dipeptidyl peptidase ( dpp)4 inhibitors enhance the activity of endogenous incretin hormones1 , which are important prandial stimulators of insulin secretion , and exhibit other physiological actions , such as reducing bowel motility1 .
in addition to their glucoselowering effects , dpp4 inhibitors have potential adverse effects due to their diverse and pleiotropic actions3 . herein we present three cases of ileus in diabetes patients that may be associated with the use of a dpp4 inhibitor .
the first patient was a 70yearold japanese man with a > 10year history of diabetes without diabetic nephropathy or retinopathy .
he had undergone surgery for appendicitis . in addition , the patient had been treated for parkinson 's disease with levodopa  carbidopa tablets for 2  years , and his condition was stable with mild rigidity .
the patient presented at the hospital complaining of persistent nausea , vomiting , and diarrhea for 2  days .
the patient had been taking mitiglinide for approximately 20  months to treat his diabetes , but had been prescribed alogliptin ( 25  mg / day ) instead of mitiglinide 11  days prior to his presentation at hospital .
the patient passed multiple diarrheal stools and his air  fluid levels subsequently resolved without intervention .
the second patient was a 61yearold japanese woman with myeloperoxidase antineutrophil cytoplasmic antibody ( anca)positive rapidly progressive glomerulonephritis being treated with prednisolone .
the patient was in a stable condition ( estimated glomerular filtration rate [ egfr ] 29  ml / min per 1.73  m ) .
the patient had undergone surgery for early gastric cancer ( iic ) 25  years previously .
she had a > 10year history of type 2 diabetes and her diabetes had been treated with mitiglinide and sitagliptin ; miglitol ( 150  mg / day ) was added to her antidiabetes regimen to control postprandial hyperglycemia , and the sitagliptin was discontinued .
the patient refused insulin and had been treated instead with a halfdose of vildagliptin ( 50  mg / day ) in addition to mitiglinide ( 30  mg / day ) and miglitol ( 225  mg / day ) for 4  months .
the patient 's prednisolone dose was decreased to 10  mg / day ( from 15  mg / day ) and she was eventually prescribed a full dose of alogliptin ( 25  mg / day ) instead of vildagliptin ( 50  mg / day ) .
she was identified with air  fluid levels in her colon and was admitted to the surgical unit for further assessment . xray and ct imaging indicated that her ileus was becoming worse ( figure  1 ) . gastrointestinal decompression was performed via a nasoenteric tube ; however , this was not effective .
so , 3.5  days later , surgical decompression and reconstructive surgery were performed for a collapsed small intestine , which revealed an internal hernia .
an upright abdominal xray ( a ) and ct scan ( b ) demonstrate small bowel obstruction .
the third patient was a 78yearold japanese man with a > 10year history of type 2 diabetes .
this patient 's right leg had been amputated 11  years ago because of atherosclerosis obliterans .
the patient had chronic kidney disease ( egfr 46  ml / min per 1.73  m ) .
the patient had undergone total gastrectomy with partial pancreatosplenectomy and left adrenalectomy 12  years ago for advanced gastric cancer .
he had had an ileus that was resolved with conservative treatment 5  years ago .
one day prior to admission , the patient experienced intermittent lower left abdominal pain with nausea and vomiting . xray and
gastrointestinal decompression via a nasoenteric tube was successful and the patient was discharged 3  weeks after admission .
his diabetes had been treated with glargine , metformin ( 500  mg / day ) , miglitol ( 225  mg / day ) , repaglinide ( 0.75  mg / day ) , and sitagliptin ( 50  mg / day ) .
the patient was also taking amlodipine , aliskiren , calcium polystyrene sulfonate , camostat mesilate , liver hydrolysate , and mosapride citrate hydrate .
his diabetes was relatively stable , with an hba1c of 8.0% ( ngsp ) , but random sampling revealed blood sugar levels > 300  mg / dl .
a diabetologist had asked the patient to use rapid insulin instead of an oral hypoglycemic agent , but the patient did not like the idea of multiple insulin injections .
thirtythree days prior to his admission for the ileus , the patient was prescribed a full dose of vildagliptin ( 100  mg / day ) instead of sitagliptin ( 50  mg ) .
the first patient was a 70yearold japanese man with a > 10year history of diabetes without diabetic nephropathy or retinopathy .
he had undergone surgery for appendicitis . in addition , the patient had been treated for parkinson 's disease with levodopa  carbidopa tablets for 2  years , and his condition was stable with mild rigidity .
the patient presented at the hospital complaining of persistent nausea , vomiting , and diarrhea for 2  days .
the patient had been taking mitiglinide for approximately 20  months to treat his diabetes , but had been prescribed alogliptin ( 25  mg / day ) instead of mitiglinide 11  days prior to his presentation at hospital .
the patient passed multiple diarrheal stools and his air  fluid levels subsequently resolved without intervention .
the second patient was a 61yearold japanese woman with myeloperoxidase antineutrophil cytoplasmic antibody ( anca)positive rapidly progressive glomerulonephritis being treated with prednisolone .
the patient was in a stable condition ( estimated glomerular filtration rate [ egfr ] 29  ml / min per 1.73  m ) .
the patient had undergone surgery for early gastric cancer ( iic ) 25  years previously .
she had a > 10year history of type 2 diabetes and her diabetes had been treated with mitiglinide and sitagliptin ; miglitol ( 150  mg / day ) was added to her antidiabetes regimen to control postprandial hyperglycemia , and the sitagliptin was discontinued .
the patient refused insulin and had been treated instead with a halfdose of vildagliptin ( 50  mg / day ) in addition to mitiglinide ( 30  mg / day ) and miglitol ( 225  mg / day ) for 4  months .
the patient 's prednisolone dose was decreased to 10  mg / day ( from 15  mg / day ) and she was eventually prescribed a full dose of alogliptin ( 25  mg / day ) instead of vildagliptin ( 50  mg / day ) .
she was identified with air  fluid levels in her colon and was admitted to the surgical unit for further assessment . xray and ct imaging indicated that her ileus was becoming worse ( figure  1 ) . gastrointestinal decompression was performed via a nasoenteric tube ; however , this was not effective .
so , 3.5  days later , surgical decompression and reconstructive surgery were performed for a collapsed small intestine , which revealed an internal hernia .
an upright abdominal xray ( a ) and ct scan ( b ) demonstrate small bowel obstruction . note that multiple air 
the third patient was a 78yearold japanese man with a > 10year history of type 2 diabetes .
this patient 's right leg had been amputated 11  years ago because of atherosclerosis obliterans .
the patient had chronic kidney disease ( egfr 46  ml / min per 1.73  m ) .
the patient had undergone total gastrectomy with partial pancreatosplenectomy and left adrenalectomy 12  years ago for advanced gastric cancer .
he had had an ileus that was resolved with conservative treatment 5  years ago .
one day prior to admission , the patient experienced intermittent lower left abdominal pain with nausea and vomiting . xray and ct scans revealed air 
gastrointestinal decompression via a nasoenteric tube was successful and the patient was discharged 3  weeks after admission .
his diabetes had been treated with glargine , metformin ( 500  mg / day ) , miglitol ( 225  mg / day ) , repaglinide ( 0.75  mg / day ) , and sitagliptin ( 50  mg / day ) .
the patient was also taking amlodipine , aliskiren , calcium polystyrene sulfonate , camostat mesilate , liver hydrolysate , and mosapride citrate hydrate .
his diabetes was relatively stable , with an hba1c of 8.0% ( ngsp ) , but random sampling revealed blood sugar levels > 300  mg / dl .
a diabetologist had asked the patient to use rapid insulin instead of an oral hypoglycemic agent , but the patient did not like the idea of multiple insulin injections .
thirtythree days prior to his admission for the ileus , the patient was prescribed a full dose of vildagliptin ( 100  mg / day ) instead of sitagliptin ( 50  mg ) .
case 1 presented as a firsttime user of a dpp4 inhibitor . in cases 2 and 3 , a dpp4 inhibitor had been used chronically and had subsequently been changed for strengthened dpp4 inhibition5 .
these two patients had also been treated with miglitol , possibly inducing defects in gastrointestinal movement .
there was no clear information regarding either diabetic gastroenteropathy or neuropathy in any of the cases .
two cases had a history of major abdominal surgery ; one of these patients also had a history of ileus .
two of the three patients had other chronic diseases , namely ancaassociated vasculitis7 and parkinson 's disease8 , which could potentially affect the motility of the gastrointestinal system , although quantitative evaluations for bowel motility had not been performed .
despite the fact that a causal relationship between ileus and the use of a dpp4 inhibitor was unclear , in all patients the onset of ileus occurred within 40  days after strengthened dpp4 inhibition ( see figure s1 available as supplementary material to this paper ) . in all three cases ,
the dpp4 inhibitors were discontinued : case 1 was treated with mitiglinide only , case 2 was prescribed insulin detemir with repaglinide , and case 3 was given insulin glulisine three times per day and basal glargine .
the glycemiclowering action of incretinassociated drugs results from their insulinotropic effects , as well as reduced bowel motility1 . however , the incretinassociated drug effects on reduced bowel motility could be harmful if produced in excess through interactions with underlying conditions , such as a history of abdominal surgery , microangiopathy in the gastrointestinal system , or autonomic defects .
all three patients in the present series were given a stronger dpp4 inhibitor before the onset of ileus , indicating pathological interactions between defects in basal bowel movement and dpp4 inhibitorreduced bowel motility .
there is no case report in the literature describing an association between the use of dpp4 inhibitors and ileus .
the three cases presented herein demonstrate the potential for adverse effects of dpp4 inhibitors in certain populations .
 abstractdipeptidyl peptidase ( dpp)4 inhibitors are a new class of antidiabetic drugs that increase incretin hormone levels to enhance blood sugar leveldependent insulinotropic effects , suppress glucagon action , and reduce bowel motility . 
 these incretin effects are ideal for blood sugar control . 
 however , the safety profile of dpp4 inhibitors is not yet established . herein , we present three cases of ileus , considered to be closely related to the use of dpp4 inhibitors , in diabetic patients . 
 each of the three patients exhibited some risk of a deficiency in bowel movement ; the onset of ileus was within 40  days after strengthened inhibition of dpp4 . 
 the use of a dpp4 inhibitor could be safe , although the cases presented herein enable us to inform the scientific community to some of the potential adverse effects of the use of dpp4 inhibitors in select populations . 
Introduction
Case Report
Case 1
Case 2
Case 3
Discussion
Supplementary Material