Here we go again

Here we go again

Once again the issue of pancreatitis and GLP-1 therapy is rearing its ugly head thanks to a study published in the most recent  issue of Internal Medicine. The study; “Glucagonlike Peptide 1–Based Therapies and Risk of Hospitalization for Acute Pancreatitis in Type 2 Diabetes Mellitus” ,  published yesterday concludes; “ In this administrative database study of US adults with type 2 diabetes mellitus, treatment with the GLP-1–based therapies sitagliptin and exenatide was associated with increased odds of hospitalization for acute pancreatitis.” (sitagliptin = Januvia, exenatide = Byetta)

Reading through the study and its numerous caveats Diabetic Investor could not help but think that this issue, just like the Avandia controversy, will not go away nor will we ever see a conclusive study that definitively proves one way or another whether there is a causal relationship between GLP-1 usage and an increased risk of pancreatitis.  Just like the last time this issue came about it’s important to note that patients with Type 2 diabetes are at an increased risk for developing pancreatitis just by the mere fact they have diabetes. The question then becomes in a group that has a higher than normal incidence rate for pancreatitis  can any study conclusively prove a causal relationship.

Considering that Januvia is a mega-blockbuster drug and that Bydureon has the potential to become a mega-blockbuster it’s almost a certainty that more studies will be done which based on previous studies already done on the subject, will only create more confusion with their findings.

To gain some perspectives on just how crazy this situation is consider the following passage from the study;

“Our findings need to be interpreted in the context of other studies. A cross-sectional analysis of spontaneous adverse events reported that the use of sitagliptin or exenatide increased the odds for reported pancreatitis 6-fold compared to the use of other antidiabetic drugs. However, that study did not have data on confounders. An administrative claims-based study reported no differences in acute pancreatitis among exenatide users, sitagliptin users, and controls but could only adjust for a limited set of cofounders. Another administrative claims study reported no difference in acute pancreatitis among exenatide users, sitagliptin users, and controls owing to limited statistical power and limited duration of follow-up. Another cohort study reported no significantly increased risk of acute pancreatitis with exposure to exenatide relative to other antihyperglycemics after propensity score adjustment but had limited statistical power and a limited exposure window. In that study, the use of exenatide beyond 32 days was associated with a significantly increased risk of pancreatitis compared with the use of other antihyperglycemics. The study did not evaluate the role of sitagliptin. A descriptive database study reported no difference in rates of acute pancreatitis among exenatide users (0.44%), sitagliptin users (0.28%), or controls (0.39%) after follow-up of 540 days without any statistical test or adjustments for cofounders. A meta-analysis of clinical trials reported  no difference for sitagliptin use compared with placebo or other oral hypoglycemics in the incidence rates of pancreatitis (0.1% and 0%, respectively), acute pancreatitis (0% and 0.1%), respectively), and chronic pancreatitis (0.1% and 0%, respectively). However, that study was limited by inadequate statistical power and incomplete ascertainment of adverse events in clinical trials.”

Granted that is not an easy passage to read nor is it easy to understand for those who don’t have an advanced medical or statistical background, but even a layman understands that with all this conflicting study data there are enough holes to drive a Max truck through. Frankly it is paragraphs like this that drive physicians crazy as they cannot answer a simple question asked by almost every patient taking these drugs; “Is this drug safe to use?” About the only people in the world who just love this stuff are lawyers who will use these studies as evidence when they file class action lawsuits. Nothing against lawyers, but the diabetes world is in a world of hurt when the only people who want to see studies such as these are class action law firms.

Diabetic Investor also gets crazy when we see the dreaded meta-analysis used as it was just this type of analysis that created the Avandia controversy and we all know how well that has worked out.  The last thing the diabetes world needs is another controversy created in a large part by how different people interrupt a set of numbers. If the Avandia controversy taught us anything it was that there are lies, damn lies and there are statistics.  At the end of day all these conflicting studies with their conflicting conclusions based on which data is or is not included all that is created is more confusion which results in even more studies. It’s about time someone said enough is enough and ends the madness.

It’s about time for everyone to understand a few facts:

  1. There is no such thing as a completely safe drug, this just isn’t possible or even realistic.
  2. Diabetes creates numerous comorbidities making it even more difficult to establish causal relationships between  drug usage and adverse events.
  3. There is no silver bullet that should be used by each and every patient with diabetes.  Just because a particular drug works on one set of patients does not mean it works with each and every patient.
  4. There is something called informed consent or what Diabetic Investor likes to call common sense, something not always present in the diabetes world, where patients need to understand both the benefits and risk associated with the drugs they are taking. Based on this information, along with input from their healthcare team, the patient can then make an informed decision on whether or not to use a particular drug.
  5. Even with the best available information it could take years before we understand the true risks of any diabetes drug. TZD’s were on the market for over seven years before we learned about the increased incidence of bone fractures.
  6. What is the cost of not using a drug? The reality is more than two thirds of patients are not properly controlling their diabetes and this leads to many complications and comorbidities. While some drugs may carry an additional risk factor, there is an equally high degree of risk letting their diabetes remain uncontrolled. Unfortunately, sometimes physicians and their patients are damned when they do and damned when they don’t.

Diabetic Investor also believes it’s time for organizations like the American Diabetes Association (ADA), the European Association for the Study of Diabetes (EASD) and American Association of  Clinical Endocrinologists (AACE) to provide clearer guidance on whether or not a study will yield any new information on an issue or just create further confusion.  There are some issues, no matter how many studies are done, that will ever be answered with a high degree of certainty.  Unfortunately treating diabetes is not like fixing a broken arm where an x-ray can used to determine that the treatment has been successful. Diabetes is a complex, chronic disease that changes over time, so even when it appears that a patient is under control that situation can, and does change over time. The simple fact is the physicians who treat diabetes need weapons at their disposal so they  can effectively treat diabetes , even if that means some of these treatments carry additional risk factors. As we noted earlier the key is to make sure the patient understands both risks and benefits of the drugs they are taking.

It’s unfortunate that the physicians who conduct these studies fail to grasp the real world implications that their studies bring about. This is not to say that these issues should not be studies rather,  that with so many studies on the same subject  each yielding conflicting conclusions there is a time to acknowledge there is no clear cut answer. We know this a hard reality for researchers to accept as they are trained to find answers and in the absence of clear conclusions their default reaction is to conduct even more research.

It’s one thing to prompt a healthy debate of an issue, it’s quite another to continue this debate when there is no definitive answer. This is like sports fan debating who the best player is when comparing players from different eras. There is no argument that Michael Jordan is amongst the greatest to ever play basketball, but one could also make a strong case for Bill Russell, Walt Chamberlin or LeBron James. The simple truth is all these players are great and there will never be a definitive answer to who is the greatest of all time. This won’t stop basketball fans from debating but at least the debate doesn’t adversely impact anyone else.

When it comes to these conflicting study conclusions, debated over and over, ultimately it’s the millions of patients with diabetes who are hurt the most. As we have seen the debate also brings with it real world consequences, just look at the diabetes drug approval process since the Avandia controversy. More than ever physicians are faced with an unwinnable situation; do they prescribe a drug that may carry some additional risk factors, a drug they believe will help the patient better control their diabetes, and therefore avoid many of the  complications associated with poorly controlled or do they avoid this drug because it might create an equally unpleasant and possibly serious adverse event.

The answer isn’t even more studies, the answer is to understand the true nature of the risks and benefits of using or not using a drug. Understanding that even when there are mountains of data on the drug, events that did not show up during the approval process can and sometimes do rear their ugly head years after the drug has been on the market. The harsh reality for many drugs used to treat diabetes, even the most popular that have been around for years, there is no simple answer to the question; “Is this drug safe?” In the absence of definitive information a judgment needs to be made as the cost of doing nothing is just unacceptable. As P C Snow noted; “Judgment is the ability to think of many matters at once, in their interdependence, their related importance, and their consequences.”