Friday, April 1, 2011

Using Actos to Prevent Diabetes

Recently, the New England Journal of Medicine published a study showing that Actos prevented the development of diabetes in patients at risk for developing diabetes (Pioglitazone for Diabetes Prevention in Impaired Glucose Tolerance). Though this has not generated significant mainstream media buzz, bloggers Matthew Herper from Forbes (Why You Don’t Want A Pill To Prevent Diabetes) and Amy Tenderich from Diabetes Mine (10 Reasons Why The Actos Pre-Diabetes Study is Dumb) strongly disagree. Since many patients follow these popular blogs (far more popular than mine), I thought it would be important to throw a clinician's point of view into the ring.

The NEJM study randomized over 600 patient who were at high risk for developing diabetes to pioglitazone (Actos) or placebo and found that after about 2.5 years, 2.1% in the pioglitazone group and 7.6% in the placebo group progressed to diabetes (which is a relative 72% risk reduction). On the down side, patients on pioglitazone gained about 7 pounds more and about 7% more had edema.

To assess the value of using TZD's like Actos to prevent diabetes, it is important to understand what diabetes really is, how it is defined, and why TZD's might be a very important option despite the associated risks. Unlike type 1 diabetes which is mostly about the destruction of the beta cells in the pancreas and subsequent lack of insulin, type 2 diabetes is a long process that is about much more than blood sugar. Type 2 diabetes is a result of genetic factors that control how individuals utilize glucose, about age, and about obesity. These factors combine to cause much more than just the body's impaired ability to utilize sugar. There is increased inflammation, worsening of cholesterol, increased blood pressure and increased blood clotting, just to name a few. All of these factors, including elevated sugar, combine over years and years to increase the risk of microvascular complications (eye, kidney, nerves) and macrovascular complications (heart attack and stroke). The process occurs for many years, and it is estimated that at the time of diagnosis of diabetes, the process (let's call it metabolic syndrome) has been going on for about a decade and that about half of the pancreas' function is lost despite having relatively high levels of insulin. Men who meet the diagnostic criteria for metabolic syndrome have three times the risk of heart attack and stroke and women who meet this criteria have six times the risk.

When we call a diabetic a diabetic is quite arbitrary. The guidelines used to classify diabetes as a fasting glucose of 140. This was lowered several years ago to 126 recognizing that complications were occurring at sugar levels lower than 140, and the cut off of 140 was too high because it was delaying treatment. More recently, in 2010 the ADA recommended that diabetes be diagnosed at a hemoglobin A1c of 6.5% or greater, recognizing a fasting glucose of 126 missed many of the diabetics with impaired post-prandial glucose, thus leading to possible delays in therapy. In fact, based on this new criteria, some of the patients in the Actos study who were not classified as having diabetes, would now be called diabetics. It is not inconceivable in the near future, that the threshold for diagnosis and treatment of diabetes occurs at an even lower fasting glucose number, A1c, or some constellation of markers. In other words, whether or not we are really preventing diabetes or just delaying the time to reach an arbitrary threshold is more of semantics. The bottom line is that in patients with impaired fasting glucose, there is an underlying disease process leading to complications that ought to be addressed.

To make an informed decision, one has to review the three main studies that looked at drugs for the "prevention" of diabetes. The study above for Actos, was very similar in design and findings to the other TZD rosiglitazone or Avandia called the DREAM study. The other major study, called the Diabetes Prevention Program (or DPP) looked at metformin vs. diet and exercise vs. placebo. Interestingly, diet and exercise beat metformin for preventing diabetes. Why would this be? It has to do with the fact that diet and exercise reverses the process of insulin resistance whereas metformin merely lowers blood sugar. Metformin was not included in the rosi or pioglitazone studies, nor was there a diet and exercise arm, so it is hard to compare all three interventions (diet/exercise, metformin, TZD) in preventing diabetes complared to placebo. However, troglitazone, an early TZD which was pulled from the market for liver complications (Actos and Avandia have not shown these problems) was initially used in the Diabetes Prevention Program (DPP), but was stopped after less than a year. Interestingly, in that short time, troglitazone did better than both metformin and diet and exercise. In other words, when you address insulin resistance and metabolic syndrome either by diet and exercise or with a TZD, you prevent diabetes much better than with a drug like metformin that only addresses blood sugar or placebo. This is important because the Actos study not only showed decreased rates of diabetes, but also showed statistically significant decreases in blood pressure, plaque build up, and increases in HDL or good cholesterol.

This begs the question, if you can prevent diabetes (or treat the underlying process that has not yet met the arbitrary criteria to be called diabetes) with Actos or lifestyle modications, why would you choose a drug? The answer is that lifestyle modifications is always preferred, but often not practical or easy to do. For the lifestyle intervention group in the DPP, participants were instructed to limit their calories to 1200-1800, get 150 minutes of exercise a week, had 16 sessions of counselling, and access to nutritionists, personal trainers, and behavioral counsellors. Another way to look at this is that anyone can go on "The Biggest Loser" and lose weight if they are given that amount of support (and time to take off from work), but this is not always practical. Interestingly, much of this support is not covered by traditional health insurance (where medication is), and once could argue that this is where we ought to devote our precious health care dollars (topic for another post).

As a physician, I need to help my patient the best way I can. I need to be practical. For all patients, diet and exercise is clearly the first step and always encouraged at every step. However, practically speaking, this just doesn't work all the time. It takes a highly motivated patient with a lot of resources and support to do this. Thus, if I can use a medication that will help reverse the underlying disease process of insulin resistance and delay the diagnosis of overt diabetes (along with diet and exercise), then I believe I am ethically obligated to do so.

Finally, the big issue that has been brought up is side effects. Mainly weight gain and heart failure. First, the TZD's do not "cause" heart failure. What I mean by this is that Actos has no direct effect on the heart. What is does do is increase fluid retention. For patients whose hearts are not working that great (pre-heart failure), a little extra fluid can push them into heart failure. Though this is a serious risk, it is not that common and can be addressed by carefully monitoring patients before and after treatment. Secondly, weight gain is a real issue. There are two components of weight gain caused by TZD's. The first is the aforementioned fluid retention. The second has to do with reversing the underlying disease process. Patients with diabetes and metabolic syndrome do not utilize glucose correctly. This causes subsequent increases in insulin and eventual pancreas failure leading to the need (over years) of supplemental insulin. By not using sugar, weight is not gained. By correcting the process, the sugar goes to where it is supposed to, which leads to weight gain. However, it is not clear that this weight gain is necessarily "bad." Studies show that TZD treated patients shift their fat from the dangerous visceral abdominal fat (associated with high cardiovascular risk) to more centralized fat stores. In other words, though not proven by a randomized control trial, reversing the disease process (glucose, cholesterol, blood pressure, weight gain) is likely to prevent more adverse events (heart attack and stroke) then events caused by additional weight.

Bottom line: Obesity is an epidemic in our country and will soon be the single leading cause of preventable death in the US. Along with obesity comes diabetes, which takes years to develop and is defined by arbitrary criteria. This diease process (metabolic syndrome) is associated with it's own consequences. Diet and exercise leading to subsequent weight loss and improved cardiovascular health is clearly the best choice. However, for most patients for very practical reasons, this method is not successful. Until there are changes to our health care system and/or public health initiatives that make intense lifestyle modifications more reasonable, pharmacotherapy to prevent diabetes has an important role. Pioglitazone has demonstrated that it can effectively prevent diabetes in most patients with known but manageable side effects, and therefore should be considered a useful tool.


Ken MacKillop said...

Hello Dr. Mintz,

I'd like to applaud your piece on the Actos prospective study. Having done a large amount of reading of the research on pre-diabetes and pathogenesis of diabetes, I find your comments much more informed and informative than those of the other bloggers mentioned (to say the least).
I am also an admirer of the work of Ralph DeFronzo and his colleagues, having read much of it.
I myself have borderline isolated IFG (i.e. FPG=~100mg/dl), and only recently discovered my hyperglycemia. I have since been very interested in quantifying, halting and (if possible) reversing my own diabetic progression. TZDs and DeFronzo's research seem to be particularly relevant to my own condition.
IFG seems to be largely a condition of aged/changed genetic expression in various tissues, while IGT is much more one of insulin resistance (and hence, more easily dealt with through lifestyle intervention).
I am 52 and have been overweight in the past, but am now quite lean (~10%BF) with very high insulin sensitivity. I already maintain a strict low-carb diet and do a lot of exercise including resistance training.
I too have noted, with interest, the impressive results of TZDs in reversing pre-diabetes. Importantly, these results appear to have persistence. This is apparently due to the fact that the TZDs operate largely by changing genetic expression in the tissues, possibly reversing or otherwise compensating for the undesired changes that occur in natural diabetic pathogenesis.
It is not yet clear to me how much I can achieve with intensive lifestyle intervention alone. Maybe this will be enough, but it looks to be a slow process so far.
Off-label use of TZDs with pre-diabetics seems promising, and the amount of resistance to this practice is somewhat surprising. The few clinicians who seem interested in this approach tend to be associated with diabetes research, from what I have observed.

Anonymous said...

But this study does have a major flaw.. and that is it is using a drug to lower blood glucose to prevent diabetes... meaning it is suppressing the very marker of what it means to have 'diabetes'.

I would much rather have seen the drug discontinued and the patietns follwed to see if the effect was persistent WITHOUT drug. How do you know that the day/month after the TZD was stopped, the blood sugar jumped up to 140+?

This was well demonstrated in the TROPHY trial in HTN a few years back, where it showed candesartan in prehypertensives delayed the onset of HTN.

I really dont think the study is that impactful unless you can show this.

Dr. Matthew Mintz said...

The flaw is not in the study, but in the term "prevent." If the sugar goes back up after Actos, is started, then technically it is not preventing diabetes, it is just delaying its onset. However, delaying the onset is critically important. It is the years and years of elevated sugar (plus other factors such as high cholesterol and high blood pressure) that cause the many complications of diabetes. Thus, if Actos prevents the progression of pre-diabetes to diabetes, even though stopping the Actos would reverse this, Actos would still be beneficial because it is truly preventing the complications of diabetes.

Anonymous said...

Yes, I see your point. Prevention is a bad term.

But realistically, what this shows then is that Actos treats prediabetes, which is no surprise to anyone, and can be equally said about metformin (and probably sulfonylureas, Byetta, Onglyza, or Precose).

So if I'm looking for the most benign way to treat a prediabetic, I'd want metformin or a DPP4 on board, where adverse effects are minimal to nonexistent.

Dr. Matthew Mintz said...

yes and know. The only other drugs that I am aware of that have been shown to "treat" pre-diabetes other than metformin and TZD's are acarbose (precose) and orlistat (xenical/alli). While it's true any glucose lowering agent will "treat" pre-diabetes, you would first want to prove it. Maybe DPP4's don't work.
However, the key is how to what degree and how long does one pill prevent an pre-diabetic from becoming a diabetic. The metformin is the most studies diabetes drug with the least amount of side effects, it does not do as well in preventing diabetes as the tzd's. I believe that this is because metformin mostly lowers sugar whereas TZD's treat the underlying condition of insulin resistance. A really good study from Europe showed that low dose Avandament (TZD + metformin) did better than anything. This may in fact be the way to do (though likely with Actoplusmet since Avandamet will be impossible to prescribe in the US.

actos lawsuit said...

While it's effectiveness can be debated, the side effects cannot. Many diabetics we've spoken to have had such awful side effects they simply stop using it. Wouldn't it make sense for diet and exercise to be prescribed and not the other?

Dr. Matthew Mintz said...

diet and exercise is always recommended as first line, both for prevention and treatment of diabetes. Problem is that this is rarely successful, which is why medications can have a major role in both preventing and treating the disease. No medications are free from side effects. Actos certainly has a few. Each patient with help from his or her physician must weight the risks and benefits, and decide whether or not a medication is right for them. In the case of Actos to prevent diabetes, for a patient who is working hard at diet and exercise but not seeing results and who has a high risk of progressing to diabetes, the risk of taking the medication may be substantially outweighed by the benefits.

Carol said...

I think the efficiency of Actos is non-questionable. But the problem is it's side-effects. What would be our next best medication for Type 2 diabetes?

JW said...

With the side effects from Actos, it seems like it was a drug that did more harm then helped

Dr. Matthew Mintz said...

Risk benefit ration is unclear.
Though there is data suggesting Actos is associated with bladder, it is not clear whether it actually causes this. Even if it does the risk is very low. On the other hand, there is very good data that Actos can prevent diabetes. Recent data presented at the ASA shows that if you are pre-diabetic and can get your sugar to normal (even just once) you significantly decrease your risk for developing diabetes.
Thus, you need to weigh small possible risk of getting bladder cancer vs. known large advantage or preventing diabetes. Finally, screening for bladder cancer must be taken into account. Though there is no good data on this, I know routine check the urine on my patients with Actos. If there is any sign of blood, I will work them up for bladder cancer. If found early, bladder cancer is easily treatable.

superhumanradio said...

thanks for the tips, it will help those who(re suffering from high blood sugar.

Anonymous said...

I was an original participant in the Troglitazone arm of the Diabetes Prevention Program (DPP) in 1996. After the Troglitazone arm was discontinued (one year later, in 1997), I asked my doctor to put me on Actos - yes, off label. I've been on it now for 19 years. My latest A1c level is 5.6. I have no doubt that my being on this preventative measure has allowed me to dodge diabetes for nearly two decades.

I'm fully aware of the side effects: edema, possible kidney cancer, etc. These risks, in my opinion, are so heavily outweighed by the otherwise almost certain morbid effects of diabetes. The risks are more than acceptable.