Table 3 The summarization of metformin clinical use for CRC

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