Table 3.
Safety data summary from the main phase 3 clinical trials of dapagliflozin, canagliflozin and empagliflozin*
| Reference | Study details | Treatment and dose (mg/day) | Patients with a special interest adverse event† | ||
|---|---|---|---|---|---|
| Hypoglycaemia (%) | Urinary tract infection (%) | Genital infection (%)‡ | |||
| Dapagliflozin | |||||
| Monotherapy 51 | Phase 3, 24 weeks | Pbo | 2.7 | 4.0 | 1.3 |
| Dapa 5/10 | 0 to 2.9 | 5.7 to 12.5 | 2.6 to 12.9 | ||
| Monotherapy (A1c ≥ 10.1) 51 | Phase 3, 24 weeks | Dapa 5/10 | 2.9/0 | 8.8/15.4 | 5.9/17.9 |
| Add‐on to MET 52 | Phase 3, 24 weeks | Pbo | 3 | 8 | 5 |
| Dapa 5/10 | 4/4 | 7/8 | 13/9 | ||
| Initial combination with MET XR 53 | Phase 3, 24 weeks | Pbo + MET XR | 0–2.9 | 7.5 | 2.0–2.4 |
| Dapa 5 + MET XR | 2.6 | 7.7 | 6.7 | ||
| Dapa 10 + MET XR | 3.3 | 7.6 | 8.5 | ||
| Add‐on to SU (GLIM) 54 | Phase 3, 24 weeks | Pbo | 4.8 | 0.7 | 0.7 |
| Dapa 5 | 6.9 | 6.9 | 6.2 | ||
| Dapa 10 | 7.9 | 5.3 | 6.6 | ||
| Add‐on to DPP4i (SITA) 55 | Phase 3, 24 weeks§ | Pbo | 1.8 | 4.0 | 0.4 |
| Dapa 10 | 2.7 | 4.9 | 8.4 | ||
| Add‐on to MET 56 | Phase 3, 52 weeks | GLIP 5–20 | 39.7 | 6.4 | 2.7 |
| Dapa 2.5–10 | 3.4 | 10.8 | 12.3 | ||
| Add‐on to TZD (PIO) 57 | Phase 3, 48 weeks | Pbo | 0.7 | 7.9 | 2.9 |
| Dapa 5/10 | 2.1/0 | 8.5/5.0 | 9.2/8.6 | ||
| Add‐on to INS (≥ 30 units/day) ± OADs 58 | Phase 3, 48 weeks | Pbo | 51.8 | 5.1 | 2.5 |
| Dapa 5 | 55.7 | 10.8 | 9.9 | ||
| Dapa 10 | 53.6 | 10.2 | 10.7 | ||
| Canagliflozin | |||||
| Monotherapy 59 | Phase 3, 26 weeks | Pbo | 2.6 | 4.2 | 2.1 (M0%, F3.8%) |
| Cana 100 | 3.6 | 7.2 | 6.2 (M2.5%, F8.8%) | ||
| Cana 300 | 3.0 | 5.1 | 6.6 (M5.6%, F7.4%) | ||
| Monotherapy (A1c >10.0 ≤ 12.0) 59 | Phase 3, 26 weeks | Cana 100 | N/r | 6.4 | 12.7 (M4.3%; F20.8%) |
| Cana 300 | N/r | 4.5 | 4.5 (M5.3%; F4.0%) | ||
| Add‐on to MET 60 | Phase 3, 52 weeks | GLIM 1–8 | 34 | 5 | 1.7 (M1%, F2%) |
| Cana 100 | 6 | 6 | 8.9 (M7%, F11%) | ||
| Cana 300 | 5 | 6 | 11.1 (M8%, F14%) | ||
| Add‐on to MET 61 | Phase 3, 52 weeks¶ | SITA 100 | 4.1 | 6.3 | 1.9 (M1.2%, F2.6%) |
| Cana 100 | 6.8 | 7.9 | 8.4 (M5.2%, F11.3%) | ||
| Cana 300 | 6.8 | 4.9 | 6.5 (M2.4%, F9.9%) | ||
| Add‐on to MET + SU 62 | Phase 3, 52 weeks | SITA 100 | 40.7 | 5.6 | 2.1 (M0.5%, F4.3%) |
| Cana 300 | 43.2 | 4.0 | 11.9 (M9.2%, F15.3%) | ||
| Add‐on to MET + SU 63 | Phase 3, 52 weeks** , †† | Pbo | 17.9 | 7.7 | 3.2 (M1.3%; F5.0%) |
| Cana 100 | 33.8 | 8.3 | 13.3 (M7.9%; F18.5%) | ||
| Cana 300 | 36.5 | 8.3 | 11.5 (M5.7%; F18.8%) | ||
| Add‐on to MET + TZD (PIO) 64 | Phase 3, 52 weeks†† , ‡‡ | Pbo / SITA | 4.4 | 7.8 | 2.6 (M0%; F7.7%) |
| Cana 100 | 6.1 | 5.3 | 8.0 (M3.9%; F16.7%) | ||
| Cana 300 | 6.1 | 7.9 | 12.3 (M4.8%; F21.6%) | ||
| Add‐on to INS (≥ 30 units/day) ± OADs 65 | Phase 3, 18 weeks efficacy substudy | Pbo | 37 | 2.1 | (M0.5%, F2.2%) |
| Cana 100 | 49 | 2.3 | (M4.0%, F11.8%) | ||
| Cana 300 | 48 | 3.4 | (M8.3%, F9.9%) | ||
| Empagliflozin | |||||
| Monotherapy 66 | Phase 3, 24 weeks | Pbo | <1 | 5 (M2%, F9%) | 0 |
| SITA 100 | <1 | 5 (M3%, F9%) | 1 (M1%, F1%) | ||
| Empa 10 | <1 | 7 (M2%, F15%) | 3 (M3%, F4%) | ||
| Empa 25 | <1 | 5 (M1%, F13%) | 4 (M1%, F9%) | ||
| Monotherapy (A1c > 10.0) 66 | Empa 25 | 0 | 3 (M3%; F4%) | 1 (M2%; F0%) | |
| Add‐on to MET 67 | Phase 3, 24 weeks | Pbo | 0.5 | 4.9 (M2.6%, F7.7%) | 0 |
| Empa 10 | 1.8 | 5.1 (M0%, F12.0%) | 3.7 (M0.8%, F7.6%) | ||
| Empa 25 | 1.4 | 5.6 (M0.8%, F11.8%) | 4.7 (M0.8%, F9.7%) | ||
| Add‐on to MET + SU 68 | Phase 3, 24 weeks | Pbo | 8.4 | 8.0 (M2.7%, F13.3%) | 0.9 (M0.9%, F0.9%) |
| Empa 10 | 16.1 | 10.3 (M2.7%, F18.0%) | 2.7 (M0.9%, F4.5%) | ||
| Empa 25 | 11.5 | 8.3 (M0%, F17.5%) | 2.3 (M0.9%, F3.9%) | ||
| Add‐on to TZD (PIO) ± MET 69 | Phase 3, 24 weeks | Pbo | 1.8 | 16.4 (M8.2%, F22.8%) | 2.4 (M1.4%, F3.3%) |
| Empa 10 | 1.2 | 17.0 (M3.6%, F30.5%) | 8.5 (M7.2%, F9.8%) | ||
| Empa 25 | 2.4 | 11.9 (M2.4%, F21.7%) | 3.6 (M1.2%, F6.0%) | ||
| Add‐on MET | Phase 3, 104 weeks | GLIM 1‐4 | 25 | 13 (M5%, F23%) | 2 (M1%, F3%) |
| Empa 25 | 4 | 14 (M7%, F22%) | 12 (M9%, F15%) | ||
*All included studies were conducted in adults (≥ 18 years). †Data are presented as reported in each publication, the changes (range where applicable) is for approved doses of the drug only. ‡Genital mycotic infection specified in canagliflozin studies. §Safety data provided for entire cohort only. ¶26 weeks Pbo + SITA; 26 weeks SITA only. **26 weeks + 26 weeks extension. †† Safety data reported at week 52. ‡‡ 26 weeks + 26 weeks extension, Pbo group switched to SITA during extension. Pbo, placebo; M, male; F, female; Dapa, dapagliflozin; A1c, glycated haemoglobin; MET, metformin; XR, extended‐release formulation; SU, sulfonylurea; GLIM, glimepiride; DPP4i, dipeptidyl peptidase‐4 inhibitor; SITA, sitagliptin; GLIP, glipizide; TZD, thiazolidinedione; PIO, pioglitazone; INS, insulin; OAD, oral antidiabetes drug; Cana, canagliflozin; Empa, empagliflozin.