Glitazones - Good or Bad?
Should we or shouldn't we?
There has been plenty of media coverage of these drugs ever since they came onto the market. One cannot help wondering how much is media hype and how much is truth.
Unfortunately I don't think we will every really know the answer to that one. All we can do is look at all the info and make our own decisions.
I have been doing just that!
Here are the facts I found, the conclusion I came to and the reasons for that conclusion.
Note:-
These are just MY opinions. I am not trying to convince you, one way or another, as to whether you personally should take these drugs or not, that is up to you. I am just sharing my reasons for what I have chosen to do.
So lets take a look at the facts:-
As you probably know there were three drugs developed in the thiazolidinedione class:-
1. Troglitazone, sold under the brand names (Rezulin, Resulin or Romozin)
2. Rosiglitazone, sold under the brand name Avandia
3. Pioglitzone, sold under the brand name Actos.
1.Troglitazone
This was the first of this class of drug to appear on the market, in the late 1990's and not much needs to be said about it now as it's manufacturer, Warner-Lambert Company, voluntarily withdrew it from the market in 2000 when it was found to cause serious liver problems in some patients (more power to them).
By that time two other drugs of the same class were already on sale and the diabetic community was assured they did not hold the same risks as Rezulin.
2. Rosiglitazone
Marketed by the pharmaceutical company GlaxoSmithKline and approved by the FDA in 1999, this became a very popular second level drug, usually given to patients once they were unable to achieve good blood glucose levels with the aid of Metformin.
It also became available as a combination drug, either as Avandamet, which, as the name suggests, is a mix of Avandia and Metformin or as Avandaryl or Avaglim, a mix of Avandia and the sulfonylurea drug Glimepiride, marketed as Amaryl.
Then in 2006 stories started to appear that made one wonder just how safe this drug really was.
Firstly there were reports of Avandia, in rare cases, causing swelling in the back of the eye, known as macular oedema, which can lead to impaired vision and blindness.
Next in February 2007 a press release by GlaxoSmithKline noted that there were a greater incidence of fractures of the upper arms, hands and feet in female diabetics given Rosiglitazone compared with those given Metformin or glyburide.
Then in June 2007 came the report in The New England Journal of Medicine that the use of rosiglitazone was associated with a slightly increased risk of heart attack. The meta-analysis findings of data from 42 clinical trials (by Dr Steven Nissen, a cardiologist from Cleveland Clinic) showed those taking Avandia to have a 43% higher risk of heart attacks and a 64% elevated rate of cardiovascular death.
About a month later, on July 30, 2007 a statement from the Advisory Committee of the FDA said that they " concluded that the use of rosiglitazone for the treatment of type 2 diabetes was associated with a greater risk of 'myocardial ischemic events' (such as angina or myocardial infarction.) than a placebo, Metformin, or sulfonylurea."
In October 2007 the EMEA (European Medicines Agency), after studying the reports, concluded that the benefits of Avandia, as well as the other drugs in the same class, such as Actos, outweighed the risks and advised people on the drug to keep taking it but to consult their doctor if they were worried about side-effects.
Following that, in November 2007, was the FDA recommendation that Avandia carry a black box warning (the strongest type of safety alert) on its labelling about the potentially increased risk for heart attacks.
This means that a strong warning is given to healthcare professionals of the possible problems associated with these drugs and advises them, so to speak, to keep and eye out for symptoms of heart failure in any patients for whom they have prescribed, or will prescribe, the drugs.
GlaxoSmithKline agreed to add this, though they continue to claim that there was little significant difference between Avandia's safety record and that of other common diabetes treatments.
Their Medical Director said , "We are confident of the safety profile of Avandia and believe in its benefits for Type 2 diabetic patients."
Note -
It pays not to get confused here. The Black Box warning was not a direct result of the controversy over Avandia. It actually just emphasised the well known side effect of the drug to worsen heart failure in people who ALREADY had significant heart failure.
The emphatic warning was deemed necessary because it appeared that some doctors were ignoring this.
The controversy over Avandia is over the possibility of its increasing the risk of heart attack and cardiac death in people NOT suffering from significant heart failure.
In early 2008 the European Medicines Agency (EMEA) asked GlaxoSmithKline to update Avandia's label to include, in the warnings and precautions section of the label, a statement such as
"Available data indicate that rosiglitazone may be associated with an increased risk of myocardial ischaemic events. As a precaution, the use of rosiglitazone is not recommended in patients with ischaemic heart disease and/or peripheral arterial disease, especially those with myocardial ischaemic symptoms."
It will also state that
'this risk was not confirmed or excluded in three long-term clinical trials and the data in their entirety on myocardial ischaemia are inconclusive'.
The European Medicines Agency also recommended that patients who were suffering from heart disease, or who were getting leg pains (which are a possible sign of heart disease) should not take Avandia.
Prescribing information to health care professionals should be updated to include a warning that,
"In patients with ischaemic heart conditions, rosiglitazone should be used only after careful evaluation of every patient’s individual risk. In addition, the combination of rosiglitazone and insulin should be used only in exceptional cases and under close supervision."
On the 24th January 2008 GlaxoSmithKline's press release stated that the label changes would apply, not only to Avandia, but also to rosiglitazone-containing products such as
Avandamet and Avaglim.
3. Pioglitazone
This is the last thiazolidinedione left. It is marketed by Takeda Pharmaceutical Co, under the name of Actos and also as the combination drugs ACTOplus met (Actos and Metformin) and Duetact (Pioglitzone and Glimepiride).
A study called PROactive, sponsored by the manufacturer, (involved 5,238 patients in 19 European countries who had experienced one or more cardiovascular events such as a heart attack, coronary artery bypass surgery or stroke), seemed to show that Actos did not have the same risks as Avandia. In fact it actually appeared to reduced the risks of heart attack & strokes, though nobody seems to know exactly how.
This would seem to then be the drug of choice but Actos was not without other side effects that showed up in the trial.
These included:-
Weight gain
Oedema (fluid retention)
Non-serious hypoglycaemia
Heart failure
However again it was felt that the benefits outweighed the risks.
The FDA has apparently asked Takeda to conduct an analysis similar to Nissen's. As yet we do not know the results.
Despite the trial results medical professionals were warned that Actos was not suitable for everybody. They are told not to prescribe it to patients with heart failure and that it could cause or worsen congestive heart failure.
Patients taking Actos who find they are suffering from rapid weight gain, fluid retention, or shortness of breath, which may be symptoms of heart disease, should contact their doctor immediately.
Also the FDA Black Box Warning included both Actos, ACTOplus met and Duetact, as can be seen below.
Boxed Warning: Congestive Heart Failure
* Thiazolidinediones (TZDs), including pioglitazone, cause or exacerbate congestive heart failure (CHF) in some patients. After initiation of ACTOS, ACTOplus met, or duetact, and after dose increases, observe patients carefully for signs and symptoms of heart failure (including excessive, rapid weight gain, dyspnea, and/or edema). If these signs and symptoms develop, the heart failure should be managed according to current standards of care. Furthermore, discontinuation or dose reduction of the TZD must be considered.
* ACTOS, ACTOplus met, and duetact are not recommended in patients with symptomatic heart failure. Initiation of these drugs in patients with established NYHA Class III or IV heart failure is contraindicated.
Conclusions
So where does that leave us diabetics? Back in the "should we or shouldn't we" situation as always, with no clear guidelines.
Lets list the known possible side effects:-
Congestive Heart Failure
Heart Attack
Stroke
Macular Oedema
Vision loss
Blindness
Bone Fractures
Water retention
Now let us consider that the reason we are given drugs to lower our blood sugar - to prevent the complications of diabetes.
One of the major complications is heart disease, in fact some statistics show that 75% of diabetics die of heart disease.
Another complication is eye problems - that is why the importance of an annual eye test is stressed by our health care professionals.
Water retention may not seem life threatening in and of itself but if you carry larger amounts of fluid your heart has to work much harder to pump this and so your chances of cardiac problems increase.
Yet it would seem that the above complications are possible side effects of the glitazones!
I feel extremely wary of taking a drug that seems to increase the risk of the very thing it is supposed to prevent.
The powers-that-be say that the benefits outweigh the risks and yes, if due care and attention was paid to each individual case before prescribing of these drugs and if each case was carefully followed up, with due note bring taken of all symptoms, however unusual, experienced by the patient, then maybe this is true.
In the days of the old family doctor who had known you from childhood and stopped off on his rounds every day to see how you were getting along this may have been possible. Medical care then was up front and personal but now……..?
Modern doctors are very busy people, they see their patients for an average of 15 minutes per appointment, all the while knowing there are a hoard of others waiting. The case of 'Mrs Brown and her diabetes' is hardly at the forefront of their minds!
Thus when Mrs Brown arrives for her appointment they check her file, note the results of her last series of tests and prescribe accordingly. That tends to mean following the progressive party line with diabetes i.e. first diet & exercise, then metformin, one of the glitazones, sulphonylurea and lastly, insulin.
I am not implying that all doctors prescribe blindly but when you are very busy the 'tried and trusted' way seems appropriate.
Unfortunately patients are individuals and while for some this system works for others it is a disaster.
There are some great medical professionals out there who are prepared to listen to their patients and discuss options when the party line does not work but there are also some who appear to feel threatened if the patient questions their decisions or presents with symptoms they do not understand.
Under these circumstances the 'risks' may well outweigh the 'benefits'.
These facts alone would make me conclude that these drugs are not for me - remember I said at the beginning of the article that this was MY opinion only, you must do what seems right for you.
However, I have an even more personal reason as you will see in the tale below:-
When I was first diagnosed with diabetes my blood sugars were way up in the 20 mmol (360 mg/dl) range and I landed up in hospital where they put me on insulin to drag them down. The consultant wanted to send me home with insulin but the diabetic nurse (bless her) persuaded him to let me try oral medication.
I was given metformin, a test meter and, armed with a diet from the dietician, I went home. However hard I tried, following the diet given, eating the right amount of carbs with every meal, (wholegrain bread, pasta, rice, potato), plus 5 fruit and veggies a day and minimal fat my blood sugars were steadily climbing.
I phoned the diabetic nurse and she added Gliclazide, a sulphonylurea drug, to my medications. This did the trick of lowering my blood sugars but by this time I had started to research this disease and knew that this drug worked by forcing the pancreatic cells to produce more insulin and basically worked them to death! Not exactly a cheerful outlook.
Gliclazide also tends to drop your sugars too far and you get hypos.
I had a follow up appointment with the consultant who looked at my latest blood test results and then told me to go home and live a normal life and he would see me in 3 years time when he would put me on insulin……..huh?!!!
I was one very confused patient.
So it was back to the research to see what I could do to help myself. What I found were a reasonably large group of people who were saying that the high carb, low fat diet did not work for everyone and suggesting an alternative - low carb, medium protein and fat.
Well, I thought, in for a penny in for a pound. What I was doing was not working so what had I to loose.
I bought some books, particularly one by a Dr Richard Bernstein, who is himself a diabetic and follows a very rigid low carb diet and set out to do the same.
Results -
My blood sugars started to come down and I was experiencing occasional 'hypos' that previously I had only read about. Not to say that I enjoyed them but they were at least an indication that my diet was working.
Fortunately at this time I was transferred from the hospital clinic to my local surgery where I met up with a very understanding diabetic nurse.
Like me she did not care for the sulphonylurea drugs and we agreed that I should drop the Gliclazide and just continue with the metformin. I said I was low carbing and though she did not come out and endorse it she also did not disagree with me. After all the results were there in my lowered A1c. Dropping the Gliclazide should also solve the hypo problems.
I carried on in this way for about 18 months, then what I will call the diabetic blues set in.
I was sick and tired of always watching my diet, of having to plan everything carefully if we were going away anywhere, of going into shops at Christmas and not being able to buy any of the special goodies so prominently displayed, in fact just being the hell in with my disease and its restrictions.
So I did what many a diabetic has done, I started to ignore what worked and began to eat foods that I knew would raise my sugars but that tasted like heaven. I carried on in this way for around 6 months, in fact until my next check-up, where the error of my ways was clearly evident in my raised A1c.
I was still reluctant to go back to my previous strict way of eating so when the nurse suggested I see my doctor and discuss medication option with her I agreed.
Like the nurse this doctor was great. She took the time to listen and discuss options. By this time I knew that low carb eating was not a favourite with the medical fraternity so I must confess that I did not tell her that that was what had controlled my sugars previously though I did say I had not been eating properly for a while.
She suggested I try Avandia and though I was not that keen as I knew it caused weight gain, something I definitely did NOT need, yet I was hoping, in my heart of hearts, that I could find a simple medical solution that would keep my sugars in check while allowing me those foods I craved.
So I started on Avandia.
The first month was okay, no noticeable changes. Then at the beginning of the second month I started to get headaches. Now like everyone else I get the occasional headache and if it seems bad enough I will take a mild painkiller to cure it. So I put the headaches down to stress, or tiredness, and went on as normal.
However I found that I was waking up about two hours after going to bed with increasingly painful headaches. In fact it was the pain in my head when I turned over that woke me.
Initially I said to myself "Just go back to sleep, by the time you get up the headache will have disappeared", but it didn't, it just got worse. So I would get up and take a painkiller and go back to sleep for a few hours when the scenario would be repeated.
By the end of the month I was having severe headaches that lasted for around 20 hours and I was losing the battle to control them with ever increasingly strong painkillers.
At work I found the machines in front of me advancing and receding alarmingly as the pain in my head seem to affect my vision. The thoughts of brain tumours and such like begin to niggle.
I phoned the doctor but could not get an appointment for a couple of weeks - headaches are not emergencies.
However my caring husband had been noting the progression of these headaches and worked out that they came on within a few hours of my taking the Avandia, lasted the 20 or so hours and then wore off, by which time it was time to take the next pill and the cycle restarted. We agreed that I should stop taking the pill and see what happened - hey presto! no more headaches!!!
I saw the doctor and described my symptoms and she said that although it was extremely rare, headaches had been reported as a side effect of Avandia and agreed with my stopping the drug. I would carry on with just the metformin until my next blood tests to allow the Avandia to be totally flushed from my system. We would then again discuss options.
Although the headaches totally occupied my attention at the time I was also having slight swelling of the ankles and gained 12 pounds in the 2 months.
Unfortunately this helpful doctor was pregnant at the time and went of on maternity leave prior to my next tests, so her patients were distributed amongst the other doctors in the practise.
Not surprisingly my A1c had not come down and the nurse (also a different one from my first one) said I was to see the new doctor as he wanted to talk about my medication and assured me he was young and innovated. "Great" I thought, "Just what I need".
By this time I had heard plenty about the new drug Byetta from folk in the USA and what I had heard made it seem the perfect choice for me - lower Bg and weight lose, great stuff. However it was only recently released in the UK and I knew that getting it could be a problem. However - young and innovated, perhaps I had a chance after all.
So Hubby and I arrived for the appointment full of expectations, only to be shot down in flames. Our young and innovated doctor was young, that was true, but innovative? - no chance.
The first thing he said to me was that he was going to put me on Actos. "Oh no you are not." I thought to myself. " not after my experience on Avandia".
I pointed that out to him politely, thinking maybe he had missed it. He was just not interested, in fact I got the impression he considered that I had made up the headache story, though who knows why I would do such a thing.
He insisted Actos was the way to go, I politely declined. He got more insistent and I got more heated, pointing out that two of these drugs had had really bad press, one had made me really ill and now he wanted me to take the third one - no way am I going to be the mouse in that experiment!
I suggest Byetta - he obviously knew nothing about it as I had to tell him about it and that it was now available in the UK. He said "It is not available on the National Health Service" and we said "That is okay, we are prepared to pay for it ourselves, we just need a prescription". He said he would not give me one as he would have to monitor me and he was not prepared to do that - stalemate.
By now both hubby and I had reached the conclusion that this doctor is one of those who subscribes to the rule - "I know best and you will do as I tell you". Any negotiations or informed discussion are out.
I decided that it was time to discuss diet options with him, maybe we could reach a compromise there. If he liked I would go and see yet another dietician and perhaps she would have a more varied approach than the first one I saw.
I broached the subject by saying "I am afraid that the recommended high carb diet does not work for me but…" and that was as far as I got. He gave a forced smile and said "you can lead a horse to water but you can't make it drink".
I was furious and decided to end the appointment there and then, this was obviously going to be a waste of time. Either I toed the party line or, as had already happened, I was going to be labelled as 'non-compliant'.
I refrained from telling him that no horse would drink what was obviously polluted water and said to just give me a repeat script for the metformin and leave it at that, which he did. I am sure he was very pleased to get rid of us.
So now I am back on the wagon -
The low carb one that is, and yes, my blood sugars are going down. Damn, I wish there was some half measures here but until Byetta or something of that sort becomes freely available I am going to have to practise serious self discipline.
Oh well, I suppose it is all character building. Besides, I am going to prove to that damn doctor that there are ways of achieving lower Bg's without his precious Actos and that maybe patients do sometimes know what they are talking about!!!
This all seems to bare out my statement that we, unfortunately, cannot rely on our medical professionals to listen to our symptoms and treat us individuals, not just one of the 'diabetic pack'.
Under those circumstances we need to do our own research and decide for ourselves what we are prepared and not prepared to accept as treatment and stick to our guns - not an easy thing to do I can assure you!