teneligliptin is a novel dipeptidyl peptidase4 ( dpp4 ) inhibitor belonging to the relatively novel pharmacological class of antihyperglycaemic agents that are now recommended as second or firstline agents in specific situations 1 , 2 , 3 . in a phase
ii clinical trial , a 4week course of teneligliptin ( 20  mg ) monotherapy produced significant least squares ( ls ) mean reductions of 2.78    0.43 , 1.93    0.51 , and 2.08    0.42 
mmol / l in 2h postprandial glucose level after breakfast , lunch and dinner , respectively , in japanese patients with type 2 diabetes ( t2 dm ) 4 .
we therefore conducted the present phase iii , randomized , doubleblind , placebocontrolled study to assess the clinical efficacy and safety of teneligliptin in korean patients with t2 dm that was inadequately controlled with diet and exercise .
the present study was designed to confirm the efficacy and safety of teneligliptin compared with placebo .
the study was conducted in accordance with the principles of good clinical practice and was approved by the appropriate institutional review boards and regulatory agencies .
participants considered eligible for the study were patients aged 18  years with t2 dm inadequately controlled [ glycated haemoglobin ( hba1c ) 7.0% and < 10.0% ] through diet and exercise for 8  weeks , who had not taken an oral antihyperglycemic agent ( oha ) for 8  weeks .
exclusion criteria included current or history of significant comorbidities such as cardiovascular , hepatic or renal disease .
patients with adequate compliance ( 80% ) after a 2week singleblind placebo runin period underwent baseline evaluation and were randomized according to hba1c ( using an 8.0% threshold ) into two parallel groups ( teneligliptin and placebo ; 2  :  1 matching ) for 24  weeks .
( hba1c < 7 and < 6.5% ) , changes in fasting plasma glucose ( fpg ) , and homeostatic model assessment of insulin resistance ( homair ) and cell function ( homa ) at week 24 .
subjects who did not meet progressively stricter glycaemic goals immediately stopped the study without rescue therapy and underwent the evaluation planned for the final visit . these subjects were included in our analysis .
threeway analysis of variance ( anova ) was used to compare the primary endpoint between the treatment groups with baseline hba1c and previous antihyperglycaemic agents as fixed effects . for other endpoints ( fpg ,
homa and homair ) , analysis of covariance was used with previous antihyperglycaemic agents as fixed effects and baseline hba1c as a covariate .
the differences between the parallel groups were calculated as ls means    standard error ( s.e . ) .
responder rate ( hba1c < 6.5% , hba1c < 7.0% ) was analysed using multiple logistic regression analysis with the same factors as used in the threeway anova .
of the 222 subjects screened , 142 eligible subjects were randomized to treatment as follows : 99 received teneligliptin and 43 received placebo . in total ,
our analysis set consisted of 141 subjects for whom baseline and postbaseline values of the primary efficacy endpoint were available ( figure s1 , file s1 ) .
the treatment groups were not significantly different with respect to demographic or clinical characteristics ( table s1 , file s1 ) .
the mean baseline hba1c value was 7.63% in the teneligliptin group and 7.77% in the placebo group .
the changes in hba1c from baseline to week 24 in the teneligliptin and placebo groups were ls mean    s.e .
0.09% and 0.03    0.12% , respectively ( p  <  0.001 ; table 1 ) . a greater decrease in hba1c was observed with teneligliptin compared with placebo at week 8 , which was sustained throughout the randomized treatment period ( figure 1 ) .
significantly more subjects in the teneligliptin group achieved an hba1c level of < 7% at week 24 than in the placebo group ( 69.39% in the teneligliptin group vs 20.93% in the placebo group ; p  <  0.001 ; figure s2 , file s1 ) .
approximately 34.69% of all subjects in the teneligliptin group achieved an hba1c level < 6.5% at week 24 , whereas only 4.65% achieved this level in the placebo group ( p  =  0.0016 ; figure s2 , file s1 ) . in subgroup analysis of subjects with high or low hba1c level ( 8.0 or < 8.0% ) at baseline , the effect of teneligliptin was greater in the hba1c 8.0% group ( 1.15    0.99% , n  =  25 ) than in the hba1c < 8.0% group ( 0.69    0.70% , n  =  73 ; p  =  0.0019 ) . effects of teneligliptin and placebo on glucose metabolism between baseline and week 24 . 

ci , confidence interval ; fpg , fasting plasma glucose ; hba1c , glycated haemoglobin ; homa , homeostatic model assessment of cell function ; homair , homeostatic model assessment of insulin resistance ; s.d . , standard deviation ; s.e . ,
* according to threeway analysis of variance ( anova ) . * * p  <  0.0001 versus placebo according to threeway anova . 

teneligliptin decreased the fpg level from baseline to week 24 , while the fpg level did not change in the placebo group . at week 24 , the difference in change in fpg between the two groups was 1.21 
mmol / l [ 95% confidence interval ( ci ) 1.72 , 0.70 ; p  <  0.0001 ( table 1 ) ] .
cell function , as assessed by homa , was improved in the teneligliptin group at week 24 but not in the placebo group . at week 24 , the difference in homa change between the groups was 12.23% [ 95% ci 5.78 , 18.67 ; p  =  0.0003 ( table 1 ) ] .
the teneligliptin group exhibited an improved homa score compared with the placebo group at week 8 and throughout the randomized treatment period ( figure s3 , file s1 ) .
no significant difference in homair was observed between the two treatment groups . during this study , 81 adverse events ( aes ) occurred in 49 ( 34.5% ) of the 142 randomized subjects . among the 81 aes , 43 occurred in 29 ( 29.59% ) teneligliptintreated subjects , and 38 occurred in 20 ( 45.5% ) placebotreated subjects .
the incidences of aes were not significantly different between the two groups at week 24 ( p  =  0.0660 ) .
hypoglycaemia occurred in one case in the placebo group but in no cases in the teneligliptin group .
the results of the present study showed that 24  weeks of teneligliptin as a monotherapy was well tolerated and significantly decreased the hba1c level in korean patients with t2 dm .
this is the first 24week , phase iii , doubleblind , randomized , placebocontrolled study on the efficacy and safety of teneligliptin . at present , more than five competitive reversible inhibitors are currently on the market , and each has different characteristics . a cochrane review that included 11 trials with sitagliptin and 14 trials with vildagliptin reported reductions in hba1c level of 0.7% and 0.6% , respectively , compared with placebo 5 . another dpp4 inhibitor , saxagliptin , was also shown to reduce hba1c by 0.450.63% compared with the placebo group 6 . in a recent phase ii study with 12  weeks of teneligliptin treatment ( n  =  324 ) , significant ls mean reductions in hba1c for 10 , 20 and 40mg groups vs a placebo group
were 0.9% ( 95% ci 1.0 , 0.7 ) , 0.9% ( 95% ci 1.1 , 0.7 ) , and 1.0% ( 95% ci 1.2 , 0.9 ) , respectively ( all p  <  0.001 ) 7 .
another recent study assessed the efficacy of teneligliptin when added to an ongoing metformin treatment at week 16 , and the mean reductions in hba1c and fasting plasma glucose level compared with placebo were 0.78% and 1.24  mmol / l , respectively 8 .
the results of the present study in week 8 are consistent with these previous reports .
specifically , the differences in changes ( baseline to week 8) in hba1c and fpg between the teneligliptin 20mg group and the placebo group were 0.80% ( 95% ci 1.02 , 0.59 ) and 0.95  mmol / l ( 95% ci 1.37 , 0.53 ) , respectively ( all p  <  0.001 ) .
moreover , the differences in hba1c and fpg changes between the teneligliptin 20mg group and the placebo group were maintained until week 24 [ 0.94% ( 95% ci 1.22 , 0.65 ) and 1.21  mmol / l ( 95% ci 1.72 , 0.70 ) , respectively ( all p  <  0.001 ) ] , and a large proportion ( 69.39% ) of patients achieved an hba1c level < 7% compared with those using other dpp4 inhibitors ( 40% ) 9 , 10 , 11 . according to our results , teneligliptin has similar efficacy in the treatment of diabetes to other orally administered dpp4 inhibitors .
cell destruction is key to the pathophysiology of t2 dm , and cell conservation delays disease progression 12 .
improvements in cell function have been observed in clinical trials with the dpp4 inhibitors sitagliptin , saxagliptin , vildagliptin , alogliptin and linagliptin 13 , 14 , 15 , 16 , 17 .
teneligliptin also resulted in increased homa index relative to placebo in the present study , suggesting that , like other dpp4 inhibitors , teneligliptin modestly improves pancreatic function . in the present study ,
the incidences of aes and adverse drug reactions were not significantly different between the teneligliptin and placebo groups at week 24 .
together , these results indicate that teneligliptin is well tolerated and safe in korean patients with diabetes . in conclusion
, this study showed that 20  mg of teneligliptin exhibits efficacy and safety after 24  weeks when administered once daily as a monotherapy to korean patients with t2 dm who are adhering to a diet and exercise control programme .
k. a. , c. h. , b. j. , h. c. , c. w. , m.k .
baseline characteristics . 
 table s2 effects of teneligliptin and placebo on weight , and lipid profiles between baseline and week 24 .
percentage of responders with hba1c < 7.0 or < 6.5% from baseline to week 24 .
* p  <  0.0001 vs. placebo by multiple logistic regression analysis with adjustment for hba1c ( < 8.0 or 8.0 ) and for antidiabetic medication ( prior to the study ) .
* * p  <  0.05 vs. placebo by multiple logistic regression analysis with adjustment for hba1c ( < 8.0 or 8.0 ) and for antidiabetic medication ( prior to the study ) . * * * p  <  0.005 vs. placebo by multiple logistic regression analysis with adjustment for hba1c ( < 8.0 or 8.0 ) and for antidiabetic medication ( prior to the study ) .
changes in mean homa score throughout the randomized treatment period . * by ancova . *
 we assessed the 24week efficacy and safety of teneligliptin , a novel dipeptidyl peptidase4 inhibitor , in korean patients with type 2 diabetes mellitus ( t2 dm ) that was inadequately controlled with diet and exercise . 
 the present study was designed as a multicentre , randomized , doubleblind , placebocontrolled , parallelgroup , phase iii study . 
 patients ( n  =  142 ) were randomized 2  :  1 into two different treatment groups as follows : 99 received teneligliptin ( 20  mg ) and 43 received placebo . 
 the primary endpoint was change in glycated haemoglobin ( hba1c ) level from baseline to week 24 . 
 teneligliptin significantly reduced the hba1c level from baseline compared with placebo after 24  weeks . at week 24 , the differences between changes in hba1c and fasting plasma glucose ( fbg ) in the teneligliptin and placebo groups were 0.94% [ leastsquares ( ls ) mean 1.22 , 0.65 ] and 1.21  mmol / l ( 1.72 , 0.70 ) , respectively ( all p  <  0.001 ) . 
 the incidence of hypoglycaemia and adverse events were not significantly different between the two groups . 
 this phase iii , randomized , placebocontrolled study provides evidence of the safety and efficacy of 24  weeks of treatment with teneligliptin as a monotherapy in korean patients with t2 dm . 
Introduction
Methods
Results
Discussion
Conflict of Interest
Supporting information