Table 1.
Nine randomized controlled trials of metformin addition to systemic anticancer therapy
| First author (year) [ref.] |
Cancer type | Phase | Setting | Treatment arm | No. of patients |
Primary endpoint | ORR | AEs | mPFS (mo) | HR for PFS (95% CI) |
mOS (mo) |
HR for OS (95% CI) |
Jadad score |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Kordes (2015) 20 |
PC | II | 1st | Gemcitabine/erlotinib + metformin (up to 2 g/d) | 60 | OS | 8.3% | 17 (28.3%)* | 4.1 | 1.18 (0.77-1.82) | 6.8 | 1.06 (0.73-1.56) P = 0.78 |
5 |
| Gemcitabine/erlotinib + placebo | 61 | 8.3% | 28 (46.7%)* | 5.4 | 7.6 | ||||||||
| Sayed (2015) 21 |
NSCLC | II | 1st | Gemcitabine/cisplatin + metformin (500 mg/d) | 15 | ORR | 46.7% | 4 (26.7%)† | 5.54 | 0.35 (0.12-1.05) P = 0.062 |
12 | 0.32 (0.08-1.34) P = 0.119 |
3 |
| Gemcitabine/cisplatin | 15 | 13.3% | 10 (66.7%)† | 5 | 6.5 | ||||||||
| Reni (2016) 22 |
PC | II | 1st | PEXG + metformin (2 g/d) | 31 | PFS | 35.5% | NA | 4.9 | 1.24 (0.87-1.77) P = 0.036 |
6.83 | 1.09 (0.64-1.84) P = 0.13 |
3 |
| PEXG | 29 | 45% | NA | 6.1 | 10.4 | ||||||||
| Zhao (2017) 23 |
H(+) BC | II | ≥2nd | Aromatase inhibitor + metformin (1 g/d) | 30 | PFS | 6.7% | 5 (16.7%)‡ | 4.7 | 1.21 (0.70-2.12) P = 0.48 |
30.9 | 1.1 (0.50-2.41) P = 0.81 |
5 |
| Aromatase inhibitor + placebo | 30 | 0% | 3 (10%)‡ | 6.0 | 32.4 | ||||||||
| Marrone (2018) 24 |
Non-Sq NSCLC | II | 1st | Paclitaxel/carboplatin/bevacizumab + metformin (2 g/d) | 19 | PFS | 56% | 10 (56%)± | 9.6 | 0.30 (0.11-0.85) P = 0.024 |
15.9 | 0.24 (0.03-1.99) P = 0.186 |
3 |
| Paclitaxel/carboplatin/bevacizumab | 6 | 33% | 2 (33%)± | 6.7 | 13.9 | ||||||||
| Nanni (2018) 25 |
HER2(-) BC | II | 1st | Doxorubicin/cyclophosphamide + metformin (2 g/d) | 57 | PFS | 48% | 31 (54%)± | 9.4 | 1.09 (0.75-1.58) P = 0.653 |
34.4 | 1.09 (0.75-1.58) P = 0.382 |
3 |
| Doxorubicin/cyclophosphamide | 65 | 49% | 47 (72%)± | 9.9 | 26.8 | ||||||||
| Pimentel (2019) 26 | BC | II | ≥1st | Chemotherapy + metformin (1.7 g/d) | 22 | PFS | 18.2% | 7 (31.8%)≠ | 5.4 | 1.2 (0.63-2.31) P = 0.58 |
20.2 | 1.68 (0.79-3.55) P = 0.18 |
3 |
| Chemotherapy + placebo | 18 | 25% | 10 (58.8%)≠ | 6.3 | 24.2 | ||||||||
| Li (2019) 27 | EGFR-mutant NSCLC | II | 1st | Gefitinib + metformin (500 mg, 2g/d) | 112 | PFS | 66% | 26 (23.4%)≠ | 10.3 | 1.04 (0.75-1.45) P = 0.8087 |
22.0 | 1.15 (0.79-1.68) P = 0.4571 |
5 |
| Gefitinib + placebo | 112 | 66.7% | 21 (18.9%)≠ | 11.4 | 27.5 | ||||||||
| Arrieta (2019) 28 | EGFR-mutant lung ADC | II | ≥1st | EGFR-TKI + metformin (1 g/d) | 69 | PFS | 71% | NA | 13.1 | 0.60 (0.40-0.94) P = 0.03 |
31.7 | 0.5 (0.28-0.90) P = 0.02 |
5 |
| EGFR-TKI | 70 | 54.3% | NA | 9.9 | 17.5 |
ADC, adenocarcinoma; EGFR, epidermal growth factor receptor; TKI, tyrosine kinase inhibitor; NSCLC, non-small-cell lung cancer; non-Sq, non-squamous; PC, pancreatic cancer; H(+), hormone positive; Her2(-), PEXG, cisplatin, epirubicin, capecitabine, and gemcitabine; AEs, adverse events; ORR, overall response rate; mOS, median overall survival; mPFS, median progression-free survival; mo, months; HR, hazard ratio; CI, confidence interval; NA, not available.
* Vomiting, †Nausea, ±Grade 3-4 neutropenia, ‡Arthralgia, ≠Grade 3-4 adverse events.