March 31, 2013

FDA Approves a Highly Questionable New Diabetes Drug, Invokana

The FDA just gave its approval to the first drug in a new class of diabetes drugs, Johnson & Johnson's canagliflozin, which will be marketed in the U.S. as Invokana.

New York Times: FDA Approves a New Diabetes Drug From J.&J. (May require subscription)

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

This class of drugs, the sodium-glucose co-transporter-2 (SGLT2) inhibitors, lowers blood sugar by blocking reabsorption of glucose by the kidney and increasing its excretion in urine. The manufacturer also claims that it causes weight loss--always a potent selling point for a diabetes drug.

As is the case with all new diabetes drugs, now that the drug is approved, drug company flacks will start saturation bombing family physicians with materials that make it sound like they should put every patient with Type 2 on this wonderful, new drug, which is priced at $8.77 a pill or $263.10 for a monthly supply.

They shouldn't.

The committee of "experts" who reviewed this drug were ambivalent about it because the company's own, [most likely, statistically manipulated], clinical study of patients at especially high risk of cardiovascular disease showed that within the first 30 days, 13 patients taking canagliflozin suffered a major cardiovascular event [mainly strokes and some heart attacks] compared with just one patient taking a placebo. After that, the imbalance was reversed, though the drug then caused a slight increase in LDL cholesterol.

However, as the New York Times report notes, " F.D.A. spokeswoman said Friday that the significance of those findings was unclear, and the label of the drug includes no warnings about heart attacks or strokes."

That means that busy family physicians who are conscientious enough to review the FDA Prescribing Information will have no idea that they may exposing some of their previously stable patients with Type 2 Diabetes to life-altering strokes and heart attacks that will either kill them or ruin their quality of life.

One third of the experts in the FDA committee who reviewed the research J&J provided about Invokana advised against approving this drug (5 out of 15). They also expressed concern that this drug might be more dangerous for people with kidney disease--which of course, describes a lot of people with Type 2 Diabetes who have followed conventional medical advice.

A very similar drug that operates on the same pathways, dapagliflozin,  was rejected by the FDA on safety grounds, which make it all the more important to worry about the safety of this one.

Johnson & Johnson's current management has shown itself criminally unconcerned with the fate of those who buy its most toxic products, as was demonstrated by the fact that the company continued to market their metal-on-metal replacement joints long after people inside the company knew that a high number of them were failing within a very few years after surgical implantation, exposing users to the risks of more major surgery and the possibility of joint deterioration that could permanently limit mobility and lead to life long pain and disability. (Details HERE)

With this kind of corporate culture, it is not impossible that J&J insiders might have tweaked the studies used to approve its drug to make them look better than those that led to the rejection of dapagliflozin.

We have learned from the history of the Incretin drugs that when members of a class can't be approved for a long time due to disturbing findings in approval testing, the members of the class that are approved often turn out to have the same effects when given to more patients.

But you can be sure that now that this money-making new drug is officially on the market, J&J will do all it can to keep the public from learning about the true toll it exerts on those who take it.

And of course, as we have now learned from every new expensive diabetes drug released in the past 20 years, the rest of the side effects of this new class of drugs won't begin to become evident until millions of prescriptions have been sold and hundreds of thousands of people suffered whatever else it is that it does to the body, because no approval testing exposes people to a new drug long enough for those effects to become clear. (And many of the effects would require microscopic studies of the tissues of people taking the drugs  which are never required for approval.)

Other Side Effects

Yeast Infections

Unmentioned in any of the news stories about this new drug is the fact, mentioned in Invokana's  Prescribing Information, that it causes serious yeast infections in women and uncircumcised men. This makes sense since sugary urine promotes the over-growth of yeast. One in ten of those who took the drug experienced this side effect.  One in twenty who took it experienced urinary tract infections.

Decreased Kidney Function

The Prescribing Information states: "INVOKANA increases serum creatinine and decreases eGFR [glomerular filtration rate.]"  It also raises the risk of dangerous low blood pressure and hyperalkemia (high potassium levels) especially in people taking blood pressure medication. (Hyperalkemia can lead to heart rhythm abnormalities. Older people, particularly those over 75 are those most likely to have the most severe kidney-based reactions to the drug.

Effect on Blood Sugar

 A low dose of the drug (100 mg) lowered  A1c on average .79%  (i.e. from 8.0% to 7.21%. The high dose (300 mg) lowered A1c, on average .94%.  In contrast, the impact of plain metformin on blood sugar, according to the Glucophage prescribing information (available HERE) is to lower blood sugar 1.4% over 29 weeks. However, when Invokana was combined with metformin, the combination only lowered A1c .79% for the low dose and .94% for the high dose--no different than when Invokana was taken alone and less than what is achieved with a proper amount of cheap generic metformin.

On average, the low dose lowered fasting blood sugar from 173 mg/dl to 155 mg/dl--a level high enough to ensure the development of all the classic diabetic complications. The high dose lowered fasting blood sugar from an average of 173 mg/dl to 138 mg/dl.

Very significantly, the Prescribing Information does NOT report the effect of this drug on post-meal blood sugars when taken alone. It only reports its effect on post-meal blood sugars when taken with metformin, where it lowers blood sugar by the same amount that metformin alone would lower it. In short, Invokana does not appear to have any significant effect on post-meal blood sugars and has no effect, overall that couldn't be achieved by taking cheap, generic metformin. 

Even when Invokana was combined with metformin, the combined impact on post-meal blood sugars was unimpressive. The average blood sugar of the untreated people in this study two hours after eating was between 258 mg/dl and 262 mg/dl--a level guaranteed to produce heart disease and other classic diabetic complications. When Invokana was taken along with metformin, their average 2 hour post-meal blood sugar was still 205 mg/dl to 210 mg/dl, a level still high enough to cause heart disease and all the classic diabetic  complications.

This makes it  clear Invokana offers no significant benefit to people with Type 2 diabetes. We know from several research studies that post-meal blood sugars over 155 mg/dl promote the development of heart disease. (Details HERE)

You can find everything that J&J will let the public know about Invokana here: Invokana Prescribing Information

Say "No" to Brand New Diabetes Drugs!

If your doctor tries to put you on this drug, say no. Wait ten years, and search the literature then to see what scientists have found out about its real effects on patients before you try it.

If you can't control your blood sugar using standard therapies the safest approach is this:

1. Try the dietary strategy described on this page: How to Lower Your Blood Sugar

2. If that doesn't lower your blood sugar to a healthy level, ask your doctor about starting metformin ER. Make sure you end up with a clinically effective dose which for most people is at least 1500 mg a day. The ER form is kinder to the stomach.

3. If you don't respond to metformin, ask your doctor to prescribe long-acting insulin, which should lower your fasting blood sugar. Read up on how to set the dose so that it is most effective.

4. If that isn't enough, ask your doctor to prescribe fast acting insulin to cover the carbs in your meals. Read up to learn how to set the dose, as most family doctors don't have the resources to give Type 2s the proper training in using this kind of insulin. (Don't use mixtures of fast and slow insulin (70/30 mixes) as they almost always make it extremely hard to get good control of blood sugar.)

These are the safe, long-tested strategies that provides the best reward for the smallest amount of risk in people with Type 2 diabetes.


13 comments:

Michael Barker said...

I pay no attention to the introduction of new diabetes drugs. The stats have generally been tweaked to death and even then the net effect is about a .5 drop in A1c. As you and others have noted, this can easily be gotten by diet and certainly with less side effects.

Scott S said...

Your analysis looks quite accurate. A look at FDA's slides [see http://1.usa.gov/14AscgR] for this drug gives insights into the risks generated by Invokana.

Regarding the cardiovascular outcomes trial, it is fully justified by the Hazard Ratio of 1:46 for "fatal or non-fatal stroke." That represents the ratio of risks between two conditions. If Invokana did not increase the cardiovascular compared to the reference drug, the Hazard ratio would be 1. In this case, the 1:46 ratio means that people who received Invokana during the study developed 46% more fatal or non-fatal stroke than the others, which is without a doubt, a significant increase. There were some differences in the profile of patients from the different groups: some groups that received Invokana contained more current smokers than there were in the placebo group, but full details (I suspect) will be buried by the FDA under the threat of revealing trade secrets and the company selling this product, J&J, whose track record on patient safety and recalls in recent years should be a big warning sign.

Invokana was also associated with an increased incidence of overall fracture. Adding to this profile, Invokana was also associated with a 4 to 7 fold increase in genital mycotic infections. How wonderful that must be!

Jenny said...

Fractures, eh? God help the patients whose doctors prescribe this new drug along with Actos, given its record for causing serious osteoporosis over the long term.

Unknown said...

I believe Berberine is thought to mimic the incretin effect. What is your opinion of supplements based on this.

Jenny said...

Re Berberine, If it really mimics the incretin effect, you have to hope it isn't doing what we now know the incretin drugs are doing: growing highly abnormal alpha and beta cells in the pancreas including tiny andenoma tumors. Read about that HERE

Every few years there's a new, over-hyped supplement, which always turns out either a) not to work long-term or b) to be dangerous. Herbal supplements from the 3rd world are often contaminated with first generation sulfonylurea drugs which will lower blood sugar but are hard on your heart.

What studies are cited for berberine are published in marginal journals, some of which may be the kind you can get any paper into if you pay a fee. Supplement sellers routinely fund this kind of research. I am not convinced the research is all that credible. Berberine promoted by all the shyster doctors (few of whom actually practice medicine and none of whom practice endocrinology) who make their money selling crap to people who want a quick, magical cure for their ills.

So my feeling is that there isn't enough data to draw a conclusion about this supplement, and even if there was, your chances of getting an adulterated product are so high that it isn't worth the high amounts of money involved. Why not stick with cheap, generic, effective metformin?

As an example of why you have to be sceptical even about supplements that might have some good qualities, a while back the herbal craze du jour was Hoodia. Dr. Richard K. Bernstein explained in a teleconference that Hoodia did seem to work as an appetite suppressant, at first, but soon the supply of Hoodia was used up, so supplement sellers started selling all kinds of fake stuff in Hoodia bottles.

My guess is that if berberine catches on big time (which it may be doing) the situation will be the same and you won't actually be getting it when you buy it in supplement bottles. Remember there is NO legal requirement that supplement bottles contain what the label says they contain. The FDA only intervenes after someone dies from a supplement or ends up in the hospital.

Unknown said...

My major reason for N=1 experiment with Berberine (glycosolve) is metformin is unavailable without perscription and I haven't been officially diagnosed nor do I wish to be. For nearly 3 years I have eliminated refined grains, refined sugars, and industrial seed oils from my diet. I eat modest amounts of tubers, potatoes, sweet potatoes, yams etc. My fasting sugars are sometimes over 105. My A1C Now tests range 5.4 - 6.3 depending upon aerobic activity, but always find time to lift weights. My one official A1C from lab was 6.0 with fasting 142 mg/dcl. I would like to be able to pass a Lab ordered test and was hopeful this may work. I've been about four weeks trying this, post prandials under 140 now,when eating carbs were about 160 no dietary changes. Need some carbs to support exercise regimen currently 53 years old, 68" 172 lbs about 18% body fat. Avoiding the system as it did not seem to help my father much, 5 way by-pass, peripheral artery disease, full on metformin insulin shooting diabetic who was appearently very strong and healthy in his prime. My Grandma was diabetic for last 40 years of her life, passed at 83, she was very strict about sugar fats and salt. I have little confidence in doctors other than for plumbing repairs. I realize I am monitoring with sub standard tools. We'll see how this goes. Berberine "trials" claim lowered blood pressure, cholesterol, and sugars, seems like a panacea. I'm also aware of the "seems to good to be true" addage. Tried gymnema, no effect. We'll see. May be unwise long term but if short term keeps plasma profile from being flagged might be worth it.

Jenny said...

Unknown,
Metformin is a legitimate prescription for prediabetes. With your family history an alert doctor should be willing to prescribe it.

The problem with many herbs that lower blood sugar is that they do it in ways that are toxic to other organs. Damaging the liver will lower blood sugar. Cheap sulf drugs added to supplements by inscrupulous sellers lower blood sugar in a wasy that will stimulate a receptor on your heart that makes heart attack more likely.

Stalina Dsouza said...

Jenny,

I discovered that Actos was the culprit in unexplained weight gain. Are there any other diabetes drugs that will work as an alternative but not cause weight gain? I already take actos, , metformin and glyburide.

Jenny said...

Stalina,

At this point, there isn't. Because two of the drugs you are taking, Actos and glyburide both can damage the heart over a long period of time, it might be worth asking your doctor about switching to using insulin. If you lower your carb intake so that you don't need to use huge doses of insulin, and use insulin to cover your meals, you may find yourself not gaining weight.

Glyburide also causes weight gain because the way it makes insulin to be secreted leads to blood sugar going up and down all day in a way that leads to physiological hunger. If you use fast acting insulin at meals correctly you can keep your blood sugar quite flat and that will eliminate hunger. Though my doctor told me that insulin always made people gain weight, I actually lost some weight after I started using it at meals because I didn't feel so much need to eat.

If you go off those two drugs, try the strategy that you will find here, too. Many people are surprised at what a difference it makes in their blood sugar: How To Lower Your Blood Sugar

Carol in MN said...

Hi Jenny. I am newly diagnosed and started Metformin 500mg/day this past Sat. Pre-medication, my fasting BG was 169 on 4/10, 149 on 4/17, 132 on 4/19. Starting literally the day after medication began (4/20), it’s been 108, 112, 98, 101 for the next 4 days. I read that Metformin takes ~3 days to kick in. Can my improved FBG be from better diet/exercise at this point and less about the 500mg of Metformin recently started? I am overweight, but am losing weight (10 lbs in the last 3 weeks) and I recently started to exercise at least 30/day. Does that indicate I may be able to control it without medication at some point?

Jenny said...

Carol,

Metformin kicks in right away, but it builds up to have more effect over that 2 weeks. Your quick response is a very good sign.

But your fasting blood sugar is NOT the measurement that determines how you do long term and whether you develop complications. Your reading 1 hour after eating is the most important. If you can keep it under 140 mg/dl you can consider your diabetes controlled.

Doing it with diet (cutting carbs, mostly) exercise, and metformin is far safer than the other oral drug alternatives.

Carol in MN said...

Thanks for your quick response! I am also testing at other times. My 2 hours after eating #'s have been 134, 96, 125, so far. My after exercise #'s 94, 89. I'm only supposed to test 1-2/day, according to my dr, but I think I need to test more often for now until I get a grip on what impact what I'm doing has. If I have to buy my own strips to do extra testing, I will. I'll start doing some 1 hour after eating samples, too. Thanks again!

Hoop said...

I bought a supply of the herb barberry for its berberine content. Its blood glucose effect seemed limited at best though perhaps my dosing was too low. Berberine sources have traditionally been taken for limited spans of time. And is very effective for one of its traditional use that of diarrhea. I don't trust capsules. Though with some herbs I do buy powdered concentrates in bulk form (not in the capsule).

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