing your renal threshold from 160-180 mg/dl down to a lower range (like 120-140 mg/dl). If your blood sugar was already 100 mg/dl then it did nothing. So I thought it would do little except reduce my after surges. But I was wrong, it actually works actively at all blood sugar levels. Yes you get increased glucose excretion at higher blood sugar levels but even at blood sugars under 100 mg/dl you still dump glucose. And as I looked into it you dump about 70 grams of carbs a day this way. Yowza. 70 grams of carbs a day is a fair bit. That is 240 calories. And my endo pointed out that it might reduce my insulin requirements. In hindsight losing 70 grams of glucose certainly would be expected to reduce insulin needs. And the other benefit is blood pressure reduction and weight loss.

So now we get to my initial experience. I started two weeks ago. I started right off looking at glucose in my urine and sure enough it was at the upper end and quite dark signifying that I was dumping lots of glucose. And right off my insulin needs dropped. I would say a drop of between 20-30% in my daily needs both basal and bolus. And I may well have dropped a pound or two. And despite my belief that it only worked with higher blood sugars my urine tests suggest that you still dump quite a bit of glucose at blood sugars under 100 mg/dl. And in addition to the lower insulin doses my blood sugars are improved with a drop of 10mg/dl on average in my morning numbers. Pretty darn good.

So my experience is actually looking pretty good and I think I am going to try a longer course of Invokana.

Has anyone else had a good or bad experience with Invokana?

2

Thanks Brian for sharing your experience with Invokana, I'm glad it is working out for you. I have been reluctant to consider this drug because of some of the not so nice side effects cause by increased sugar in ones urine.

Your positive report has at least caused me to take a second look.

3

I don't know if you have read the link at bg 101 but apparently invokana has been causing heart attacks and strokes. I remember when it was first mentioned and I thought it wasn't a good idea due to causing yeast infections and due to it's effects on the kidneys... it seems like it could cause kidney damage in the long run.

http://www.phlaunt.com/diabetes/36474059.php

4

Thanks meee, I've seen the comments Jenny made about Invokana. In one sense she is right that the path that get's drugs approved is corrupt and this can result in drugs with dangerous side effects being approved (i.e. Vioxx and Avandia). But at times she is a bit alarmist. She also raged against DPP-4 inhibitors. The heart concern was for a short initial period of time in a single study occurrence and was actually such a small number that it was possibly due to chance. Broader assessment of the CVD rates actually demonstrated that Invokana reduced CVD rates and it was unlikely due to chance. Yes, maybe high risk patients have some risks when starting therapy. The FDA is requiring further study. But overall there isn't evidence that there is any general CVD risk, in fact it is probably beneficial for most. And now Invokana has probably accumulated millions of patient years of use. It appears the biggest risks are due to poor kidney function and UTIs. But you are right, we should always understand side effects, be wary of new drugs and never just trust pharmaceutical companies to fully reveal the truth.

5

I read at invokana's site on their drug info that risk of stroke is increased by 43% I think. Cvd seemed to be less conclusive but it also says that it can increase small density ldl. But for me the chance of kidney damage alone due to the way it acts, not enough is understood clearly, would be enough for me to never use it, as well as causing yeast infections. I would be very cautious to use this drug, we really don't know long term side effects and there have already been severe short term effects for some people. Imo, insulin and metformin are the only relatively safe means to treat high bg.

6

I've looked through the Invokana site and not seen anything related to increased risks related to stroke. There was nothing in the studies that suggested that Invokana caused any kidney damage. Rather it is a caution that the drug may not be properly metabolized if your kidneys are already compromised. The same caution is present in a wide range of drugs (including metformin) that are metabolized by the kidneys. If you have an pointers to the increased risks I would like to see them.

7

This article is where the stroke risks are discussed and I'm wondering why they're not mentioned at invokana's website. I think they mentioned it shouldn't be used in people with renal impairment as it will cause renal impairment, but this means it will most likely do the same in people without any currently and everyone with diabetes is already at higher risk for this anyway with or without high bp.

http://www.medscape.com/viewarticle/791602

Here are the adverse effects at their website:

The following important adverse reactions are described below and
elsewhere in the labeling:
•
Hypotension
[see Warnings and Precautions (5.1)]
•
Impairment in Renal Function
[see Warnings and Precautions (5.2)]
•
Hyperkalemia
[see Warnings and Precautions (5.3)]
•
Hypoglycemia with Concomitant Use with Insulin and Insulin
Secretagogues
[see Warnings and Precautions (5.4)]
•
Genital Mycotic Infections
[see Warnings and Precautions (5.5)]
•
Hypersensitivity Reactions
[see Warnings and Precautions (5.6)]
•
Increases in Low-Density Lipoprotein (LDL
-
C)
[see Warnings and
Precautions

See Product info for more detailed info on all listed adverse effects:

http://www.invokana.com/prescribing-information.pdf

http://www.invokana.com/

8

Great feedback Meee!

The medscape article from April 2013 summarizes the FDA review of February 2013 that was reported here. This was the FDA meeting which approved Invokana. The Invokana site and the Invokana prescribing information make no mentioned of CVD or strokes as potential adverse effects. Should the FDA have considered there to be a risk they would have at least made Janssen list it in the prescribing information but they didn't. Here is the salient part of the FDA review:

The interpretation of the results from the meta-analysis is complicated by evidence suggesting that the assumption of proportional hazards was not met. Further analysis of the CANVAS dataset revealed a numerical imbalance in the number of early cardiovascular events. During the first 30 days after randomization, there were reports of cardiovascular events for 13 subjects (0.45%) in the canagliflozin group and for 1 subject in the placebo group (0.07%). The estimated hazard ratio during the first 30 days for CANVAS was 6.50 (95% CI: 0.85, 49.66); however, it was not significant due to small number of events. There were no major differences between subjects receiving canagliflozin who had early cardiovascular events compared to those receiving canagliflozin who had cardiovascular event after 30 days (HR = 0.89, 95% CI: 0.64, 1.25), or compared to subjects who received placebo and had a cardiovascular event in CANVAS.

The statistical reviewer, Dr. Eugenio Andraca-Carrera, noted in his review “… due to the small number of events in this analysis, the estimated hazard ratio is highly sensitive to any additional events. … Due to the small number of events within this time window, and as represented by the wide confidence interval of the hazard ratio, these findings cannot definitely conclude a significant increase in risk within 30 days associated with canagliflozin. It is possible that the observed imbalance of MACE-plus in the first 30 days of CANVAS might be attributable to chance.”18

So what does this mean? The CANVAS study enrolled 4,330 patients who either had already had heart problems or who were at risk. Of the 2/3 of the patients taking Invokana, 13 had CVD events in the first thirty days, but there was only 1 in the placebo group. The biostatistics expert suggested this was possible due to chance. And most importantly after thirty days no increased CVD risk was found. And further overall assessment of all/most (of the many) trials found that Invokana actually reduced the risks of various CVD events. But none of these results had significance. Apparently there were not enough CVD events to make a conclusion one way or another.

And it is not like there wasn't a fair amount of data. The trials of Invokana included 40 phase 1 trials, 3 phase 2 trials and 9 phased 3 trials including one focused on CVD. The FDA had a meta analysis done looking at CVD in most/all trials in addition to the specific CVD trial. Overall the FDA found that CVD risks seem to go down with Invokana use (although again this result also could be by chance.)

Despite this, the FDA is being careful and has required 5 further trials to be performed looking further at the CVD issues.

In general, Invokana may on average reduce CVD risk in patients (perhaps because it also reduces blood pressure). And yes a high risk population was observed to have a higher CVD occurrence in the first 30 days but it was entirely possible that it was just due to chance and I am not in that population.

I think as patients we all struggle with how to interpret all this information. Like meee I don't really trust the information I am presented about risks. I dig deep. And unfortunately when you dig deep you get all this scientific gobbledygook that is really hard to understand in context. And it isn't just patients, I'm not clear doctors can understand this stuff. My endo doesn't even understand the concept of absolute and relative risk.

9

Thanks Brian!

I believe it is very important that we carefully read all that gobblygook and try to decipher it as best we can. I read my beloved kitty Angelina's necropsy report and I understood most of it, and the important conclusions, with help researching terms etc. She was given Convenia which cause a severe and deadly anemic reaction, which contributed to her death. I know she had no anemia prior to this because I did blood work 1-2 days before. I would never have allowed the use of the drug if I had known about the deadly side effects, which I wasn't warned about and I already thought it wasn't a good idea due to staying in the system too long.

I agree with Dr. Nathan, this drug is not worth it's potential risks, and the risks with the exception of stroke seem to all be listed at their site. The first thing I do now with any drug I take is read all of this information. Also be aware that companies "revamp" drugs which are eventually removed from the market due to safety issues, such as one I refused when I was in the icu, which causes arrythmia, I was surprised to hear that it was back on the market again. It is a good thing I refused it because due to two complications I had, one already present, it could have lead to serious consequences including death.

The risk of cvd may be low but it is still a possibility, the risk of kidney impairment is quite troubling. Sometimes you have to go with a hunch. My uncle, who was a pulmonary specialist and an excellent overall diagnostition always gave us his opinion on the safety of drugs based on how they work and what he thought potential dangers were and he was nearly always right I think. I use that same hunch based on facts myself and it tells me No to Invokana. I also find it interesting that Dr. Nathan is among the two doctors on the panel who have no apparent interest in any pharma companies including the one producing invokana. Obviously he has more info which was not released about the risk of stroke.

10

I was on innvokana and had some pretty good results until I got a urinary tract infection. This would not go away until I came off it and then had a fourth cycle of antibiotics. That scared me enough to stay off it.

11

@Cat, thanks for sharing your experience. I've been hearing more and more about those with T1 using Invokana. I'm sorry you got a UTI, that is probably the major adverse effect and unfortunately women are at higher risk. I'd be interested in what your good results were. Did you reduce insulin doses or weight? Did your blood sugars improve?

@meee. I think we are in general agreement. I carefully read Nathan's comments. For those that don't know he is an elite among the elite of diabetes researchers having a central role in a number of major studies from the DCCT to the ADAG. That being said, he isn't a clinician and he has a track record of odd, confusing and just wrong statements. We recently discussed his confusion over T1 and T2. He's also expressed the opinion that diabetes can be prevented and cured with a calorie restricted low fat diet.

That being said, he expressed share by a fair number of others that we should be ultra conservative before letting drugs on the market. Some believe that the FDA has become to lax and has let drugs on the market which have ended up harming many patients (i.e. Vioxx). Part of this has to do with the corruption that the pharmaceutical companies fund the studies and can manipulate outcomes. He also notes that it isn't as effective in blood sugar lowering as other drugs already on the market, but you can say basically the same thing about every other drug since metformin. And he doesn't point out any specific risk other than not enough study has been done on the drug. And many believe that Invokana will be clinically very beneficial even if it isn't as effective as metformin since it works in markedly different ways. In the end if we want to accelerate the development and availability of diabetes treatments we will have to wisely balance the benefits of new drugs against the risks. And I do agree with Nathan that you should be cautious with new drugs which is one reason I waited 18 months.

ps. And I'm sorry you had such a reaction. I had a terrible reaction to statins and doctors just dismiss my complaints. My tactic was to announce that I was "fatally allergic" to statins and have them write that down on my chart. No doctor in their right mind will insist that you take a drug for which you have pre declared will kill you.

pps. Dr. Nathan was not on the FDA panel and it is not clear he actually read the underlying studies only the panel summary report.