We herein conducted a systematic review and meta-analysis to summarize the available literature and appraise the safety profiles of SGLT2 inhibitors in Japanese patients with DM. The results obtained revealed that SGLT2 inhibitors were associated with similar risks of hypoglycemia, UTI, genital infection, hypovolemia, and fracture as a placebo. The safety data of the present analysis had negligible heterogeneity (I2 ≤ 18%).
The result showing that SGLT2 inhibitors had a similar risk of hypoglycemia as a placebo [risk ratio 1.16 (95%CI 0.93 to 1.45), I2 = 16%] was consistent with the findings of a previous study 35; however, their data differed from the present study, which partially included patients with type 1 DM. Moreover, SGLT2 inhibitors as monotherapy among Asian and non-Asian patients with type 2 DM did not increase the risk of hypoglycemia 7, 35. The addition of combination therapies to an oral hypoglycemic agent(s) or insulin is known to generally increase the risk of hypoglycemia; however, multiple meta-analyses including patients with type 1 DM and with no restrictions in race/ethnicity revealed that even dual combination therapy with a SGLT2 inhibitor and insulin did not increase the risk of hypoglycemia over that with a placebo 2, 3, 36. This can be attributed to the insulin-independent antihyperglycemic effects of SGLT2 inhibitors, rather than racial or ethnic differences.
The present study demonstrated that SGLT2 inhibitors had a similar risk of UTI [risk ratio 0.78 (95%CI 0.47 to 1.31)] as a placebo. This result supports the findings of two previous studies including Asian patients with type 2 DM 7, 35. Furthermore, a larger meta-analysis of more than 100 RCTs and with no racial or ethnic restrictions showed that the risk of UTI was similar between SGLT2 inhibitors and a placebo 37. A large population-based cohort study using U.S. databases of patients with employer-based insurance also reported that in comparisons with glucagon-like peptide-1 receptor agonists, treatments with SGLT2 inhibitors were not associated with the risk of severe and non-severe UTI 38. These findings suggest that SGLT2 inhibitors are unlikely to increase the risk of UTI regardless of whether patients are Asians or non-Asians. Two previous meta-analyses of Asian populations showed that SGLT2 inhibitors consistently increased the risk of genital infection 7, 35. Furthermore, a few meta-analyses with long-term follow-ups reported an increased risk of genital infection with SGLT2 inhibitors 39, 40. One possible explanation for the inconsistency between the present results and these findings is that the RCTs retrieved had relatively short-term follow-ups (at most 24 weeks). Three meta-analyses consistently showed that a treatment with DAPA was likely to dose-dependently increase the risk of UTI and genital infection 37, 39, 41; however, DAPA did not increase the risk of either event in sub-analyses (Figs. 2, 3).
The present results showed that in comparisons with a placebo, SGLT2 inhibitors had a similar risk of hypovolemia [risk ratio 1.12 (95%CI 0.48 to 2.61)]. A previous study on East Asian patients with type 2 DM found no significant difference in the risk of hypotension between SGLT2 inhibitors and a placebo 35. In contrast, one RCT with a long-term follow-up of more than 100 weeks among mainly Caucasian patients with type 2 DM showed that the prevalence of volume depletion-related adverse events was three-fold higher with SGLT2 inhibitors than with a placebo 4. Since they reported that these events with SGLT2 inhibitors generally occurred within 26 weeks and that a longer exposure to SGLT2 inhibitors may have resulted in a higher incidence of these events 4, the incidence of hypovolemia in a short-term follow-up may be lower among Japanese patients treated with SGLT2 inhibitors than among Caucasian patients; however, these data need to be interpreted with caution because the definition of hypovolemia or volume depletion varied among the studies retrieved. Moreover, a meta-analysis of patients with type 2 DM and chronic kidney disease showed a slightly elevated risk of hypovolemia with SGLT2 inhibitors 42. Further studies with a standardized definition of adverse events and involving more diverse populations are needed to support the present results.
The present analysis indicated that SGLT2 inhibitors were associated with a similar risk of fracture as a placebo [risk ratio 0.85 (95%CI 0.20 to 3.61)] (Supplementary Table S1). This was consistent with a meta-analysis of East Asian patients 35 and with a network meta-analysis including approximately 80% Caucasian patients 43; however, a sub-analysis of the network meta-analysis showed the opposite findings, namely, Asian populations had a slightly higher risk of fracture 43. The reason for this disparity is unclear. The treatment duration of SGLT2 inhibitors continuously increased the risk of fracture 44. Cohort or case-control studies rather than RCTs with short-term durations are generally more likely to show long-term or rare adverse events. Therefore, the duration of the follow-up in our analysis was too short to assess the risk of fracture; previous reports that evaluated the risk of fracture had the same limitation as our analysis 35, 43, 45. Additionally, our fracture outcome did not include all types of SGLT2 inhibitors. Collectively, the present results and previous findings indicate that more RCTs with long-term follow-ups and individual SGLT2 inhibitors are needed in the future.
Our sub-analysis including only type 2 DM indicated that the risk of hypoglycemia was higher with SGLT2 inhibitors than with a placebo [RR 1.30 (95%CI 1.01 to 1.65)]. This result was partially in line with the findings of an earlier meta-analysis of Asian patients with type 2 DM 7. Since the excluded RCT 18 had the shortest study duration of 4 weeks and the greatest weight of 38.5% in the hypoglycemia outcome (Fig. 1), the RCT may have affected this result.
The present study has some strengths. To the best of our knowledge, this is the first systematic literature review and meta-analysis to appraise the safety profiles of SGLT2 inhibitors in Japanese patients with DM. Furthermore, the safety data of our analyses consistently had negligible heterogeneity (I2 ≤ 18%) and the majority of the studies retrieved were high-quality RCTs (Supplementary Figure S2). However, the present study also had some limitations. It may have had a publication bias because we only retrieved published studies. We were unable to rule out the impact of anti-hyperglycemic agents or to exclude type 1 DM patients; the former is because some studies included patients who were treated with an oral hypoglycemic agent or insulin, while the latter is due to one RCT including patients with type 1 DM 18. Therefore, we were only able to evaluate the safety profiles of SGLT2 inhibitors in all Japanese patients with DM; however, we confirmed that the results of the sub-analysis of patients with type 2 DM only were consistent with those of the main analyses among all patients with DM (Supplementary Table S1). Other limitations are that the RCTs retrieved did not always set the adverse events that we evaluated as their primary endpoint, and also that the numbers of different types of SGLT2 inhibitors pooled were unbalanced. Therefore, our data may be biased.