type  2 diabetes continues to present a public health burden across the world , and asia is considered to be at the epicenter of this diabetes epidemic , with 60% of the disease burden borne by this region1 .
the increase in diabetes prevalence across asia has been rapid , fuelled by increasing obesity , aging populations and urbanization , which in turn have been driven by rapid economic development , a sedentary lifestyle and increased consumption of refined foods3 .
these socioeconomic changes have been particularly significant in countries across southeast asia4 , and reflected by dramatic rises in type  2 diabetes prevalence over the past decade ( figure  1 ) .
indeed , indonesia and the philippines are projected to be among the top 10 countries in the world with the highest number of estimated cases by 20301 .
another issue curtailing the type  2 diabetes rise in asia is the high number of undiagnosed individuals .
for instance , in hong kong and taiwan it was reported that almost 53% of diabetic patients remain undiagnosed5 .
furthermore , the prevalence of prediabetes ( impaired glucose tolerance ) further adds to the already burgeoning burden of overt diabetes and its consequences in this region ( figure  1 ) .
comparative prevalence of diabetes in countries across southeast asia in 2011 ( calculated by assuming that every country and region has the same age profile ) .
these data are based on figures compiled by the international diabetes federation in the international diabetes atlas , 2011 ( available at : http://www.idf.org/atlasmap/atlasmap ) .
it is widely recognized that diabetes is a major source of morbidity , mortality and economic burden6 .
prolonged and poor glucose control increases the risk of developing macrovascular ( coronary artery disease , stroke ) and microvascular ( nephropathy , retinopathy and neuropathy ) complications7 , which can greatly reduce life expectancy and quality of life8 .
in fact , the risk of allcause mortality ( cardiovascular and noncardiovascular ) is higher in diabetic than nondiabetic patients9 . consequently , the rapidly growing prevalence of diabetes in asia is likely to result in large increases in diabetesassociated mortality10 . from an economic perspective
, the impact of diabetes on healthcare resources and personal expenditure , as well as the financial implications associated with loss in productivity and disability , is enormous11 . in taiwan ,
the direct healthcare cost associated with diabetes was 11.5% of the total national healthcare cost and was 4.3fold higher than the care of nondiabetic individuals12 . in hong kong , the annual total cost of type  2 diabetes equated to usd  1,725    2,044 per patient .
furthermore , complications increased treatment costs associated with inpatient hospital stay by between 6 and 300% compared with treatment of type  2 diabetes patients without complications14 .
of note is the considerable heterogeneity in healthcare spending for diabetes between countries across southeast asia .
the international diabetes federation estimated that , in 2010 , treatment of diabetes accounted for 5 and 7% of the total healthcare expenditure in vietnam and indonesia , respectively , compared with 15 and 16% in singapore and malaysia , respectively11 .
taken together , it is clear that early diagnosis and disease control are important healthcare initiatives to improve the lives , outcomes and economies of these atrisk countries . in determining the optimal management approach , recognizing the differences in clinical characteristics and risk of diabetes between asian and caucasian populations is important to understand .
for instance in asians , diabetes develops over a shorter time , in younger people and in those with a lower body mass index ( bmi)15 .
furthermore , asians have a higher proportion of body fat and abdominal obesity , putting them at a higher risk of developing insulin resistance16 .
reports that asians show early cell dysfunction might further explain their increased susceptibility to type  2 diabetes16 .
the thrifty gene and thrifty phenotype hypotheses have been proposed as plausible explanations for the increasing diabetes epidemic seen across asia18 .
although considered protective during periods of famine or food shortage , thrifty genes have rendered individuals highly predisposed to obesity in times of plenty .
alternatively , the thrifty phenotype relates to the impact of an unfavorable intrauterine environment ( e.g. undernutrition ) and low birth weight on the subsequent development of diabetes and metabolic syndrome in adults18 .
several diabetesassociated genes have been implicated to account for the heightened predilection in asians , especially asian indians , and include polymorphisms of the peroxisome proliferatoractivated receptor coactivator1 alpha ( pgc1 alpha ) gene , plasma cell glycoprotein ( pc1 ) gene and insulin receptor substrate ( irs2 ) gene ( reviewed in radha and mohan)19 .
given the increased prevalence of diabetes among younger populations in asia and early exposure to hyperglycemia , it has been suggested that they are also at a high risk of endorgan damage and are likely to have to live with complications for longer20 .
indeed , the asia  pacific cohort studies collaboration ( apcsc ) , which assessed the impact of diabetes on cardiovascular outcomes and mortality , found a greater risk of fatal coronary heart disease , hemorrhagic and ischemic stroke among younger compared with older individuals21 .
apcsc also showed an association between diabetes and increased risk of death as a result of renal disease , cancer , respiratory infections , and other infective and inflammatory causes21 .
although optimal blood glucose control has been shown to reduce the risk of both macrovascular and microvascular complications6 , the marked prevalence of renal dysfunction in asia reflects , in part , the continuing challenge in achieving this goal22 .
the aim of the present article was to review the barriers to achieving optimal blood glucose control in asian patients with type  2 diabetes who have declining renal function and to discuss the treatment modalities that might be appropriate for the management of these special patient populations .
of the diabetesassociated complications , the most debilitating is chronic kidney disease ( ckd ) and its pathogenic progression to endstage renal disease ( esrd ) that requires dialysis or transplantation23 .
defining and diagnosing ckd in clinical practice has evolved since its first classification by the national foundation kidney disease outcomes quality initiative ( nkfkdoqi ) in 200224 . in these guidelines ,
ckd was categorized into five stages according to the severity of disease as defined by decreasing glomerular filtration rates ( gfr ) alone24 . in the more recent update ,
the assessment criteria have been modified to encompass both gfr and albuminuria measures as correlates of a patient 's prognosis .
in addition , a subdivision of the previously described gfr stage  3 has been proposed to help further define the severity of kidney dysfunction in patients with ckd25 .
risk factors for the development of reduced kidney function in southeast asian populations have been identified and include the presence of diabetes , systolic hypertension ( > 159  mmhg ) , hyperuricemia ( > 6.29  mg / dl ) , elevated bmi ( > 24.9  kg / m ) and hypercholesterolemia ( > 248.3  mg / dl)26 .
microalbuminuria is the earliest clinical manifestation of ckd in type  2 diabetes and persistent microalbuminuria represents an early clinical marker for the development of diabetic nephropathy ( dn)27 . although the number of studies exploring the epidemiology of microalbuminuria across asia has been limited , the microalbuminuria prevalence study ( maps ) of 6,800 hypertensive diabetic patients from 10 countries in the region reported an overall prevalence rate of 39.8% ( 95% confidence interval [ ci ] 39.240.5)22 .
these data show how a high proportion of hypertensive , type  2 diabetes asian patients are showing early signs of declining renal function , and further support a need for early intervention so as to reduce accelerated progression of cardiorenal complications and the associated healthcare burden28 . with the exception of taiwan ( chiang sc et  al .
jcma 2011 ; 74 : 310 ) , these data are based on subanalyses of the microalbuminuria prevalence study of 6,800 hypertensive diabetic patients from 10 countries across asia ( wu ay et  al .
2005 ; 48 : 1726 . ) in recognition of the utility of measuring microalbuminuria , guidelines recommend annual screening of this clinical marker for identifying atrisk populations32 .
patients identified with microalbuminuria early in the course of disease might require stricter glycemic and blood pressure control targets .
indeed , several prospective studies have shown the importance of tight glycemic control alone and combined with blood pressure lowering in the prevention of microvascular complications .
for instance , the uk prospective diabetes study compared the effects of intensive bloodglucose control with either sulfonylureas or insulin and conventional treatment ( including diet ) on the risk of microvascular and macrovascular complications in type  2 diabetes patients .
intensive glucose control with sulfonylureas or insulin resulted in a 33% relative risk reduction in the development of microalbuminuria .
furthermore , this reduction in risk was sustained in the 10year followup study during which longterm benefits on cardiovascular disease ( cvd ) risk also emerged33 . in the kumamoto study ,
the frequency and severity of diabetic microvascular complications were assessed in japanese type  2 diabetes patients after treatment with either intensive glucose control ( multiple insulin injections of three or more ) or conventional therapy ( insulin injections administered once or twice daily )
. there was a significant reduction in the progression of nephropathy and other microvascular complications ( retinopathy ) after intensive insulin therapy ( p  <  0.05)35 .
the effect of an intensive , stepwise multifactorial intervention , targeting hyperglycemia , hypertension , dyslipidemia and microalbuminuria , on the initiation and progression of microvascular complications in type  2 diabetes patients with microalbuminuria was assessed in the steno2 study .
type  2 diabetes patients receiving early intensive diabetes management including tight glucose control and angiotensin converting enzyme inhibitors ( acei ) to reduce blood pressure were significantly less likely to develop nephropathy than patients receiving standard therapy ( odds ratio 0.27 ; 95% ci 0.100.75 ) .
this reduction in risk was maintained in an observational follow up of 5.5  years36 . in the most recent analysis of the action in diabetes and vascular disease : preterax and diamicronmodified release controlled evaluation ( advance ) trial , which included a large number of asian type  2 diabetes patients , further support for the benefits of combining bloodpressure lowering with intensive blood glucose control was provided38 .
patients received either intensive glucose control ( target glycated hemoglobin [ hba1c ]   6.5% ) or standard glucose control ( defined by local guidelines ) with placebo or acei plus indapamide therapy .
a combination of intensive glucose control plus acei plus indapamide therapy led to a significant percentage in risk reduction in new or worsening nephropathy ( 95% ci 1250% ; p  =  0.005 ) ; a 54% reduction in the development of newonset macroalbuminuria ( 95% ci 3568% ; p  <  0.001 ) , and a 25% reduction in the risk of newonset microalbuminuria ( 95% ci 1633% ; p  <  0.001 ) .
furthermore , the effects of blood pressure lowering and intensive glucose control were independent of each other , so that on combining these agents , additive benefits were observed , particularly on renal outcomes38 . indeed , the benefits of early and tight target control strategies on the prevention of dn in chinese type  2 diabetes patients have been observed . in this asian cohort with normoalbuminuria , achievement of american diabetes association ( ada)recommended targets of hba1c ( < 7% ) , systolic blood pressure ( < 130  mmhg ) , diastolic blood pressure ( < 80  mmhg ) and lipid profiles ( lowdensity lipoprotein [ ldl ] < 100  mg / dl ; triglycerides < 150  mg / dl ; highdensity lipoprotein > 4050  mg / dl ) reduced the risk of developing newonset microalbuminuria compared with those who were unable to attain these targets39 .
interestingly , in a separate study of taiwanese type  2 diabetes patients with microalbuminuria , almost 36% of patients achieved remission to normoalbuminuria following a tight , multifactorial target control approach40 .
worldwide , rates of ckd have been increasing , and have accompanied the increasing prevalence of type  2 diabetes , hypertension and cvd .
for instance , in the usa , it is estimated that 30% of patients with type  2 diabetes will develop some form of kidney disease as reflected by protein leakage , microalbuminuria , macroalbuminuria or a decline in the glomerular filtration rate ( gfr)41 .
nephropathy is a common complication of asians with type  2 diabetes , as reflected by the accelerating prevalence and incidence rates of observed ckd23 .
indeed , incidence rates of esrd across asia have shown increases over a 6year period ( 20032008 ) of 15.8% in hong kong , 22% in malaysia and thailand , 24% in singapore , and up to 31% in the philippines43 .
although incidence rates of esrd appear to have declined in taiwan since 2005 , this country has the third highest rate of esrd in the world , with an incidence rate of 384 per million population ( pmp ) , highlighting the disparity between the rate of kidney disease and a country 's economic status42 .
furthermore , it has become apparent that a high proportion of esrd cases are as a result of diabetes , ranging from 41% to 62% in individual countries across southeast asia ( figure  2)43 .
incidence of endstage renal disease ( esrd ) as a result of diabetes in selected countries across southeast asia in 2008 .
these data are based on figures compiled by the us renal disease system ( figure adapted from 2010 us renal disease system annual report chapter 12 international comparisons ; volume 2 ; pages 383396 ) . for singapore ,
the 2008 data have been extracted from the national registry of diseases office , released 1 march 2011 ( inp111 ) .
the presence of ckd is also associated with a high cvd risk , which is further exacerbated by the presence of diabetes and hypertension45 .
indeed , cvd remains the main cause of death in patients with ckd rather than kidney failure , and it is estimated that cvdassociated mortality is 1030fold higher in patients with advanced ckd receiving dialysis than the general population46 .
given that the prevalence of hypertension in asia is increasing , and that diabetes and hypertension commonly coexist ( type  2 diabetes patients are twice as likely to have elevated blood pressure than nontype  2 diabetes patients ) , screening these highrisk patients for ckd early might help slow the course of renal function decline and reduce the greater cardiovascular mortality risk observed in such individuals47 .
microalbuminuria is the earliest clinical manifestation of ckd in type  2 diabetes and persistent microalbuminuria represents an early clinical marker for the development of diabetic nephropathy ( dn)27 . although the number of studies exploring the epidemiology of microalbuminuria across asia has been limited , the microalbuminuria prevalence study ( maps ) of 6,800 hypertensive diabetic patients from 10 countries in the region reported an overall prevalence rate of 39.8% ( 95% confidence interval [ ci ] 39.240.5)22 .
these data show how a high proportion of hypertensive , type  2 diabetes asian patients are showing early signs of declining renal function , and further support a need for early intervention so as to reduce accelerated progression of cardiorenal complications and the associated healthcare burden28 . with the exception of taiwan ( chiang sc et  al .
jcma 2011 ; 74 : 310 ) , these data are based on subanalyses of the microalbuminuria prevalence study of 6,800 hypertensive diabetic patients from 10 countries across asia ( wu ay et  al . diabetologia .
2005 ; 48 : 1726 . ) in recognition of the utility of measuring microalbuminuria , guidelines recommend annual screening of this clinical marker for identifying atrisk populations32 .
patients identified with microalbuminuria early in the course of disease might require stricter glycemic and blood pressure control targets .
indeed , several prospective studies have shown the importance of tight glycemic control alone and combined with blood pressure lowering in the prevention of microvascular complications .
for instance , the uk prospective diabetes study compared the effects of intensive bloodglucose control with either sulfonylureas or insulin and conventional treatment ( including diet ) on the risk of microvascular and macrovascular complications in type  2 diabetes patients .
intensive glucose control with sulfonylureas or insulin resulted in a 33% relative risk reduction in the development of microalbuminuria .
furthermore , this reduction in risk was sustained in the 10year followup study during which longterm benefits on cardiovascular disease ( cvd ) risk also emerged33 . in the kumamoto study ,
the frequency and severity of diabetic microvascular complications were assessed in japanese type  2 diabetes patients after treatment with either intensive glucose control ( multiple insulin injections of three or more ) or conventional therapy ( insulin injections administered once or twice daily ) .
there was a significant reduction in the progression of nephropathy and other microvascular complications ( retinopathy ) after intensive insulin therapy ( p  <  0.05)35 .
the effect of an intensive , stepwise multifactorial intervention , targeting hyperglycemia , hypertension , dyslipidemia and microalbuminuria , on the initiation and progression of microvascular complications in type  2 diabetes patients with microalbuminuria was assessed in the steno2 study .
type  2 diabetes patients receiving early intensive diabetes management including tight glucose control and angiotensin converting enzyme inhibitors ( acei ) to reduce blood pressure were significantly less likely to develop nephropathy than patients receiving standard therapy ( odds ratio 0.27 ; 95% ci 0.100.75 ) .
this reduction in risk was maintained in an observational follow up of 5.5  years36 . in the most recent analysis of the action in diabetes and vascular disease : preterax and diamicronmodified release controlled evaluation ( advance ) trial , which included a large number of asian type  2 diabetes patients , further support for the benefits of combining bloodpressure lowering with intensive blood glucose control was provided38 .
patients received either intensive glucose control ( target glycated hemoglobin [ hba1c ]   6.5% ) or standard glucose control ( defined by local guidelines ) with placebo or acei plus indapamide therapy .
a combination of intensive glucose control plus acei plus indapamide therapy led to a significant percentage in risk reduction in new or worsening nephropathy ( 95% ci 1250% ; p  =  0.005 ) ; a 54% reduction in the development of newonset macroalbuminuria ( 95% ci 3568% ; p  <  0.001 ) , and a 25% reduction in the risk of newonset microalbuminuria ( 95% ci 1633% ; p  <  0.001 ) .
furthermore , the effects of blood pressure lowering and intensive glucose control were independent of each other , so that on combining these agents , additive benefits were observed , particularly on renal outcomes38 . indeed , the benefits of early and tight target control strategies on the prevention of dn in chinese type  2 diabetes patients have been observed . in this asian cohort with normoalbuminuria , achievement of american diabetes association ( ada)recommended targets of hba1c ( < 7% ) , systolic blood pressure ( < 130  mmhg ) , diastolic blood pressure ( < 80  mmhg ) and lipid profiles ( lowdensity lipoprotein [ ldl ] < 100  mg / dl ; triglycerides < 150  mg / dl ; highdensity lipoprotein > 4050  mg / dl ) reduced the risk of developing newonset microalbuminuria compared with those who were unable to attain these targets39 .
interestingly , in a separate study of taiwanese type  2 diabetes patients with microalbuminuria , almost 36% of patients achieved remission to normoalbuminuria following a tight , multifactorial target control approach40 .
worldwide , rates of ckd have been increasing , and have accompanied the increasing prevalence of type  2 diabetes , hypertension and cvd .
for instance , in the usa , it is estimated that 30% of patients with type  2 diabetes will develop some form of kidney disease as reflected by protein leakage , microalbuminuria , macroalbuminuria or a decline in the glomerular filtration rate ( gfr)41 .
nephropathy is a common complication of asians with type  2 diabetes , as reflected by the accelerating prevalence and incidence rates of observed ckd23 .
indeed , incidence rates of esrd across asia have shown increases over a 6year period ( 20032008 ) of 15.8% in hong kong , 22% in malaysia and thailand , 24% in singapore , and up to 31% in the philippines43 .
although incidence rates of esrd appear to have declined in taiwan since 2005 , this country has the third highest rate of esrd in the world , with an incidence rate of 384 per million population ( pmp ) , highlighting the disparity between the rate of kidney disease and a country 's economic status42 .
furthermore , it has become apparent that a high proportion of esrd cases are as a result of diabetes , ranging from 41% to 62% in individual countries across southeast asia ( figure  2)43 .
incidence of endstage renal disease ( esrd ) as a result of diabetes in selected countries across southeast asia in 2008 .
these data are based on figures compiled by the us renal disease system ( figure adapted from 2010 us renal disease system annual report chapter 12 international comparisons ; volume 2 ; pages 383396 ) . for singapore ,
the 2008 data have been extracted from the national registry of diseases office , released 1 march 2011 ( inp111 ) .
the presence of ckd is also associated with a high cvd risk , which is further exacerbated by the presence of diabetes and hypertension45 .
indeed , cvd remains the main cause of death in patients with ckd rather than kidney failure , and it is estimated that cvdassociated mortality is 1030fold higher in patients with advanced ckd receiving dialysis than the general population46 .
given that the prevalence of hypertension in asia is increasing , and that diabetes and hypertension commonly coexist ( type  2 diabetes patients are twice as likely to have elevated blood pressure than nontype  2 diabetes patients ) , screening these highrisk patients for ckd early might help slow the course of renal function decline and reduce the greater cardiovascular mortality risk observed in such individuals47 .
despite the advent and availability of a range of antidiabetic and blood pressure lowering agents , many patients in asia remain suboptimally controlled and therefore at risk of developing complications . in the maps study , just 10.6% of type  2 diabetes asian patients with microalbuminuria achieved blood pressure targets below 130/80  mmhg and mean hba1c levels of 7.9%22 .
similarly , in a crosssectional survey in china , the majority of type  2 diabetes patients with nephropathy ( 66.9% ) had a mean hba1c level of > 7.5% , indicating poor glycemic control in patients with complications50 .
these data are supported by the recent international diabetes management practice study ( idmps ) that explored the barriers to achieving optimal glycemic control across asia , latin america and eastern europe51 . in asia , of the 5,372 type  2
diabetes patients assessed , 35.8% had microalbuminuria and just 37.3% achieved the hba1c target of < 7.0% ; 21.8% achieved the blood pressure target of < 130/80  mmhg ; and 37% achieved the ldl cholesterol target of < 100  mg / dl .
another significant and worrying finding was that just 4.7% of patients in asia attained all three treatment targets51 .
factors that might be contributing to such low control rates have been reported to include : difficult medical access by patients in some developing countries , physician perception of target levels , prescribing habits , as well as knowledge of guidelines 
an aging population provides additional challenges in managing type  2 diabetes , as aging itself is associated with changes in kidney structure and function , and these agerelated renal changes can be accelerated by the presence of comorbid conditions52 .
furthermore , a study of the hong kong diabetes registry revealed how long disease duration and complexity of treatment regimens might also play a role in suboptimal glycemic control54 .
poor control might also result in type  2 diabetes patients who present and commence treatment when their renal function is normal , but subsequently go on to develop kidney disease . without appropriate monitoring of gfr levels and diagnosis of kidney disease or its progression , the need for dose adjustments or reevaluation of prescribed therapies might be missed and , consequently , adverse sideeffects might arise55 .
hypoglycemia is a particular challenge in the management of type  2 diabetes , especially in patients with a decline in renal function .
for instance , diabetic patients with ckd are twice as likely to experience hypoglycemic events than those without kidney disease56 .
this might be a result of reduced insulin clearance , reduced gluconeogenesis by the kidney and increased accumulation of drugs excreted by the kidney57 .
the reduction in drug clearance results in prolonged exposure to the drug itself or its metabolites , which can lead to adverse sideeffects .
this is a major issue in moderate to severe ckd ( stages 35 ) when renal dysfunction is particularly pronounced55 .
the american diabetes association guidelines recommend target hba1c levels of < 8% for patients with more advanced microvascular complications and increased risk of hypoglycemia , such as those with more advanced ckd .
however , in practice , the use of antidiabetic medications in achieving these glycemic targets is often challenging58 .
there are now an array of antihyperglycemic agents available that include both injectable , such as insulin and the incretin mimetics 
glp1 analogs ( exenatide , liraglutide ) , and oral antidiabetics ( oads ) . among the oads are biguanides ( metformin ) , second generation sulfonylureas ( glimepiride , glipizide , glicazide ) , meglitinides ( nateglinide , repaglinide ) glucosidase inhibitors ( acarbose ) , thiazolidinediones ( tzd ; pioglitazone ) and incretinbased therapies that include dipeptidylpeptidase  iv ( dpp4 ) inhibitors ( linagliptin , sitagliptin , vildagliptin , saxagliptin ) .
in addition , oral sodiumglucose transporter  2 ( inhibitors are currently in development ( empagliflozin , dapagliflozin ) . despite the range of medications available for the treatment of type  2 diabetes and its complications , many of these require dose modification or avoidance and close monitoring55 .
this poses a particular challenge in more advanced disease ( ckd stages  35 ) , where contraindications or the increased risk of hypoglycemia serve to limit the number of treatment options ( table  2)55 .
as all these agents differ in their mechanism of action , efficacy , sideeffects and costs , the choice of therapy should be guided by several factors .
patient demographics , presence of comorbid conditions , risk or severity of renal function decline , tolerability , and risk of developing adverse events , such as hypoglycemia , weight gain and edema , should help in the treatment decision process57 .
with most of the oads currently available for the treatment of type  2 diabetes , their use in patients with kidney dysfunction is compromised55 .
however , sulfonylureas and their metabolites are affected by kidney function by increasing in potency as renal function declines . furthermore , in type  2 diabetes patients with esrd receiving dialysis , treatment with sulfonylureas might lead to severe and prolonged episodes of hypoglycemia61 .
however , secondgeneration sulfonylureas , such as gliclazide and glipizide , which have inactive metabolites , carry less risk of hypoglycemia than the firstgeneration sulfonylureas and might therefore be used in type  2 diabetes patients with declining renal function , but with caution .
similarly , the meglitinide , nateglinide , undergoes hepatic metabolism that gives rise to weakly active metabolites that are excreted predominantly through the kidneys . furthermore , 15% of the drug
is excreted unchanged in urine . given the reduced clearance in ckd and the likelihood of hypoglycemic episodes , cautious use in these special populations , particularly in more advanced stages of ckd , is warranted .
in contrast , repaglinide appears to have a lower risk of hypoglycemia and might be of use in ckd stages  3 and 4 , but requires low initial dosing and careful dose titration in these patients62 .
the use of metformin , the standard firstline therapy of type  2 diabetes , also poses a risk for diabetic patients with ckd as a result of lactic acidosis , and is therefore contraindicated in patients with advanced renal dysfunction57 . whether this medication provides an additional risk to the underlying comorbidity or acts directly to bring about lactic acidosis requires further investigation63 .
treatment with glycosidase inhibitors in type  2 diabetes patients with ckd ( stage  35 ) is also not recommended , because of the potential risk of hepatic damage as a result of cumulated dose effects57 .
in contrast , a few small , shortterm studies have implicated a renoprotective role for tzd , as it resulted in greater reductions in albuminuria than metformin or sulfonylureas .
whether this translates into direct prevention of renal function decline , however , requires further study64 .
nevertheless , tzd undergo hepatic metabolism and have a low risk of hypoglycemia , making them appropriate for use in ckd . of note ,
fluid retention is a known sideeffect of tzd , and in ckd patients this outcome could be exacerbated .
dpp4 inhibitors are the most recent addition to the type  2 diabetes treatment paradigm and have been developed in recognition of the multifactorial nature of type  2 diabetes pathology .
this drug class mediates its antihyperglycemic effects by preventing the degradation of the incretin hormones 
these hormones are released in the intestine after a meal , and target the pancreas by increasing glucosedependent insulin secretion and suppressing glucagon secretion , which subsequently improves both fasting plasma glucose ( fpg ) and postprandial glucose ( ppg ) levels .
dpp4 inhibitors are therefore important in regulating glucose homeostasis67 . furthermore , beneficial effects on pancreatic cells have also been reported with this drug class and therefore it might play a role in preventing or slowing the progression of cell dysfunction68 .
there are currently five dpp4 inhibitors approved for type  2 diabetes : sitagliptin , vildagliptin , saxagliptin , alogliptin ( japan ) and linagliptin ; and their efficacy and tolerability have been studied in several clinical trials72 .
although there are limited direct headtohead studies between dpp4 inhibitors that have been carried out to date , observations across studies suggest that all five agents have comparable efficacy as reflected in their levels of hba1c reduction .
when compared with other antihyperglycemic agents , headtohead studies showed dpp4 inhibitors to have similar efficacy to metformin , sulfonylureas , tzd and glycosidase inhibitors73 . in terms of tolerability
, all five dpp4 inhibitors have been shown to be well tolerated with low rates of adverse effects and , in general , comparable with placebo or comparator72 .
furthermore , the issues of hypoglycemia and weight gain frequently seen with the more traditional antihyperglycemic therapies are not readily observed with dpp4 inhibitors .
although there is little to differentiate between these agents in terms of observed efficacy , each differs in their chemistry and pharmacokinetic profile , which might translate into differences in their clinical applicability79 .
indeed , dpp4 inhibitors differ in their halflives : sitagliptin , alogliptin and linagliptin have longhalf lives , allowing for oncedaily administration ; vildagliptin has a short halflife and twicedaily dosing is recommended .
saxagliptin has a short halflife , but given its active metabolite , oncedaily dosing is adequate79 .
furthermore , on examining their metabolism and excretion profiles , differences between the dpp4 inhibitors have emerged .
sitagliptin , vildagliptin , alogliptin and saxagliptin are predominantly excreted through the kidneys72 . despite the renal excretion profiles of these agents , their favorable tolerability in patients with various severity of renal dysfunction still permits their use in such patients ,
although dose modifications are recommended in line with increasing kidney dysfunction ( table  2 ) .
in contrast , linagliptin is excreted through the bile and with approximately 5% being renally excreted80 .
furthermore , recent data suggest that dose modifications of linagliptin are not required irrespective of the severity of renal dysfunction ( table  2)81
. linagliptin might therefore represent an important addition to the currently limited therapeutic armamentarium for achieving glycemic control in type  2 diabetes patients with declining renal function . in recognition of the favorable clinical profile of dpp4 inhibitors ,
recent international guidelines recommend dpp4 inhibitors as an option in both firstline ( when fpg and ppg levels are elevated ) and combination therapy82 .
thus , type  2 diabetes patients , particularly special populations like those who are renally impaired , benefit from the emergence and evolution of newer antidiabetic agents , such as the dpp4 inhibitors , that address the limitations of older therapies , and allow for a more tailored and effective approach to disease control .
longterm studies to assess the impact of dpp4 inhibitors on reducing the risk of diabetes complications are awaited .
dpp4 inhibitors represent a good choice of oad for patients with type  2 diabetes .
within this drug class , linagliptin , a novel dpp4 inhibitor , possesses favorable and comparable profiles in terms of both efficacy and adverse events , and is indicated for use in all patients with type  2 diabetes .
furthermore , linagliptin is the only dpp4 inhibitor that is not predominantly dependent on renal metabolism .
many antidiabetic therapies are often of little use in renallyimpaired type  2 diabetes patients because of contraindications or increased risk of hypoglycemia .
the favorable pharmacokinetic profile of linagliptin has advantageous implications given the importance of addressing the decline in renal function in asian patients with type  2 diabetes early .
in addition , the lack of dose modification requirements and ease of dosing ( one dose , once daily ) further support the suitability of linagliptin in these difficulttotreat populations .
 abstractit is well recognised that asia is at the epicenter of the global type  2 diabetes epidemic . driven by socioeconomic changes involving industrialization , urbanization and adoption of western lifestyles , 
 the unprecedented increases in the prevalence of diabetes are particularly evident in southeast asia . 
 the impact of diabetes is immense , and despite evidence of the benefit of optimal glucose control in reducing the risk of disease progression and development of macrovascular and microvascular complications , many individuals in this region remain poorly controlled . 
 chronic kidney disease ( ckd ) is an increasingly common diabetesassociated complication in asian patients . 
 furthermore , southeast asia has one of the highest rates of endstage renal disease ( esrd ) in the world . 
 consequently , ckd in diabetes is associated with considerable morbidity and cardiovascularrelated mortality , highlighting the need to screen and assess patients early in the course of the disease . 
 the management of type  2 diabetes patients with declining renal function represents a significant challenge . 
 many of the older antidiabetic agents , such as metformin and sulfonylureas , are limited in their utility in ckd as a result of contraindications or hypoglycemic episodes . 
 in contrast , dipeptidylpeptidase  iv inhibitors have provided a welcome addition to the therapeutic armamentarium for achieving glycemic control in these special populations . with comparable efficacy to and more favorable pharmacokinetic and sideeffect profiles than traditional therapies , 
 agents in this drug class , such as linagliptin , offer a more tailored approach to disease control in type  2 diabetes patients with declining renal function . 