Meta-analysis of insulin detemir treatment of pregnancy with diabetes

Zi-Yang Ren ,Shi-Chuang Zhang ,Dan Zhang ,Chuan-Xin Liu*

1Clinical Medical College of Henan University of Science and Technology,branch of national metabolic disease clinical medical research center of Endocrinology and Metabolism,Department of the First Affiliated Hospital of Henan University of Science and Technology,Luoyang 471003,China.2Sichuan Kelun Botai biomedical Co.,Ltd.,Chengdu 611130,China.

Abstract Objective: To evaluate the meta-analysis of evaluate the clinical efficacy and safety of insulin deside in improving pregnancy with diabetes,and to conduct a Meta-analysis study on the treatment of pregnancy with diabetes.Methods: Before this study,we comprehensively and systematically searched the major literature websites at home and abroad.From the establishment of the database to January 9,2022,we searched the Chinese and English literature on the randomized controlled trial (RCT) of insulin detemir in the treatment of pregnancy complicated with diabetes.We screened them in strict accordance with the acceptance criteria.The bias risk assessment tool in Cochrane system evaluator manual 5.1.0 was used to evaluate the quality of the selected literature,and the Review Manager 5.4 software was used for meta-analysis.Results: Finally,24 RCTs target literatures were obtained,with a cumulative sample size of 2,362 cases.The results of meta-analysis showed that the reduction range of fasting blood glucose,2 h postprandial blood glucose and glycosylated hemoglobin in patients with insulin detemir combined with routine treatment was greater than that in the control group (P ＜0.05);compared with conventional treatment,the incidence of premature delivery,macrosomia and cesarean section of the diabetes group were lower than those of the control group (P ＜0.05).Among them,preterm birth (RR=0.44,95% CI [0.28,0.68], P=0.0002),macrosomia (RR=0.35,95% CI [0.21,0.59], P ＜0.0001),cesarean section (RR=0.82,95% CI [0.72,0.94],P=0.005),fasting blood glucose(SMD=–1.21,95%CI[–1.54,–0.88],P ＜0.00001),2 h postprandial blood glucose (SMD=–1.63,95% CI [–1.91,–1.35], P ＜ 0.00001),glycosylated hemoglobin (SMD=–2.41,95% CI [–3.12,–1.70], P ＜ 0.00001).Conclusion: Routine treatment can improve the clinical effect of pregnancy with diabetes.However,there are low limits on the reference level of this study,so this conclusion has some limitations.

Keywords: insulin detemir;pregnancy associated with diabetes;meta-analysis;randomized controlled trial

Background

Gestational diabetes mellitus is due to abnormal hormones during pregnancy,similar to abnormal glucose metabolism[1-3].In the event of pregnancy complicated with diabetes,if the treatment is not timely or improper use of drugs will cause serious bodily harm to mothers and infants [1-3].According to authoritative survey data,in China,the incidence of pregnancy with diabetes has reached 30%,and showed a rising trend [4].Therefore,it has important clinical significance to use reasonable methods to control blood glucose in patients with gestational diabetes mellitus [5].More than 95% of pregnant women with diabetes can be controlled by diet and exercise guidance [5-7].Only less than 5% of pregnant women with diabetes require interventions such as insulin to achieve glycemic control [8].Insulin detemir is a new type of long-acting insulin drug developed recently.Although it has been published for a short time,it has an obvious inhibitory effect on diabetes and few adverse reactions[9-11].In clinical treatment,the introduction of insulin detemir into treating gestational diabetes,overall performance is excellent.Although protamine biosynthesized human insulin and insulin aspart are effective in the traditional treatment of gestational diabetes mellitus.Due to the high number of adverse reactions,whether protamine biosynthesis of human insulin and insulin aspart should be used in the daily treatment of gestational diabetes is still controversial[12-14].This study analyzes the effect of insulin detemir combined with conventional therapy on maternal and infant outcomes in gestational diabetes mellitus by Meta-analysis.

Information and methods

Inclusion criteria

Subjects of the literature are in line with the “Guidelines for the Prevention and Treatment of Type 2 Diabetes in China(2020 Edition)”[15].They related diagnostic criteria for gestational diabetes mellitus,single pregnancy with typical hyperglycemia symptoms,and insulin detemir treatment.The literature is complete and the language is limited to Chinese or English.

Exclusion criteria

There is no clear research conclusion in literature review,repeated literature,meta-analysis,animal experiment and retrospective studies;literatures such as the absence of control group design in clinical studies and incomplete data in control experiments (case reports,etc.)were excluded.

Intervention measures

The control group was treated with conventional western medicine in the treatment of gestational diabetes mellitus,namely diet therapy +exercise therapy+insulin aspart+lipid-lowering drugs +protamine biosynthetic human insulin comprehensive treatment;based on the treatment methods of the control group,the observation group combined with insulin detemir,and the dose and time of administration were not clearly defined.

Outcome index

Related safety and efficacy indicators for clinical evaluation.Such as safety indicators include:adverse pregnancy outcomes (premature delivery),incidence of complications (macrosomia),cesarean section;efficacy indicators include:the incidence of neonatal hypoglycemia,fasting blood glucose,postprandial 2 h blood glucose and other indicators.

Retrieval strategy

Keyword search was performed on three Chinese literature databases,namely CNKI,VIP and Wanfang,as well as PubMed,Cochrane Library and Web of Science English literature databases.The retrieval deadline is January 2022.Key words in Chinese were “Insulin detemir” (#1),“Gestational diabetes mellitus” (#2) and “Randomized controlled trials” (#3);key words in English are “Insulin detemir”(#1),“Gestational diabetes mellitus” (#2),“Randomized controlled trial” (#3).Keyword merge search,search scheme for #1 and #2 and#3.This method aims to retrieve more accurate results and find more valuable and analytical literature.After obtaining the basic literature information,download and manage.

Data extraction and risk assessment

Review Manager 5.4 is used to extract key data one by one for the references finally included in the selection range.Two researchers,“independent,” extracted key data from each literature,including basic information such as topics,and authors and key indicators such as treatment interventions and treatment outcomes.If there are questions or differences in data extraction,discuss them with the corresponding author and make the final judgment to ensure the scientificity and accuracy of the final included data.The literature risk assessment was achieved through the bias risk assessment tool recommended by Cochrane Systematic Reviewer Manual 5.1.0,and was archived according to the results.

Statistical analysis

Review Manager 5.4 software was used for meta-analysis.WhenP≥0.1 and I2≤50%,the fixed effect model is adopted;on the contrary,the random effect model is adopted.When the literature has large heterogeneity,subgroup analysis is introduced to trace the source of heterogeneity.The count and measurement data were expressed by 95% CI,and the test level was α=0.05.The count data were described by risk ratio (RR),and the measurement data were expressed by standard mean difference (SMD).

Results

Literature search

35 articles with reference value were retrieved from CNKI,84 articles with reference value and research value were retrieved from Wanfang database,31 articles with reference value were retrieved from VIP database,and 0 effective English references were retrieved.A total of 150 Chinese literatures and 0 English literatures were obtained.By removing the repetitive operation,91 effective literatures were obtained.Through further analysis and summary of the literature,the participation of nondetemir insulin in the treatment literature was excluded.Finally,2,362 cases of gestational diabetes mellitus mentioned in 24 Chinese literature were included in the study.The screening process and results are shown in Figure 1.

Basic characteristics of included literature

After rigorous literature screening,24 RCTs were finally determined.A total of 2,362 samples were involved in the literature.According to the case screening requirements of the control group,1,181 cases of the observation group and 1,181 cases of the control group were finally obtained.According to the above statistical results analysis is comparable,statistically significant,specific information is shown in Table 1.

Table 1 Basic information included in the study

Table 1 Basic information included in the study (Continued)

Table 1 Basic information included in the study (Continued)

Literature risk assessment

The bias risk assessment tool was used to evaluate the systematic risk quality of 24 articles included in the study.The results were detailed in Figure 2.In this study,Leng Jingjing 2018 [34],Meng Qinghong 2020 [20],Meng Guiqin 2019 [37],Xu Yanfang 2020 [38] and other 9 research literatures were randomly selected.Liu Danxia 2020 [35],Liu Yeqiu 2021 [27] and other 5 research papers adopted the specified method,and 10 papers did not describe the scheme.In all the literature,there were no halfway exits and other situations;all literatures were non-selective reported experimental data.Based on the above evaluation,9 of the 24 articles were medium quality,accounting for 37.5%,and their quality was low.Overall article’s evidence level is medium.There is a certain risk.

Figure 1 Literature screening process

Figure 2 Overall risk assessment of the included literature

Figure 3 Meta subgroup analysis of glycosylated hemoglobin

Figure 4 Meta subgroup analysis of adverse pregnancy outcomes(premature delivery)

Figure 5 Meta subgroup analysis of incidence of complications (macrosomia)

Figure 6 Meta-analysis of cesarean section

Figure 7 Meta-analysis of fasting blood glucose

Figure 8 Meta-subgroup analysis of 2 h postprandial blood glucose

Figure 9 funnel plot of macrosomia

Meta-analysis results

Glycosylated hemoglob.in In figure 3 Glycosylated hemoglobin[16-18,20,21,24-27,31,34-38] was mentioned in 15 literatures,with a cumulative sample size of 1,254 cases.The homogeneity test results based on Revman showed that the above literature had certain heterogeneity [Chi2=1,698.09,df=14 (P＜0.00001),I2=99%].Therefore,subgroup analysis was further conducted.In this study,the literature was divided into two subgroups:insulin detemir alone group and combination group.

The 12 references adopted the combination of insulin detemir and other drugs [16-18,20,21,24-27,31,34-38],with a total sample size of 914 cases.Compared with the control group,the glycosylated hemoglobin of the experimental group had a certain statistical difference (SMD=-2.27,95% CI [ -2.99,-1.55],P＜0.00001),that is,basis on conventional treatment,combined application of insulin detemir has a certain effect on reducing glycosylated hemoglobin.

The three literatures used insulin detemir alone [16-18,20,21,24-27,31,34-38],the cumulative sample size was 340 cases.Compared with the control group,the glycosylated hemoglobin of the experimental group had a certain statistical difference (SMD=-2.93,95%CI[ -5.33,-0.53],P=0.02),that is,compared with conventional treatment,insulin detemir alone has a certain effect on reducing glycosylated hemoglobin.After subgroup analysis,it can be seen that the literature of combination group and single group has certain heterogeneity.In conclusion,compared with conventional treatment,combined application or single insulin detemir,to reduce glycosylated hemoglobin has a certain curative effect.

Adverse pregnancy outcomes (premature delivery).in In figure 4 Ten articles reported adverse pregnancy outcomes (preterm birth)[16,21,22,24,25,27-29,38,39],with a cumulative sample size of 876 cases.The homogeneity test results based on Revman showed that there was no clear heterogeneity in the above literature [Chi2=2.42,df=9 (P=0.98),I2=0%].Therefore,based on the fixed effect model,the results showed that compared with the control group,the adverse pregnancy outcome (premature birth) in the insulin detemir test group was statistically different (RR=0.44,95% CI [0.28,0.68],P=0.0002),that is,compared with conventional treatment,combined application or single use of insulin detemir could reduce the incidence of adverse pregnancy with diabetes.

Incidence of complications (macrosomia)in In figure 5 Fifteen articles reported the incidence of complications (macrosomia) [16,18,21,22,25,27-34,37,39] with a cumulative sample size of 1,644 cases.The homogeneity test results based on Revman showed that there was no clear heterogeneity in the above literature [Chi2=4.80,df=14 (P=0.99),I2=0%].Therefore,based on the fixed effect model,the results showed that compared with the control group,the incidence of complications (macrosomia) in the insulin detemir test group was statistically different (RR=0.35,95% CI[0.21,0.59],P＜0.0001),that is,compared with conventional treatment,combined application or single use of insulin detemir can reduce the incidence of complications(macrosomia).

Comparative analysis of cesarean sectionin In figure 6 Twelve articles reported cesarean section[16,17,22,27,31-34,36-39] with a cumulative sample size of 1,394 cases.The homogeneity test results based on Revman showed that there was no clear heterogeneity in the above literature [Chi2=13.99,df=11 (P=0.23),I2=21%].Therefore,based on the fixed effect model,the results showed that compared with the control group,the cesarean section in the experimental group had statistical difference (RR=0.82,95% CI[0.72,0.94],P=0.005),that is,compared with conventional treatment,combined application or single use of insulin detemir,the incidence of cesarean section could be reduced.

Fasting blood glucosein In figure 7 23 papers reported fasting blood glucose[16-22,24-39],the cumulative sample size of 2,286 cases.The homogeneity test based on Revman showed that the above literature had certain heterogeneity [Chi2=1,013.81,df=22 (P＜0.00001),I2=98%].Therefore,subgroup analysis was further performed based on the random effect model.In this study,the literature was divided into two subgroups:insulin detemir alone group and combination group.

The 18 articles used insulin detemir combined with other drugs[16-22,24-39],the cumulative sample size of 1,806 cases.Compared with the control group,the fasting blood glucose in the experimental group had a certain statistical difference(SMD=–1.07,95% CI[–1.4 6,–0.69],P＜ 0.00001),that is,on the basis of conventional treatment,combined application of insulin detemir had a certain effect on reducing fasting blood glucose.

Five articles used insulin detemir alone [16-22,24-39],the cumulative sample size of 480 cases.Compared with the control group,the fasting blood glucose in the experimental group had a certain statistical difference (SMD=–1.69,95% CI [–1.97,–1.41],P＜0.00001).In other words,compared with conventional treatment,single-site insulin had a certain effect on reducing fasting blood glucose.

After subgroup analysis,it can be seen that the heterogeneity of the literature mainly comes from the combination group,and the heterogeneity of the single group is significantly lower than that of the combination group,but there is still a certain heterogeneity.In conclusion,compared with conventional treatment,combined application or single insulin,to reduce fasting blood glucose has certain curative effect.

2 h postprandial blood glucosein In figure 8 23 papers reported 2 h postprandial blood glucose[16-22,24-39],the cumulative sample size of 2,286 cases.The homogeneity test based on Revman showed that the above literature had certain heterogeneity [Chi2=544.41,df=22 (P＜0.00001),I2=96%].Therefore,subgroup analysis was further performed based on the random effect model.In this study,the literature was divided into two subgroups:insulin detemir alone group and combination group.

The 18 articles used insulin detemir combined with other drugs[16-22,24-39],the cumulative sample size of 1,806 cases.Compared with the control group,the postprandial 2 h blood glucose of the experimental group had a certain statistical difference (SMD=–1.58,95% CI [–1.93,–1.23],P＜ 0.00001),that is,on the basis of conventional treatment,combined with insulin detemir has a certain effect on reducing postprandial 2h blood glucose.

Five articles used insulin detemir alone [16-22,24-39],the cumulative sample size of 480 cases.Compared with the control group,the postprandial 2 h blood glucose of the experimental group had a certain statistical difference (SMD=–1.84,95% CI [–2.12,–1.56],P＜0.00001),that is,compared with conventional treatment,single insulin,to reduce postprandial 2 h blood glucose has a certain effect.

After subgroup analysis,it can be seen that the heterogeneity of the literature mainly comes from the combination group,and the heterogeneity of the single group is significantly lower than that of the combination group,but there is still a certain heterogeneity.In conclusion,compared with conventional treatment,combined application or single insulin has a certain effect on reducing postprandial 2 h blood glucose.

Bias analysisin In figure 9 The funnel plot was drawn with macrosomia,and the data were basically symmetrically distributed.Most of the data were located in the middle of the inverted funnel plot,and some data points were distributed in the upper and lower parts of the inverted funnel plot.The inverted funnel plot was still available,indicating that there might be publication bias.

Discussion

Clinical efficacy and safety analysis

The pathogenesis of gestational diabetes is very complex,and may be closely related to many factors such as genetic genes,lifestyles of patients and special hormone secretion patterns in the body during pregnancy [40].If the treatment of gestational diabetes is not timely and effective,it is likely to lead to serious maternal and infant complications,thereby increasing the incidence of adverse delivery outcomes [1,41].Specifically,for pregnant women,the main hazards of hyperglycemia during pregnancy are poor perinatal clinical outcomes and increased incidence of postpartum diseases.Studies have shown that the probability of developing type 2 diabetes in pregnant women with diabetes is 22 times higher than that in normal pregnant women [1,42].For fetuses,pregnancy with diabetes may result in increased incidence of multiple adverse outcomes,including fetal intrauterine abnormalities,asphyxia,neonatal malformations,macrosomia,premature infants,neonatal hypoglycemia and neonatal respiratory distress syndrome [1,43-46].In order to avoid the occurrence of these adverse maternal and neonatal outcomes,blood glucose should be strictly controlled in patients with gestational diabetes to maintain the normal blood glucose index.

In general,when the patient’s condition is not serious,the patient is usually treated with diet guidance and exercise guidance [8,47].When the ideal blood glucose control cannot be achieved through dietary treatment.The common treatment is to stabilize blood sugar by injecting insulin [48-50].But previous insulin such as protamine biosynthetic human insulin,if the dosage adjustment is not perfect,may appear at night hypoglycemia symptoms [14,51],which may cause some harm to patients.But insulin detemir is a new basic insulin analogue with a unique biological structure.It connects a carbon fatty acid in the insulin chain,making forming a polymer easier,and the binding rate with albumin is about 98% [10,11,52].Moreover,insulin detemir is not easy to pass through the capillary endothelial barrier after binding to albumin,but it can fully contact with hepatocytes in the liver,effectively reducing the output of liver glucose [10,11,53].Compared with other types of insulin,insulin detemir has better efficacy and safety [9,11,54].Insulin detemir is a stable hexamer structure and its mechanism of action makes it very similar to physiological insulin [10].It belongs to the side chain of fatty acids that can enter human cerebrospinal fluid.It can reduce weight gain by regulating the central nervous system of appetite [10,11].It does not require a specific acidic environment,and it can be fully dissolved in neutral solutions,and there is no precipitation.It can greatly reduce the discomfort symptoms of patients after use.Its pharmacokinetic curve is relatively stable,and the peak of action is relatively flat,which can prevent the occurrence of adverse events such as nocturnal hypoglycemia and severe fluctuation of blood glucose.It makes the treatment of clinical pregnancy complicated with diabetes safer and more effective [9,55].In addition,the dosage of insulin detemir is small,and patients are injected once a day,which can play an ideal basic insulin secretion,so as to achieve the effect of controlling blood glucose [56].Studies have shown that the probability of adverse reactions in the use of insulin detemir is much lower than that in protamine biosynthetic human insulin [12,57,58].These unique properties enable them to enter the blood circulation more slowly and eventually reach the target tissue,to maintain the patient’s blood glucose index within a reasonable range,thus playing a long-term and lasting hypoglycemic effect [9].To avoid hypoglycemia in patients and fetuses and improve the quality of blood glucose control,the impact on patients and fetuses is relatively small.The results of this study show that compared with conventional treatment,combined application of insulin detemir can reduce the incidence of macrosomia,and the safety is ideal.

All the indicators were statistically significant for the 24 articles included in this study,as well as Meta subgroup analysis.The results of comparative analysis showed that compared with conventional treatment,combined application or single insulin,can reduce the incidence of adverse pregnancy (premature delivery),complications(macrosomia),cesarean section and other adverse maternal and infant outcomes,and has obvious effect in reducing fasting blood glucose,postprandial 2 h blood glucose,glycosylated hemoglobin.Therefore,the application of insulin detemir has a good effect on controlling gestational diabetes mellitus and improving maternal and infant outcomes.

Clinical research recommendations

Although in this study,we strictly control the inclusion and exclusion criteria,we still can not avoid the differences between the included literature.Therefore,the course of treatment,treatment cycle and dose of each independent study are still different,and some studies have a small sample sizes,low quality of random trials and high risk.Therefore,studies on insulin detemir in the treatment of gestational diabetes still need a large samples,high-quality,randomized controlled trials to prove.Therefore,it is suggested that clinical trials in this field should further improve the scientificity,standardize the test standards,use strict random test methods,and especially improve the quality of test methodology.In the research reports,the randomization methods should be clarified in detail,and the results of clinical randomized controlled trials should be standardized.Clinical randomized controlled trials should be recommended [59].At the same time,education and training should be improved to further improve the comprehensive quality of medical staff,especially in the development of clinical trials,to train medical staff in the relevant knowledge of standardized clinical randomized controlled trials,so as to ensure the implementation of high-quality clinical studies.

Limitations of this study

Firstly,there is a certain heterogeneity in the literature included in this study,especially in the analysis of continuous variables such as fasting blood glucose,postprandial 2 h blood glucose,glycosylated hemoglobin and other indicators.We found a large heterogeneity in the literature,which has a certain impact on the accuracy of the final analysis results.Secondly,the overall quality of the included literature was not high,only 9 articles were randomized,accounting for 37.5%,and the overall literature was risky.In addition,in the literature included in this study,the treatment plan,dosage and treatment course of each study are not consistent,which may affect the stability of the test results;and the literature included in this study are mostly Chinese literature,less foreign literature,more single;it should also be noted that the number of test samples in the included literature is generally not high,and is limited to a single center.The lack of multi-center,large cohort cooperative RCT studies may lead to poor stability of the conclusions.

Conclusion

In summary,based on the results of this study combined with other studies,compared with other conventional treatments,insulin detemir combined with conventional treatment can improve the clinical efficacy of gestational diabetes mellitus,such as fasting blood glucose(SMD=–1.21,95% CI [–1.54,–0.88],P＜0.00001),postprandial 2 h blood glucose(SMD=–1.63,95% CI[–1.91,–1.35],P＜0.00001)and so on,which are statistically significant,but affected by the above limitations.This conclusion still needs more high-quality,non-obvious heterogeneity studies to prove.