type 2 diabetes mellitus ( t2 dm ) is a common chronic health condition in the elderly . the number of elderly t2 dm patients has been growing worldwide , especially in upper - middle income countries such as thailand . based on the findings of the fourth thai national health examination survey in 2009 , diabetes was most prevalent in women , the elderly , and urban areas . the prevalence of impaired fasting glucose and undiagnosed diabetes increased with age , peaking at age 75 years and 5564 years , respectively.1 diabetes in the elderly is associated with a greater risk of t2dm - related micro- and macrovascular complications , cognitive disorders , physical disability , morbidity , and mortality;25 the selection of antidiabetic treatment for elderly t2 dm patients poses many challenges for a number of reasons . first , elderly t2 dm patients have a greater incidence of hypoglycemia6 which can precipitate serious events such as falls and accompanying fractures . the study by zhao et al7 showed that hypoglycemia patients had higher rates of fall - related fractures than those without hypoglycemia , within 30 days and 1 year ( 0.64% vs 0.02% and 2.11% vs 0.50% , respectively ) . second , elderly t2 dm patients are more likely to have comorbidities with their diabetes , leading to the use of polypharmacy.4,8,9 third , chronic kidney disease often occurs in elderly t2 dm patients;10 the prevalence of chronic kidney disease among t2 dm patients in australia,11 india,12 finland,13 singapore,14 and the us15 ranged from 40% to 70% . with these associated challenges for elderly t2 dipeptidyl peptidase-4 ( dpp-4 ) inhibitors show particular promise for treating elderly t2 dm patients because they have excellent tolerability profiles , low risk of hypoglycemia , and little effect on body weight.4,16,17 therefore , this study evaluated the cost - effectiveness of dpp-4 inhibitor monotherapy compared with sulfonylurea ( sfu ) monotherapy or metformin monotherapy for treating elderly t2 dm patients in the thai context . from a thai health care system perspective , we conducted a cost - utility analysis and used a validated ims core diabetes model ( cdm ) , version 8.5 , to estimate long - term costs and outcomes associated with each treatment over a lifetime horizon . details of this model are described elsewhere.18,19 a 3% discount rate per annum was applied to both costs and outcomes in line with the thai health technology assessment ( hta ) guideline.20 the cohort population was thai people with t2 dm aged at least 65 years . table 1 presents the baseline demographics , risk factors , and clinical complications of the cohort , which were obtained from published data and hospital databases in thailand.2128 the all - cause mortality rate was also adjusted with the age - specific mortality rate of thai people.29 utility values used in the cdm were based mostly on published studies conducted in other countries.3034 this study was approved by the buddhachinaraj regional hospital ethics committee on august 8 , 2014 . as the patient data is de - identified patient consent was not required . these medications were administered as a monotherapy and then compared with either metformin monotherapy or sfu monotherapy . metformin and sfu are considered as usual care for elderly t2 dm patients in thailand . second , we convened a panel of stakeholders to discuss the scope and appropriate comparators of the study , including endocrinologists , and policy makers , and then followed the consensus of the meeting . this study used the normal daily dose of each treatment option : saxagliptin ( 5 mg ) , sitagliptin ( 100 mg ) , vildagliptin ( 100 mg ) , glipizide ( 10 mg ) , and metformin ( 2,000 mg ) . only the direct medical costs , such as cost of intervention , concurrent medications , diabetic screening , management , and treatment complications , were included in the cost - effectiveness analysis . cost data were derived from the published literature and retrospective hospital database analyses ( table 2).3641 all costs were inflated using thailand s consumer price index42 and presented in the year 2014 thb value . costs were converted to us$ at a rate of thb32.96 per us$ as of december 30 , 2014.43 the cost of dpp-4 inhibitors was proposed to the subcommittee for the development of the national list of essential medicine by the pharmaceutical companies . total cost per year of saxagliptin , sitagliptin , and vildagliptin was thb13,492 ( us$409.34 ) , thb16,570 ( us$502.73 ) , and thb15,900 ( us$482.40 ) , respectively . glipizide and metformin we used a median of the median prices of those generic products44 as recommended by the thai hta guideline.45 the annual total costs of metformin and sfu were thb496 ( us$15.05 ) and thb149 ( us$4.52 ) , respectively . due to limited evidence of treatment efficacy in thailand , we performed a systematic review and meta - analysis to estimate the pooled efficacy of dpp-4 inhibitor monotherapy compared to sfu monotherapy and metformin monotherapy in elderly t2 dm patients . the medline , embase , and clinicaltrial.gov databases were systematically searched from their inception to august 2014 . we found only one study46 that indicated noninferiority of alogliptin compared to glipizide in hba1c reduction ( the weighted mean difference 0.09 ; 95% ci ,  to 0.06 ) , substantially lower risk of hypoglycemia ( risk ratio [ rr ] 0.21 ; 95% ci , 0.110.41 ) , lower risk of severe hypoglycemia ( rr 0.23 ; 95% ci , 0.031.99 ) , and no weight gain with dpp-4 inhibitor monotherapy compared to glipizide monotherapy in elderly t2 dm patients ( table 3 ) . three studies5,47,48 compared metformin with dpp-4 inhibitor monotherapy and concluded that dpp-4 inhibitor was an effective and well - tolerated treatment option for elderly t2 dm patients . in addition , reduction in hba1c after treatment with dpp-4 inhibitors in elderly t2 dm patients was not significantly different from those in younger patients.49 therefore , we decided to systematically search a meta - analysis study that compared dpp-4 inhibitor monotherapy with metformin monotherapy in t2 dm patients , and found two eligible studies.50,51 both were high quality studies ( with scores of at least 9 of 11 ) based on the assessment of multiple systematic reviews , we decided to use wu et als51 meta - analysis as it was the most up - to - date . the efficacy of hba1c reduction from the baseline of metformin monotherapy was estimated from the pooled analysis of seven studies48,5257 included in the meta - analysis of wu et al.51 of those studies,48,5257 severe hypoglycemia was presented in two studies,52,55 for which the rr was estimated . the calculation details are shown in table 3 . to determine the robustness of the findings , we undertook a probabilistic sensitivity analysis and presented the relationship between the probability of favoring dpp-4 inhibitors and the value of the willingness to pay for an additional unit of quality - adjusted life year ( qaly ) as a cost - effectiveness acceptability curve . the current acceptable thai ceiling threshold of thb160,000/qaly ( us$4,854.37/qaly ) was recommended by the subcommittee for the development of the universal health coverage benefit package and service delivery in thailand.58 a series of one - way sensitivity analyses were also performed to determine the effect of hba1c change , risk of hypoglycemia , drug cost , and discount rate . from a thai health care system perspective , we conducted a cost - utility analysis and used a validated ims core diabetes model ( cdm ) , version 8.5 , to estimate long - term costs and outcomes associated with each treatment over a lifetime horizon . details of this model are described elsewhere.18,19 a 3% discount rate per annum was applied to both costs and outcomes in line with the thai health technology assessment ( hta ) guideline.20 the cohort population was thai people with t2 dm aged at least 65 years . table 1 presents the baseline demographics , risk factors , and clinical complications of the cohort , which were obtained from published data and hospital databases in thailand.2128 the all - cause mortality rate was also adjusted with the age - specific mortality rate of thai people.29 utility values used in the cdm were based mostly on published studies conducted in other countries.3034 this study was approved by the buddhachinaraj regional hospital ethics committee on august 8 , 2014 . as the patient data is de - identified patient consent was not required . these medications were administered as a monotherapy and then compared with either metformin monotherapy or sfu monotherapy . metformin and sfu are considered as usual care for elderly t2 dm patients in thailand . second , we convened a panel of stakeholders to discuss the scope and appropriate comparators of the study , including endocrinologists , and policy makers , and then followed the consensus of the meeting . this study used the normal daily dose of each treatment option : saxagliptin ( 5 mg ) , sitagliptin ( 100 mg ) , vildagliptin ( 100 mg ) , glipizide ( 10 mg ) , and metformin ( 2,000 mg ) . only the direct medical costs , such as cost of intervention , concurrent medications , diabetic screening , management , and treatment complications , were included in the cost - effectiveness analysis . cost data were derived from the published literature and retrospective hospital database analyses ( table 2).3641 all costs were inflated using thailand s consumer price index42 and presented in the year 2014 thb value . costs were converted to us$ at a rate of thb32.96 per us$ as of december 30 , 2014.43 the cost of dpp-4 inhibitors was proposed to the subcommittee for the development of the national list of essential medicine by the pharmaceutical companies . total cost per year of saxagliptin , sitagliptin , and vildagliptin was thb13,492 ( us$409.34 ) , thb16,570 ( us$502.73 ) , and thb15,900 ( us$482.40 ) , respectively . glipizide and metformin we used a median of the median prices of those generic products44 as recommended by the thai hta guideline.45 the annual total costs of metformin and sfu were thb496 ( us$15.05 ) and thb149 ( us$4.52 ) , respectively . due to limited evidence of treatment efficacy in thailand , we performed a systematic review and meta - analysis to estimate the pooled efficacy of dpp-4 inhibitor monotherapy compared to sfu monotherapy and metformin monotherapy in elderly t2 dm patients . the medline , embase , and clinicaltrial.gov databases were systematically searched from their inception to august 2014 . we found only one study46 that indicated noninferiority of alogliptin compared to glipizide in hba1c reduction ( the weighted mean difference 0.09 ; 95% ci ,  to 0.06 ) , substantially lower risk of hypoglycemia ( risk ratio [ rr ] 0.21 ; 95% ci , 0.110.41 ) , lower risk of severe hypoglycemia ( rr 0.23 ; 95% ci , 0.031.99 ) , and no weight gain with dpp-4 inhibitor monotherapy compared to glipizide monotherapy in elderly t2 dm patients ( table 3 ) . three studies5,47,48 compared metformin with dpp-4 inhibitor monotherapy and concluded that dpp-4 inhibitor was an effective and well - tolerated treatment option for elderly t2 dm patients . in addition , reduction in hba1c after treatment with dpp-4 inhibitors in elderly t2 dm patients was not significantly different from those in younger patients.49 therefore , we decided to systematically search a meta - analysis study that compared dpp-4 inhibitor monotherapy with metformin monotherapy in t2 dm patients , and found two eligible studies.50,51 both were high quality studies ( with scores of at least 9 of 11 ) based on the assessment of multiple systematic reviews , we decided to use wu et als51 meta - analysis as it was the most up - to - date . the efficacy of hba1c reduction from the baseline of metformin monotherapy was estimated from the pooled analysis of seven studies48,5257 included in the meta - analysis of wu et al.51 of those studies,48,5257 severe hypoglycemia was presented in two studies,52,55 for which the rr was estimated . to determine the robustness of the findings , we undertook a probabilistic sensitivity analysis and presented the relationship between the probability of favoring dpp-4 inhibitors and the value of the willingness to pay for an additional unit of quality - adjusted life year ( qaly ) as a cost - effectiveness acceptability curve . the current acceptable thai ceiling threshold of thb160,000/qaly ( us$4,854.37/qaly ) was recommended by the subcommittee for the development of the universal health coverage benefit package and service delivery in thailand.58 a series of one - way sensitivity analyses were also performed to determine the effect of hba1c change , risk of hypoglycemia , drug cost , and discount rate . in the base - case scenario , all three dpp-4 inhibitors incurred higher costs and yielded fewer qalys ( 5.965 qalys vs 5.986 qalys ) . in other words , all dpp-4 inhibitors were dominated , making metformin monotherapy a cost - saving treatment in elderly t2 dm patients in thai context ( table 4 ) . all three dpp-4 inhibitors were more effective ( equal 0.031 higher qalys ) but more costly than sfu . saxagliptin yielded the lowest incremental cost per qaly , followed by vildagliptin and sitagliptin ( thb3,632,604/qaly or us$110,212.50/qaly , thb4,335,273/qaly or us$131,531.34/qaly , and thb4,530,556/qaly or us$137,456.19/qaly , respectively ) . with the current thai threshold of thb160,000/qaly ( us$4,854.37/qaly ) , dpp-4 inhibitors were not cost - effective compared to sfu for treating elderly t2 dm patients in the thai context ( table 4 ) . as vildagliptin and sitagliptin were dominated by saxagliptin , the results of one - way sensitivity analysis , therefore , were displayed on saxagliptin compared to sfu . the change in hba1c from the baseline of dpp-4 inhibitors , discount rate , risk of severe hypoglycemia , and cost of saxagliptin had some effect on the incremental cost - effectiveness ratio ( icer ) ( figure 1 ) . the greater the effect of dpp-4 inhibitors on the reduction of hba1c from baseline , the lower icer ( figure 1 ) . based on the cost - effectiveness acceptability curve ( figure 2 ) , all dpp-4 inhibitors were not a cost - effective treatment compared to sfu at the ceiling threshold of 160,000 thb / qaly . compared to metformin , the probability of dpp-4 inhibitors being cost - effective was even smaller than being compared to sfu . in the base - case scenario , all three dpp-4 inhibitors incurred higher costs and yielded fewer qalys ( 5.965 qalys vs 5.986 qalys ) . in other words , all dpp-4 inhibitors were dominated , making metformin monotherapy a cost - saving treatment in elderly t2 dm patients in thai context ( table 4 ) . all three dpp-4 inhibitors were more effective ( equal 0.031 higher qalys ) but more costly than sfu . saxagliptin yielded the lowest incremental cost per qaly , followed by vildagliptin and sitagliptin ( thb3,632,604/qaly or us$110,212.50/qaly , thb4,335,273/qaly or us$131,531.34/qaly , and thb4,530,556/qaly or us$137,456.19/qaly , respectively ) . with the current thai threshold of thb160,000/qaly ( us$4,854.37/qaly ) , dpp-4 inhibitors were not cost - effective compared to sfu for treating elderly t2 dm patients in the thai context ( table 4 ) . as vildagliptin and sitagliptin were dominated by saxagliptin , the results of one - way sensitivity analysis , therefore , were displayed on saxagliptin compared to sfu . the change in hba1c from the baseline of dpp-4 inhibitors , discount rate , risk of severe hypoglycemia , and cost of saxagliptin had some effect on the incremental cost - effectiveness ratio ( icer ) ( figure 1 ) . the greater the effect of dpp-4 inhibitors on the reduction of hba1c from baseline , the lower icer ( figure 1 ) . based on the cost - effectiveness acceptability curve ( figure 2 ) , all dpp-4 inhibitors were not a cost - effective treatment compared to sfu at the ceiling threshold of 160,000 thb / qaly . compared to metformin , the probability of dpp-4 inhibitors being cost - effective was even smaller than being compared to sfu . elderly patients with diabetes have an increased risk of t2dm - related morbidity and mortality . the treatment goal for elderly t2 dm patients is to optimize glycemic control while minimizing the risk of drug - associated adverse events . thus , this study was conducted to generate economic evidence of dpp-4 inhibitors for t2 dm treatment in response to a request by the subcommittee for the development of the national list of essential medicine in 2014 . the findings of the study were submitted and presented to the subcommittee in 2015 to justify policy decision in terms of the value for money . this cost - effectiveness study followed the thai national hta guideline.59 our findings indicated that dpp-4 inhibitor monotherapy was not a cost - effective treatment for elderly t2 dm patients in thailand compared to either sfu monotherapy or metformin monotherapy . efficacy in hba1c reduction , risk of severe hypoglycemia , and cost of dpp-4 inhibitors play an important role in the findings of the study . we are not aware of other studies evaluating the cost - effectiveness of dpp-4 inhibitor monotherapy in elderly t2 dm patients . geng et al60 conducted a systematic review of cost - effectiveness of dpp-4 inhibitors for treating t2 dm ; the eleven included studies assessed dpp-4 inhibitors as an add - on therapy . of those , seven studies compared dpp-4 inhibitors and metformin with sfu and metformin . six studies concluded that dpp-4 inhibitors were cost - effective compared to sfu for treating t2 dm patients for whom metformin monotherapy failed to achieve glycemic control . our study was strengthened by incorporating input parameters , such as costs , baseline cohort characteristics , and adverse events , from data sources that were reliable and relevant to the thai context . . first , based on our systematic review , we found only one study46 that evaluated the efficacy and safety of a dpp-4 inhibitor monotherapy compared to sfu monotherapy in elderly t2 dm patients . this study indicated noninferiority in hba1c reduction but a lower risk of hypoglycemia and no weight gain with the dpp-4 inhibitor monotherapy compared to sfu monotherapy . only three studies5,47,48 compared dpp-4 inhibitor monotherapy with metformin monotherapy in elderly t2 dm patients . however , hba1c reduction after treatment with dpp-4 inhibitors was not significantly different in elderly t2 dm patients vs younger t2 dm patients.49 we addressed this limitation by the pooled analysis of seven studies48,5257 included in the meta - analysis study by wu et al51 that compared metformin monotherapy with dpp-4 inhibitor monotherapy in t2 dm patients . second , we tried our best to use resource utilization and cost data from thailand . some cost data were not available , such as the cost of an infected ulcer ; we assumed them equal to zero . we reanalyzed our base - case analysis , assuming the cost of an infected ulcer similar to an uninfected ulcer . the results showed a slightly lower icer from thb3,632,604/qaly ( us$110,212.50/qaly ) to thb3,630,697/qaly ( us$110,154.64/qaly ) comparing saxagliptin to sfu . metformin monotherapy was still a dominant treatment compared to dpp-4 inhibitor monotherapy , when assuming equal cost of an infected and uninfected ulcer . even though costs , baseline cohort characteristics , and adverse events were obtained from published studies or hospital databases in thailand , this study relies on utility values and transition probabilities within the cdm from studies conducted in other countries . given these limitations , the confirmation of this study s however , the findings indicate that treating elderly t2 dm patients using dpp-4 inhibitor monotherapy in a thai context may not be cost - effective . for treating elderly t2 dm patients in thailand , dpp-4 inhibitor monotherapy is not a cost - effective treatment compared to metformin monotherapy . in addition , dpp-4 inhibitor monotherapy is not a cost - effective treatment compared to sfu monotherapy at the current thai threshold of thb160,000/qaly . the high acquisition cost of dpp-4 inhibitors is one of the key factors in the findings of this study .
backgroundthe management of type 2 diabetes mellitus ( t2 dm ) in elderly population poses many challenges . 
 dipeptidyl peptidase-4 ( dpp-4 ) inhibitors show particular promise due to excellent tolerability profiles , low risk of hypoglycemia , and little effect on body weight . 
 this study evaluated , from the health care system s perspective , the long - term cost - effectiveness of dpp-4 inhibitor monotherapy vs metformin and sulfonylurea ( sfu ) monotherapy in thai elderly t2 dm patients.methodsthe clinical efficacy was estimated from a systematic review and meta - analysis . 
 baseline cohort characteristics and cost parameters were obtained from published studies and hospital databases in thailand . a validated ims core diabetes model version 8.5 
 was used to project clinical and economic outcomes over a lifetime horizon using a 3% annual discount rate . 
 costs were expressed in 2014 thai baht ( thb ) ( us dollar value ) . 
 incremental cost - effectiveness ratios were calculated . 
 base - case assumptions were assessed through several sensitivity analyses.resultsfor treating elderly t2 dm patients , dpp-4 inhibitors were more expensive and less effective , ie , a dominated strategy , than the metformin monotherapy . compared with sfu , treatment with dpp-4 inhibitors gained 0.031 more quality - adjusted life years ( qalys ) at a total cost incurred over thb113,701 or us$3,449.67 , resulting in an incremental cost - effectiveness ratio of thb3.63 million or us$110,133.50 per qaly . at the acceptable thai ceiling threshold of thb160,000/qaly ( us$4,854.37/qaly ) , 
 dpp-4 inhibitors were not a cost - effective treatment.conclusiondpp-4 inhibitor monotherapy is not a cost - effective treatment for elderly t2 dm patients compared with metformin monotherapy and sfu monotherapy , given current resource constraints in thailand .