diabetes mellitus ( dm ) is one of the most prevalent worldwide endocrine system diseases . according to a report by wild et al1 there were 171 million patients diagnosed with dm worldwide in the year 2000 , and this number is predicted to increase to 366 million by the year 2030 . characteristics of dm include hyperglycemia and disturbances in carbohydrate levels and , typically , there is also insulin deficiency and insulin resistance.2 in clinical practice , type 2 diabetes mellitus ( t2 dm ) is more common,3 and the main monitoring indices of t2 dm are glycosylated hemoglobin ( hba1c ) levels and fasting blood glucose ( fbg ) levels.4 thus , the main strategy for t2 dm therapy is to control the levels of hba1c and fbg . at present , oral hypoglycemic agents ( ohas ) are the most commonly used treatment for t2 dm . some of these ohas include sulfonylurea , the biguanide class of drugs , dipeptidyl peptidase-4 ( dpp-4 ) inhibitors , and glucagon - like peptide-1 ( glp-1 ) agonists.5 sitagliptin is an important oha used for t2 dm . it was the first dpp-4 inhibitor to be used in clinical practice in 2006.6 dpp-4 is an enzyme located in the endothelium and has a high affinity toward glp-1 as a substrate.7 sitagliptin is a highly selective dpp-4 inhibitor that can increase concentrations of intact plasma glp-1 and lower or normalize blood glucose levels in t2 dm patients.8 in monotherapy of t2 dm patients , sitagliptin improved hba1c , fbg , and postprandial glucose with doses of 100 mg and 200 mg once daily.9 fbg was dose - dependently reduced by 17.1 mg / dl ( 100 mg ) and 21.3 mg / dl ( 200 mg ) ; hba1c was also reduced by 0.79% and 0.94% , respectively . in another monotherapy study,10 sitagliptin also improved glycemic parameters , including hba1c and fbg . there are also reports of diarrhea with sitagliptin as monotherapy.9,11 however , data concerning diarrhea with sitagliptin use in different clinical trials have not been evaluated , and the overall incidence and risk of diarrhea with sitagliptin use have not been well defined . as diarrhea could lead to a discontinuation of sitagliptin use and could be fatal in many instances , it is important to fully recognize the risk of diarrhea induced by sitagliptin . therefore , we conducted this systematic review and meta - analysis to investigate the incidence and risk of diarrhea in t2 dm patients treated with sitagliptin . we searched embase from the dates of 1974 through 2014 , pubmed from 1967 through 2014 , and the cochrane library electronic databases . specifically , we used the following search terms treated as medical subject headings ( mesh ) terms or free text :  diabetes ,  diabetes mellitus  ,  type 2 diabetes  , or  noninsulin - dependent diabetes mellitus  ;  sitagliptin  ; and  randomized controlled trials  ,  clinical trials  ,  controlled clinical trials  ,  clinical trial as topic  , or randomized controlled trial as topic  . additionally , we searched the clinical trial registration website ( clinicaltrials.gov ) to obtain information on the registered clinical trials . clinical trials that reported the occurrence of diarrhea with sitagliptin use in adult t2 dm patients were eligible for inclusion . other inclusion criteria included : 1 ) the diagnosis of t2 dm based on either the american diabetes association criteria12 or the world health organization criteria,13 2 ) patients who were assigned to treatment with sitagliptin , and 3 ) treatment with sitagliptin for a minimum duration of 12 weeks . this duration was chosen based on the fact that a study of this duration could provide relevant information on diarrhea . data extraction was conducted by two independent investigators ( zqw and hds ) , and studies were retrieved for further consideration if judged pertinent by one or two reviewers . discrepancies were identified and resolved by consensus or , as needed , by a third investigator ( wbh ) and confirmed by consensus . when there were multiple reports from the same trial , the most complete and/or most recently reported data were chosen . for each study , the following information was extracted : first author s name , year of publication , the clinical trials registry number ( no nct ) , treatment arm , treatment duration , mean age , number of patients in the treatment and control groups , adverse outcomes ( diarrhea ) , change from baseline of hba1c and fbg in treatment and control groups , and dosage of sitagliptin . all of the randomized controlled trials ( rcts ) included in this review had their quality assessed using the jadad criteria.14 scores ranged from 0 to 5 , with a high score indicating a high - quality study . the number of patients with diarrhea in the sitagliptin group and the total number of patients receiving sitagliptin were extracted from the selected trials to calculate the incidence of diarrhea . for each study , the proportion of patients with diarrhea and the 95% confidence interval ( ci ) were derived . the odds ratio ( or ) of diarrhea was calculated only with those assigned to the control group in the same trial . we used the peto method to calculate the or and the 95% ci because this method provides the best ci coverage and it was more powerful and relatively less biased when dealing with low event rates.15 heterogeneity was assessed by using the q statistic and i tests among trials.16 heterogeneity was considered statistically significant when pheterogeneity<0.1 or i>40% . if heterogeneity existed , the data were analyzed using a random - effects model ; if heterogeneity did not exist , a fixed - effects model was used . the presence of publication bias was evaluated by using the begg s and egger s tests.11,17 all data analyses were performed by using stata software , version 12.0 ( stata corporation , college station , tx , usa ) and r software , version 3.0.3 ( the r foundation for statistical computing , http://www.r-project.org).18 we searched embase from the dates of 1974 through 2014 , pubmed from 1967 through 2014 , and the cochrane library electronic databases . specifically , we used the following search terms treated as medical subject headings ( mesh ) terms or free text :  diabetes ,  diabetes mellitus  ,  type 2 diabetes  , or  noninsulin - dependent diabetes mellitus  ;  sitagliptin  ; and  randomized controlled trials  ,  clinical trials  ,  controlled clinical trials  ,  clinical trial as topic  , or randomized controlled trial as topic  . additionally , we searched the clinical trial registration website ( clinicaltrials.gov ) to obtain information on the registered clinical trials . clinical trials that reported the occurrence of diarrhea with sitagliptin use in adult t2 dm patients were eligible for inclusion . other inclusion criteria included : 1 ) the diagnosis of t2 dm based on either the american diabetes association criteria12 or the world health organization criteria,13 2 ) patients who were assigned to treatment with sitagliptin , and 3 ) treatment with sitagliptin for a minimum duration of 12 weeks . this duration was chosen based on the fact that a study of this duration could provide relevant information on diarrhea . data extraction was conducted by two independent investigators ( zqw and hds ) , and studies were retrieved for further consideration if judged pertinent by one or two reviewers . discrepancies were identified and resolved by consensus or , as needed , by a third investigator ( wbh ) and confirmed by consensus . when there were multiple reports from the same trial , the most complete and/or most recently reported data were chosen . for each study , the following information was extracted : first author s name , year of publication , the clinical trials registry number ( no nct ) , treatment arm , treatment duration , mean age , number of patients in the treatment and control groups , adverse outcomes ( diarrhea ) , change from baseline of hba1c and fbg in treatment and control groups , and dosage of sitagliptin . all of the randomized controlled trials ( rcts ) included in this review had their quality assessed using the jadad criteria.14 scores ranged from 0 to 5 , with a high score indicating a high - quality study . the number of patients with diarrhea in the sitagliptin group and the total number of patients receiving sitagliptin were extracted from the selected trials to calculate the incidence of diarrhea . for each study , the proportion of patients with diarrhea and the 95% confidence interval ( ci ) were derived . the odds ratio ( or ) of diarrhea was calculated only with those assigned to the control group in the same trial . we used the peto method to calculate the or and the 95% ci because this method provides the best ci coverage and it was more powerful and relatively less biased when dealing with low event rates.15 heterogeneity was assessed by using the q statistic and i tests among trials.16 heterogeneity was considered statistically significant when pheterogeneity<0.1 or i>40% . if heterogeneity existed , the data were analyzed using a random - effects model ; if heterogeneity did not exist , a fixed - effects model was used . the presence of publication bias was evaluated by using the begg s and egger s tests.11,17 all data analyses were performed by using stata software , version 12.0 ( stata corporation , college station , tx , usa ) and r software , version 3.0.3 ( the r foundation for statistical computing , http://www.r-project.org).18 a total of 1,761 articles and 94 clinical trials were identified initially through our search . after reviewing each study , the remaining 30 studies , with 8,891 subjects , which met our inclusion criteria , were included in our analyses . the basic characteristics of the trials included in the meta - analysis are summarized in table 1 . seven of them had jadad scores of 5,1925 which described the methods of randomization and blinding appropriately and provided the number of patients who withdrew and dropped from the trials . thirteen clinical trials had jadad scores of 4.9,10,2636 this lower score was due to the fact that the researchers did not describe the methods of randomization or blinding appropriately . ten studies had jadad scores of 3 , which included seven articles3743 and three clinical trials from the clinical trial registration website . we performed this meta - analysis in accordance with the guidelines of the preferred reporting items for systematic reviews and meta - analyses ( prisma ) statement44 ( table s1 ) . a total of 5,362 patients who were treated with sitagliptin monotherapy were available for analysis . the incidence of diarrhea ranged from 0% to 10.8% , and the highest incidence occurred in the trials of patients treated with 50 mg of sitagliptin once daily during a 54-week period.20 no events of diarrhea were reported in the two trials.39,40 based on data from 5,362 patients , the overall incidence of diarrhea was 4.48% ( 95% ci : 3.59%5.58% ; figure 2 ) according to the random - effects model . the incidence of diarrhea might be different due to the duration and dosage of sitagliptin treatment ; therefore , we performed a subgroup analysis according to the duration and dosage of sitagliptin administration . if the dosage of sitagliptin was 100 mg , the incidence of diarrhea for treatment times < 30 weeks ( 3.83% , 95% ci : 3.02%4.84% ; figure 3 ) was lower than that for treatment times > 30 weeks ( 5.41% , 95% ci : 3.62%8.01% ; figure 3 ) however , if the dosage of sitagliptin was < 100 mg , the incidence of diarrhea did not significantly vary between groups with treatment times < 30 weeks ( 4.81% , 95% ci : 1.68%12.97% ; figure 3 ) and treatment times > 30 weeks ( 4.83% , 95% ci : 2.83%8.15% ; figure 3 ) . through our subgroup analysis , our results suggest that under the conditions of high sitagliptin dosage ( 100 mg ) , a long treatment time ( > 30 weeks ) might increase the incidence of diarrhea , but low sitagliptin dosages ( < 100 mg ) showed no significant variation between the groups of different treatment times . to investigate the specific contribution of sitagliptin to the incidence of diarrhea and exclude the influence of confounding factors such as food , the disease itself , and the history of other therapeutic interventions , we determined the ors of diarrhea between sitagliptin and placebo groups.9,19,24,26,27,29,32,33,3739,42,45 the pooled ors of diarrhea showed that there were no differences in diarrhea risk between treatments with sitagliptin and placebo with an or of 1.10 ( 95% ci : 0.781.55 ; p=0.58 ; figure 4 ) , according to a fixed - effects model ( i=0% , pheterogeneity=0.8081 ) . we observed no significant evidence of publication bias for the or of diarrhea events in this analysis by a funnel plot ( figure 5 ) , egger s test ( p=0.991>0.05 , 95% ci : 1.64 , 1.62 ) , or begg s test ( z=0<1.96 , p=1.0>0.05 ) . a total of 1,761 articles and 94 clinical trials were identified initially through our search . after reviewing each study , the remaining 30 studies , with 8,891 subjects , which met our inclusion criteria , were included in our analyses . the basic characteristics of the trials included in the meta - analysis are summarized in table 1 . seven of them had jadad scores of 5,1925 which described the methods of randomization and blinding appropriately and provided the number of patients who withdrew and dropped from the trials . thirteen clinical trials had jadad scores of 4.9,10,2636 this lower score was due to the fact that the researchers did not describe the methods of randomization or blinding appropriately . ten studies had jadad scores of 3 , which included seven articles3743 and three clinical trials from the clinical trial registration website . we performed this meta - analysis in accordance with the guidelines of the preferred reporting items for systematic reviews and meta - analyses ( prisma ) statement44 ( table s1 ) . a total of 5,362 patients who were treated with sitagliptin monotherapy were available for analysis . the incidence of diarrhea ranged from 0% to 10.8% , and the highest incidence occurred in the trials of patients treated with 50 mg of sitagliptin once daily during a 54-week period.20 no events of diarrhea were reported in the two trials.39,40 based on data from 5,362 patients , the overall incidence of diarrhea was 4.48% ( 95% ci : 3.59%5.58% ; figure 2 ) according to the random - effects model . the incidence of diarrhea might be different due to the duration and dosage of sitagliptin treatment ; therefore , we performed a subgroup analysis according to the duration and dosage of sitagliptin administration . if the dosage of sitagliptin was 100 mg , the incidence of diarrhea for treatment times < 30 weeks ( 3.83% , 95% ci : 3.02%4.84% ; figure 3 ) was lower than that for treatment times > 30 weeks ( 5.41% , 95% ci : 3.62%8.01% ; figure 3 ) . however , if the dosage of sitagliptin was < 100 mg , the incidence of diarrhea did not significantly vary between groups with treatment times < 30 weeks ( 4.81% , 95% ci : 1.68%12.97% ; figure 3 ) and treatment times > 30 weeks ( 4.83% , 95% ci : 2.83%8.15% ; figure 3 ) . through our subgroup analysis , our results suggest that under the conditions of high sitagliptin dosage ( 100 mg ) , a long treatment time ( > 30 weeks ) might increase the incidence of diarrhea , but low sitagliptin dosages ( < 100 mg ) showed no significant variation between the groups of different treatment times . to investigate the specific contribution of sitagliptin to the incidence of diarrhea and exclude the influence of confounding factors such as food , the disease itself , and the history of other therapeutic interventions , we determined the ors of diarrhea between sitagliptin and placebo groups.9,19,24,26,27,29,32,33,3739,42,45 the pooled ors of diarrhea showed that there were no differences in diarrhea risk between treatments with sitagliptin and placebo with an or of 1.10 ( 95% ci : 0.781.55 ; p=0.58 ; figure 4 ) , according to a fixed - effects model ( i=0% , pheterogeneity=0.8081 ) . we observed no significant evidence of publication bias for the or of diarrhea events in this analysis by a funnel plot ( figure 5 ) , egger s test ( p=0.991>0.05 , 95% ci : 1.64 , 1.62 ) , or begg s test ( z=0<1.96 , p=1.0>0.05 ) . however , due to the high background incidence of diarrhea , it may be very difficult to distinguish between spontaneous and actual drug - related diarrhea events in t2 dm patients . wu et al46 found that , compared with controls , dpp-4 inhibitor monotherapy , which included sitagliptin , was associated with a lower risk of gastrointestinal ( gi ) adverse events involving diarrhea ( relative risk = 0.63 , 95% ci : [ 0.550.70 ] , p<0.00001 ) . therefore , we have conducted this study to determine the overall incidence and risk of diarrhea in t2 dm patients treated with sitagliptin . sitagliptin as a novel t2 dm therapy improves alpha islet function due to the increased concentrations of active glp-1 , which stimulates insulin secretion and inhibits glucagon secretion.47 in one study,48 sitagliptin ( 100 mg ) reduced hba1c by 0.6% from a baseline of 7.7% in 555 subjects . another study,49 comprising 743 subjects , reported that sitagliptin reduced hba1c by 0.8% from a baseline of 7.8% . the improved hyperglycemia during sitagliptin monotherapy was sustained over at least 2 years , as shown in a 52-week study of an open - label extension.21 sitagliptin at 100 mg reduced hba1c by 0.7% from a baseline of 7.5% . a placebo - controlled , multicenter study37 showed that sitagliptin at 100 mg or 200 mg once daily reduced hba1c by 0.6% and 0.5% , respectively , from a baseline of 8.1% . all of these studies have shown that sitagliptin has a positive clinical effect in reducing glycemia as a monotherapy . however , the etiology and pathophysiology of sitagliptin - related diarrhea are largely unknown . in our study , we strictly defined inclusion criteria to collect the rcts of t2 dm patients treated with sitagliptin . this method of meta - analysis could increase clinical samples and improve productivity based on statistics , and we were able to obtain a more accurate conclusion to choose a suitable therapeutic scheme in clinical practice . in our study , 8,891 patients from 30 rcts demonstrated that the pooled incidence of sitagliptin - associated diarrhea was 4.48% ( 95% ci : 3.59%5.58% ) . according to a subgroup analysis , we found that the incidence of diarrhea was related to the duration and dosage of sitagliptin treatment . if the dosage of sitagliptin was 100 mg , the incidence of diarrhea with treatment times < 30 weeks ( 3.83% , 95% ci : 3.02%4.84% ) was lower than that with treatment times > 30 weeks ( 5.41% , 95% ci : 3.62%8.01% ) . of note , we also found no differences in diarrhea risk between sitagliptin and placebo therapies ( or=1.10 , 95% ci : 0.781.55 , p=0.58 ; figure 4 ) . one possible explanation for this finding is that diarrhea is due to the t2 dm itself . as we know , gi disorders are a common complication of t2 dm , including abdominal distension , diarrhea , and constipation . moreover , a large population survey asking participants about gi - related disorders51 indicated that the or was 2.06 in diabetic patients compared with controls , and the prevalence of diarrhea was 15.6% . histological evidence of sympathetic and parasympathetic nerve impairment has been observed in t2 dm patients.52 sympathetic and parasympathetic nerves regulate the movement of the small intestine , and the damaged nerve tracts could impair gi motility . previous studies have shown similar results with sympathetic nerve selective deletion in the islets of diabetic rats.53 based on the autonomic nerve changes in t2 dm , the risk of diarrhea may easily increase in t2 dm patients compared with normal people . another possible explanation for this finding is the underreporting of diarrhea ; in fact , diarrhea as an independent adverse event reported in trials is low . in our research , 30.2% of rcts additionally , only 14 rcts were included in our study to investigate the risk of diarrhea associated with sitagliptin . because sitagliptin is increasingly used in routine treatment of t2 dm patients and in clinical trials with other agents , endocrinologist and primary care physicians should be aware of the incidence and risk of diarrhea associated with sitagliptin . heterogeneity is a potential confounding factor that can influence the results of all meta - analyses . in the present study , first , the rcts were performed at various international institutions by different investigators and may have some potential bias in reporting the types of adverse events . second , the results are from patients at a follow - up time and thus may not be fully reflective of general patients , nor of a more prolonged use . third , although diarrhea data are prospectively collected in individual studies , there are potentially important differences among the studies , including race , dosage and administration schedules of sitagliptin , duration of the study , and investigators . additionally , our study includes a mixed population of patients treated with sitagliptin - based combination therapy or sitagliptin monotherapy . therefore , the design of treatment is not the same in all arms , and this might be another source of heterogeneity . despite these limitations , the present meta - analysis provides some clinical reference for the treatment of diabetic diarrhea . in the treatment of diabetic diarrhea , metformin , which belongs to the biguanide class of drugs , is the first - line oha for the treatment of t2 dm , and has been shown to reduce the rate of glucose production through reductions in hepatic gluconeogenesis.54,55 however , treatment with metformin is generally associated with a high incidence of adverse gi effects , including diarrhea , nausea , and vomiting.5658 diarrhea is the most commonly reported symptom of adverse gi effects , and metformin can lead to malabsorptive diarrhea ranging from 10% to 53% in t2 dm patients.59 furthermore , in 5% of t2 dm cases , diarrhea led to the discontinuation of metformin use.60 our results indicate that sitagliptin did not increase the risk of diabetic diarrhea . the pooled or of sitagliptin compared with a placebo was 1.10 ( 95% ci : 0.781.55 , p=0.58 ; figure 4 ) . if diabetic diarrhea occurred , sitagliptin may be a better choice compared with metformin in t2 dm patients . in conclusion , our study has shown that there is no difference in diarrhea risk between sitagliptin and controlled therapies . furthermore , sitagliptin is not a medicine that potentially increases the risk of diabetic diarrhea . cochrane library search strategy . abbreviations : ab , abstract ; kw , keyword ; ti , title . prisma 2009 checklist reproduced from moher d , liberati a , tetzlaff j , et al . preferred reporting items for systematic reviews and meta - analyses : the prisma statement . 2009;6(7 ) : e1000097.1 abbreviations : no , number ; picos , patient , intervention , comparison , outcome and study ; prisma , preferred reporting items for systematic reviews and meta - analyses .
backgroundsitagliptin is an important drug used for diabetes treatment and is used as a monotherapy in diabetic patients . 
 however , there are also reported cases of diarrhea with sitagliptin use . 
 unfortunately , data concerning the relationship of diarrhea with sitagliptin use in various conditions have yet to be identified . 
 therefore , the overall incidence and risk of diarrhea with sitagliptin use have not been well defined.methodswe conducted searches on embase , pubmed , and the cochrane library databases for relevant randomized controlled trials . registered relevant trials at the clinical trials registration website were also searched . 
 statistical analyses were conducted to calculate the overall incidence , odds ratios , and 95% confidence intervals ( ci ) by using either random - effects or fixed - effect models according to the heterogeneity of the included studies.resultsa total of 8,891 subjects with diabetes from 30 randomized clinical trials were included in the meta - analysis . 
 the overall incidence of sitagliptin - associated diarrhea was 4.48% ( 95% ci : 3.59%5.58% ) . compared with the controls , 
 the use of sitagliptin was not associated with a significantly increased risk of diarrhea with an odds ratio of 1.10 ( 95% ci : 0.78%1.55% ; p=0.58 ) . 
 no evidence of publication bias was observed.conclusionour study has shown that there is no difference in diarrhea risk between sitagliptin and controlled therapies . 
 moreover , sitagliptin is not a medicine that potentially increases the risk of diabetic diarrhea . 
 more studies are recommended to further investigate this association .