Initial analysis of TECOS trial showed that Januvia/Sitagliptin does not increase the risk of cardiovascular disease, heart failure and death from any cause.
Further investigation, just published in Diabetes Care reveals that Januvia has slight tendency to protect from pancreatic cancer but cause more pancreatitis, although these contributions were not statistically convincing. Important to be aware that baseline pancreatic cancer or pancreatitis are rare and multifactorial.
About 15,000 patients with type 2 diabetes and cardiovascular disease were randomized to receive Sitagliptin or placebo for 3 years.
OBJECTIVE: We evaluated the incidence of acute pancreatitis and pancreatic cancer in patients with type 2 diabetes and cardiovascular disease who were treated with sitagliptin, a dipeptidyl peptidase-4 inhibitor (DPP-4i).
RESEARCH DESIGN AND METHODS: In the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) study, a cardiovascular safety study of sitagliptin, all suspected cases of acute pancreatitis and pancreatic cancer were collected prospectively for 14,671 participants during a median follow-up time of 3 years, and were adjudicated blindly.
RESULTS: Baseline differences were minimal between participants confirmed to have no pancreatic events, acute pancreatitis, or pancreatic cancer. Among those participants randomized to receive sitagliptin, 0.3% vs 0.2% to receive placebo had pancreatitis (hazard ratio 1.93, P = 0.065; with 25 vs. 17 events, respectively. Severe pancreatitis (two fatal) occurred in four individuals allocated to receive sitagliptin. Cases of pancreatic cancer were numerically fewer with sitagliptin 0.1% versus placebo 0.2% (9 vs. 14) (hazard ratio 0.66, P = 0.32;
Meta-analysis with two other DPP-4i cardiovascular outcome studies showed an increased risk for acute pancreatitis (risk ratio 1.78, P = 0.01) and no significant effect for pancreatic cancer (risk ratio 0.54, P = 0.07).
CONCLUSIONS: Pancreatitis and pancreatic cancer were uncommon events with rates that were not statistically significantly different between the sitagliptin and placebo groups, although numerically more sitagliptin participants developed pancreatitis and fewer developed pancreatic cancer. Meta-analysis suggests a small absolute increased risk for pancreatitis with DPP-4i therapy.
John B. Buse, M. Angelyn Bethel, Jennifer B. Green, Susanna R. Stevens, Yuliya Lokhnygina, Pablo Aschner, Carlos Raffo Grado, Tsvetalina Tankova, Julio Wainstein, Robert Josse, John M. Lachin, Samuel S. Engel, Keyur Pate, Eric D. Peterson, Rury R. Holman
More from the article:
Increased risks of pancreatitis and pancreatic carcinoma are linked to type 2 diabetes, obesity, and insulin resistance in epidemiological studies and animal models. Dipeptidyl peptidase-4 inhibitors (DPP-4i) have become widely adopted as effective and well-tolerated glucose-lowering agents since the introduction of sitagliptin in 2006.. A potential association between DPP-4i treatment and pancreatitis and pancreatic cancer was suggested in 2009, based on studies in rats carrying the human islet amyloid polypeptide transgene treated with sitagliptin, in which increased pancreatic ductal turnover, ductal metaplasia, and isolated pancreatitis were observed. Although subsequent preclinical studies have not confirmed this finding, this potential association has triggered intense interest and clinical assessment. Pharmacovigilance efforts, epidemiological studies, and meta-analysis of randomized control studies with DPP-4is have suggested a small increase in or no increased risk of pancreatitis or pancreatic cancer, but they all have methodological limitations.
The Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) assessed the long-term cardiovascular safety of adding sitagliptin to usual care, compared with usual care alone, in patients with type 2 diabetes and established cardiovascular disease during a 3-year median follow-up period. We describe the presentation, features, and incidence of pancreatitis and pancreatic cancer cases confirmed in TECOS, and perform a meta-analysis of these events with two recently reported DPP-4i cardiovascular safety trials, the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus—Thrombolysis in Myocardial Infarction (SAVOR-TIMI) 53 trial and the Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care (EXAMINE) trial.
The TECOS study was a global, double-blind, placebo-controlled clinical trial of sitagliptin in individuals ≥50 years of age with type 2 diabetes and established cardiovascular disease. The TECOS study demonstrated, on a background of usual care, that there was no difference between treatment groups in the rates of major cardiovascular events, heart failure, or death from any cause. This study examined whether there was an association between the use of sitagliptin and pancreatic disease.
The overall rate of confirmed acute pancreatitis was low (0.095 events/100 patient-years) with a numerically increased but not statistically significant risk for acute pancreatitis with sitagliptin therapy (0.107/100 patient-years for sitagliptin treatment vs. 0.056/100 patient-years for placebo treatment). Cases of confirmed severe acute pancreatitis were rare, but numerically greater with sitagliptin treatment compared with placebo treatment (four vs. zero, including two fatal cases). For both fatal cases, an etiology other than study treatment was suspected. Pancreatitis is often associated with multiple risk factors, and it is unclear to what extent sitagliptin contributed to the pancreatitis in each case. That said, the finding of other potential etiologies should not provide reassurance that treatment with sitagliptin was perhaps not a contributor, as the alternative hypothesis would be that treatment with sitagliptin magnifies the penetrance of risk factors on pancreatitis development and severity.
Pancreatic cancer was also an uncommon event in the TECOS study (0.054 events/100 patient-years). Numerically, there were fewer cases of pancreatic cancer with sitagliptin treatment than with placebo treatment, but the difference was not statistically significant. The per-protocol analysis for pancreatic cancer essentially eliminates the discrepancy between arms. Although the median 3-year follow-up period during the TECOS study is longer than in many other diabetes outcome trials, it is insufficient to permit a robust assessment of the long-term risk of pancreatic cancer.
SAVOR-TIMI 53 and EXAMINE are two recently reported, double-blind, placebo-controlled, cardiovascular safety trials of DPP-4is that evaluated saxagliptin and alogliptin, respectively. These trials have important differences with the TECOS study Both the SAVOR-TIMI 53 and EXAMINE trials enrolled patients with a wider range of HbA1c levels at diagnosis and a shorter duration of study treatment exposure. The SAVOR-TIMI 53 trial used different criteria in the adjudication of pancreatitis, whereas the EXAMINE trial did not adjudicate cases of pancreatitis and reported no cases of pancreatic cancer. These factors preclude head-to-head comparisons of the rates of pancreatitis and could impact on the meta-analysis presented here, which means that these findings should therefore be interpreted with caution.
The primary goal of the Tecos study was to examine the cardiovascular safety of sitagliptin. The trial demonstrated unequivocal evidence for no increased risk of major cardiovascular events, heart failure, or all-cause mortality. Sitagliptin was associated with good tolerability and glycemic efficacy. These analyses of acute pancreatitis and pancreatic cancer from the TECOS study, and the meta-analysis with two other large, well-conducted studies involving other members of the DPP-4i class of drugs, provide prescribers and patients greater precision around the question of pancreatic safety.
If this difference had been statistically significant, the number needed to harm would have been 1,974 to have 1 additional affected individual with pancreatitis. Pancreatic cancer, a condition that is almost uniformly fatal, occurred in roughly half as many participants as pancreatitis, and the risk did not appear to be increased with sitagliptin.