Comment on Gan et al. Efficacy of Modern Diabetes Treatments DPP-4i, SGLT-2i, and GLP-1RA in White and Asian Patients With Diabetes: A Systematic Review and Meta-analysis of Randomized Controlled Trials. Diabetes Care 2020;43:1948–1957

We read the article by Gan et al. (1) with great interest and appreciate their exemplary work. The authors have concluded that among the newer antidiabetes drugs of 24 weeks’ duration, sodium–glucose cotransporter 2 inhibitors (SGLT-2i) lower HbA_1c better in studies predominantly of Asian ethnicity (∆ −0.32%, P = 0.0003) compared with White ethnicities, but dipeptidyl peptidase 4 inhibitors (DPP-4i) and glucagon-like peptide 1 receptor agonists (GLP-1RA) do not. Moreover, this meta-analysis also finds that both SGLT-2i (∆ −0.28%, P = 0.02) and DPP-4i (∆ −0.24%, P = 0.01) lower HbA_1c further in studies predominantly of Asians ethnicities at 12 weeks but the GLP-RA do not, when compared with White participants. These findings would likely encourage clinicians to use more SGLT-2i and perhaps less GLP-1RA for patients of Asian ethnicity, in addition to other inherent reasons such as oral versus injectable route and the cost. The authors also claim that this is the first meta-analysis that studied the ethnic differences in glycemic response with SGLT-2i.

While acknowledging these results, we would also like to appraise some issues that need attention. First, an earlier larger meta-analysis by Cai et al. (2) that analyzed the effects of SGLT-2i in Asians compared with non-Asians found no meaningful difference (∆ −0.05%, P > 0.05) in HbA_1c lowering at 12 weeks. These differential findings in two meta-analyses may be due to the difference in the criteria used to define Asian versus non-Asian studies (>50% Asian or non-Asian in Cai et al. vs. >70% Asian or White in Gan et al.) or due to the number of pooled studies analyzed (17 Asian and 39 non-Asian studies in Cai et al. vs. 9 Asian and 12 White studies in Gan et al.) or variability in response due to genetic, cultural, and environmental factors. Second, while the meta-analysis by Gan et al. did not study the side effects of these newer antidiabetes drugs ethnicity-wise, Cai et al. reported a significant increase in ketosis in Asian participants (odds ratio 3.30; 95% CI 1.27–8.59) with SGLT-2i. Third, another recent meta-analysis that studied the ethnic differences in the 3-point major adverse cardiovascular events (3P-MACE) pooled from all cardiovascular outcomes trials (CVOT) with SGLT-2i and GLP-1RA has shown a significant benefit with GLP-1RA (hazard ratio [HR] 0.71; 95% CI 0.59–0.86; P < 0.001) but not with the SGLT-2i (HR 0.88; 95% CI 0.67–1.15; P = 0.35) in Asians (3). Fourth, as noted by the authors, a separate analysis of empagliflozin CVOT (BI 10773 [Empagliflozin] Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients [EMPA-REG OUTCOME]) found a significant reduction in the 3P-MACE (HR 0.68; 95% CI 0.48–0.95) and composite of cardiovascular death or heart failure hospitalization in Asians (HR 0.57; 95% CI 0.36–0.89) (4); however, no such benefit in Asians was apparently observed in the CVOT of canagliflozin and dapagliflozin. Moreover, the meta-analysis from the pooled CVOT of all SGLT-2i did not find a significant benefit in composite of cardiovascular death or heart failure hospitalization (HR 0.86; 95% CI 0.55–1.36; P = 0.53) in Asians (3). Collectively, these findings suggest that cardiovascular benefits of GLP-1RA are more pronounced than those of SGLT-2i in Asians.

Finally, Asians with type 2 diabetes tend to develop cardiovascular disease much earlier and of more extensive variety compared with non-Asians. In view of these inconsistent findings, we would suggest following the American Diabetes Association–European Association for the Study of Diabetes 2020 Consensus Report recommendation for Asians for the use of both GLP-1RA and SGLT-2i, owing to their cardiovascular and renal benefits (5). We also recommend that further specific studies are conducted to determine the cardiovascular efficacy of these novel therapies in Asian populations.