【Article Title】Efficacy and safety of calcium polycarbophil tablets in the treatment of diabetes mellitus complicated with chronic constipation

【Article author】Ma Dan, Tang Fengyan, Cui Hao, Zhang Li

【Journal Date】October 2024

【Published in】Practical Medicine and Clinical

【Magazine Type】Chinese Science and Technology Core Journal

【Research Institution】Department of Endocrinology, Kunshan First People's Hospital

Summary

01 Purpose

To evaluate the efficacy and safety of calcium polycarbophil tablets in the treatment of patients with diabetes and chronic constipation.

02 Method

A total of 48 patients with diabetes and chronic constipation recruited from the outpatient department of the Department of Endocrinology of Kunshan First People's Hospital from January 2022 to June 2023 were selected and treated with calcium polycarbophil tablets (1.0 g, tid, po) for 2 weeks. The number of spontaneous bowel movements (SBM), the number of completely spontaneous bowel movements (CSBM), the incidence of SBM within 24 h or 48 h after the first dose, and the average time to SBM after the first dose of calcium polycarbophil tablets per week were recorded; the Bristol Stool Shape Scale (BSFS) was used to evaluate stool characteristics, and the Chinese version of "Quality of Life Assessment for Patients with Constipation" (PAC-QOL) was used to evaluate the quality of life of patients; the main efficacy indicator was the change in the number of SBMs in the 2 weeks of the trial; the secondary efficacy indicators were the changes in patients' CSBM, stool shape, quality of life, and blood sugar.

03 Results

There were 48 eligible patients enrolled, and 46 completed the study. The median number of SBMs per week increased from 5.0 (3.0, 7.0) times at baseline to 6.0 (4.0, 7.0) times after 2 weeks of treatment. The number of SBMs increased significantly after 2 weeks of treatment with calcium polycarbophil tablets, and the difference was statistically significant (P<0.05). The average time for the first SBM to occur after taking calcium polycarbophil tablets weekly was 14 hours. The proportion of patients who experienced SBM within 24 hours and 48 hours after taking the first dose of calcium polycarbophil tablets was 80.2% and 95.8%, respectively. After 2 weeks of medication and 2 weeks after stopping medication, compared with baseline, BSFS and PAC-QOL scores increased significantly (P<0.05), and fasting blood glucose decreased significantly (P<0.05). Stratified analysis showed that patients with low baseline SBM had a significant increase in SBM and CSBM frequency after treatment, especially in women, the elderly, and those with BMI≤25. No adverse reactions beyond the drug instructions occurred in patients with 40 kg/m2, chronic constipation, and those not taking other laxatives.

04 Conclusion

Calcium polycarbophil tablets are effective and safe in the treatment of diabetes mellitus and chronic constipation, especially in patients with low baseline SBM frequency. Calcium polycarbophil tablets can also reduce fasting blood glucose after 2 weeks of treatment, which may become a new treatment option for patients with diabetes mellitus and chronic constipation.

Introduction

Diabetes is the third largest disease in the world after cardiovascular and cerebrovascular diseases and tumors. It is a metabolic disorder caused by insufficient secretion or blocked action of insulin in the body, which leads to continuous increase in blood sugar levels. Long-term high blood sugar levels in the body can lead to microvascular complications such as neuropathy, retinopathy and nephropathy. Constipation is the most common gastrointestinal symptom in patients with diabetes, and the prevalence of constipation in patients with diabetes is as high as 10% to 60%. Studies have shown that chronic constipation increases the total mortality rate and the incidence of cardiovascular events in the elderly population. Although the pathogenesis of chronic constipation in patients with diabetes is still unclear, existing studies believe that it may be related to neurodegeneration caused by apoptosis, oxidative stress, and decreased neuronal growth factor. In clinical practice, exercise and diet therapy are often used as the first choice for the treatment of chronic constipation, but the treatment effect is limited, and it is often necessary to rely on drugs for the next step of treatment.

At present, the commonly used drugs for treating chronic constipation in China include bulk, osmotic and irritant laxatives. Calcium polycarbophil (CP) is a bulk laxative, a hydrophilic polymer that improves stool characteristics by absorbing water and swelling in the intestine to form a hydrophilic gel, while regulating intestinal transit, thereby improving constipation. CP is not absorbed into the blood in the intestine, has few adverse reactions, and is especially suitable for elderly patients; no adverse reactions related to adverse pregnancy outcomes have been observed in women with constipation during pregnancy, and is safer than other types of laxatives. The Expert Consensus on the Evaluation and Treatment of Chronic Constipation in the Elderly (2017) recommends calcium polycarbophil as a treatment for diabetic patients with chronic constipation. Studies have shown that serum high-sensitivity C-reactive protein (CRP) is significantly reduced in patients with constipation-type irritable bowel syndrome (IBS) after treatment with calcium polycarbophil. CRP levels reflect the degree of systemic micro-inflammation in patients with diabetes and other diseases, and play an important role in diabetic microangiopathy. Lowering CRP levels in the body can significantly improve the prognosis of diabetic patients. There are currently no studies on the clinical efficacy and safety of calcium polycarbophil in patients with diabetes and constipation. Therefore, this study explored the efficacy and safety of calcium polycarbophil tablets in the treatment of diabetes and chronic constipation, and evaluated the effect of calcium polycarbophil tablets on blood glucose levels in the body.

Materials and Methods

01Study design and patient selection

This study is a 2-week prospective, single-arm, single-center study. The sample size was calculated based on the references. It is planned to recruit 48 patients with diabetes and chronic constipation who visited the endocrinology department of Kunshan First People's Hospital from January 2022 to June 2023 as subjects.

02 Subject inclusion criteria

① Age ≥ 18 years old;

② Meet the diagnostic criteria in the "Chinese Expert Consensus on Diagnosis and Classification of Diabetes (2022 Edition)";

③ Combined constipation: the diagnosis of constipation meets the definition of chronic functional constipation according to the Rome IV criteria, that is, the subjective symptoms have existed for 6 months, and in the past 3 months, at least 2 of the following 6 criteria are met: spontaneous bowel movement (SBM) less than 3 times per week, at least 25% of the stools are dry and hard, at least 25% of the stools have a sense of incomplete bowel movement, at least 25% of the anorectal blockage, at least 25% of the bowel movements require manual defecation, and at least 25% of the bowel movements are time-consuming.

03Exclusion criteria

① History of CP allergy;

② Confirmed or suspected intestinal obstruction caused by tumor, hernia, etc.;

③ Severe liver function abnormalities [such as alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) levels more than 3 times the upper limit of the normal range)];

④ Difficulty swallowing;

⑤ Suspected organic constipation;

⑥ Women who are pregnant, planning to become pregnant, or breastfeeding;

⑦ Change in glycosylated hemoglobin (HbA1c) ≥ 0.5% in the 12 weeks before recruitment;

⑧ History of hospitalization due to poor blood sugar control in the past 6 months.

This trial was approved by the Medical Ethics Committee of Kunshan First People's Hospital (No. 2021047) and complied with the ethical guidelines of the revised Declaration of Helsinki, and all patients signed informed consent.

04Treatment methods

To avoid the impact of active treatment on this trial, all subjects need to undergo a 12-week run-in period, maintain the original treatment regimen, and measure the baseline value at week 12. During the study phase, all drug treatment regimens during the baseline period were maintained, and polycarbophil calcium tablets (trade name: Libofei, Suzhou Chung-Hwa Chemical & Pharmaceutical Industrial Co., Ltd., national medicine standard: H20110109) were given at the same time, 2 tablets (1.0 g) each time, 3 times a day, at least 250 ml of water after meals, for 2 consecutive weeks, and followed up for 2 weeks after drug withdrawal. Subjects used a bowel diary to record the stool condition after each bowel movement, whether there was a feeling of uncompleted stool after bowel movement, bowel movement time, daily polycarbophil calcium tablets taking time and dosage. The bowel diary was reviewed at the beginning of treatment and in the first week, second week, and 2 weeks after the end of treatment.

05Efficacy indicators

The main efficacy measure was the change in SBM from baseline to week 2 of the trial. SBM was defined as bowel movements that could be achieved without medication or other auxiliary means, counted in weeks.

The main supplementary efficacy indicators were: the incidence of the first SBM within 24 h or 48 h after the first medication, and the time required for the first SBM after weekly medication.

Secondary efficacy indicators:

① Change in the number of completely spontaneous bowel movements (CSBM) per week: the change in the number of CSBMs from baseline to 2 weeks after the end of the trial. CSBM refers to SBMs without a sense of incomplete defecation, which are counted in weeks.

② Bristol stool form: The Bristol stool form scale (BSFS) is used to assess stool properties and consistency. BSFS divides stool form into 7 levels, with 1-2 indicating constipation, 3-4 indicating normal, and 5-7 indicating mild, moderate, and severe loose stools. 1-7 scores are 1-7 points respectively.

③ Patients’ quality of life with constipation: The Chinese version of the Patients with Constipation Quality of Life Scale (PAC-QOL) was used to assess patients’ quality of life with constipation. PAC-QOL includes 4 aspects: physiology, social psychology, worry, and satisfaction, with a total of 28 items. The higher the score, the lower the quality of life.

④ Changes in blood sugar in patients: Blood sugar indicators include changes in fasting blood glucose (FPG), glycosylated hemoglobin (HbA1c), and glycosylated albumin (GA) levels from baseline to the end of treatment.

⑤ Safety indicators: During the entire trial, medical staff will record adverse drug reaction events and evaluate their type, incidence, severity and causal relationship with the drug.

⑥ Statistical analysis: The full analysis set (FAS) includes all subjects who were randomly enrolled, received at least one medication, and had at least one visit record. The full analysis data set was used for intention-to-treat (ITT) analysis. The per protocol set (PPS) includes a collection of cases that meet the inclusion criteria, have no missing values for baseline variables, and complete the treatment regimen, that is, the cases that meet the trial protocol, have good compliance, and complete the case report form as required are analyzed. The safety data set (SS) includes all subjects who received at least one treatment after randomization and had at least one safety assessment. SPSS 26.0 software was used to analyze the full text data, and the Shapiro-Wilk test was used for normality of the data. Data that conform to the normal distribution are expressed as mean ± standard deviation, and data that do not conform to the normal distribution are expressed as median (quartile). Paired t-test and Wilcoxon signed rank test were used to evaluate the changes in relevant indicators before and after medication. Bilateral P < 0.05 was considered statistically significant. A stratified exploratory analysis was performed based on age, gender, body mass index (BMI), duration of diabetes, and whether other laxatives were used concurrently.

Result

01 Basic information of subjects 64 patients participated in this study, and 14 patients did not meet the inclusion criteria and were excluded. 2 patients withdrew from the study after signing the informed consent and randomization, and finally 48 patients were included for FAS and SS analysis. During the study, 2 patients did not take polycarbophil calcium tablets as prescribed and forgot to take them, and the date deviated from the original treatment plan. Only 46 patients were analyzed according to PPS. FAS and PPS were used to analyze the main efficacy indicators, SS was used to analyze the safety indicators, and PPS was used to describe other indicators. The analysis subject screening flow chart is shown in Figure 1.

The general data of the subjects included 29 females, aged (57.4±10.7) years, BMI (25.6±4.0) kg/m2, and duration of diabetes (13.2±8.4) years. There were 42 cases of type 2 diabetes and 4 cases of type 1 diabetes. The fasting blood glucose was (8.1±1.7) mmol/L, HbA1c and GA were 7.4%±1.2% and 18.9%±4.5%, respectively. Twelve subjects (26.1%) used other laxatives.

02 Evaluation of main efficacy indicators

FAS analysis showed that the number of SBMs increased from 5.0 (3.0, 7.0) times at baseline to 6.0 (4.0, 7.0) times at 2 weeks, and the difference was statistically significant (P<0.05). PPS analysis showed that the number of SBMs increased from 5.0 (3.0, 7.0) times at baseline to 6.0 (4.0, 7.0) times at 2 weeks, and the difference was statistically significant (P<0.05).

03 Evaluation of primary efficacy supplementary indicators and secondary efficacy indicators

① Effect of CP on SBM and CSBM: After CP treatment, the weekly frequency of SBM and CSBM did not increase significantly in the first week, but was higher than the baseline in the second week and 2 weeks after drug withdrawal, with statistically significant differences (P<0.05) (see Table 1). The average time to the first occurrence of SBM after taking CP weekly was (14±3.9) hours. During the trial, the proportion of patients who had their first SBM within 24 hours and 48 hours after taking CP for the first time was 80.2% and 95.8%, respectively.

② Effect of CP on BSFS and PAC-QOL scores: Compared with the baseline, the BSFS score did not change much in the first week of treatment, and the difference was not statistically significant (P>0.05); it increased significantly in the second week, and the difference was statistically significant (P<0.01), and the stool characteristics returned to normal; 2 weeks after CP was discontinued, the BSFS score was still higher than the baseline, and the difference was statistically significant (P<0.05). Compared with the baseline, the PAC-QOL score did not change significantly in the first week of treatment (P>0.05), and the psychological state, satisfaction, and total score were significantly reduced in the second week after treatment, and the difference was statistically significant (P<0.05). After 2 weeks of CP discontinuation, the total score of PAC-QOL was still lower than the baseline, and the difference was statistically significant (P<0.05). See Table 2.

③ Effect of CP on blood sugar: In the second week of CP treatment, FPG level decreased significantly, and the difference was statistically significant (P<0.05); GA showed a slight downward trend, but there was no statistically significant difference between HbA1c and GA after the first and second weeks of treatment and FPG in the first week compared with the baseline (P>0.05). See Table 3.

04 Subgroup stratification analysis

After stratification by gender (male, female), age (≤60 years, >60 years), BMI (≤25 kg/m2, >25 kg/m2), average duration of disease (≤10 years, >10 years), and combination of other laxatives (yes, no), correlation analysis between indicators was performed. The results showed that compared with the baseline, the BSFS after 2 weeks of treatment was statistically significant in all subgroups (P<0.05); after 2 weeks of treatment, the SBM, CSBM, and PAC-QOL total scores of the female group, the group aged >60 years, the group with BMI≤25 kg/m2, the group with constipation duration >10 years, and the group without combined laxatives were significantly improved compared with the baseline, and the differences were statistically significant (P<0.05). See Table 4.

05 Security Analysis

During the trial, only 2 cases (4.3%) experienced nausea and vomiting, which were adverse reactions within the scope of the instructions and were well tolerated by the subjects. The symptoms improved rapidly after drug discontinuation, and there were no serious adverse reactions.

Discuss

Diabetes combined with chronic constipation is a diabetic gastrointestinal lesion that is difficult to cure and prone to recurrence, aggravating diabetic symptoms and forming a vicious cycle. The bulk laxative calcium polycarbophil tablets are composed of calcium salt of divinyl glycol cross-linked acrylic acid copolymer, which is decalcified into polycarbophil in the acidic environment of the stomach and absorbs a large amount of water in the intestine to form a hydrophilic gel, thereby increasing the water content and volume of the stool, improving stool characteristics and regulating intestinal transit, and directly playing a role in treating constipation in the intestine.

This study is the first to report the efficacy and safety of calcium polycarbophil tablets in the treatment of patients with diabetes and chronic constipation. The frequency of bowel movements is an important factor in evaluating the efficacy of constipation treatment. Although there is no consensus on the standard frequency of bowel movements, the frequency of bowel movements varies greatly from individual to individual, ranging from 3 times a day to 3 times a week, but most patients expect to have bowel movements every day. This study found that after 2 weeks of treatment with calcium polycarbophil tablets, the weekly frequency of SBM increased by 1.0 times, especially in patients with a low frequency of SBM at baseline. Tramonte et al. listed 6 trials of fiber laxative treatment, and the frequency of bowel movements in patients with chronic constipation increased by 1.4 times per week. Slightly higher than this result, it may be because the baseline frequency of SBM in the patients in this study was not low, or some patients took previous laxatives during treatment.

Some studies set up a washout period, and patients were not allowed to take other laxatives during the trial. This study did not change the patient's treatment plan, which can more truly reflect the actual situation in clinical practice. This study found that after 2 weeks of treatment and 2 weeks of discontinuation, the BSFS scores were significantly increased compared with the baseline, and the total score of PAC-QOL and the physiological condition and satisfaction of the sub-dimensions were significantly lower than the baseline; the BSFS score was close to the normal value of 4, indicating that when the BSFS score is less than 4, there may be a correlation with PAC-QOL, which is consistent with the results of a previous study. Stool morphology and bowel movement frequency are related to the quality of life of patients with constipation, especially hard stools (BSFS<4 type) are of great significance to improving the quality of life of patients with constipation.

This study also found that after 2 weeks of treatment, the patient's FPG level decreased significantly, and GA showed a slight downward trend, but HbA1c and GA were not significantly different from the baseline levels, suggesting that calcium polycarbophil tablets have a certain effect on lowering blood sugar in patients with diabetes and chronic constipation. Micro-inflammation level is an important factor in the development of diabetes, and inhibiting inflammatory factors significantly delays the development of diabetes. The elevated serum high-sensitivity C-reactive protein (CRP) level in diabetic patients may be one of the targets for the treatment of type 2 diabetes. Che Weiping et al. found that lowering serum CRP levels can significantly reduce FPG, 2hPG, and HbAlc levels in diabetic patients. Constipated patients will have metabolic endotoxemia and systemic low inflammation, leading to metabolic disorders in diabetic patients. A previous study exploring serum cytokines before and after calcium polycarbophil tablets improved abdominal symptoms in IBS patients found that calcium polycarbophil tablets can significantly reduce CRP levels in patients with constipation-type IBS. Therefore, we speculate that calcium polycarbophil tablets may reduce FPG and reduce CRP in patients. A cross-sectional study in South Korea showed that there is a correlation between inflammatory markers represented by CRP and HbA1c, and it is believed that HbA1c levels increase significantly with the increase of high-sensitivity CRP, but this study did not find any difference in HbA1c before and after treatment. GA is the product of the combination of glucose and serum albumin in the blood, which can reflect the average level of blood sugar in the past 2 to 3 weeks. This study may have only found a slight decreasing trend due to insufficient dosage and administration time, but the difference was not statistically significant. Therefore, a larger sample size, larger dose and longer action time are needed in the future to reveal the effect of polycarbophil calcium tablets on blood sugar levels.

In the stratified analysis, calcium polycarbophil tablets were more effective in patients with lower baseline SBM, especially in women, elderly patients (>60 years old), BMI≤25 kg/m2, patients with long-term constipation (>10 years), and patients not taking other laxatives. However, due to the small number of patients in each stratum, this result needs to be confirmed by further research. The incidence of adverse reactions during the trial was 4.3%, which was lower than the 7.13% incidence of adverse reactions in the drug instructions. This may be due to the fact that the subjects in the drug instructions were Japanese, which was related to racial differences with the Chinese. In addition, the difference between clinical trials and the real world may also be one of the reasons. In addition, no serious adverse reactions were observed in this study, and all adverse reactions did not exceed the scope of the instructions.

In summary, this study confirmed the effectiveness and safety of calcium polycarbophil tablets in the treatment of patients with diabetes and chronic constipation. Among patients with chronic constipation who meet the Rome IV criteria, calcium polycarbophil tablets are more effective in patients with low baseline SBM, especially women, the elderly, BMI≤25 kg/m2, long-term constipation (>10 years) and patients without other laxatives. In addition, calcium polycarbophil tablets have a significant effect on reducing fasting blood glucose levels, and the specific mechanism needs further analysis. This study also has certain limitations, such as the small sample size, open-label, single-arm, single-center design, and randomized, controlled studies are needed in the future to confirm the efficacy of calcium polycarbophil tablets. Despite this, the results of this study still provide a safe and effective laxative treatment for the treatment of diabetes and chronic constipation.

References

[1] Ma Dan, Tang Fengyan, Cui Hao, et al. Efficacy and safety of calcium polycarbophil tablets in the treatment of diabetes mellitus combined with chronic constipation[J]. Practical Medicine and Clinical Practice, 2024, 27(10): 744-749. DOI: 10.14053/j.cnki.ppcr.202410005.