From: Metformin in colorectal cancer: molecular mechanism, preclinical and clinical aspects
Study population (Diabetic/Age/Gender/Stage) | Chemotherapy/Radiation/Surgery | Placebo/ Combined intervention/Drugs history | Dose & Duration of Treatment | HR /RR/Survival | Primary endpoint/secondary analysis | Life quality/Side-effects | Summary findings |
---|---|---|---|---|---|---|---|
Non-diabetic,151 patients 79 metformin, 72 placebo Randomized phase 3 trial single or multiple colorectal adenomas or polyps resected by endoscopy87 | All had history of resection | i. Placebo controlled ii. Colonoscopies after one year treatment (71 metformin & 62 placebo) | 250 mg/day for one year | i. Total polyps RR 0·67, 95% CI 0·47–0·97 ii. Adenomas RR 0·60, 95% CI 0·39–0·92 | i. Total polyps Metformin vs Placebo 38% vs 56.5% ii. Total adenomas Metformin vs Placebo 30.6% vs 51.6% | 11% side effects grade 1 No serious adverse effects | Low-dose metformin reduced metachronous adenomas or polyps after polypectomy |
Diabetic and non-diabetic 50 patients with refractory metastatic CRC Age above 18 year-old (mean – 57 year-old)92 | All were treated with chemotherapy and radiotherapy prior to study entry | 5-fluorouracil (5-FU) Leucovorin | i. Metformin – 850 mg orally 2 times/day ii. 5-FU 425 mg/m2 iii. Leucovorin – 50 mg by I.V. Treatment were given for 28 days/cycle until patients death | Not mentioned | i. Disease control rate (DCR) at 8 weeks from staring of study ii. Progression-free survival (PFS), OS, and toxicity | Diarrhea, nausea, vomiting, and myelotoxicity | i. Treatment - median PFS of 1.8 months and OS of 7.9 months ii. 22% met primary end-point – median PFS of 5.6 months and OS of 16.2 months iii. Prolonged survival for obese and 5-FU off patients |
482 patients (422 non-diabetic, 40 diabetic non-metformin, 20 diabetic metformin) with locally advanced rectal adenocarcinoma Age median is 58 to 63 year-old70 | All were treated with chemotherapy, total mesorectal excision (TME) and radiotherapy prior to study entry | 5-fluorouracil-based chemotherapy (98%) followed by adjuvant chemotherapy (81.3%) 15% insulin use in both diabetic merformin and non-metformin group | Not mentioned | Not mentioned | Pathologic complete response (pCR) | Not mentioned | i. Patients taking metformin had significantly increased disease-free (P = 0.013) and overall survival (P = 0.008) ii. Patients taking metformin had a significantly higher rate of pCR than either nondiabetics or diabetics non-metformin |
86 diabetic CRC underwent resection 36 – metformin 50 – non user Age 29–88 years45 | All had history of resection 37 – neither chemotherapy nor radiation history | 5-fluorouracil (5-FU) | Not mentioned | Not mentioned | Metformin vs non-users i. incidence of metastasis 5.60% vs 21.6%, ii. CD133 expression 21.1% vs 50% iii. β-catenin expression 36.85 vs 72.2% iv. Poorly differentiated adenoma 2.78% vs 16.0% | Not mentioned | Metformin synergize 5-FU in reducing risk of poorly differentiated adenoma and metastasis incidence |
240 diabetic without CRC history Age, metformin 58.8 ± 9.9 non user 61.6 ± 10.390 | No | i. Aspirin ii. NSAIDs iii. Sulfonylurea | Not mentioned | Metformin - Advanced adenoma RR 0.071 | Colorectal adenocarcinoma – size, occurrence, number | Not mentioned | Metformin lower the risk of advanced CRC Adenomas in newly diagnosed patients |
2088 cases (66–80 years) and 9060 control (61–77 years) January 2000 – December 200977 | YES | i. Aspirin ii. NSAIDs iii. Sulfonylurea | Cumulative 2000 g (DDD) within 5 years | i. Reduced risk of CRC OR 0.83, 95% CI 0.68–1.00 ii. Protective in women vs men (OR 0.66, 95% CI 0.49–0.90) vs (OR 0.96, 95% CI 0.75–1.23) | Not mentioned | Not mentioned | Dose and duration response - reduced risk of CRC metformin > 250 DDD and > 1 year Protective effect of long-term metformin against CRC in women |
424 patients January 2004 – December 2008108 | YES | i. Insulin ii. ADDs iii. Anti-cholesterol iv. Aspirin | Dose not mentioned, duration between 2005 and 2008 | i. Metformin vs Non user − 76.9 vs 56.9 months (CI 61.4–102.4) vs CI 44.8–68.8) ii. 30% enhancement in overall survival (OS) | HbA1c level | Not mentioned | Metformin provided 30% improvement in OS as compared to other ADDs |
2066 postmenopausal Women, 50–79 years 1854 non-diabetic 84 diabetic(+metformin) 128 diabetic(−metformin)105 | YES | i. Insulin ii. Aspirin iii. NSAIDs | Median 4.1 years (3 days - 14.4 years) | i. Diabetic Metformin vs Non user - Non-significant (HR 0.78, 95% CI 0.38–1.55) ii. overall survival (HR 0.86, 95% CI 0.49–1.52) | i. Tumor size ii. Positive lymph nodes | Not mentioned | Non-significant difference specific survival in metformin compared to non-users |
315 patients with stage I–III colorectal cancer from 2001 to 200677 | YES | i. 52% - Metformin + sulfonylurea ii. 72% -non metformin + sulfonylurea iii. Insulin iv. Other ADDs | Low and high intensity Duration - none | Low intensity HR 0.81, 95% CI 0.41–1.58 High intensity HR 0.44, 95% CI 0.20–0.95 | Tumor grade/Size - Nonsignificant between metformin and non-users | Not mentioned | High-intensity metformin dosing reduced CRC-specific mortality |
A) i. 856 patients with CRC from 2003 to 2005 ii. Age: men and women < 40 years B) i. 814 patients with CRC from 2003 to 2005 ii. Age: men and women > 40 years C). Diabetes status: ≥ 1 year and ≥ 3 years76 | YES | None | i. <  1 year ii. 1–3 years iii. ≥ 3 years | <  40 years i. <  1 year - 0.876 ii. 1–3 years - 0.859 iii. ≥ 3 years - 0.643 > 40 years i. <  1 year - 0.896 ii. 1–3 years - 0.843 iii. ≥ 3 years - 0.646 | none | Reduced incidence of COPD in metformin users compared to non-users | Significantly lower risk CRC by 27% Longer use of metformin inversely proportional to CRC |
3775 underwent colonoscopy (May 2001 - March 2013) 912 with metformin 2193 non users Age > 40 years88 | Colonoscopy | Not mentioned | i. <  1 year ii. 1–2 years iii. 2–3 years iv. ≥ 3 years | Not mentioned | i. Colorectal polyp - metformin vs non users (39.4% vs 62.4%) ii. adenoma - metformin vs non users (15.2% vs 20.5%) iii. Advanced adenoma - metformin vs non users (12.2% vs 22%) | Not mentioned | Metformin is beneficial in prevention of CRC |
106 patients with stage IV CRC83 | 81chemotherapy 25 curative resection | Not mentioned | Not mentioned | Metformin improved free survival rate for curative group (HR0.024,95% CI0.001–0.435) | i. tumor response, ii. target lesion size Chemotherapy – non-significant | Lower recurrence incidence | Metformin reduced tumor recurrence after curative resection |
8046 patient 2682 case group 5364 control group (60% male & 40% female each group) Age mean 55 and 5772 | YES | i. statins ii. insulin iii. Sulfonylurea iv. NSAIDs v.Thiazolidinedione vi. Health care adjustment | i. Intake mean and median duration − 218 days and 240 days ii. Daily dose mean and median metformin − 1500 mg | i. Multivariate model, any metformin use - 15% reduced odds of CRC (AOR 0.85, 95% CI, 0.760.95) ii. Adjustment health care + metformin - 12% reduced odds of CRC (AOR 0.88, 95% CI 0.77–1.00) | Not mentioned | Not mentioned | No significant association with metformin dose, duration, or total exposure |
920 diabetic patients with CRC Age 70.2 ± 8.6 years 63.3% male, 36.7% female120 | YES | i. statins ii. insulin iii. Sulfonylurea iv. NSAIDs | Not mentioned | i. Extensive use –increased CRC risk, OR 1.43, 95% CI 1.08–1.90 ii. Significant increased risk in men, OR 1.81, 95% CI: 1.25–2.62 Ko0l | Not mentioned | Not mentioned | Extensive metformin intake increased risk of CRC |
i. 675 with Type 2 DM from 1999 to 2009 ii. Age: 5 patients < 50, 269 patients between 50 and 69 and 401 patients above 70 iii. 437 males and 238 females iv. Stage I – IV of CRC119 | Within the first 6 months of exposure | i. 6 months within CRC diagnosis - 88.7% surgery 28% chemotherapy 15% radiotherapy ii.63.1% sulfonylureas iii. 23.1% insulin | Metformin used after CRC diagnosis; Follow up – i. 6 months after diagnosis until death ii. within 5 years up to 14 years | i. HR 1.06, 95% CI 0.80, 1.40 ii. | i. cancer-specific mortality ii. HbA1C levels | Lesser incidence of congestive heart disease, myocardial infarction and peripheral vascular disease | No protective association between metformin use and CRC mortality |