|SGLT2 Inhibitors, Farxiga, Invokana, Jardiance. Questionable New Drugs|
The FDA recently gave its approval to several new drugs that are part of a new class of diabetes drugs, the SGLT2 inhibitors. All have very troubling side effects. More are awaiting approval. The first of these was Johnson & Johnson's drug canagliflozin, which is marketed in the U.S. as Invokana. It is also sold in a combination pill containing metformin as Invokamet.
These sodium-glucose co-transporter-2 (SGLT-2) inhibitors lower blood sugar by blocking reabsorption of glucose by the kidney and increasing its excretion in urine. However, recent findings suggest that though these drugs ramp up excretion of glucose, they also ramp up production of glucose by stimulating the secretion of glucagon. More about that can be read HERE.
The manufacturers also claim that they cause 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 are 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.
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. .(Details HERE and HERE)
However, as the New York Times report notes here, " 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.
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.)
Serious Side Effects of This Entire Class of Drugs
Ketoacidosis in Type 2The FDA issued a warning on 5/15/2015 stating that it had received a significant number of aftermarket reports linking this class of drugs to ketoacidosis. Ketoacidosis is a very serious, potentially fatal condition where the acid level in the blood rises dangerously high. Ketoacidosis makes people very sick and if untreated can be fatal. It requires a trip to the emergency room. Symptoms of ketoacidosis include: difficulty breathing, nausea, vomiting, abdominal pain, confusion, and unusual fatigue or sleepiness.
What is particularly worrisome here is that ketoacidosis usually ONLY occurs in people with Type 1 diabetes who have very high blood sugars--those above 300 mg/dl. However, in these cases the ketoacidosis was occurring in people with Type 2 diabetes who had only modestly elevated blood sugars. It is likely that these drugs are promoting ketoacidosis because of the way they affect the kidneys, which may make it harder for the body to eliminate ketones as they build up.
Typically, people eating very low carb diets are told that as long as their blood sugar isn't high, it's perfectly safe to have raised ketone levels in blood and/or urine. But this may NOT be the case if you are taking one of these drugs because they may block the normal processes that keep ketone levels within a safe range. Until it is 100% clear what is leading to ketoacidosis in people taking these drugs it is not a good idea not to take them if you are eating a ketogenic low carb diet. You can read the entire FDA warning at:
FDA Drug Safety Communication: FDA warns that SGLT2 inhibitors for diabetes may result in a serious condition of too much acid in the blood
Bone Fracture Risk and Decreased Bone Mineral DensityOn Sept 10, 2015, the FDA issued a Safety Alert for Invokana and Invokamet, stating that "Bone fractures have been seen in patients taking the type 2 diabetes medicine canagliflozin [Invokana].Fractures can occur as early as 12 weeks after starting canagliflozin. Canagliflozin has also been linked to decreases in bone mineral density at the hip and lower spine."
Though the warning specifically mentioned Invokana, the oldest drug in this class, the warning bulletin also said "FDA is continuing to evaluate the risk of bone fractures with other drugs in the SGLT2 inhibitor class, including dapagliflozin (Farxiga, Xigduo XR) and empaglifozin (Jardiance, Glyxambi, Synjardy), to determine if additional label changes or studies are needed."
FDA:Invokana and Invokamet (canagliflozin): Drug Safety Communication - New Information on Bone Fracture Risk and Decreased Bone Mineral Density
Note that once your bones have become weakened, it is very hard or possibly impossible to rebuild them. This side effect probably occurs because messing with how the kidneys excrete glucose also affects how they handle the minerals used build bones: phosphorus, calcium, and magnesium.
If your doctor prescribes one of these drugs, ask him or her if they are aware of these two recent FDA safety warnings. Chances are that they may have missed them.
Other Side Effects of This Entire Class of DrugsYeast Infections
Unmentioned in any of the news stories about this new drug class is the fact, mentioned in the drugs' Prescribing Information (the official FDA "Label"), that they 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 Invokana experienced this side effect. One in twenty who took it experienced urinary tract infections.
Decreased Kidney Function
This too is a class effect applying to all drugs in the SGLT-2 inhibitor family.. The Prescribing Information for Invokana 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.
The Diabetes.co.uk web site describing this class of drugs also says that in the studies used for approving the drug there were more cases of liver failure, breast and bladder cancer, though the effect was not strong enough to block approval of 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. The combination of metformin and Invokana did not make any change in the drop in A1c which remained, on average, the same as it would be with Invokana alone and less than could be achieved with optimal metformin dosing.
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. I
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 none, overall that couldn't be achieved by taking the cheap generic, metformin, alone.
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
Farxiga, a Second, Even Worse Drug in this Same ClassFarxiga, mysteriously named "Forxiga" outside of the U.S. (both are generically named dapagliflozin) also sold as Xigduo, a combination Farxiga/metformin pill, is a second drug in this same SGLT-2 inibitor class, which has all the same side efects as Invokana, along with the possibility that it increases LDL-C, the so called "bad" cholesterol.
The FDA originally rejected it as too dangerous, but approved it in January of 2014. There were more cases of bladder cancer among those taking Farxiga than in the group that did not take it. AstraZeneca, the company selling it, assures you that the numbers in the study were too small to determine if this was statistically significant. Why would you want to participate in the much larger and, to AstraZeneca highly profitable" "study" conducted on paying human lab rats that will, by the time the patent expires on this drug, make it crystal clear just how dangerous it really is?
Jardiance, Yet Another Drug in this ClassJardiance is the same empagliflozin that the FDA did not approve a year ago supposedly because of unspecified manufacturing problems. It was approved in August 2014.
Like the other drugs we just discussed Jardiance causes urinary tract infections and vaginal and penile yeast infection.
Misleading Claims Jardiance Prevents Heart Attacks Increase Its PopularityThe FDA demanded post-marketing cardiovascular tests, so it is likely that the same disturbing signals emerged in its clinical trials as emerged with the other drugs. However, on September 18, 2015 when the first of these cardiovascular studies was published, it generated headlines that claimed that Jardiance prevented heart attacks in people with Type 2 diabetes.
Needless to say, this was blockbuster news, since no other drug currently on the market for Type 2 diabetes can make this claim. But the truth was far more complex, and though the drug did appear to decrease heart attacks in people who were already diagnosed with significant heart disease--i.e. those who had already had heart attacks, the actual numbers were small. More importanlty, Jardiance also seemed to increase the incidence of strokes in these same people. Beyond that, this study made it clear that Jardiance did a poor job of lowering blood sugar. You can read the details about this study in This Blog Post
It is not known whether a cancer signal appeared in the clinical trials for Jardiance. But since these trials only involved a total of 4,500 people and did not last more than a few years, the cancer signal seen in other drugs in the same class should not be ignored.
Say "No" to Brand New Diabetes Drugs!
If your doctor tries to put you on these new drugs, 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.