A total of 1475 publications were obtained from the search databases. After elimination of irrelevant articles, 78 full-text publications were assessed for eligibility.
Further full-text articles were eliminated based on the following criteria:
Meta-analyses/literature reviews/observational studies/case studies/letters to editors (7);
Reported only efficacy outcomes without mentioning adverse drug events (4);
Did not involve a placebo group (5);
Reported data that could not be used in this analysis (3);
Protocol of previous or upcoming trials (5);
Duplicated studies (46).
Finally, only eight randomized studies [10,11,12,13,14,15,16,17] were confirmed for this analysis, as shown in Fig. 1.
Features of the Randomized Studies and the Included Participants
Eight randomized studies with a total of 1519 participants with T2DM (1069 were assigned to ipragliflozin and 450 to placebo) were included in this analysis. The time period of patient enrollment varied from the years 2011 to 2017, as shown in Table 2.
Table 3 lists the baseline features of the participants. The participants had mean age ranging from 53.3 to 65.7 years with a pre-dominance of male participants. HbA1c varied from 7.53 to 8.67%. Duration of diabetes mellitus varied from 4.67 to 14.3 years.
Main Results of This Analysis
This analysis showed that total treatment-emergent adverse events (RR: 1.06, 95% CI: 0.96–1.16; P = 0.26), including mild treatment-emergent adverse events (RR: 0.95, 95% CI: 0.79–1.13; P = 0.54), moderate treatment-emergent adverse events (RR: 1.04, 95% CI: 0.72–1.51; P = 0.83) and severe treatment-emergent adverse events (RR: 0.72, 95% CI: 0.26–1.96; P = 0.52) were not significantly different in those patients who were assigned to ipragliflozin versus placebo for the treatment of T2DM, as shown in Fig. 2.
Moreover, drug-related adverse events (RR: 1.04, 95% CI: 0.69–1.58; P = 0.85), adverse events leading to drug discontinuation (RR: 1.09, 95% CI: 0.57–2.10; P = 0.79), urinary tract infection (RR: 1.03, 95% CI: 0.60–1.77; P = 0.91), naso-pharyngitis (RR: 0.54, 95% CI: 0.19–1.52; P = 0.25), constipation (RR: 1.94, 95% CI: 0.90–4.20; P = 0.09), dizziness (RR: 0.81, 95% CI: 0.20–3.23; P = 0.76), gastrointestinal disorders (RR: 0.96, 95% CI: 0.68–1.36; P = 0.82) and dehydration (RR: 2.26, 95% CI: 0.38–13.43; P = 0.37) were also not significantly different, as shown in Figs. 3 and 4.
However, genital infection (RR: 4.53, 95% CI: 1.48–13.85; P = 0.008) and hypoglycemia (RR: 1.68, 95% CI: 1.03–2.74; P = 0.04) rates were significantly higher in patients who were assigned to ipragliflozin, as shown in Fig. 3.
The results were summarized in Table 4.
Sensitivity Analysis and Publication Bias
When sensitivity analysis was carried out, excluding the Fonseca (2012) study (RR: 1.69, 95% CI: 1.03–2.78; P = 0.04), excluding the Han (2018) study (RR: 1.77, 95% CI: 1.07–2.93; P = 0.03), excluding the Kashiwagi (2015) study (RR: 1.69, 95% CI: 1.03–2.78; P = 0.04) and excluding the Wilding (2012) study (RR: 1.77, 95% CI: 1.05–2.98; P = 0.03) did not show any significant difference compared to the main result, which already showed hypoglycemia to be significantly higher with ipragliflozin. However, excluding the Ishihara (2016) study (RR: 0.92, 95% CI: 0.30–2.85; P = 0.89) showed hypoglycemia was not significantly higher with ipragliflozin. Sensitivity analysis showed that the main result representing hypoglycemia was influenced by the Ishihara (2016) study and that hypoglycemia might actually not have been significantly higher in those patients who were treated with ipragliflozin. For all the other subgroups, sensitivity analyses showed consistent results throughout.
Publication bias was visually assessed through funnel plots, and low evidence of publication bias was observed across all the randomized studies that assessed the different adverse drug events throughout, as shown in Figs. 5 and 6.