the most common combination of oral antihyperglycaemic agents used for patients with type 2 diabetes is metformin and sulphonylurea [ 1 , 2 ] . despite good initial efficacy , for most patients , this dual therapy is associated with progressive worsening of blood glucose control over time , requiring additional medication . clinicians and researchers currently debate the question of which additional agent is best in this situation [ 4 , 5 ] . in clinical studies , dpp-4 inhibitors have been shown to improve hba1c significantly when administered as monotherapy or as dual therapy in conjunction with metformin or a sulphonylurea [ 611 ] . however , information on its use as a third agent in triple therapy is relatively scant . two studies have demonstrated the efficacy of dpp-4 inhibitors when added to the metformin and sulphonylurea combination [ 12 , 13 ] . also of interest is a meta - analysis of 55 studies that has suggested that dpp-4 inhibitors may be more effective in asian patients . as type 2 diabetes is becoming more common in asia with the progressive increase in affluence of this region , it is important to determine if the better response to dpp-4 inhibitors in asian patients can be confirmed . the purpose of the present study is , therefore , to examine the efficacy of dpp-4 inhibitors when given as add - on therapy to the combination of metformin and sulphonylurea in patients with type 2 diabetes and suboptimal glycaemic control . whether asian patients respond better to triple therapy was also determined . patients were selected from those who attended the diabetes centre of royal prince alfred hospital , sydney , australia . their clinical and demographic data were extracted from a purpose built diabetes database which included approximately 25,000 patients collected over two decades . a total of 688 patients with type 2 diabetes were found to be treated with dpp-4 inhibitor ( sitagliptin , linagliptin , saxagliptin , or vildagliptin ) over the previous 5 years ( from 2008 to 2013 ) . amongst these , 169 patients were on triple oral therapy using sulphonylurea , metformin , and dpp-4 inhibitors . from this group , patients were selected for this analysis if they met the following exclusion and inclusion criteria : added dpp-4 inhibitor at the maximum recommended dosage to the combination of metformin and sulphonylurea treatment ( metformin > 1.5  gm / day or > 1.0  gm / day if on xr preparation , or maximum tolerated dose ; diamicron > 160  mg / day , diamicron mr  60  mg / day , amaryl 4  mg / day , or minidiab 10  mg / day);had no change in the dosage of sulphonylurea or metformin after dpp-4 inhibitor was added;remained on triple therapy for 12 weeks;had hba1c results available ( i ) within the 12 months prior to and ( ii ) between 3 to 12 months after addition of dpp-4 inhibitor therapy;were not on insulin or glp agonist or other diabetes medications.eighty-nine patients were excluded from the analysis . of these , 49 were on dpp-4 inhibitors as the second agent of the triple therapy and 40 had hba1c measured at a time outside the specified window . ethnicity of the individuals was determined by self - report of the patients ( asian group n = 41 : 36 chinese and 5 from the indian subcontinent ; non - asian group n = 39 : 21 anglo - celtics , 3 middle eastern , 1 indigenous australians , and 14 europeans ) . permission to record and analyze the computerized data was given by the ethics committee of the hospital . added dpp-4 inhibitor at the maximum recommended dosage to the combination of metformin and sulphonylurea treatment ( metformin > 1.5  gm / day or > 1.0  gm / day if on xr preparation , or maximum tolerated dose ; diamicron > 160  mg / day , diamicron mr  60  mg / day , amaryl 4  mg / day , or minidiab 10  mg / day ) ; had no change in the dosage of sulphonylurea or metformin after dpp-4 inhibitor was added ; remained on triple therapy for 12 weeks ; had hba1c results available ( i ) within the 12 months prior to and ( ii ) between 3 to 12 months after addition of dpp-4 inhibitor therapy ; were not on insulin or glp agonist or other diabetes medications . numerical data are presented as percentage or mean  standard deviation or median and interquartile range . the change in hba1c before and after dpp-4 inhibitor add - on treatment was the primary endpoint and tested by student 's t - test , wilcoxon signed rank test , or analysis of variance ( anova ) . the change in hba1c was examined as the dependent variable and tested against duration of diabetes , gender , body mass index ( bmi ) , age , ethnicity , and baseline hba1c as independent variables by multiple regression analysis . the change in hba1c was also studied by analysis of covariance adjusted for baseline hba1c , duration of diabetes , bmi , and ethnicity . statistical significance was based on 2-sided tests and accepted at the p < 0.05 level . amongst the 80 patients studied , 64 were taking sitagliptin , 12 were on saxagliptin , and 4 were on vildagliptin . after triple oral therapy duration of 4.6 ( 3.66.6 ) months , their mean hba1c decreased from 8.3% ( 7.78.9 ) [ 67  mmol / mol , 6174 ] to 7.2% ( 6.87.6% ) [ 55  mmol / mol , 5160  mmol / mol ] with 26 patients ( 32.5% ) achieving an hba1c of < 7% ( 53  mmol / mol ) . weight before ( 79.6  19.5  kg ) and after ( 78.8  19.3  kg ) triple therapy did not change significantly in the 66 patients with readings available before and after this treatment . the mean changes in hba1c from pre- to posttriple therapy , according to clinical characteristics , are shown in table 2 . patients with higher baseline hba1c , absence of obesity , and younger age showed a greater response . by multiple regression analysis gender , the duration of diabetes , and bmi analyzed as a continuous variable were not significant factors . the duration of triple therapy analyzed categorically (  or < 6 months ) or by regression did not affect response ( r = 0.17 ) . the asian and non - asian groups have similar age , duration of diabetes , and baseline glycaemic control . the hba1c reduction after the implementation of triple therapy was not different between the asian ( 1.00 , 0.61.3% ) and non - asian group ( 0.90 , 0.41.6% ) . metformin and sulphonylurea are commonly prescribed together in patients with type 2 diabetes [ 1 , 2 ] . when such combination therapy can no longer maintain acceptable glycaemic control , many other antihyperglycaemic agents are available to be added as the third agent of triple therapy . mcintosh et al . conducted a systematic review and meta - analysis of 33 controlled trials to evaluate the comparative safety and efficacy of various classes of antihyperglycaemic therapies in this scenario . insulins , dpp-4 inhibitor , glucagon - like peptide-1 ( glp-1 ) analogues , and thiazolidinediones ( tzds ) all produced statistically significant reductions in hba1c ranging from 0.89% to 1.17% , whereas meglitinides and alpha - glucosidase inhibitors did not . in their analysis , insulins and tzds were associated with weight gain of 1.855.00  kg , glp-1 analogues were associated with modest weight loss , and dpp-4 inhibitor was weight - neutral and did not show any increase in hypoglycaemia which was found when insulin was used . in the analysis of mcintosh , only one dpp-4 inhibitor ( sitagliptin ) was included and when used in triple therapy , a fall in hba1c of 0.89% was demonstrated . in another study not included in the analysis , linagliptin administrated for a 24-week period as triple therapy significantly improved glycaemic control ( hba1c , 0.62% ) and was well tolerated . study showed that sitagliptin as the 4th agent also reduced hba1c by about 1% when added to the combination of metformin , sulphonylurea , and glucosidase - inhibitor . based on these studies , dpp-4 inhibitorsas a third - line oral antihyperglycaemic agent appear to be effective and safe , without weight gain . overall , despite its increasing usage , there have been few reports on the efficacy of dpp-4 inhibitors as the third oral agent in a clinical setting . also of considerable interest , kim et al . in their review of dpp-4 inhibitors provided evidence that this class of agents may be more effective in asian patients . however , the great majority of the studies included in the analysis pertained to mono- or dual therapies . the categorization of ethnicity was not based on an individual patient basis . instead , it assigned the total cohort of a trial as asian or non - asian ethnicity according to whether the study included more or less than 50% asian participants or was conducted in an asian dominant country . the superiority of any pharmacological agent in an asian population could have important medicoeconomic implications due to the high and progressively increasing prevalence of diabetes in asia . based on these considerations we have audited the efficacy of dpp-4 inhibitors as the third oral agent in our clinic and also made comparison of the response in asian and non - asian patients . our results confirmed the usefulness of dpp-4 inhibitors in improving glycaemic control in this context . one - third of patients reached an optimal level of glycaemic control , as defined by an hba1c of less than 7% ( 53  mmol / mol ) . the efficacy of dpp-4 inhibitors in this clinical setting seems quite effective although we could not dissect out the impact of a concerted effort at lifestyle changes by the patients when faced with the possibility of insulin requirement . baseline glycaemic control , degree of obesity , and age of patients were identified by both univariate and multivariate analyses to be important determinants of response . not unexpectedly , the drop in hba1c was greater in those with worse initial glycaemic control . there was also a better response in those with lesser obesity , perhaps a reflection that these subjects are relatively more insulin deficient than insulin resistant in the pathogenesis of their diabetes . they would be expected to respond better to an agent that can increase insulin availability . our observation that the younger patients appeared to respond better is a potential advantage of the ddp-4 inhibitors as the need for better glycaemic control is obviously more in this age group . it is interesting that duration of diabetes does not seem to impair response , suggesting that the ability of dpp-4 inhibitors to augment meal associated insulin secretion does not decline with time of having diabetes . moreover , there was no evidence of a significant decline in its efficacy up to 12 months of such triple therapy . however , the benefits of such treatment regimen for the longer term would need to be examined . the findings of seino et al . suggest a better response of asian patients to dpp-4 inhibitors , raising the possibility that patients of asian ethnicity have relatively more defects in meal associated insulin secretion [ 17 , 18 ] . a better response to glucagon - like peptide analogues in asians has also been shown in a meta - analysis . our study did not provide evidence to support this notion of difference in ethnic response . in comparison with the reviews and meta - analyses mentioned above , our study has the advantage of categorizing ethnicity specifically at an individual level but had examined only 80 subjects . therefore , we can not exclude the possibility that a small difference may be missed . our study also only examined patients on triple oral agent therapy which was not comprehensively evaluated in the kim analysis . so the possibility remains that asian patients would respond better to dpp-4 inhibitors in mono- or dual therapies . being a retrospective study , we can not be certain that there was no selection bias for using dpp-4 inhibitor as the third agent but , during the period examined , the safety of the thiazolidinediones had come into question and the sglt-2 inhibitors were not yet available . it would have been informative to know the relative efficacy of the dpp-4 inhibitor in comparison with insulin or glp - agonist in this clinical scenario . however , this would require a randomized clinical trial and is beyond the scope of this analysis . however , our study confirmed the effectiveness of dpp-4 inhibitors as the third oral agent in improving glycaemic control in type 2 diabetes .
aims . 
 the aim of this study is to examine the efficacy of adding a dipeptidyl peptidase-4 ( dpp-4 ) inhibitor to patients with type 2 diabetes inadequately controlled by metformin and sulphonylurea combination treatment . 
 the response of asian and non - asian patients to this regimen was also examined . methods . 
 the medical and computerized records of 80 patients were examined . 
 these patients had baseline hba1c levels ranging from 7.0 to 12.5% and had a dpp-4 inhibitor add - on therapy for a minimum period of 12 weeks . 
 the primary endpoint was the change in hba1c level before and after dpp-4 inhibitor treatment . 
 results . during oral triple therapy 
 , there was a reduction of hba1c from 8.3% ( 7.78.9 ) to 7.2% ( 6.87.6 ) and 26 patients ( 32.5% ) achieved an hba1c < 7% . 
 poor baseline glycaemic control , lower bmi , and younger age were associated with a better response , but duration of diabetes and gender did not affect outcome . 
 the hba1c reduction was not different between asians and non - asians group [ 1.00% ( 0.61.3 ) vs 0.90% ( 0.41.6 ) ] . 
 conclusions . 
 dpp-4 inhibitor as a third - line add - on therapy can achieve significant glycaemic improvement in patients with type 2 diabetes inadequately controlled on the combination of metformin and sulphonylurea . 
 the improvement in hba1c was similar between asian and non - asian patients .