Januvia and Pancreatitis – Why this could be a bigger problem.

Januvia and Pancreatitis – Why this could be a bigger problem.

As Diabetic
Investor more closely examines the latest alert from the FDA about the possible
relationship between Januvia™ and pancreatitis the possibility exists that this
could be a larger problem for Merck (NYSE:MRK) than originally anticipated.

to the FDA statement under the heading Background Data Summary (Note Diabetic
Investor added the highlighting):

has completed a review of 88 cases of acute pancreatitis in patients using
sitagliptin or sitagliptin/metformin. The cases were reported to FDA’s Adverse
Event Reporting System (AERS) between October 2006 and February 2009.
Hospitalization was reported in 58/88 (66%) of the patients, 4 of whom were
admitted to the intensive care unit (ICU). Two cases of hemorrhagic or
necrotizing pancreatitis were identified in the review and both required an
extended stay in the hospital with medical management in the ICU. The most
common adverse events reported in the 88 cases were abdominal pain, nausea and

the analysis found that 19 of the 88 reported cases (21%) of pancreatitis
occurred within 30 days of starting sitagliptin or sitagliptin/metformin. 
Furthermore, 47 of the 88
cases (53%) resolved once sitagliptin was discontinued.
It is important
to note that 45 cases (51%) were associated with at least one other risk factor
for developing pancreatitis, such as diabetes, obesity, high cholesterol and/or
high triglycerides.

Based on the temporal relationship of
initiating sitagliptin or sitagliptin/metformin and development of acute
pancreatitis in the reviewed cases, FDA believes there may be an association
between these events.
Because acute pancreatitis is
associated with considerable morbidity and mortality, and early recognition is
important in reducing adverse health outcomes, FDA is recommending revisions to
the prescribing information to alert healthcare professionals to this
potentially serious adverse drug event.”

that statement to the one the FDA issued back in October of 2007 when this
issue appeared with Byetta:

has reviewed 30 post marketing reports of acute pancreatitis in patients
treated with Byetta.  Twenty-seven of the 30 patients had at least one
other risk factor for acute pancreatitis such as gallstones, severe
hypertriglyceridemia, and alcohol use.  In six patients the symptoms of
pancreatitis began or worsened soon after the dose of Byetta was increased from
5 micrograms twice daily to 10 micrograms twice daily.  Twenty-one
patients were hospitalized.  There were no reports of hemorrhagic or
necrotizing pancreatitis.  However, five patients developed serious
complications including dehydration and renal failure; suspected ileus;
phlegmon; and ascites.  Twenty-two of the 30 reports indicated that the
patients improved after discontinuing Byetta.

in three reports indicated that the symptoms of acute pancreatitis returned
when Byetta was restarted.  Nausea and vomiting returned in two patients
when Byetta was restarted.  In a third patient, abdominal pain returned
when Byetta was restarted and abated after Byetta was permanently

has asked and the maker of Byetta, Amylin Pharmaceuticals, Inc. has agreed to
include information about acute pancreatitis in the Precautions section of the
product label.”

missing from the Byetta statement is the following passage; “Based on the
temporal relationship of initiating sitagliptin or sitagliptin/metformin and
development of acute pancreatitis in the reviewed cases, FDA believes there may
be an association between these events.” This may seem like a small difference
yet it could signal a shift in the how the agency views the pancreatitis issue
and Januvia. It appears the agency seems a more causal relationship between Januvia
and pancreatitis.

As Diabetic
Investor noted yesterday Merck did make a label change for Januvia back in
March of this year. The new label contains the following passage; “
6.2 Post marketing Experience

The following additional adverse reactions
have been identified during post approval use of JANUVIA. Because these
reactions are reported voluntarily from a population of uncertain size, it is
generally not possible to reliably estimate their frequency or establish a
causal relationship to drug exposure. Hypersensitivity reactions include
anaphylaxis, angioedema, rash, urticaria, cutaneous vasculitis, and exfoliative
skin conditions including Stevens-Johnson syndrome [see Warnings and
Precautions (5.3)]
; hepatic enzyme elevations; pancreatitis.” (Highlighting added by
Diabetic Investor)

Obviously the agency was aware of this
label change which leads Diabetic Investor to believe that yesterday’s action by
the agency could lead to another, likely stronger, change in the Januvia label.
While we do not believe this change will result in a Black Box warning, which would
do serious damage to Januvia sales, stronger label language appears to be
almost a certainty.

Diabetic Investor also sees a strong possibility
that the agency would require this stronger label language for Onglyza™.
Currently the word pancreatitis does not appear anywhere on the Onglyza label.

The safety of
Januvia and the entire class of DPP-4 drugs has been questioned before. Some
recall that back in July 2006 a study was published in Regulatory Peptides
entitled; “
DPPIV inhibitors
extend GLP-2 mediated tumour promoting effects on intestinal cancer cells” by K.
Masur, F Schwartz, F. Entschladen, B. Niggemann, K.S. Zaenker. The study states
of an extended half-life of the peptides these tumour promoting effects will
last longer. Especially in patients with chronic diseases like type II diabetes
or inflammatory bowel disease, where a treatment for many years is very likely,
the effects of accumulated, not degraded CD26 substrates will exponentiate over
time. This possible risk of DPPIV inhibitors in combination with GLP-2 needs to
be clarified by further studies.”

This study was followed by another published in the July 2007
issue of the Journal of the American Medical Association entitled; “
and Safety of Incretin Therapy in Type 2 Diabetes” by
Renee E.
Amori, MD; Joseph Lau, MD; Anastassios G. Pittas, MD,
MSc. This study concluded; “
Incretin therapy
offers an alternative option to currently available hypoglycemic
agents for nonpregnant adults with type 2 diabetes, with modest
efficacy and a favorable weight-change profile. Careful post marketing
surveillance for adverse effects, especially among the DPP4
inhibitors, and continued evaluation in longer-term studies and in
clinical practice are required to determine the role of this new class
among current pharmacotherapies for type 2 diabetes
(Highlighting added by Diabetic Investor)

Also in
February of 2007 in the New England Journal of Medicine Dr. David Nathan wrote:

the approval of sitagliptin (Januvia, Merck) on October 17, 2006, and the
pending approval of vildagliptin (Galvus, Novartis), we now have a ninth class
of antidiabetes medications. The concept behind these dipeptidyl peptidase IV
(DPP-IV) inhibitors, known as the gliptins, derives from the recognition that glucagon-like
peptide (GLP) 1,7- 37 — a naturally occurring gastrointestinal peptide that
stimulates insulin secretion, suppresses glucagon levels, and slows gastric emptying
— is rapidly inactivated by DPP-IV. Given that the main therapeutic
effectiveness of the gliptins is mediated by their ability to increase levels
of GLP, which is not a very effective glucose lowering agent, it is not
surprising that these agents are relatively ineffective in lowering glycated hemoglobin
levels. Moreover, although they have been developed to be relatively specific
for the GLP substrate and not to increase the levels of the many other DPP-IV
substrates, none of them is so selective as to preclude alteration of the other
substrates, including proteins involved in immunity and other hormones. The potential for unexpected consequences
thus remains relatively high.
” (Highlighting added by Diabetic Investor)

Looking over the statement made by the FDA and comments made
by several noted researchers one has to wonder if this problem will grow from a
minor one to a major one. Based on several interviews with respected
researchers, diabetologiests and endocrinologists Diabetic Investor does not believe
there is a causal relationship between usage of DPP-4’s and pancreatitis. As we
have noted before the incidence rate of pancreatitis is higher for patients
with diabetes than the general population.

However, the FDA is still smarting over the Avandia
controversy and appears to be taking a harder look at all diabetes related
medications. The agency does not want to be called before Congress yet again and
get reamed for not protecting the public. This is same reason why the agency is
taking so long to approve drugs like Victoza® or approve Byetta® as a
monotherapy. The fact is the agency is afraid of making any mistake and will
take as long as necessary to make adjustments no matter how much this aggravates
drug companies.

It is also clear after all the Diabetic Investor interviews
that the agency needs to communicate with public in simple, understandable language.
 To the majority of the population the
phrase “there may be an association” leads the non-medical professional to
believe that the drug actually caused this event. Just as everyone understands
that smoking causes lung cancer, the diabetic population needs to know the true
level of risk they are facing with the drugs they take every day of their
lives. Although Diabetic Investor isn’t a big fan of the color coding system
used to classify the threat of terrorism, perhaps a somewhat similar system can
be developed so that patients can easily understand risk levels. Granted this
is not a perfect system but it’s better than using language that physician view
one way and the public another.

The bottom line here is that changes are in store for all
DPP-4’s and most likely GLP-1’s as well. Not wanting to take any chances the
FDA will require both drug classes to carry label language on the risk of
pancreatitis. Hopefully this language will make it clear that these drugs do
not cause pancreatitis and that should there be any signs of pancreatitis
patients should discontinue using the drug. The fact is patients with diabetes need
these drugs and the risk of therapy non-compliance will only lead to greater,
more serious adverse events.

In the real world all drugs carry some level of risk and no
amount of study or research will change this. It is equally true that there is
no way to accurately predict the long term effect of any drug used with chronic
diseases such as diabetes. Just look at Avandia and Actos, drugs which were on
the market for nearly seven years before we discovered an increased incidence
of bone fractures. Drug discovery would grind to a halt if the FDA required
even longer clinical trials.

Finally everyone involved here would be well to remember
that in the continuing quest to keep the public informed and protected,
something Isaac Bashevis Singer once said; “Our knowledge is a little island in
a great ocean of non-knowledge.”