Metformin and its (and other) discontents
Januvia and Janumet's launch, in 2006 and 2007, respectively, and their ongoing success in the market is due in no small part
to the fact that sitagliptin was the first DPP-4 and the first new oral Type 2 diabetes drug since 1999 to enter the market.
Regulators like new drug classes, particularly when the new product in question has a better side effect profile than the
standard of care; metformin's label (and thus Janumet's, as well) contains a boxed warning, FDA's most severe safety precaution,
due to the serious (although exceedingly rare) incidence of lactic acidosis in some patients. Lactic acidosis is fatal in
50 percent of patients where it does occur.
Merck enslisted several celebrities to help educate patients about Type 2 diabetes. Musician and American Idol star Randy
Jackson describes life with diabetes in an online video.
Other, less severe but still distasteful side effects are much more common with metformin. Just over half of patients experience
diarrhea, and a quarter experience nausea or vomiting, according to studies conducted by Bristol-Myers Squibb for Glucophage
(metformin), a blockbuster drug now widely available in generic form. Those percentages are much lower in extended release
formulations of metformin, and in Janumet, but some patients are allergic to metformin, or are unable to use it for other
reasons (like renal disease). In terms of comparative efficacy, Januvia proved to be "non-inferior" to metformin as a monotherapy
in clinical studies, and that's good enough for regulators and patients, given the strength of its safety profile (questions
about Januvia and pancreatitis and pancreatic cancer will be discussed later in this article).
As for serendipity, "the path to approval, at the time, was pretty straightforward with the FDA and with other regulatory
authorities around the world," says Riad El-Dada, senior vice president and general manager, diabetes franchise, Merck. "It's
a bit more complicated now, because of the requirements to have a certain threshold of cardiovascular outcomes data…it takes
longer nowadays to develop a drug for Type 2 then it did back then." That's because, less than a year after FDA approved Januvia
(and about a month before Janumet received approval), Steve Nissen and his Cleveland Clinic colleague Kathy Wolski published
a study titled "Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes" in The New England Journal of Medicine, which linked rosiglitazone, better known as Avandia, with "a significant increase in the risk of myocardial infarction and
with an increase in the risk of death from cardiovascular causes that had borderline significance."
As a result of this publication, and other subsequent studies done on Avandia, FDA announced in 2008 that it would no longer
approve diabetes drugs solely on the basis of their ability to help control blood glucose levels. Drug-makers would need to
provide data from studies lasting at least two years to show that medicines don't have significant cardiovascular side effects,
and that they improve the length or quality of a diabetic patient's life, a significant raising of the clinical bar in terms
of development cost and lead time to commercialization. By expediting its early clinical program, Merck unwittingly sped Januvia
onto the market before these new requirements came into effect. As for GSK's drug Avandia, FDA severely restricted its use
in 2010, and the EMA pulled it from the market entirely.
In the mid-2000s, Novartis's Galvus was running neck and neck with Januvia to be the first approved DPP-4 for Type 2 diabetes.
That lit a fire under the Merck DPP-4 development team, but Galvus never won FDA approval. It was approved by the EMA in 2008,
but Novartis withdrew its application in the United States after FDA requested additional studies on potential skin lesions
and kidney impairment that occurred during an early animal study. Merck thus found itself with a compelling story to tell.