dipeptidyl peptidase4 ( dpp4 ) inhibitors belong to a novel class of antidiabetic agents that increase the incretin hormones , glucagonlike peptide1 ( glp1 ) and glucosedependent insulinotropic polypeptide ( gip ) .
sitagliptin is the first dpp4 inhibitor in japan , where it has been available for approximately 2  years .
the oral diabetes drugs that were available for clinical use before this were sulfonylureas , biguanides , thiazolidines , glucosidase inhibitors ( gi ) and glinides .
however , blood glucose can not actually be well controlled in many type  2 diabetes patients with these drugs , and improved glycemic control in a greater number of diabetic patients is anticipated with sitagliptin , given its novel mechanism of action .
japanese people have genetically low insulin secretory capacity , and sulfonylurea drugs are the most commonly used drug therapy for type  2 diabetes . in monotherapy , sitagliptin is expected to be effective for a wide range of diabetes patients , as well as cases of secondary sulfonylurea failure , but there are currently no reported results on the efficacy and safety of sitagliptin in large numbers of patients in actual clinical practice .
the study group of the diabetes committee has carried out several observational studies in kanagawa , such as looking at the prevalence of diabetic complications ( neuropathy and nephropathy ) .
our committee carried out a retrospective , observational study of sitagliptin , which was given to type  2 diabetes patients in the community by the diabetes specialists of our committee .
a largescale analysis of the efficacy and safety of sitagliptin monotherapy and combination therapy for 12  weeks in actual clinical practice , in which the primary outcome was glycated hemoglobin ( hba1c ) , is reported .
the survey participants were type  2 diabetes patients receiving outpatient treatment at 28 hospitals or clinics specializing in diabetes belonging to the diabetes committee of the kanagawa physicians association from december 2009 to august 2010 .
oral consent for participation in the present study was obtained from type  2 diabetes patients who were using diet and exercise therapy , and from patients with insufficient glycemic control despite the use of hypoglycemic agents .
sitagliptin monotherapy or sitagliptin in addition to other drugs was then given , starting at a dose of 25  mg or 50  mg .
if good glycemic control was not obtained after this , the sitagliptin dose could be increased to 100  mg .
the monotherapy group ( n  =  110 ) enrolled drugnaive patients who were given sitagliptin when glycemic control was inadequate on diet and exercise therapy , and the combination therapy group ( n  =  631 ) enrolled patients who were given sitagliptin in addition to the previously prescribed medications when other oral medications were insufficient . in order to evaluate the efficacy of sitagliptin without the effects of discontinuation of conventional drugs ,
those in whom one or more conventional antidiabetes drugs were discontinued at the start of sitagliptin were not enrolled .
the present study was an observational study that aimed to evaluate the efficacy and adverse events of sitagliptin , and approval was obtained from the ethics review board of the kanagawa physicians association . 
the patients baseline characteristics were as follows : monotherapy group , n  =  110 ( 64 men , 46 women ) , mean age 63.4    11.8  years , duration of diabetes 8.2    6.4  years and body mass index ( bmi ) 23.84    4.36 
kg / m ; and combination therapy group n  =  631 ( 360 men , 271 women ) , mean age 63.4    11.2  years , duration of diabetes 12.8    8.2  years and bmi 24.85    4.35  kg / m . in these combined 741 patients ( 424 men , 317 women ,
mean age 63.4    11.3  years , duration of diabetes 12.1    8.1  years , bmi 24.70    4.37  kg / m ) , hba1c , the primary outcome measure , was measured at the start , and after 4 and 12  weeks of sitagliptin therapy .
hba1c , expressed in national glycohemoglobin standardization program ( ngsp ) unitsequivalent value , was measured by highperformance liquid chromatography .
coadministered drugs in the combination therapy group were analyzed ( figure  1 ) , and the numbers of patients taking sulfonylureas , biguanides , pioglitazone , gi and glinides were 508 , 379 , 179 , 73 and 37 , respectively . of 508 patients ( 297 men , 211 women ,
mean age 64.3    10.7  years , duration of diabetes 13.8    8.2  years , bmi 24.50    4.30  kg / m ) using sulfonylureas , the dose of sulfonylurea was reduced at the start of sitagliptin in 66 patients and not reduced in 442 patients . in both the reduced and nonreduced sulfonylurea dose groups ,
hba1c was analyzed at baseline and after 4 and 12  weeks , and bodyweight was analyzed at baseline and after 12  weeks . to identify factors contributing to the achievement of hba1c < 7.0% and factors contributing to responsiveness to sitagliptin treatment after administration of sitagliptin for 12  weeks
, logistic regression analyses were carried out for age at baseline , sex , duration of diabetes , baseline bmi , baseline hba1c and whether hba1c < 7.0% was reached after 12  weeks or whether hba1c after12  weeks was decreased from the baseline value .
unresponsiveness to sitagliptin treatment was defined as hba1c after 12  weeks equal to or higher than baseline hba1c .
all analyses were carried out using spss version 19 for windows ( spss , chicago , il , usa ) .
statistical analysis comparing the baseline characteristics of the responsive and unresponsive groups was carried out using the mann 
the patients baseline characteristics were as follows : monotherapy group , n  =  110 ( 64 men , 46 women ) , mean age 63.4    11.8  years , duration of diabetes 8.2    6.4  years and body mass index ( bmi ) 23.84    4.36 
kg / m ; and combination therapy group n  =  631 ( 360 men , 271 women ) , mean age 63.4    11.2  years , duration of diabetes 12.8    8.2  years and bmi 24.85    4.35  kg / m . in these combined 741 patients ( 424 men , 317 women ,
mean age 63.4    11.3  years , duration of diabetes 12.1    8.1  years , bmi 24.70    4.37  kg / m ) , hba1c , the primary outcome measure , was measured at the start , and after 4 and 12  weeks of sitagliptin therapy .
hba1c , expressed in national glycohemoglobin standardization program ( ngsp ) unitsequivalent value , was measured by highperformance liquid chromatography .
coadministered drugs in the combination therapy group were analyzed ( figure  1 ) , and the numbers of patients taking sulfonylureas , biguanides , pioglitazone , gi and glinides were 508 , 379 , 179 , 73 and 37 , respectively . of 508 patients ( 297 men , 211 women ,
mean age 64.3    10.7  years , duration of diabetes 13.8    8.2  years , bmi 24.50    4.30  kg / m ) using sulfonylureas , the dose of sulfonylurea was reduced at the start of sitagliptin in 66 patients and not reduced in 442 patients . in both the reduced and nonreduced sulfonylurea dose groups ,
hba1c was analyzed at baseline and after 4 and 12  weeks , and bodyweight was analyzed at baseline and after 12  weeks . to identify factors contributing to the achievement of hba1c < 7.0% and factors contributing to responsiveness to sitagliptin treatment after administration of sitagliptin for 12  weeks
, logistic regression analyses were carried out for age at baseline , sex , duration of diabetes , baseline bmi , baseline hba1c and whether hba1c < 7.0% was reached after 12  weeks or whether hba1c after12  weeks was decreased from the baseline value .
unresponsiveness to sitagliptin treatment was defined as hba1c after 12  weeks equal to or higher than baseline hba1c .
all analyses were carried out using spss version 19 for windows ( spss , chicago , il , usa ) .
statistical analysis comparing the baseline characteristics of the responsive and unresponsive groups was carried out using the mann 
the analysis included 741 patients , 110 patients who received sitagliptin monotherapy and 631 patients who received combination therapy .
most patients in the combination therapy group had either two coadministered drugs ( 33.9% ) or one coadministered drug ( 33.6% ) , followed by three ( 15.5% ) and four coadministered drugs ( 2.2% ) .
the most common coadministered drugs were sulfonylureas ( 80.5% of the combination therapy group ) .
more than half ( 60.1% ) also used biguanides , followed by pioglitazone ( 28.4% ) , gi ( 11.6% ) and glinides ( 5.9% ) . in the monotherapy and combination therapy groups ,
hba1c was 7.88    1.54% and 8.07    1.06% , respectively , at the start of sitagliptin , decreasing significantly to 7.59    1.20% ( p  <  0.01 vs baseline ) and 7.71    0.97% ( p  <  0.01 vs baseline ) after 4  weeks and 7.09    0.71% ( p  <  0.01 vs baseline or 4  weeks ) and 7.31    0.88% ( p  <  0.01 vs baseline or 4  weeks ) after 12  weeks ( table  1 )
. the decrease in hba1c from baseline to 12  weeks ( hba1c 012  weeks ) was 0.79    1.33% points and 0.76    0.77% points , respectively .
the results of an analysis that was stratified on the basis of the baseline hba1c showed that hba1c 012  weeks was 1.45    1.21% points in the 8.5% group , 0.65    0.52% points in the 7.5% to < 8.5% group , and 0.34    0.44% points in the < 7.5% group . hba1c
012  weeks was larger in patients with higher baseline hba1c ( figure  2a ) .
anova : vs baseline * p  <  0.01 , vs 4  weeks * * p  <  0.01 .
( a ) change in hba1c between 0 and 12  weeks ; ( b ) proportion of patients with hba1c < 7.0% at 12  weeks . in all patients , the monotherapy group and the combination therapy group ,
the blood glucose treatment target of hba1c < 7% was achieved at rates of 39.1 , 44.5 and 38.2% , respectively . in all groups ,
a logistic regression analysis of all patients was carried out to identify factors that affect the achievement of hba1c < 7% .
the results showed that the strongest factor was hba1c at the start of sitagliptin therapy , whereas baseline bmi and duration of diabetes were also significant ( higher rates of patients with lower basal bmi or with shorter duration of diabetes are expected to achieve the target ; table  2 ) .
no correlation was seen for age , sex or whether the therapy was monotherapy or combination therapy .
individual differences in the glucoselowering effects of sitagliptin were observed in the present study , and 82 patients ( 11% ) were unresponsive to 12  weeks treatment with this drug .
the characteristics of the two groups ( 659 patients who responded and 82 patients who did not respond to sitagliptin ) are shown in table  3 .
the baseline bmi was significantly higher ( p  <  0.05 ) and the baseline hba1c was significantly lower ( p  <  0.01 ) in unresponsive patients than in patients who responded to sitagliptin .
a logistic regression analysis was also carried out to identify factors contributing to responsiveness to sitagliptin .
the results show that baseline hba1c ( odds ratio [ or ] 2.24 , 95% confidence interval [ ci ] 1.573.20 , p  <  0.01 ) and baseline bmi ( or 0.91 , 95% ci 0.860.97 , p  <  0.05 ) were significant factors .
bmi , body mass index ; hba1c , glycated hemoglobin ; ns , not significant .
sulfonylurea dosage was analyzed in the 508 combination therapy group patients , and the dosage trends for each sulfonylurea drug are shown in table  4 .
it was found that the dose decreased with time , even during the treatment course of up to 12  weeks .
administration of sulfonylurea drugs was discontinued in 18 patients during the 12  weeks ( glimepiride 12 patients , glibenclamide 4 patients and gliclazide 2 patients ) .
it was found that the sulfonylurea dose was reduced at the start of sitagliptin therapy in 66 patients ( 13.0% ) .
both the 66 patients in the reduced dose group and the other 442 patients in the nonreduced dose group showed significantly lower hba1c levels , from 7.97    0.77% to 8.11    1.08% at baseline to 7.31    0.76% ( p  <  0.01 ) and 7.38    0.92% ( p  <  0.01 ) at 12  weeks , respectively .
the respective hba1c 012  weeks values were 0.65    0.67% points and 0.73    0.77% points .
no significant difference in bodyweight was seen between baseline and 12  weeks in the nonreduced dose group , but a significant difference ( p  < 
0.05 ) was seen between bodyweight at baseline ( 62.15    15.00  kg ) and after 12  weeks ( 61.75    14.86  kg ) in the reduced dose group ( table  5 ) .
hypoglycemia occurred in 24 patients using sulfonylureas ( glimepiride 16 patients , glibenclamide 8 patients and gliclazide 0 patients ) .
all cases were mild , and the dose of sulfonylurea drugs was decreased after the occurrence of hypoglycemia in 20 patients , but there were no cases in which the administration of sitagliptin was discontinued .
gastrointestinal adverse events included constipation ( n  =  3 ) and abdominal bloating ( n  =  1 ) ; dizziness ( n  =  4 ) , eczema ( n  =  1 ) and edema ( n  =  1 ) were also reported .
four patients dropped out because of adverse events : constipation ( n  =  1 ) , eczema ( n  =  1 ) and dizziness ( n  =  2 ) . in these patients , all symptoms improved after sitagliptin was discontinued .
dpp4 inhibitors have a novel mechanism of action , and their efficacy and safety in monotherapy or combination therapy with conventional oral diabetes drugs have not yet been reported in large numbers of patients in actual clinical settings . in the present observational study of japanese type  2
diabetes patients receiving sitagliptin , a very large number of patients ( 741 patients ) was enrolled .
the analyses included 110 monotherapy patients and 631 combination therapy patients at 3  months after the start of sitagliptin .
it was found that , in the combination therapy group , sitagliptin was used together with a wide range of 14 other drugs .
sulfonylurea drugs were the most common coadministered drugs , used in approximately 80% of cases . in recent results for type  2
diabetes patients being treated by diabetes specialists in japan , sulfonylurea was used in more than 60% of patients treated with oral drugs .
the accumulated results for coadministered drugs in the present study are thought to reflect this state of oral drug use in japan . in the current patient group ,
hba1c decreased significantly in both the sitagliptin monotherapy and combination therapy groups after administration for 12  weeks , whereas hba1c 012  weeks was 0.79    1.33% points and 0.76    0.77% points , respectively .
the glycemic control target is a hba1c of < 7% to prevent diabetic complications , and with the administration of sitagliptin , this target was achieved in 39.1% of all 741 patients after administration for 12  weeks . in a metaanalysis of sitagliptin ,
the hba1c < 7% achievement rate was reported to be approximately 40% , similar to the results in the present study . in actual clinical practice ,
glycemic control is attempted with various drug combinations depending on the patient s condition and other factors , and sitagliptin was shown to be efficacious even in these various combinations .
the effect of sitagliptin is also known to vary greatly among individuals . in the present study , therefore , with the aim of identifying factors that contribute to achieving the target of hba1c < 7% , a regression analysis was carried out in which the dependent variable was whether the target hba1c of < 7% had been reached at 12  weeks , and the explanatory variables were patient background and baseline hba1c .
three factors were found to have significant effects : ( i ) baseline hba1c ; ( ii ) baseline bmi ; and ( iii ) duration of diabetes .
similar to earlier reports , it was also found that patients with a low baseline hba1c were more likely to reach the target hba1c . however , this is the first report to show that patients with low baseline bmi and patients with short duration of diabetes have a higher rate of achieving the target hba1c .
the two factors of baseline bmi and duration of diabetes were much weaker than baseline hba1c , but they were identified as significant factors . because these two factors have been shown to affect the hypoglycemic action of sitagliptin , the hypoglycemic characteristics of sitagliptin might also affect the target achievement rate .
the characteristics of the glucoselowering effects of sitagliptin were also examined in the patients who were responsive and those who were unresponsive to sitagliptin treatment .
overall , 11% of patients were unresponsive to sitagliptin , and the baseline bmi was significantly higher and the baseline hba1c was significantly lower in the unresponsive group than in the responsive group .
the subsequent logistic regression analysis showed that these two factors , baseline bmi and hba1c , were significantly related to responsiveness to sitagliptin therapy .
although the regulation of incretin systems and the actions of dpp4 inhibitors have been under intensive investigation , they are not fully understood .
therefore , the mechanisms by which baseline bmi and duration of diabetes contribute to the efficacy of dpp4 inhibitors are still unknown .
interestingly , given that it has been reported that people with low bmi secrete a large amount of glp1 , at least some of the contribution of bmi to the efficacy of dpp4 inhibitors can be explained by differences in glp1 secretion .
japanese people have genetically low insulin secretion , and sulfonylurea drugs are the most commonly used drugs for the treatment of type  2 diabetes in japan . as the glycemic control of many such patients has not reached the target level , there is much interest in the efficacy of sulfonylurea drugs combined with sitagliptin .
the results of the present study show that significant glycemic control improvement was achieved in patients whose glycemic control was inadequate even with therapy centered on sulfonylurea drugs .
in addition , an analysis of the trends in sulfonylurea dosage showed that the sulfonylurea dose was greatly decreased compared with before the administration of sitagliptin .
thus , it was shown that good glycemic control could be achieved with lower sulfonylurea doses by administering sitagliptin .
these results suggest that cell function is actually well activated with combined use of sulfonylurea drugs and dpp4 inhibitors , although the effect of sitagliptin to lower glucagon might also contribute to the reduced sulfonylurea doses .
it is coming to be understood that incretin not only promotes the insulin release reaction in cells , but it also stimulates the insulin secretion response through multiple actions , such as promoting adenosine triphosphate generation in mitochondria , and both sulfonylurea and incretin act on exchange protein directly activated by cyclic adenosine monophosphate  2a in cells .
therefore , incretin and sulfonylurea are supposed to stimulate insulin secretion in coordinated and synergistic manners , and the present results appear to reflect these stimulatory effects of incretin and sulfonylureas on pancreatic cells .
of particular note is that bodyweight was also significantly , even in the short observation period of 12  weeks when the sulfonylurea dose was decreased at the start of sitagliptin therapy .
it was shown in the present study that , by reducing the dose of sulfonylurea drugs , with which bodyweight is known to increase over time , and adding dpp4 inhibitors , which have been shown to be neutral with regard to bodyweight , bodyweight decreased in actual treatment cases .
as weight gain is an undesirable effect of sulfonylurea therapy , weight loss is thought to be a positive characteristic of the combined use of sulfonylurea drugs and sitagliptin . in an investigation of the safety of combination therapy with sitagliptin and sulfonylurea drugs , the most common adverse event was hypoglycemia , although it was mild in all cases .
the dose of sulfonylurea drugs was decreased after the occurrence of hypoglycemia in 20 patients , but there were no cases in which the administration of sitagliptin was discontinued .
the present paper has presented the results of an analysis of a very large number of patients receiving sitagliptin monotherapy and combination therapy in actual clinical settings . however , because this was an observational study without control , the results of the present study could include some limitations , such as bias in selecting patients .
in addition , because the observational period of the present study was 12  weeks , longerterm investigation about the durability of the efficacy and about the safety of sitagliptin treatment will be required , which is now being carried out .
the analysis showed that sitagliptin is widely used in actual treatment , and its efficacy in both monotherapy and combination therapy was shown .
in particular , with the addition of sitagliptin in cases when an insufficient effect is obtained with sulfonylurea drug therapy , we can expect not only improved glycemic control , but also a reduction in sulfonylurea dose and decreased bodyweight .
this is thought to be a desirable characteristic of dpp4 inhibitor combination therapy , and it will be important to take advantage of this characteristic in diabetes therapy . these results showing the efficacy and safety of sitagliptin will surely be of value to clinical practitioners .
 abstract 
 ( j diabetes invest , doi : 10.1111/j.20401124.2012.00221.x , 2012 ) 
 aims / introduction :   to determine the efficacy and safety of sitagliptin monotherapy and combination therapy in japanese type  2 diabetes patients after 3  months therapy.materials and methods :   a retrospective , observational study of 741 type  2 diabetes patients was carried out ; 110 received sitagliptin monotherapy , and 631 received combination therapy with sitagliptin when other oral medications were insufficient . 
 the primary outcome measure was glycated hemoglobin ( hba1c ) measured at 0 , 4 and 12  weeks of sitagliptin therapy.results :   in the monotherapy and combination therapy groups , hba1c decreased significantly after 12  weeks . 
 target hba1c 
 ( < 7% ) was achieved in 39.1% overall . on logistic regression analysis , 
 baseline hba1c was the strongest contributing factor for achieving target hba1c ; baseline body mass index and duration of diabetes were also significant factors . 
 a total of 82 patients ( 11% ) were unresponsive to sitagliptin . 
 these patients baseline body mass index was significantly higher and their baseline hba1c was significantly lower than those of patients who responded to sitagliptin . 
 the most commonly coadministered drugs were sulfonylureas ( 508 patients ) . in these patients , 
 the dose of sulfonylurea decreased with time . in 66 patients 
 whose sulfonylurea dosage was reduced when sitagliptin was started , hba1c and bodyweight decreased significantly after 12  weeks . 
 a total of 24 patients receiving sulfonylureas had mild hypoglycemia , but none discontinued sitagliptin.conclusions :   sitagliptin was effective and safe as both monotherapy and combination therapy in japanese type  2 diabetes patients . when sulfonylureas were ineffective , sitagliptin improved glycemic control . in patients 
 whose sulfonylurea dose was reduced at the start of sitagliptin , blood glucose improved and bodyweight decreased after 12  weeks . 
Introduction
Materials and Methods
Outcome Measures
Statistical Analysis
Results
Discussion