Comparative Safety of Dipeptidyl Peptidase-4 Inhibitors Versus Sulfonylureas and Other Glucose-lowering Therapies for Three Acute Outcomes

Abstract

Although the glucose lowering effect of dipeptidyl peptidase-4 (DPP4) inhibitors is well established, several potential serious acute safety concerns have been raised including acute kidney injury, respiratory tract infections, and acute pancreatitis. Using the UK-based Clinical Practice Research Datalink (CPRD), we identified initiators (365-day washout period) of DPP4 inhibitors and relevant comparators including initiators of sulfonylureas, metformin, thiazolidinediones, and insulin between January 2007 and January 2016 to quantify the association between DPP4 inhibitors and three acute health events – acute kidney injury, respiratory tract infections, and acute pancreatitis. The associations between drug and study outcomes were estimated using Cox proportional hazard models adjusted for deciles of high-dimensional propensity scores and number of additional glucose lowering agents. After controlling for potential confounders, the risk was not significantly increased or decreased for initiators of DPP4 inhibitors compared to sulfonylureas (hazard ratio (HR) [95% confidence interval (CI)] for acute kidney injury: 0.81 [0.56–1.18]; HR for respiratory tract infections: 0.93 [0.84–1.04]; HR for acute pancreatitis 1.03 [0.42–2.52], metformin (HR for respiratory tract infection 0.91 [0.65–1.27]), thiazolidinediones (HR for acute kidney injury: 1.12 [0.60–2.10]; HR for respiratory tract infections: 1.02 [0.86–1.21]; HR for acute pancreatitis: 1.21 [0.25–5.72]), or insulin (HR for acute kidney injury: 1.40 [0.77–2.55]; HR for respiratory tract infections: 0.74 [0.60–0.92]; HR for acute pancreatitis: 1.01 [0.24–4.19]). Initiators of DPP4 inhibitors were associated with an increased risk of acute kidney injury when compared to metformin initiators (HR [95% CI] for acute kidney injury: 1.85 [1.10–3.12], although this association was attenuated when DPP4 inhibitor monotherapy was compared to metformin monotherapy exposure as a time-dependent variable (HR 1.39 [0.91–2.11]). Initiation of a DPP4 inhibitor was not associated with an increased risk of acute kidney injury, respiratory tract infections, or acute pancreatitis compared to sulfonylureas or other glucose-lowering therapies.

Linagliptin in patients with type 2 diabetes and cardiovascular and/or renal disease: results from a cardiovascular and renal outcomes trial

“…Evidence from ongoing trials and continued pharmacovigilance will provide further insights into the long-term pancreatic safety of this drug class. The safety findings of CARMELINA are consistent with findings observed for the DPP-4 inhibitor class as a whole; these agents have been shown to be well tolerated with a favorable safety profile, including a low risk of hypoglycemia [7,24,25].…”

Assessment of risk, severity, mortality, glycemic control and antidiabetic agents in patients with diabetes and COVID-19: A narrative review

“…Although there was an initial report of increase in nasopharyngitis with the DPP-4Is during the phase 3 clinical development program, however, the later larger trials with their meta-analysis and the longer cardiovascular outcome trials (CVOTs) with these class did not show any such signals. Similarly, the UK-based Clinical Practice Research Datalink (CPRD) database that studied 103,159 patients of diabetes over 8-years that compared the respiratory tract infection with DPP-4Is to SUs, metformin, TZD and insulin, found no significant increase in risk [65]. These findings were further reassured by few studies conducted in immunocompromised patients with human immunodeficiency virus (HIV), showing no increase in infection with the DPP-4Is [66].…”

Dipeptidyl peptidase 4 inhibitors and their potential immune modulatory functions

“…It has been previously demonstrated that both CD8(+)CD26(high) and CD8(+)CD26(−) cells represent activated cell phenotypes and may offer a characteristic marker of successful memory development (Hatano, Ohnuma, Yamamoto, Dang, & Morimoto, 2013;Ibegbu et al, 2009). CD28 is one of the molecules expressed in T cells, which provides co-stimulatory signals for T cell activation (Gamble et al, 2018). Interestingly, CD26-mediated co-stimulation of CD8(+) T cells results in greater cytotoxic effect than that induced by CD28 co-stimulation pathway (Hatano et al, 2013).…”

“…Increased risk of nasopharyngitis and urinary tract infection but no association of upper respiratory tract infections in T2DM patients (Amori et al, 2007;Gamble et al, 2018) Potential adverse effect on MERS patients (Inn et al, 2018;Raj et al, 2013) Potential therapeutic effect on HCV patients (Decalf et al, 2016;Riva et al, 2014) No effect on HIV patients (Dube et al, 2019;Goodwin et al, 2013)…”

“…A meta-analysis including 29 clinic trials concluded that DPP4is could increase the risk of infections for nasopharyngitis (risk ratio, 1.2) and urinary tract infection (risk ratio, 1.5) but not for upper respiratory tract infections (Amori, Lau, & Pittas, 2007). Using the UKbased CPRD, Gamble also identified that initiation of a DPP4i is not associated with an increased risk of respiratory tract infections compared to other glucose-lowering therapies (Gamble et al, 2018). However, there is no experimental studies that investigate the molecular/immunerelated mechanisms in DPP4i-related bacterial infections.…”