Metformin administration in prevention of colorectal polyps in type 2 diabetes mellitus patients

Abstract

BACKGROUND

Colorectal polyps are frequently observed in patients with type 2 diabetes mellitus (DM), posing a significant risk for colorectal cancer. Metformin, a widely prescribed biguanidine drug for type 2 DM, has been suggested to have potential chemoprophylactic effects against various cancers.

AIM

To explore the correlation between colorectal polyps and metformin use in type 2 DM patients.

METHODS

Type 2 DM patients were categorized into polyp and non-polyp groups. Following this, all patients were categorized into the type 2 DM-metformin, type 2 DM-non-metformin, and non-type 2 DM groups. Based on the baseline colonoscopy results, we performed pairwise comparisons of the incidence of colorectal polyps among the three groups. Additionally, we analyzed the relationship between colorectal polyps and the duration of metformin use and between the size and number of polyps and metformin use. Simultaneously, we focused on the specific pathological types of polyps and analyzed their relationship with metformin use. Finally, we compared the incidence of polyps between metformin and non-metformin groups according to the interval colonoscopy results.

RESULTS

The rate of metformin use in patients with colorectal polyps was 0.502 times that of patients without colorectal polyps [odds ratio (OR) = 0.502, 95% confidence interval (CI): 0.365-0.689; P < 0.001]. The incidence of colorectal polyps did not differ significantly between the type 2 DM-metformin and non-type 2 DM groups (P > 0.05). Furthermore, the correlations between the duration of metformin use and the incidence of colorectal polyps and between the size and number of polyps and metformin use were not statistically significant (P > 0.05). Metformin use did not affect the incidence of colorectal polyps during interval colonoscopy (P > 0.05).

CONCLUSION

Metformin use and colorectal polyp incidence in type 2 DM patients showed a negative correlation, independent of the hypoglycemic effect of metformin.

Key Words: Colorectal cancer, Colorectal polyps, Biguanidine drug, Diabetes mellitus, Metformin

Core Tip: Studies have shown that oral metformin can safely and effectively reduce the incidence of colorectal adenomas. There is also literature suggesting that metformin has potential efficacy in preventing the development of colonic polyps in patients with acromegaly.

INTRODUCTION

Colorectal cancer is the third most prevalent type of cancer and the fourth most common cause of cancer-related mortality in the world, following lung, liver, and gastric cancers, and it is responsible for nearly 700000 deaths annually[1]. The incidence and mortality of colorectal cancer have shown a consistent rise recently in China[2], partly due to the large number of people adopting a Western diet and lifestyle. According to the classical colorectal cancer formation model, colorectal polyps are precursors of most colorectal cancers[3]. This evolution is driven by the accumulation of DNA mutations and epigenetic alterations. Most colorectal cancers develop from a polyp with an aberrant crypt, evolving into an early adenoma, gradually progressing to an advanced adenoma, and finally developing into colorectal cancer[4]. Therefore, the early identification of colorectal polyps is crucial, especially for endoscopic evaluation[5]. However, the patient awareness of regular follow-up is often weak, which delays the optimal time for diagnosis and treatment of colorectal cancer. Therefore, there is an urgent need to develop effective preventive strategies, such as pharmacological prophylaxis. Metformin is a safe, widely used, cheap biguanidine drug, which has been in use for almost a century and is currently among the most commonly used medications for treating type 2 diabetes mellitus (DM)[6]. Different uses of metformin have been identified over time, and the most important of them is cancer prevention, including breast cancer, colorectal cancer, bone cancer, melanoma, and endometrial cancer[7]. However, evidence on whether metformin can prevent the occurrence of colorectal polyps remains unclear.

Studies have shown that oral metformin can reduce the incidence of colorectal adenomas safely and effectively[8-10]. Moreover, the literature suggests that metformin has potential efficacy in stopping the progression of colonic polyps in patients with acromegaly[11,12]. However, whether metformin can reduce colorectal polyp incidence in a larger population has not been elucidated[13-15].

MATERIALS AND METHODS

Study design and participants

This single-center study was conducted at Peking University People's Hospital in Beijing. We enrolled patients hospitalized in the Geriatrics Department of Peking University from May 2018 to March 2022 who fulfilled the inclusion criteria. The type 2 DM group included patients aged > 18 years who were diagnosed with type 2 DM based on the Chinese Guideline for the Prevention and Treatment of type 2 Diabetes Mellitus (2020 edition)[16] and the American Diabetes Association 2020 criteria[17], those using standard doses of glucose-lowering agents for > 6 mo, and those who had undergone electronic colonoscopy with related pathological findings during hospitalization. The non-type 2 DM group included patients aged > 18 years who were hospitalized in the same period without previous history of type 2 or other types of DM and those who had undergone electronic colonoscopy with related pathological findings during hospitalization. We excluded patients with a history of intestinal surgery, family adenomatous polyps, inflammatory bowel disease, hereditary nonpolyposis colorectal cancer, or non-intestinal malignant tumors; those with a history of cardiac dysfunction, renal insufficiency, liver cirrhosis, or chronic liver failure; those with a long-term history of consuming non-steroidal anti-inflammatory drugs; and those with incomplete data. This study was reviewed and approved by the Ethics Review Committee of Peking University People's Hospital (Approval No. 2021B012-00). All study participants provide informed written consent prior to study registration.

Data collection

Demographic data, specifically height, weight, age, and sex, were collected. Body mass index (BMI) was calculated as “weight (kg)/height² (m²)”[18]. Body surface area was calculated as “0.0057 × height (cm) + 0.0121 × weight (kg) + 0.0082” for males and “0.0073 × height (cm) + 0.0127 × weight (kg) − 0.2106” for females[19]. Hypertension, coronary artery disease, fatty liver, atherosclerosis, aspirin use, statin use, alcohol consumption, and smoking were recorded according to the medical history.

We used an automatic biochemical analyzer to evaluate routine blood tests, blood glucose metabolism, and other biochemical indicators including liver enzymes, such as aspartate aminotransferase and alanine aminotransferase, and other markers, such as total serum protein, serum uric acid, serum albumin, serum creatinine (Cr), total cholesterol, triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C). Simultaneously, we recorded the urinary microalbumin/creatinine ratio (urinary ACR), estimated glomerular filtration rate (eGFR), glycosylated hemoglobin (HbA1c), and C-reactive protein and calculated the Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) score as “fasting insulin (mU/L) × fasting plasma glucose (mmol/L)/22.5”[20]. The patients were examined using ACUSON SC-2000 full digital color Doppler echocardiography. Furthermore, we obtained the ejection fraction (EF) and the ratio of the mitral valve's maximum flow velocity in the early diastole of the left ventricle to the maximum flow velocity of the systolic mitral valve in the left atrium (E/A ratio).

We adopted various methods to clarify the metformin use in patients, including collecting data regarding history of present illness and past illness from the admission records, tracking the patient’s drug use from the outpatient prescription records in the Clinical Data Repository, and conducting telephone follow-up for some patients. Thus, we tried to ensure that the data of this retrospective case-control study was as authentic and reliable as possible.

Olympus electronic colonoscopy was conducted to detect colorectal polyps and exclude other intersectional lesions. Patients were required to refrain from eating high-cellulose vegetables and fruits 1–2 d before the examination and consume one packet of polyethylene glycol electrolyte powder (III) with 2000–3000 mL of lukewarm water within 2 hours at 19:00 the previous day and at 5:00 and 7:00 next day morning. We asked patients if they passed water-like stools and then decided whether to perform the drug enema. To ensure the quality of endoscopic examination, each endoscopic examination and operation was performed by an experienced gastroenterologist accompanied by at least one associate director physician or director physician, and every endoscopic report was written and reviewed by the two doctors. We consulted the endoscopic reports of patients and recorded in detail the presence or absence of polyps and their size, number, location, and pathological type. Usually, endoscopic doctors instruct patients with colorectal polyps to undergo re-examination after 1 year. We screened out patients who were re-examined at our hospital (median interval, 1 year) and analyzed the association between metformin use and the incidence of colorectal polyps during interval colonoscopy (n = 39).

Overview

In the first part of our study, the type 2 DM group patients were further categorized into the colorectal polyp group and non-colorectal polyp group based on the electronic colonoscopy observations. In the second part, the type 2 DM group patients were further categorized into the metformin group and non-metformin group based on the use of glucose-lowering agents (Figure 1).

Figure 1 Study flow chart. DM: Diabetes mellitus.

Of 568 patients in our study, 16 had a history of intestinal surgery or non-intestinal malignant tumors; 5 had a history of family adenomatous polyps, hereditary nonpolyposis colorectal cancer, or inflammatory bowel disease; 31 had a history of cardiac dysfunction, renal insufficiency, liver cirrhosis, or chronic liver failure; 3 had a long-term history of taking non-steroidal anti-inflammatory drugs; and 11 had incomplete data. Finally, 233 patients were included in the type 2 DM group and 269 in the non-type 2 DM group.

Statistical analysis

Statistical Product and Service Solutions 26.0 software package (IBM) was used for data analyses. Normally distributed data from assays conducted in triplicate are presented as means ± SD. Analysis of variance or t-tests (independent sample) were applied for inter-group comparisons of the variables. Non-normally distributed data are presented as medians (P25–P75). These data were compared using a non-parametric test. Meanwhile, categorical variables were statistically analyzed using the chi-square test. Confounding variables were determined by employing univariate logistic regression. A binary logistic regression model (backward: Likelihood Ratio method) was employed to analyze the correlation between colorectal polyps and metformin use among type 2 DM patients. P-values < 0.05 were considered statistically significant.

RESULTS

Patient characteristics

After applying the inclusion and exclusion criteria, 502 patients were included, with 233 and 269 patients in the type 2 DM and non-type 2 DM groups, respectively (Figure 1). The proportion of men was greater in the polyp group than in the non-polyp group (63.1% vs 45.7%), with a statistically significant difference (P < 0.05). The mean age was significantly greater in the polyp group than in the non-polyp group (P < 0.05). Notably, the BMI did not vary significantly between the polyp and non-polyp groups (Table 1).

Table 1 Comparison of the demographic characteristics of type 2 diabetes mellitus patients with and without colorectal polyps.

Characteristic	Polyp group	Non-polyp group	t-value/chi-square value	P value
Sex
Male	89 (63.10)	42 (45.70)
Female	52 (36.90)	50 (54.30)	7.772	0.005a
Age in yr	67.62 ± 10.33	64.57 ± 9.76	2.252	0.025a
BMI in kg/m2	25.43 ± 3.12	25.29 ± 3.50	-0.322	0.748
BSA in m2	1.79 ± 0.20	1.75 ± 0.17	1.372	0.172

^aP < 0.05.

Data are presented as n (%) or mean ± standard deviation.

BMI: Body mass index; BSA: Body surface area.

Complications, medications, and personal history

The proportion of patients with high blood pressure was higher in the polyp group than in the non-polyp group (66.67% vs 53.26%). Nevertheless, these differences were not statistically significant (P > 0.05). The incidence of atherosclerosis was significantly greater in the polyp group than in the non-polyp group (78.01% vs 70.65%; P < 0.01). The complications of coronary artery disease (P = 0.209) and fatty liver disease (P = 0.569) did not differ significantly between the two groups. Moreover, the use of aspirin and statins and the history of smoking and drinking did not differ significantly between the polyp and non-polyp groups (P > 0.05) (Table 2 and Figure 2).

Figure 2 Comparison of the complications, drug history, and history of smoking and drinking between type 2 diabetes mellitus patients with and without colorectal polyps. CAD: Coronary artery disease.

Table 2 Comparison of the complications, drug history, and history of smoking and drinking between type 2 diabetes mellitus patients with and without colorectal polyps.

Parameter	Polyp group	Non-polyp group	Chi-square value	P value
High blood pressure	94 (66.67)	49 (53.26)	4.421	0.054
CAD	36 (25.53)	17 (18.48)	1.576	0.209
Fatty liver	74 (52.48)	45 (48.91)	0.324	0.569
Atherosclerosis	110 (78.01)	65 (70.65)	2.833	0.002a
Aspirin use	36 (25.53)	18 (19.57)	1.113	0.291
Statin use	88 (62.41)	59 (64.13)	0.071	0.790
Smoking	59 (41.84)	29 (31.52)	2.524	0.112
Drinking	49 (34.75)	29 (31.52)	0.261	0.610

^aP < 0.05. CAD: Coronary artery disease.

Serological data and cardiac function

The Cr levels were significantly higher in the polyp group than in the non-polyp group (P = 0.033). Furthermore, the eGFR was significantly lower and the urinary ACR was significantly higher in the polyp group than in the non-polyp group (P = 0.002 and 0.016, respectively). Differences in other serological data were not statistically significant between the two groups (P > 0.05). Glucose metabolism markers did not differ significantly between the polyp and non-polyp groups (HbA1c, P = 0.328; HOMA-IR, P = 0.845). Additionally, the EF (P = 0.919) and E/A ratio (P > 0.614) did not differ significantly between the polyp and non-polyp groups (Table 3).

Table 3 Comparison of the serological and biochemistry data and indexes of cardiac function between type 2 diabetes mellitus patients with and without colorectal polyps.

Parameter	Polyp group	Non-polyp group	t/chi-square/Z-value	P value
ALT in U/L	17.00 (12.25, 24.00)	18.00 (13.00, 26.00)	−0.558	0.577
AST in U/L	18.00 (15.00, 22.00)	18.00 (15.00, 22.00)	−0.009	0.993
TP in g/L	66.60 (61.75, 70.65)	66.20 (63.40, 71.10)	−0.715	0.475
Alb in g/L	40.47 ± 4.75	41.15 ± 3.52	1.181	0.239
UA in µmol/L	359.88 ± 100.63	348.97 ± 90.37	0.843	0.400
Cr in µmol/L	71.50 (59.00, 82.75)	65.00 (57.00, 76.00)	−2.132	0.033a
TC in mmol/L	4.16 (3.51, 4.84)	4.23 (3.54, 4.70)	−0.451	0.652
TG in mmol/L	1.56 (1.14, 2.09)	1.52 (1.01, 2.22)	−0.004	0.997
HDL-C in mmol/L	1.09 ± 0.29	1.16 ± 0.25	1.869	0.063
LDL-C in mmol/L	2.63 ± 0.81	2.45 ± 0.76	1.682	0.094
eGFR in mL/min × 1.73 m2	88.23 (75.79, 97.76)	95.42 (81.07, 101.79)	−3.171	0.002a
Urinary ACR in mg/g	7.48 (3.11, 21.47)	5.52 (3.34, 11.79)	−2.410	0.016a
Ejection fraction in %	68.40 (64.45, 72.50)	68.30 (64.70, 73.45)	−0.102	0.919
E/A ratio	0.76 (0.64, 0.94)	0.79 (0.65, 0.93)	−0.504	0.614
CRP in mg/L	0.80 (0.50, 1.87)	0.70 (0.50, 1.90)	−0.394	0.693
HbA1C in %	6.80 (6.10, 7.50)	6.80 (6.48, 7.40)	−0.978	0.328
HOMA-IR score	2.64 (1.53, 4.08)	2.69 (1.70, 4.12)	−0.196	0.845

^aP < 0.05.

Data are presented as medians (P25, P75) or mean ± standard deviation.

Alb: Serum albumin; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; Cr: Serum creatinine; CRP: C-reactive protein; E/A ratio: Ratio of the maximum flow velocity of mitral valve in the early diastole of the left ventricle to that of the systolic mitral valve in the left atrium; eGFR: estimated Glomerular filtration rate; HbA1c: Glycosylated hemoglobin; HDL-C: High-density lipoprotein cholesterol; HOMA-IR: Homeostatic model assessment for insulin resistance; LDL-C: Low-density lipoprotein cholesterol; TC: Total cholesterol; TG: Triglyceride; TP: Serum total protein; UA: Serum uric acid; urinary ACR: Urinary microalbumin/creatinine ratio.

Metformin and colorectal polyps

The factors with P-value < 0.1 were analyzed as confounding factors. Finally, sex, age, high blood pressure, atherosclerosis, Cr, HDL-C, LDL-C, eGFR, and urinary ACR were included as confounding factors in the multivariate logistic regression analysis. Metformin use remained independently correlated with colorectal polyps [odds ratio (OR) = 0.505, 95% confidence interval (CI): 0.367–0.694; P < 0.001] after adjusting for all confounding factors. Moreover, age (P < 0.05) and LDL-C (P < 0.05) independently predicted the risk for colorectal polyps (Table 4 and Figure 3).

Figure 3 Multivariate logistic regression analysis of colorectal polyps. LDL-C: Low-density lipoprotein cholesterol.

Table 4 Multivariate logistic regression analysis of colorectal polyps.

Parameter	Odds ratio	95% Confidence interval	P value
Metformin	0.502	(0.365–0.689)	< 0.001a
Age	1.033	(1.004–1.061)	0.023a
LDL-C	1.440	(1.007–2.060)	0.046a

^aP < 0.05. LDL-C: Low-density lipoprotein cholesterol.

Bonferroni correction was performed to assess and compare the incidence of colorectal polyps in the type 2 DM-metformin group, type 2 DM-non-metformin group, and non-type 2 DM group. The incidence of polyps was significantly lower in the type 2 DM-metformin group than in the type 2 DM-non-metformin group (P < 0.001). As expected, the incidence of colorectal polyps did not vary significantly between the type 2 DM-metformin and non-type 2 DM groups (P > 0.05) (Table 5).

Table 5 Comparison of colorectal polyps among the groups.

Parameter	Patients with polyps	Patients without polyps	Chi-square test (Bonferroni correction)
			Chi-square value	P value
Type 2 DM-metformin Group	44 (40.70)	64 (59.30)1,2
Type 2 DM-non-metformin group	97 (77.60)	28 (22.40)	57.046	< 0.001a
Non-type 2 DM group	102 (37.90)	167 (62.10)	0.196	0.658

^aP < 0.05.

¹Statistically significantly different from the non-metformin group.

²No significant differences were detected in the non-type 2 diabetes mellitus group. DM: Diabetes mellitus.

Data are presented as n (%).

We used the Mann–Whitney rank-sum test to assess the correlation between the duration of metformin use and the incidence of colorectal polyps in patients with type 2 DM. No significant difference was noted between the duration of metformin use and colorectal polyps (Z = −1.075, P = 0.282; Figure 4).

Figure 4 Comparison of the duration of metformin use between type 2 diabetes mellitus patients with and without colorectal polyps.

Additionally, we studied whether there were differences in the size and number of polyps between the metformin and non-metformin groups. Mann–Whitney rank-sum test was employed to analyze the statistical association between metformin use and polyp size in type 2 DM patients. No significant association was found between metformin use and polyp size (Z = −0.370, P = 0.711). The results of the correlation between metformin use and the number of polyps (Z = −0.768, P = 0.443) are shown in Figure 5.

Figure 5 Comparison of the size and number of polyps between patients with and without metformin use.

Based on the endoscopic results collected, the patients with adenoma as the pathology type were screened. We compared the correlation between metformin use and the occurrence of adenoma, including risk factors for the occurrence of adenoma (Figure 6).

Figure 6 Multivariate logistic regression analysis of adenoma. BMI: Body mass index.

As mentioned previously, metformin use correlated negatively with the incidence of colorectal polyps during baseline colonoscopy. However, this association did not exist during interval colonoscopy (P > 0.05; Figure 7).

Figure 7 Comparison of polyps between patients with and without metformin use during interval colonoscopy.

DISCUSSION

After adjusting for all confounding factors, we found that metformin use was independently correlated with the incidence of colorectal polyps in type 2 DM patients. Notably, the rate of metformin use in patients with colorectal polyps was 0.502 times that in patients without colorectal polyps (OR = 0.502, 95%CI: 0.365–0.689; P < 0.001). Moreover, the incidence of colorectal polyps in the type 2 DM-metformin and non-type 2 DM groups did not differ significantly (P > 0.05, Bonferroni correction). Particularly, the type 2 DM-non-metformin group excluded type 2 DM patients who did not use any glucose-lowering agents. Meanwhile, we included blood glucose-related indicators, glycosylated Hb1Ac, and HOMA-IR as confounding factors. Our results indicate that the negative correlation between colorectal polyps and metformin is independent of the hypoglycemic effect of metformin.

Cho et al[21] assessed the incidence of colonic polyps and adenomas in 3105 type 2 DM patients without a history of colorectal cancer and subjected to colonoscopy for the first time. The incidence of polyps and adenomas was significantly decreased in the metformin group, which corroborates the findings of this study. Krigel et al[22] reported a negative association between metformin use and the incidence of colorectal adenomas during baseline colonoscopy after a 4.5-year follow-up period. However, the history of the use of glucose-lowering agents in the non-metformin group in these studies was unclear, and they did not include patients without type 2 DM for comparison. Type 2 DM patients who did not use glucose-lowering agents (such as those who controlled blood glucose only by lifestyle adjustment) were excluded. Therefore, the effect of metformin on colorectal polyps, in addition to controlling blood glucose, can be further analyzed and compared with other glucose-lowering agents. Mansourian et al[14] included 11 studies (51991 patients) in a meta-analysis and found that metformin use correlated significantly and negatively with advanced adenoma risk (OR = 0.51; P < 0.001). However, total adenoma risk did not correlate significantly with metformin use (OR = 0.86; P = 0.274). Moreover, the risk of adenoma recurrence did not correlate significantly with metformin use (OR = 0.89, P = 0.137). The reason for the inconsistency between the findings of this meta-analysis and our study could be the different concerned groups and ages of the participants. For example, patients with type 2 DM were not categorized into those using metformin and other glucose-lowering agents.

Several published reports have demonstrated that type 2 DM patients are at great risk of colorectal polyps and colorectal cancer. This may be due to hyperinsulinemia caused by insulin resistance in patients with diabetes, resulting in enhanced levels of insulin-like growth factor-1, proliferation, and atypia of normal cells and cancer cells, which affects the occurrence of colorectal polyps and colorectal cancer[23]. Therefore, regular endoscopy is required to identify polyps early in type 2 DM patients and arrest the progression of colorectal cancer. Metformin is believed to reduce the incidence of colorectal tumors by several possible mechanisms as follows: (1) Metformin may follow the LKB1/AMPK-related pathway, mainly by inhibiting the mTOR signaling pathway to impede tumorigenesis[24,25]. It can also inhibit cell proliferation and protein synthesis by activating the p53 protein[26] and keeping the cell cycle at the G1 phase; (2) Reducing insulin levels: Insulin can promote mitosis; therefore, tumor cells often increase the expression of insulin receptors. Thus, the ability of metformin to reduce insulin levels plays a key role in its anticancer activity[27]; (3) By inhibiting unfolded protein reaction (UPR): UPR is a survival mechanism in solid tumor cells. Metformin can inhibit the activation of the UPR, leading to the death of many tumor cells[28]; and (4) Furthermore, the anticancer activity of metformin could be related to immune system activation and cancer stem cell elimination among others.

However, the mechanism of metformin in preventing colorectal polyps remains unclear. Although metformin has been confirmed to reduce the risk of colorectal cancer, the results of different studies on whether metformin can prevent colorectal polyps remain inconsistent and controversial.

Nonetheless, this study also found that advanced age and enhanced LDL-C levels were risk factors for colorectal polyps. A case-control study by Xie et al[29] showed that increased LDL-C and TG levels correlated with the occurrence of polyps, which corroborates our results. However, the specific mechanisms of action need to be explored.

Few studies have elucidated the correlation between metformin use and the incidence of colorectal polyps in China. Comprehensive clinical indicators were considered in this study with a relatively large sample size of inpatients. Metformin use is independently associated with colorectal polyps in type 2 DM patients. This study explored the potential efficacy of metformin in preventing the development of colorectal polyps in patients, which is of clinical significance and requires prospective studies to explore and confirm the protective effect of metformin in a wider population. Additionally, this may open up the prospect of future chemoprophylaxis with metformin in patients at an increased risk of colorectal cancer. Early intervention to delay progression may help prevent colorectal cancer development from colorectal polyps.

With the increase in the diameter of polyps, the degree of intraepithelial neoplasia is aggravated, significantly increasing the risk of cancer development. Moreover, multiple polyps are more likely to become cancerous than solitary polyps, which is a high-risk factor for carcinogenesis[30]. Therefore, in patients with multiple polyps, we chose the maximum diameter as the size of the polyps. We then analyzed the relationship between the number and size of polyps and metformin use but did not find a significant difference.

Colorectal polyps are classified as conventional adenomas and serrated lesions[31]. Almost 50%–70% of colorectal cancers arise from adenomatous polyps. It is generally believed that inflammatory polyps and proliferative polyps do not become cancerous[32]. Therefore, it is necessary to screen adenomatous polyps from all pathological types of polyps and analyze the association between their incidence and metformin use. The results showed that metformin (OR = 0.136, 95%CI: 0.071– 0.261; P < 0.001) is an independent risk factor for colorectal adenomatous polyps.

Our study examined the association between metformin use and colorectal polyps during baseline colonoscopy and interval colonoscopy, which differed from previous Asian studies. However, no significant difference between metformin use and the incidence of polyps was observed during interval colonoscopy (P > 0.05). Corroborating our results, a retrospective analysis of an average-risk cohort by Krigel et al[22] found that this inverse association between metformin use and colorectal polyps did not persist during interval colonoscopy. They believed that the relatively short follow-up period influenced the results[33]. Meanwhile, patients with continued metformin exposure may have been less responsive to metformin.

This study has some limitations. First, we included inpatients from our hospital whose characteristics may differ from those of the general population to some extent; therefore, a multicenter study is necessary to increase the outreach of the results. Second, since this was a cross-sectional study, it mainly depended on medical records, and the causal relationship between metformin use and colorectal polyps could not be determined; therefore, further prospective cohort studies are warranted. Third, the mechanism of action of metformin in colorectal polyps is not clear. However, this study cannot interpret their relationship regarding pathophysiological mechanisms. Further basic experiments are required to overcome the limitations of this study.

CONCLUSION

Metformin can decrease the risk of colorectal polyps in type 2 DM patients, independent of its hypoglycemic effect. Therefore, the correct early administration of metformin in these patients could be crucial in preventing the occurrence and development of colorectal polyps. Furthermore, a large-scale, prospective, randomized study including various confounding factors is warranted to prove the effectiveness of metformin in preventing colorectal polyps.