We Really Don’t Need This

We Really Don’t Need This

“The American Diabetes Association (the Association) is asking all pharmaceutical companies involved in the development or marketing of incretin-based medications, used to lower blood glucose levels, to make patient-level data on their products available for an independent review that could help settle the question of whether such therapies contribute to the development of pancreatitis or pancreatic cancer.”

This statement comes from an ADA press release well back on June 10th just about the same time some researchers were questioning the safety of GLP-1’s and DPP4’s . The question of whether there is a casual relationship between GLP-1/DPP4 usage and adverse pancreatic events is not a new one and has plagued this category since Byetta and then Januvia first hit the market. Some may recall that when these issues first surfaced Amylin conducted an analysis of insurance databases which noted that the incidence rate of pancreatic events and Byetta usage was actually lower than the incidence rate of pancreatic events in the general diabetes population.  It’s also important to note that patients with diabetes are at an increased risk of pancreatic events to start with.

Still the issue would not go away and back in February a study was published in Internal Medicine, entitled “Glucagonlike Peptide 1–Based Therapies and Risk of Hospitalization for Acute Pancreatitis in Type 2 Diabetes Mellitus” ,  which concluded “ 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)

In a classic case of history repeating itself the questions surrounding these drugs provided ammunition to a group of zealots lead by Dr. Peter Butler the director of the Larry Hillblom Islet Research Center David Geffen School of Medicine at UCLA.  A group that is convinced that GLP-1’s and DPP4’s should be pulled from the market even though there is little hard evidence to suggest such a move is justified. Following the path of that crusading cardiologist Dr. Steven Nissen, the data these zealots are promoting as fact is dubious at best.

Still the ruckus created by Dr. Butler and his followers lead the ADA and American Association of Clinical Endocrinologists (AACE) to issue a joint statement supporting the use of these drugs. According to the statement “The American Association of Clinical Endocrinologists (AACE) and the American Diabetes Association believe that the study by Singh et al, Glucagon-like Peptide 1-Based Therapies and Risk of Hospitalization for Acute Pancreatitis in Type 2 Diabetes Mellitus, published online February 25th in JAMA Internal Medicine does not provide the basis for changing treatment in people with diabetes.”

Now just when it looked this situation couldn’t get any stranger Dr. Butler picked up a partner in crime Edwin A M Gale, emeritus professor of diabetic medicine Department of Diabetes and Metabolism, Southmead Hospital, Bristol UK who published an editorial in the British Medical Journal (BMJ) which stated; “Investment companies knew that the Food and Drug Administration safety database carried a signal for acute pancreatitis with the antidiabetic drug exenatide (a glucagon-like peptide 1 (GLP-1) agonist) in 2006, a year before the agency alerted doctors—a curious reflection on the way we mix business with medicine. The signal had reached astronomical dimensions (more than 10 times that in control drugs) by 2011 and has accelerated since.2 Furthermore, all GLP-1 based agents that have been on the market for more than two years have also generated a signal for acute pancreatitis, suggesting a class effect.”

He concluded his editorial by stating:

“Why have the companies been so slow to respond to this threat? Because of the “three monkey paradigm,” which operates as follows. Companies are legally responsible for monitoring the safety of their own products, but self evidently cannot be held responsible for tackling a safety concern that does not exist. A concern that can be plausibly doubted or denied carries no legal liability, whereas one that gives rise to serious consideration (even in internal emails, which are discoverable) leaves the door wide open to litigation. Inviting companies to monitor the safety of their own products thus provides them with the strongest possible incentive for failing to do so, an instance of the law of  unintended   consequences. The three monkeys, who neither hear nor see nor speak, have been allowed to flourish at the heart of our system for protecting the public. The regulators should not follow this example.”

Ultimately the ADA had little choice but to step in with the admirable goal of settling for all time this issue. The problem here as Diabetic Investor pointed out on numerous occasions this issue cannot be settled to anyone’s satisfaction. The facts are, as we noted earlier, patients with diabetes are at an increased risk of adverse pancreatic events just because they diabetes. Even with mountains of data it would be difficult if not impossible to determine the role these drugs played should the patient develop an adverse pancreatic event. Simply put it’s virtually impossible to say these drugs caused the adverse pancreatic event. Is it possible that the usage of these drugs was a contributing factor, it would foolish not to consider this possibility. However to state that these drugs actually caused the event is equally foolish as the data just doesn’t support that conclusion.

Still Diabetic Investor thought it might be a good idea to see how the ADA was doing as frankly since their announcement back in June the organization has been silent on the issue. After speaking with the Robert E. Ratner, MD, FACP, FACE Chief Scientific and Medical Officer at the ADA we now understand the silence. According to Dr. Ratner the ADA did reach out to the companies in the GLP-1/DPP4 market however they the ADA did not ask for data rather they asked what data was available and how it could be transmitted. Based on their responses the ADA concluded that the data from Phase II and Phase III trials was insufficient to yield any new insights. Therefore they switched gears a little and decided that ongoing cardiovascular trials such as FAVOR and EXAMINE would yield better data. Dr. Ratner did note these ongoing trials are monitored by safety committees which have allowed the trails to continue.

Given that some trials are ongoing and not all the data is available from the trials that have been concluded Diabetic Investor believes it will be some time before the ADA has to say what we already know; basically there isn’t any hard scientific evidence to support a claim that either GLP-1 or DPP4 usage actually causes adverse pancreatic events. That it is possible these drugs may play a role but to what extent is hard to determine with any degree of certainty. Finally while physicians should be aware of this possibility for adverse pancreatic events they should continue to prescribe GLP-1 and DPP4 therapy.

The reality here is that no matter what the ADA states, zealots like Dr. Butler and his followers will continue to believe that these drugs should be pulled from the market.  They just cannot accept the possibility that there are no clear answers to the questions they have raised. That reasonable people can agree to disagree. No what these zealots want is complete and utter capitulation from the diabetes community that they are right, everyone else is wrong no matter how much damage their efforts impact patients with diabetes in the real world.

Frankly the most disturbing fact about their efforts is that these supposedly educated people, who supposedly care about patients with diabetes really don’t give a damn about patients at all; that they would rather have their 15 minutes of fame than to consider the real world impact of their dubious accusations.  While Diabetic Investor applauds the ADA for trying to provide some much needed clarity on this issue, clarity that would shut these people up once and for all, sadly clarity is one thing they won’t find. Honestly we really don’t need this.