Association Between DPP-4 Inhibitors and Events of Colorectal and Liver Cancers in Patients With Diabetes Receiving Second-Line Agents: A Nested Case-Control Study

Abstract

ObjectivePlasma dipeptidyl peptidase-4 (DPP4) levels were significantly lower in patients with colorectal and liver cancers, and animal studies also showed DPP4 inhibitors (DPP4is) have procarcinogenic effects in colorectal cancer. Until now, whether DPP4is therapy affects the progression of liver cancer and colorectal cancer in patients with T2DM has not been well investigated. We investigated the association between cumulative defined daily dose (cDDD) of DPP4is exposure and risks of liver and colorectal cancers in patients with type 2 diabetes.Materials and MethodsWe identified 268,520 patients with diabetes receiving DPP4is as second-line agents between March 1, 2009, and December 31, 2013, from Taiwan’s National Health Insurance Research Database, Taiwan Cancer Registry, and National Death Registry of Taiwan. The amount of DPP4is were divided into three groups (low, medium, and high) based on the interquartile range of the cDDD of the DPP4is.ResultsThe data showed that the low cDDD of DPP-4is was associated with a reducing risk of colorectal cancer [adjusted odds ratio (OR), 0.49; 95% CI, 0.32–0.75; P=0.001]. However, the high cDDD of DPP-4is was associated with an increasing risk of colorectal cancer (adjusted OR, 1.86; 95% CI, 1.32–2.61; P<0.001). No association between DPP4is use and liver cancer risk was observed.ConclusionsThis nested case study revealed a J-shaped association between the cDDD of DPP-4is and colorectal cancer risk, but not liver cancer risk. Therefore, the effects of long-term DPP4is use on colorectal cancer risk warrant further study.

Sodium-glucose cotransporter 2 inhibitors versus dipeptidyl peptidase 4 inhibitors on new-onset overall cancer in type 2 diabetes mellitus: a population-based study

“…However, although these results may reflect much of the current school of thought concerning DPP4I, there have been some recent investigations that have suggested the possible existence of either a dose-dependent or cancer-type-dependent correlation. As to the former, Chou et al presented a higher incidence of colorectal cancer in patients on DPP4I who were receiving a high cumulative daily dose, but a corresponding lower risk of colorectal cancer amongst low cumulative dose users (26). As it pertains to the latter, there is evidence to suggest that whilst a relationship between DPP4I and overall cancer risk may not exist, these drugs are associated with specific cancer types when categorized, namely bladder, kidney and liver cancer as well as melanoma (11).…”

“…As to the former, Chou et al . presented a higher incidence of colorectal cancer in patients on DPP4I who were receiving a high cumulative daily dose, but a corresponding lower risk of colorectal cancer amongst low cumulative dose users (26). As it pertains to the latter, there is evidence to suggest that whilst a relationship between DPP4I and overall cancer risk may not exist, these drugs are associated with specific cancer types when categorized, namely bladder, kidney and liver cancer as well as melanoma (11).…”

Sodium‐glucose cotransporter 2 inhibitors versus dipeptidyl peptidase 4 inhibitors on new‐onset overall cancer in Type 2 diabetes mellitus: A population‐based study

“…However, although these results may reflect much of the current school of thought concerning DPP4I, there have been some recent investigations that have suggested the possible existence of either a dose‐dependent or cancer‐type‐dependent correlation. As to the former, Chou et al presented a higher incidence of colorectal cancer in patients on DPP4I who were receiving a high cumulative daily dose, but a corresponding lower risk of colorectal cancer amongst low cumulative dose users 33 . As it pertains to the latter, there is evidence to suggest that whilst a relationship between DPP4I and overall cancer risk may not exist, these drugs are associated with specific cancer types when categorised, namely bladder, kidney and liver cancer as well as melanoma 11 …”

“…As to the former, Chou et al presented a higher incidence of colorectal cancer in patients on DPP4I who were receiving a high cumulative daily dose, but a corresponding lower risk of colorectal cancer amongst low cumulative dose users. 33 As it pertains to the latter, there is evidence to suggest that whilst a relationship between DPP4I and overall cancer risk may not exist, these drugs are associated with specific cancer types when categorised, namely bladder, kidney and liver cancer as well as melanoma. 11 Likewise, very much akin to that of DPP4I, the data centred around SGLT2I are also controversial.…”

Role of SGLT2 Inhibitors, DPP-4 Inhibitors, and Metformin in Pancreatic Cancer Prevention

“…In a study conducted by Chou et al, it was identified that while a low cumulative defined daily dose of DPP-4 inhibitors was associated with a decreasing risk of colorectal cancer, a high cumulative defined daily dose showed an increasing risk. The authors concluded that there was a J-shaped association and emphasized the need for further studies [76].…”