Small, but Detectable, Pancreatitis Risk With DPP-4 Inhibitors

Miriam E Tucker

December 08, 2015

VANCOUVER, British Columbia — There is a small but statistically significant increased risk for acute pancreatitis among the dipeptidyl peptidase-4 (DPP-4) inhibitor class of glucose-lowering agents used in type 2 diabetes treatment, a new meta-analysis from three major clinical trials finds.

Results of the pooled data, which also suggest no major concerns regarding heart-failure hospitalizations, renal function, and pancreatic cancer, at least out to 3 years, were presented December 2 here at the World Diabetes Congress 2015 by Rury R Holman, MD, director of the University of Oxford Diabetes Trials Unit, United Kingdom.

Dr Holman and colleagues examined combined data from three recent cardiovascular outcomes trials with DPP-4 inhibitors:Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS); Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus (SAVOR-TIMI 53); and Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care in Patients with Type 2 Diabetes Mellitus and Acute Coronary Syndrome (EXAMINE ).

Pancreatitis Risk: Small but Significant

There has been concern about the effect of DPP-4 inhibitors on the pancreas going back at least to 2009, when the US Food and Drug Administration issued a warning about the risk for sitagliptin (Januvia, Merck).

In 2013, the BMJ claimed that the pharmaceutical industry had downplayed the risk for all incretin-based drugs (which includes glucagonlike peptide 1 [GLP-1] agonists as well as DPP-4 inhibitors), but a subsequent investigation conducted by a US National Institutes of Health panel found no clear signal.

In each of the three big DPP-4 trials, TECOS, SAVOR-TIMI 53, and EXAMINE, the number of patients with acute pancreatitis was higher with the study drug than placebo. While none of those end points reached statistical significance individually, when the data are combined, there is a significant hazard ratio (HR) of 1.578 (P = .033), Dr Holman reported.

However, he emphasized, the absolute risk is small. In TECOS, the percentages were 0.31% (23) of 7332 patients taking sitagliptin vs 0.16% (12) of 7339 on placebo. All four cases of severe pancreatitis happened in patients on sitagliptin, however. Similar findings were seen for saxagliptin (Onglyza, Bristol-Myers Squibb/AstraZeneca) and alogliptin (Nesina, Takeda Pharmaceuticals) in the other two trials.

"The data suggest a small increased risk of acute pancreatitis from all the DPP-4 inhibitors. It's a very uncommon event. Nevertheless, if you had patients with previous risk factors for pancreatitis, you might be more cautious," Dr Holman told Medscape Medical News.

"It's extremely helpful information because it puts the risk in context. It's a small risk, but it's detectable. It's not a massive risk. I think for practicing physicians and patients, it helps them make a sound judgment," he added.

Indeed, session moderator Daisuke Yabe, MD, PhD, director, Center for Diabetes, Endocrinology and Metabolism, Kansai Electric Power Hospital, Osaka, Japan, told Medscape Medical News: "I won't change my practice, but I think we need to be a little bit careful about how to differentiate suitable and unsuitable patients."

In Japan, 70% of people with type 2 diabetes who take medication are using DPP-4 inhibitors, Dr Yabe noted.

Unsuitable patients would include those with prior pancreatitis, gallstones, biliary disease, very high triglyceride levels, or high alcohol consumption, Dr Holman said, noting that the package labels already urge caution in using the agents in such patients.

These new data, he said, "just put the risk in context."

For pancreatic cancer, the meta-analysis was conducted just for SAVOR TIMI and TECOS since there were no cases in EXAMINE. Here, the hazard ratio was a nonsignificant 0.542 (P = .066).

In speaking with Medscape Medical News, Dr Holman acknowledged that the follow-up — about 3 years for the trials combined — probably isn't long enough for examining pancreatic cancer risk but is longer than what was available at the time that the BMJ raised its concern. "Ten or 15 years from now we can't say, but here and now it's very reassuring."

Heart Failure and Kidney Function

As with each of the individual trials, the overall risk for 3-point major adverse cardiovascular events (cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke) was not elevated in the meta-analysis, with a hazard ratio of 0.99.

Hospitalization for heart failure, which had been significantly elevated in SAVOR-TIMI (HR, 1.27, P = .007) but not in the other two trials, was nonsignificantly elevated for the three trials combined (HR, 1.14).

Dr Yabe commented: "Something funny is going on with saxagliptin. So, [the heart failure] might not be a class effect but a drug effect. That would probably change my practice. It might be tough for us to change prescriptions, but when we initiate therapy, we might consider the difference."

Dr Holman, responding to an audience member's question about the heart-failure elevation seen in SAVOR-TIMI, commented: "The results of SAVOR TIMI were completely unexpected. We don't have a good causal mechanism that would cause a DPP-4 inhibitor to increase heart failure, so we have to treat the data with caution."

"It's reassuring that we see no signal with sitagliptin, but it doesn't mean there might not be pharmacologic differences….It's nearly impossible to infer causality retrospectively in a randomized controlled trial."

With regard to renal function, in TECOS, of the 3669 patients for whom data on this were available, both mean urinary albumin/creatinine ratios and mean estimated glomerular filtration rates (eGFR) were lower with sitagliptin than placebo, by 1.0 mg/g and 1.3 mL/minute/1.73 m2, respectively. The difference in eGFR was statistically significant (P < .001), but probably not clinically significant, Dr Holman said.

Overall, TECOS participants with lower eGFR values tended to have higher urinary albumin/creatinine ratios, be older, have a longer duration of diabetes, and were more often female. Kidney function did not differ by HbA1c or body mass index.

Previous studies have shown that eGFR drops slightly when glycemic control improves, Dr Holman said, adding that the differences seen here are based on starting eGFR and not driven by some patients dropping by large amounts.

"We showed that it's completely symmetrical....This is a very small change, which is across the board, and isn't hiding a group of people who might have done badly."

Dr Holman receives funding for academically run trials for Bayer, AstraZeneca, and Merck. He has received honoraria from Amgen, Bayer, Elcelyx, GlaxoSmithKline, Janssen, Intarcia, Merck, Novartis, and Novo Nordisk. Dr Yabe received consulting and/or speaker fees from Eli Lilly Japan, MSD, Sanofi, Novo Nordisk, Nippon Boehringer Ingelheim, Takeda Pharmaceutical, and Taisho Pharmaceutical. He received clinical commissioned/joint research grants from Nippon Boehringer Ingelheim, Eli Lilly, and MSD.

World Diabetes Congress 2015. Presented December 2, 2015.

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