Here we go again

Here we go again

Just when it seemed as if the controversy over GLP-1 usage and pancreatitis was put to bed, like the shark in the movie Jaws this issue has reemerged thanks largely to a study that appeared in Gastroenterology. Entitled “Pancreatitis, Pancreatic, and Thyroid Cancer With Glucagon-Like Peptide-1–Based Therapies” where the authors concluded; “These data are consistent with case reports and animal studies indicating an increased risk for pancreatitis with glucagon-like peptide-1−based therapy. The findings also raise caution about the potential long-term actions of these drugs to promote pancreatic cancer.”

Now before we go further it’s important to note that the authors also have concerns with DPP-4 inhibitors stating; “The attributes of GLP-1−based therapy for type 2 diabetes have been extensively reviewed. Interest has recently been focused on the potential adverse effects of these new therapies. Nausea is relatively common with the injected GLP-1 receptor agonists. Acute pancreatitis after administration of exenatide was originally reported in the form of case reports, but then followed by a cautionary letter from the US Food and Drug Administration (FDA). Recently, a similar caution was made by the FDA with regard to pancreatitis associated with sitagliptin treatment.”  (Bold and underlining added by Diabetic Investor.)

Reading through this study Diabetic Investor was amazed it was even published as the author noted numerous possible flaws with the study. It’s almost as if the authors were going out of their way to note that their conclusion may not be valid and is really more of an opinion than a conclusion based on scientific facts. Here is just a sample of what they wrote:

“Analysis of the FDA AERS database is not the ideal mechanism to compare adverse event rates between drugs. Limitations of the FDA AERS database, including incomplete data and reporting biases, are well-known.”

“The approach we have taken should be robust against a range of potential reporting biases. In particular, if the test drugs have an overall increased reporting rate for events, the OR will be unaffected. Similarly, if the test events have an overall increased reporting rate, the OR will be unaffected. However, the approach has significant weaknesses. The analysis is retrospective.” (Bold and underlining added by Diabetic Investor)

“Also, although the controls (drugs and events) were prospectively defined, the analysis makes certain assumptions about these controls that cannot be easily tested.”

“A potential confounding factor for the present analysis is obesity.”

“Another potential confounder is gender.”

“In contrast to the findings here, several studies recently reported no increase in pancreatitis in patients treated with GLP-1 receptor mimetic therapy.”

Simply put the authors cannot draw a direct line or causal relationship between GLP-1 usage and pancreatitis. The authors also seem to dismiss several facts such as the following:

Patients with diabetes are at greater risk of pancreatitis just because they have diabetes. An issue Diabetic Investor addressed when these concerns first came to light and when we also noted that the incidence rate of pancreatitis for patients using Byetta was actually LOWER than patients with diabetes in general, a fact that was omitted from this study.

Using a retrospective analysis the authors also failed to consider many important factors beyond the ones they acknowledge (obesity and gender). One of the most difficult aspects when doing a retrospective analysis is the lack of information regarding where the patient was BEFORE they began using a GLP-1. Or put another way we have no idea how much damage was done BEFORE GLP-1 therapy was initiated. Given what we know about diabetes management where nearly two-thirds of all patients are NOT properly controlling their diabetes, it’s plausible that the patients who used a GLP-1 and developed pancreatitis developed the pancreatitis PRIOR to going on a GLP-1.

Given that Byetta has been on the market for over 6 years and that nearly one million patients are using the drug one would think that if there was a causal relationship between GLP-1 and pancreatitis it would be clear by now. This is especially true when you consider the reporting bias noted by the authors. Does anyone really think in this hypersensitive regulatory environment that the FDA would not notice or investigate fully if they truly believed there was a causal relationship here as they do have access to all the data including the adverse event reports.

We also find it interesting that endocrinologists are not nearly as concerned about this issue as primary care physicians. While primary care providers may treat 80% of the diabetes population, endocrinologists have greater knowledge of diabetes and the many factors that influence complications. Having spoken with several noted endocrinologists, diabetologiests and researchers – experts who understand diabetes- we have yet to find one who believes there is a causal relationship between GLP-1 usage and pancreatitis. They correctly acknowledge that physicians should be aware of the issue but they feel very comfortable prescribing a GLP-1.

To these experts who understand diabetes the decision on which therapy option to pursue for their type 2 patients comes down to a risk/reward analysis. These experts understand that there is no such thing as a drug which has absolutely no adverse events. They also understand the damage that can be done form poorly controlled diabetes. The see the many benefits of GLP-1 therapy – solid glucose control, simple dosing, little risk of hypoglycemia and the added benefit of being at minimum weight neutral and often times producing significant weight loss and balance these benefits against the possible risk of pancreatitis and complications from poorly controlled diabetes.

Most importantly of all these experts acknowledge that no one therapy option is right for every patient and that diabetes is not a one size fits all disease state, that what works for one patient does not necessarily translate to another. As we have noted on numerous occasion diabetes is a complex disease state with multiple factors that influence outcomes and which drugs a patient uses is just one of these factors.

We also find it interesting that the authors acknowledge that physicians are using GLP-1’s far early in the treatment regimen stating “in clinical practice in the field, the new drugs are being used as early monotherapies.” The reason is simple and quite frankly obvious given the many benefits of GLP-1 therapy outlined earlier.

Alias the authors ultimately state; “For now this analysis of the FDA data base does not establish that pancreatitis, pancreatic and thyroid cancer are caused by GLP-1 based therapy. It simply raises the level of concern that they may be and that the appropriate prospective studies are required to rule them out.”

Quite frankly these authors should be ashamed of themselves as should the editors of Gastroenterology, as using conjecture and NOT hard scientific evidence they have added nothing of value to this issue. This is not unlike the attack leashed upon Lantus which tried to link the drug to cancer, an issue thankfully debunked by the facts. Like so many others who have tried to link GLP-1 usage to pancreatitis, pancreatic and thyroid cancer the authors don’t have any solid evidence which ultimately leads them to issue the standard cop out that the issue requires further study. Just once Diabetic Investor would like to see these researchers have the stones to issue a statement that doesn’t have more disclaimers than Chicago has corrupt politicians.

Diabetes is growing at epidemic rates and the facts clearly show that the majority of patients are not properly controlling their diabetes. Patients who need more, not less, treatment options as the complications from poorly controlled diabetes are not just well documented but costing our economy a small fortune. Just what do these authors expect physicians to do, treat diabetes with the current set of drugs which by all factual accounts just aren’t getting the job done? Have they become so detached from the real world that they cannot see the damage that results from unwarranted and unsubstantiated conclusions that are not drawn from scientific facts?

Diabetic Investor is not claiming that GLP-1 therapy is some sort of wonder drug that should be the only option used to treat type 2 diabetes. Nor are we stating that this issue should be ignored. Both positions would be ludicrous. The point here is simple the time has come for researchers to stop using conjuncture, speculation and opinion to support what they believe may be true. If these ivory tower types really want to do some good they should put their money where their big mouths are and go out and do the studies they claim will prove their point and let scientific evidence either prove or disprove what really is just a theory.

Or as we like to say here in Chicago – PUT UP OR SHUT UP!