Memorandum

FDA updates DPP-4 inhibitor Januvia label with heart failure warning – August 18, 2017

Executive Highlights

  • We recently learned that the FDA has updated the product labels for Merck’s DPP-4 inhibitor Januvia (sitagliptin), Janumet (sitagliptin/metformin), and Janumet XR (sitagliptin/metformin extended-release). The change reflects a heightened risk for heart failure seen in two other DPP-4 inhibitor CVOTs, namely the SAVOR-TIMI study of AZ’s Onglyza (saxagliptin) and the EXAMINE trial of Takeda’s Nesina (alogliptin).
  • Notably, the TECOS CVOT of Januvia found a resoundingly neutral hazard ratio for heart failure hospitalization (HR=1.00, 95% CI: 0.8-1.20); nonetheless, FDA seems to be taking a conservative approach here. In April, the agency issued a Complete Response Letter (CRL) for inclusion of the TECOS dataset on the Januvia label.

The FDA recently issued a label update for Merck’s sitagliptin family of products to reflect a heightened risk for heart failure with two other DPP-4 inhibitors – AZ’s Onglyza (saxagliptin) and Takeda’s Nesina (alogliptin). This change applies to standalone DPP-4 inhibitor Januvia, fixed-dose combination Janumet (sitagliptin/metformin), and Janumet XR (sitagliptin/metformin extended-release). Notably, this warning was already listed on the OnglyzaNesina, and Tradjenta (Lilly/BI's linagliptin) product labels . Onglyza showed a worrisome 27% increase in heart failure hospitalizations in the SAVOR-TIMI CVOT (p=0.007), while heart failure hospitalizations in EXAMINE for Nesina trended in the wrong direction without reaching statistical significance. Merck’s TECOS trial reported a resoundingly neutral hazard ratio of 1.00 for sitagliptin and heart failure hospitalizations, but this past April, the company received a Complete Response Letter (CRL) from the FDA for inclusion of TECOS data on the Januvia label. These results could have put to bed concerns surrounding sitagliptin/heart failure, as we had expected,, but FDA instead seems to be taking a conservative approach, cautioning against prescription of any DPP-4 inhibitor therapy to patients at risk for heart failure (including Januvia, Janumet, and Janumet XR despite the lack of signal associated with sitagliptin).

The precise language added to the Januvia label is copied below. It closely mirrors the warning on the Onglyza and Nesina labels, urging providers to very carefully consider the risks/benefits of the DPP-4 inhibitor prior to initiating treatment in people at risk for heart failure, and advising providers to monitor symptoms and discontinue the medication if heart failure develops. Without a doubt, safety is key when it comes to prescribing a drug (diabetes or otherwise), and we understand FDA’s reservations about DPP-4 inhibitors/heart failure rooted in SAVOR-TIMI. That said, we think this raises an important discussion of where class effects begin and end. TECOS was a rigorously-conducted outcomes trial, and it found no imbalance in hospitalizations for heart failure in sitagliptin vs. placebo groups, so perhaps this is one way in which not all DPP-4 agents are alike. We’ve noticed similar differentiation in the SGLT-2 and GLP-1 classes: J&J’s SGLT-2 inhibitor Invokana (canagliflozin) showed a ~two-fold increase in lower limb amputations in the CANVAS study and the FDA has added a boxed warning to this effect on the product label, but Lilly/BI’s Jardiance (empagliflozin) has not shown the same amputation signal and does not have the same boxed warning. Novo Nordisk’s GLP-1 agonist Victoza (liraglutide) demonstrated significant CV risk reduction in the LEADER trial, while Sanofi’s Adlyxin (lixisenatide) and AZ’s Bydureon (exenatide once-weekly) have shown neutral CV effects in their respective CVOTs. There is so much to unpack when it comes to class effects, and we won’t pretend to have grasped all of it, especially because many of these issues will require more data and standardization of CVOT design to be truly settled. Still, we hope providers aren’t discouraged from using Januvia or another sitagliptin product in patients for whom it is safe and for whom it could be incredibly beneficial – DPP-4 inhibitors on the whole have shown CV safety, glucose-lowering efficacy, and weight neutrality, and the class boasts a long history of safety/tolerability.

  • The new Januvia warning reads: “An association between dipeptidyl peptidase-4 (DPP-4) inhibitor treatment and heart failure has been observed in cardiovascular outcomes trials for two other members of the DPP-4 inhibitor class. These trials evaluated patients with type 2 diabetes mellitus and atherosclerotic cardiovascular disease. Consider the risks and benefits of Januvia prior to initiating treatment in patients at risk for heart failure, such as those with a prior history of heart failure and a history of renal impairment, and observe these patients for signs and symptoms of heart failure during therapy. Advise patients of the characteristic symptoms of heart failure and to immediately report such symptoms.  If heart failure develops, evaluate and manage according to current standards of care and consider discontinuation of Januvia.”

 

-- by Payal Marathe and Kelly Close