Table 5.
Summary of efficacy and safety data from published Phase III clinical trials (≥24 weeks) using DPP-4 inhibitors in combination with SGLT2 inhibitors
| Study, duration (primary outcome) | Combinationa | Background therapy | N | Treatment and dose (mg/day) | Efficacy parameters (change from baseline) b
|
Safety parameters (percentage of patients with a special interest adverse event)
|
||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| HbA1c (%) |
FPG (mg/dL)c |
Body weight (kg) |
SBP (mmHg) |
Hypoglycemia, n (%) |
Urinary tract infection, n (%) |
Genital infection, n (%) |
Volume depletion events, n (%) |
|||||
| Jabbour et al68 24-week double- blind treatment period (+ 24-week extension) |
DAPA 10 mg/day add-on to SITA 100 mg/day ± MET | (With/without) MET ≥ 1,500 mg/day |
Loose-pill combinationd | (Week 8 vs week 24) | (Hypotension or dehydration or hypovolemia at 48 weeks) | |||||||
| 224 | PBO + SITA 100 | 0 | 3.8 | −0.3 | −5.1 | 4/226 (1.8) | 9/226 (4.0) | 1/226 (0.4) | 2/226 (0.9) | |||
| 223 | DAPA 10 + SITA 100 | −0.5 | −24.1 | −2.1 | −6.0 | 6/225 (2.7) | 11/225 (4.9) | 19/225 (8.4) | 3/225 (1.3) | |||
| Rosenstock et al69 24-week double- blind treatment period |
DAPA 10 mg/day + SAXA 5 mg/day as dual add-on to MET | MET XR ≥1,500 mg/day |
Loose-pill combinationd | |||||||||
| 179 | SAXA 5 + DAPA 10 + MET | −1.47 | −38 | −2.1 | −1.9 | 2 (1) | 1 (0.6) | 0 | Not reported | |||
| 176 | SAXA 5 + MET | −0.88 | −14 | 0 | 0.3 | 2 (1) | 9 (5) | 1 (0.6) | Not reported | |||
| 179 | DAPA 10 + MET | −1.20 | −32 | −2.4 | −3.5 | 2 (1) | 7 (5) | 10 (6) | Not reported | |||
| Mathieu et al70 24-week double- blind treatment period (+ 28-week extension) |
DAPA 10 mg/day add-on to SAXA 5 mg/day + MET | MET IR ≥1,500 mg/day |
Loose-pill combinationd | |||||||||
| 160 | PBO + SAXA 5 + MET | −0.10 | −5 | −0.4 | 2.0 | 0 | 10 (6.3) | 1 (0.6) | Not reported | |||
| 160 | DAPA 10 + SAXA 5 + MET | −0.82 | −33 | −1.9 | −1.9 | 2 (1.3) | 8 (5.0) | 8 (5.0) | Not reported | |||
| Matthaei et al71 24-week double- blind treatment period (+ 28-week extension) |
SAXA 5 mg/day add-on to DAPA 10 mg/day + MET | MET IR ≥1,500 mg/day |
Loose-pill combinationd | |||||||||
| 162 | PBO + DAPA 10 + MET | −0.16 | −5 | −0.51 | Reported as <1 mmHg change in both treatment arms | 4 (2.5) | 6 (3.7) | 4 (2.5) | 2 (1.2) | |||
| 153 | SAXA 5 + DAPA 10 + MET | −0.51 | −9 | −0.53 | (As above) | 2 (1.3) | 8 (5.2) | 0 | 0 | |||
| Lewin et al72 24 weeks; study duration 52 weeks |
EMPA 10 or 25 mg/day + LINA 5 mg/day | Treatment- naïve | Single-pill combinationd | (Week 24) | (Week 24) | (Week 24) | (Week 52) | |||||
| 134 | EMPA 25/LINA 5 | −1.08 | −29.55 | −2.0 | −2.5 | 0 | 17 (12.5) | 8 (5.9) | 1 (0.7) | |||
| 135 | EMPA 10/LINA 5 | −1.24 | −28.21 | −2.7 | −2.1 | 0 | 21 (15.4) | 4 (2.9) | 3 (2.2) | |||
| 133 | EMPA 25 | −0.95 | −24.24 | −2.1 | −2.1 | 1 (0.7) | 14 (10.4) | 6 (4.4) | 0 | |||
| 132 | EMPA 10 | −0.83 | −22.39 | −2.3 | −2.2 | 4 (3.0) | 22 (16.3) | 7 (5.2) | 0 | |||
| 133 | LINA 5 | −0.67 | −5.92 | −0.8 | −0.4 | 1 (0.7) | 14 (10.4) | 4 (3.0) | 0 | |||
| DeFronzo et al73 24 weeks; study duration 52 weeks |
EMPA 10 or 25 mg/day + LINA 5 mg/day as add-on to MET | MET IR ≥1,500 mg/day, MTD, or maximum dose per local label |
Single-pill combinationd | (Week 24) | (Week 24) | (Week 24) | (Week 52) | |||||
| 134 | EMPA 25/LINA 5 + MET | −1.19 | −35.3 | −3.0 | −3.6 | 5 (3.6) | 14 (10.2) | 3 (2.2) | 1 (0.7) | |||
| 135 | EMPA 10/LINA 5 + MET | −1.08 | −32.2 | −2.6 | −2.8 | 3 (2.2) | 13 (9.6) | 8 (5.9) | 2 (1.5) | |||
| 140 | EMPA 25 + MET | −0.62 | −18.8 | −3.2 | −2.8 | 5 (3.5) | 19 (13.5) | 12 (8.5) | 2 (1.4) | |||
| 137 | EMPA 10 + MET | −0.66 | −20.8 | −2.5 | −3.5 | 2 (1.4) | 16 (11.4) | 11 (7.9) | 1 (0.7) | |||
| 128 | LINA 5 + MET | −0.70 | −13.1 | −0.7 | 0.3 | 3 (2.3) | 20 (15.2) | 3 (2.3) | 4 (3.0) | |||
| Søfteland et al74 24 weeks |
EMPA (10 or 25 mg/day) add-on to LINA 5 mg/day + MET | MET IR ≥1,500 mg/day, MTD, or maximum dose per local label |
Single-pill combinationd | (FPG converted) | ||||||||
| 108 | PBO + LINA + MET | 0.14 | 5.4 | −0.3 | −1.7 | 1 (0.9) | 8 (7.3) | 2 (1.8) | Not reported | |||
| 109 | EMPA 10/LINA 5 + MET | −0.65 | −27.0 | −3.1 | −3.0 | 0 | 8 (7.1) | 2 (1.8) | Not reported | |||
| 110 | EMPA 25/LINA 5 + MET | −0.56 | −32.4 | −2.5 | −4.3 | 3 (2.7) | 4 (3.6) | 5 (4.5) | Not reported | |||
| Tinahones et al75 24 weeks |
LINA 5 mg/day add-on to EMPA 10 or 25 mg/day + MET | MET IR ≥1,500 mg/day, MTD, or maximum dose per local label |
Single-pill combinationd | (FPG converted) | ||||||||
| 125 | PBO + EMPA 10 + MET | −0.21 | 3.6 | −0.8 | 1.0 | 0 | 10 (7.8) | 4 (3.1) | Not reported | |||
| 122 | LINA 5/EMPA 10 + MET | −0.53 | −7.2 | −0.2 | 0 | 0 | 12 (9.5) | 3 (2.4) | Not reported | |||
| 110 | PBO + EMPA 25 + MET | −0.10 | −3.6 | −0.3 | −1.6 | 3 (2.7) | 9 (8.0) | 9 (8.0) | Not reported | |||
| 110 | LINA 5/EMPA 25 + MET | −0.58 | −12.6 | −0.2 | −0.2 | 0 | 15 (13.4) | 3 (2.7) | Not reported | |||
Notes:
Prespecified analyses of Phase III clinical trials data for DPP-4 inhibitor plus canagliflozin combination therapy were not available.
Data are presented as reported in each publication for the randomized double-blind arm(s), unless otherwise stated; change in mean, least square mean, or adjusted mean data presented.
Units converted from mmol/L to mg/dL where stated (mmol/L value × 18.0182 = mg/dL value).
Loose pill refers to separate dosage forms of each active agent (ie, separate pills for DPP-4 inhibitor and SGLT2 inhibitor), whereas single pill refers to a fixed-dose formulation containing both the active agents in a single dosage form (ie, single pill containing DPP-4 inhibitor and SGLT2 inhibitor).
Abbreviations: DAPA, dapagliflozin; DPP-4, dipeptidyl pepti dase-4; EMPA, empagliflozin; FPG, fasting plasma glucose; HbA1c, glycated hemoglobin; IR, immediate release (formulation); LINA, linagliptin; MET, metformin; MTD, maximum tolerated dose; PBO, placebo; SAXA, saxagliptin; SBP, systolic blood pressure; SITA, sitagliptin; SGLT2, sodium-glucose cotransporter 2; XR, extended release (formulation).