Comparing the risks of new-onset gastric cancer or gastric diseases in type 2 diabetes mellitus patients exposed to SGLT2I, DPP4I or GLP1A: a population-based cohort study

ObjectiveTo compare the risks of gastric cancer and other gastric diseases upon exposed to sodium-glucose cotransporter 2 inhibitors (SGLT2I), dipeptidyl peptidase-4 inhibitors (DPP4I) and glucagon-like peptide-1 receptor agonists (GLP1A). DesignThis was a retrospective population-based cohort study of prospectively recorded data on type-2 diabetes mellitus (T2DM) patients prescribed either SGLT2I or DPP4I between January 1st 2015 and December 31st 2020 from Hong Kong. The primary outcome was new- onset gastric cancer, peptic ulcer (PU), acute gastritis, non-acute gastritis, and gastroesophageal reflux disease (GERD). Propensity score matching (1:1 ratio) using the nearest neighbour search was performed and multivariable Cox regression was carried out. A three-arm analysis including the GLP1A cohort was subsequently conducted. ResultsA total of 62858 T2DM patients (median age: 62.2 years old [SD: 12.8]; 55.93% males; SGLT2I: n=23442; DPP4I: n=39416) were included. After matching, the incidence of gastric cancer was significantly lower in SGLT2I users (Incidence rate, IR: 0.32; 95% confidence interval, CI: 0.23-0.43) than DPP4I users (IR: 1.22; CI: 1.03-1.42). SGLT2I use was associated with lower risks of gastric cancer (HR: 0.30; 95% CI: 0.19-0.48) after adjusting for significant covariates compared to DPP4I use. SGLT2 use was also associated with lower risks of PU, acute gastritis, non-acute gastritis, and GERD (all p<0.05). The three-arm analysis demonstrated higher risks of gastric cancer and GERD in GLP1A than in SGLT2I. ConclusionsSGLT2I was associated with lower risks of new-onset gastric cancer, PU, acute gastritis, non-acute gastritis, and GERD after matching and adjustments compared to DPP4I. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=113 SRC="FIGDIR/small/23292063v1_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@18177a0org.highwire.dtl.DTLVardef@d4e397org.highwire.dtl.DTLVardef@aa054corg.highwire.dtl.DTLVardef@41e0b8_HPS_FORMAT_FIGEXP M_FIG C_FIG Key messages What is already known on this topicT2DM was associated with higher risks of gastric cancer. Anti-diabetic drugs such as SGLT2I and DPP4I are commonly used second-line drugs to help manage diabetes mellitus. SGLT2I was previously suggested to lower the risks of cancer compared to DPP4I. What this study addsIn this population-based cohort study, SGLT2I was associated with a 70% lower risk of gastric cancer, 34% low risks of peptic ulcer, 69% lower risks of acute gastritis, 65% low risks of non-acute gastritis, and 38% of gastroesophageal reflux disease (GERD) than DPP4I users. The three arm sensitivity analysis involving DPP4I and GLP1A using stabilized inverse probability treatment weighting demonstrated higher risks of gastric cancer and GERD in GLP1A users compared to SGLT2I users. How this study might affect research, practice or policyThe findings of this study may influence the choice of novel second-line anti-diabetic therapy in T2DM patients in terms of the gastric safety profile especially gastric cancer. This study may inspire further mechanistic studies and studies on the long-term cancer benefits of SGLT2I.