the combination of a sulfonylurea and a thiazolidinedione may be a particularly effective treatment option in the early stages of type 2 diabetes when -cell function is at its highest .
this allows maximal benefit to be obtained from the insulin secretion - promoting abilities of the sulphonylureas and the -cell - protective effects of the thiazolidinediones .
evidence was identified through a search of medline and embase from january 1996 to october 2006 , using the search terms 
patients with type 2 diabetes characteristically experience a gradual decline in glycaemic control and progression from oral glucose - lowering monotherapy to combination therapy and ultimately to exogenous insulin therapy ( 1,2 ) .
a decrease in the number of functional insulin - producing -cells contributes to the pathological decline in glycaemic control typically seen in type 2 diabetes ( 3 ) and preserving -cell function has emerged as a vital component of long - term management strategies . already at diagnosis of type 2 diabetes about 50% of insulin secretion capacity
there is now increasing evidence available that near to normal glucose control prevents progressive deterioration of insulin secretion .
therefore , a move towards introducing combination therapy earlier in the course of type 2 diabetes with the aim of preserving glycaemic control and -cell function and thereby improving long - term outcomes is considered as a better approach to meet the dual defect in pathophysiology of type 2 diabetes .
such an approach poses the challenge of defining optimal combination regimens and the point at which to introduce them .
recent studies suggest that early , aggressive dual or even triple combination therapy in newly diagnosed patients slows the decline in glycaemic control compared with standard monotherapies ( 5,6 ) .
intervening before the onset of frank type 2 diabetes in high - risk groups , such as those with gestational onset diabetes ( 7,8 ) or individuals with impaired glucose tolerance ( 9,10 ) , is also emerging as a relevant approach to reducing the long - term morbidity and mortality of this chronic disease .
although not all individuals with insulin resistance will go on to develop type 2 diabetes , in those that do , overt type 2 diabetes develops when -cells are no longer able to compensate for insulin resistance .
insulin resistance in itself may contribute to the decline in -cell function by inducing endoplasmic reticulum stress as a consequence of an increased demand for insulin ( 11 ) .
this is in addition to the toxic effects of elevated glucose and lipid levels because of their impaired metabolic processing in the presence of insulin resistance ( 12 ) .
today , a variety of agents of differing modes of action are available to improve glycaemic control .
the sulfonylureas ( e.g. glipizide , glyburide , glimepiride and gliclazide ) are insulin secretagogues that act to increase insulin secretion
. biguanides ( principally metformin ) , reduce hepatic glucose output and increase the uptake of glucose by peripheral tissues .
more recently , the thiazolidinediones ( pioglitazone and rosiglitazone ) have emerged as novel , effective glucose - lowering agents ( 13 ) . the thiazolidinediones are peroxisome proliferator - activated receptor gamma ( ppar)-stimulating insulin sensitisers that also act without increasing insulin secretion .
other , less widely used agents include the -glucosidase inhibitor , acarbose , the incretin mimetic , exenatide , and the new short - acting insulin secretagogues , repaglinide and nateglinide .
a variety of agents with novel mechanisms of action are currently in development and their role in future management regimens has yet to be defined .
recent research effort has focused on defining the effect of oral glucose - lowering agents in this respect to guide decisions on appropriate combination therapies to achieve long - term outcomes beyond glycaemic control .
this review examines the mechanistic distinctions in terms of glycaemic control and -cell functional preservation and the latest clinical data that support the rationale for thiazolidinedione  sulfonylurea combination therapy in patients with type 2 diabetes .
the sulfonylureas and biguanides formed the mainstay of oral glucose - lowering therapy from their introduction in the early 1940s until the 1990s when thiazolidinediones became available .
sulfonylureas stimulate endogenous insulin secretion via their action at the katp channel in the plasma membrane of pancreatic -cells ( 14 ) and effectively decrease hba1c levels by between 0.8% and 2.0% ( 15 ) . as sulfonylureas act by enhancing insulin secretion
, they are most effective in the early stages of type 2 diabetes when -cell function is at its greatest . despite their initial efficacy , glycaemic control
is inevitably lost over time with the sulfonylureas , necessitating the introduction of combination therapy to regain control and prolong the time before progression to exogenous insulin therapy . in the united kingdom
prospective diabetes study ( ukpds ) , 53% of newly diagnosed type 2 diabetics initially treated with sulfonylureas subsequently required additional treatment within 6 years to maintain glycaemic control ( 16 ) . in the recently published adopt study , the proportion of the patients with type 2 diabetes exceeded the target fasting blood glucose level of 180 mg / dl after follow - up ( 17 ) . given the direct effects of the sulfonylureas on the -cell and the potential for -cell exhaustion , combination regimens with agents that improve glycaemia by different modes of action , such as the thiazolidinediones , are recommended .
this combination may be particularly effective given the known positive effects of the thiazolidinediones on -cell function discussed below .
the thiazolidinediones act as insulin - sensitising agents and increase the peripheral action of insulin .
they act as ligands of ppar , which is involved with the regulation of genes that control glucose homeostasis and lipid metabolism and is found in high concentrations in adipose tissue , hepatocytes and skeletal muscle .
these agents have also proved effective in reducing hba1c levels and maintaining glycaemic control , with average reductions in hba1c levels of between 0.5% and 1.5% ( 15,18 ) .
recent evidence suggests that the thiazolidinediones may be more effective than sulfonylureas in maintaining glycaemic control over the long term ( 17,19 ) . in a direct comparison of pioglitazone vs. gliclazide as monotherapy ,
significantly more pioglitazone - treated patients maintained their glycaemic control at 2 years than did patients treated with gliclazide ( 19 ) .
short- and long - term studies with thiazolidinediones and sulfonylurea in combination have shown that this combination offers sustained glycaemic control ( 2027 ) .
( 20 ) found that , compared with the addition of bedtime insulin to maximal doses of sulfonylurea or metformin , the addition of pioglitazone resulted in comparable improvements in glycaemic control and less hypoglycaemia after 16 weeks of treatment . although this study did not report separate results for the sulfonylurea and metformin groups , there was an overall reduction in hba1c of 1.9% compared with 2.3% for insulin ( 20 ) . in another short - term study ,
sulfonylurea combination exclusively and reported decreases of 0.9% and 1.3% for pioglitazone doses of 15 and 30 mg , respectively , over 16 weeks .
long - term studies also support the sustained beneficial effects of this combination on glycaemic control ( table 1 ) . in a 6-month study ,
comaschi et al . ( 23 ) reported significant and sustained reductions in hba1c when pioglitazone was added to either sulfonylurea or metformin .
four further studies of increasing duration have also confirmed the maintenance of glycaemic control following the addition of pioglitazone to sulfonylurea therapy . in the quartet study ,
the addition of pioglitazone to existing sulfonylurea therapy resulted in a 1.2% reduction in hba1c after 1 year in 319 patients with inadequately controlled type 2 diabetes ( 25 ) .
( 28 ) also reported significant ( 1.3% ; p < 0.01 from baseline ) and sustained reductions in hba1c levels when either rosiglitazone or pioglitazone were added to failing glimepiride in 91 patients with type 2 diabetes and the metabolic syndrome after 1 year . in the 2-year end point of the quartet study described above ,
comparing the addition of pioglitazone or metformin to failing sulfonylurea therapy , found that after a rapid decrease in hba1c levels over the first 20 weeks of the study plateaued with overall reductions of 1.03% and 1.16% for the pioglitazone plus sulfonylurea and metformin plus sulfonylurea add - on groups , respectively , after 104 weeks of treatment ( 21 ) .
the recently presented glycaemic results of the prospective pioglitazone clinical trial in macrovascular events ( proactive ) study ( 22 ) of 5238 patients with type 2 diabetes and evidence of macrovascular disease further support the maintenance of glycaemic control following the addition of pioglitazone to existing sulfonylurea therapy .
a subgroup analysis of the proactive study looked at the 1001 patients who were managed with sulfonylurea therapy at baseline .
patients treated with pioglitazone experienced significant decreases from baseline in hba1c levels that were sustained up to the 34.5-month assessment and fewer patients switched to or required addition of metformin or insulin compared with those who received placebo [ figure 1 ; ( 22 ) ] .
maintenance of long - term glycaemic control with combination sulfonylurea and pioglitazone therapy [ charbonnel and scheen , 2006 ( 22 ) ] .
55 , 2006 ; a478 . reprinted with permission from the american diabetes association long - term glycaemic and lipidaemic effects of combined sulfonylurea and thiazolidinedione therapy in patients with type 2 diabetes
-cell stress is reduced with thiazolidinedione therapy , but enhanced with sulfonylurea therapy ( 29 ) .
studies have shown that chronic exposure to glibenclamide can lead to an acceleration of -cell apoptosis and -cell exhaustion or desensitisation ( 3034 ) . the precise mechanism by which glibenclamide initiates -cell apoptosis remains unclear , but may involve closure of the inwardly rectifying k sulfonylurea receptor subtype of the atp - sensitive potassium channel ( 32,34 ) , the sustained enhancement of ca influx mediated by glibenclamide leading to elevated and toxic cytosolic ca levels ( 33 ) and nitric oxide production ( 30 ) .
in addition , prolonged exposure to sulfonylurea renders -cells less responsive to subsequent sulfonylurea stimulation .
( 31 ) found that prolonged in vitro exposure of human pancreatic islets to various insulin secretagogues , including sulfonylureas , resulted in a reduced capacity to respond to further secretory stimulation .
interestingly , certain sulfonylureas may offer a protective effect from hydrogen peroxide - induced -cell damage ( 35 ) .
several lines of evidence support the beneficial effects of thiazolidinediones in terms of improving insulin secretion , preserving -cell mass and islet structure and also protecting -cells from oxidative stress ( 3642 ) .
how the thiazolidinediones exert these protective effects remains unclear . in the presence of chronically elevated glucose levels ( glucotoxicity ) , elevated free fatty acid ( ffa ) levels ( lipotoxicity ) appear to play an important role in -cell damage during the early stages of type 2 diabetes , impairing their functionality and inducing cell death ( 43,44 ) . in the presence of both chronic hyperglycaemia and elevated ffa levels ,
-cells synthesise less insulin and lose the glucose - stimulated insulin secretion response ( 45,46 ) .
thiazolidinediones may protect against the toxic effects of chronically elevated lipid levels by limiting the exposure of -cells to circulating ffas ( 47 ) and by their effects on triglyceride partitioning in tissues .
they may also protect against -cell apoptosis and facilitate -cell proliferation more directly by preventing nuclear factor ( nf)kb activation in -cells ( 37,48 ) .
amyloid deposition has also been associated with increased -cell apoptosis ( 49 ) and a reduction in amyloid deposition with thiazolidinediones has been demonstrated in vivo ( 50 ) .
the protective effects of the thiazolidinediones in this respect may be exerted via activation of a phosphatidylinositol 3-kinase ( pi3k ) akt cascade , which acts to inhibit the human islet amyloid polypeptide ( h - iapp ) induction of apoptosis ( 51 ) . recently
a strong effect of pioglitazone on low - grade - inflammation in patients with cardiovascular disease ( cvd ) without diabetes has been described , which may be another way to protect the -cells ( 52 ) .
clinical studies have also provided indirect support for the preservation of -cell function with thiazolidinedione therapy . homeostasis model assessment ( homa ) is a mathematical tool that models the glucose  insulin feedback loop in the homeostatic state .
it permits estimations of insulin sensitivity ( % s ) and -cell function ( % b ) from pairs of fasting glucose and insulin ( or c - peptide ) measurements .
a 23-week study of pioglitazone monotherapy showed that there was an increase in homa-%b ( 53 ) . in a separate study in drug - nave patients with type 2 diabetes , wallace et al .
( 54 ) reported an increase in homa-%b during 3 months of pioglitazone therapy compared with a small decrease among patients receiving placebo .
in addition , they reported a significant decrease in the pro - insulin / insulin ratio suggesting that the -cells were under less stress .
other studies have also reported improvements in the insulinogenic index ( provides a measure of -cell function during an oral glucose tolerance test ) and the disposition index ( in which the value is corrected for underlying insulin resistance ) ( 5658 ) .
for example , in studies comparing pioglitazone and gliclazide either as monotherapies ( 19 ) or as add - on treatments to existing therapy ( 59 ) , both agents were associated with an initial improvement in the homa-%b .
however , only patients treated with pioglitazone were able to maintain this improvement during 2 years of treatment , while those treated with gliclazide experienced a continued gradual decline , despite a greater initial improvement [ figure 2 ; ( 19,59 ) ] .
improvement in -cell function over 2 years of treatment with either pioglitazone or gliclazide [ tan et al
the pioglitazone group is shown by the dashed line and diamonds ; * p < 0.0001 , p < 0.01 , p < 0.05 .
reprinted with permission from the american diabetes association studies support an effect for both thiazolidinediones and sulfonylureas in improving insulin resistance in the short term in type 2 diabetes using techniques such as the hyperinsulinaemic / euglycaemic clamp ( which allows the determination of the amount of glucose necessary to compensate for an increased insulin level without causing hypoglycaemia ) and homa-%s ( 54,6064 ) .
however , direct comparisons during long - term treatment suggest that the thiazolidinediones may be better able to improve and maintain improvements in insulin sensitivity ( 19,65 ) . during 1 year of treatment , pioglitazone therapy was associated with significant reductions in homa-%s ( p = 0.002 from baseline ) , whereas no significant decrease was recorded for gliclazide in patients with type 2 diabetes ( 65 ) .
( 19 ) found that pioglitazone was associated with an improvement in homa-%s , while gliclazide was associated with a worsening in this measure of insulin resistance . combining sulfonylurea therapy with thiazolidinediones
may ensure long - term benefits in terms of insulin resistance ( 66 ) . in the adopt study , comparing rosiglitazone with glibenclamide and with metformin in early type 2 diabetes , rosiglitazone improved insulin resistance and -cell function to a significantly greater extent than both competitors did ( 17 ) .
in addition to the toxic effects of elevated ffas on -cells , the abnormal lipid profile  including elevated small dense ldl , lowered hdl - cholesterol and elevated triglycerides  associated with type 2 diabetes poses a further burden in terms of increasing the risk of cvd .
thus , most studies of glucose - lowering therapy now also include an assessment of lipid effects .
older sulfonylureas appear to be associated with adverse cardiovascular risks , possibly due to their binding to atp - sensitive potassium channels in cardiomyocytes and vascular smooth muscle cells ( 67,68 ) .
however , how these effects might translate into clinical implications is poorly defined and the newer sulfonylureas appear to be associated with a lower risk of adverse cardiovascular events , such as myocardial infarction and may in fact inhibit atheromatous plaque formation ( 69,70 ) .
patients with pre - existing cvd may be particularly sensitive to the effects of sulfonylureas in this respect ( 71,72 ) , as studies in which such patients were excluded showed no increased risk of cardiovascular mortality ( 73 ) .
pioglitazone has been shown to improve the lipid profile in patients with type 2 diabetes by increasing hdl - cholesterol levels , decreasing triglyceride levels and increasing the lipoprotein particle size of ldl in combination regimens with sulfonylurea ( 20,27,74 ) .
evidence is emerging of a differential effect between the thiazolidinediones in this respect ( 75,76 ) .
( 76 ) described above , the addition of pioglitazone to metformin and/or sulfonylurea therapy was associated with a decrease in triglyceride levels and an increase in hdl - cholesterol levels .
the addition of rosiglitazone also resulted in an increase in hdl - cholesterol , but with no significant improvement in triglyceride levels and an overall increase in total cholesterol levels ( 76 ) .
( 75 ) reported on the improvement in lipid parameters in patients switched from rosiglitazone  sulfonylurea combination therapy to pioglitazone  sulfonylurea therapy in addition to continued stable statin therapy .
after 17 weeks of treatment , replacement of rosiglitazone with pioglitazone was associated with significant improvements in triglyceride and total cholesterol levels and more modest improvements in ldl - cholesterol ( 75 ) .
long - term studies have shown that the beneficial effects associated with pioglitazone therapy are maintained over months and years [ table1 ; ( 21,24,74,7779 ) ] .
thiazolidinediones have other advantages over traditionally employed oral agents , including additional potential cardioprotective effects , such as improving the pro - thrombotic state and blood pressure .
when given in combination with the sulfonylurea , glimepiride , both rosiglitazone and pioglitazone have been shown to improve key components of the prothrombotic state associated with type 2 diabetes [ including plasminogen activator inhibitor 1 levels ] ( 28 ) . in a study of patients with type 2 diabetes and the metabolic syndrome failing on initial therapy with a sulfonylurea or metformin , combination therapy with glimepiride and either pioglitazone or rosiglitazone
was associated with significant improvements in both systolic and diastolic blood pressure over 12 months ( 80 ) .
in addition , thiazolidinediones have been shown to lower the levels of a number of inflammatory parameters , including high sensitivity c - reactive protein and matrix metalloproteinase ( 52,8184 ) . in a recently published study comparing the efficacy of simvastatin , pioglitazone and the combination of both in patients with cvd , but without diabetes , the combination of pioglitazone and statin had additive and complimentary effects on a broad spectrum of inflammatory parameters and the lipoprotein profile independent of hba1c level ( 52 ) .
type 2 diabetes manifests in an insulin - resistant individual when pancreatic -cells are unable to produce sufficient insulin to overcome insulin resistance in the muscles and liver . intervening early to attain glycaemic control and protect -cell function
is now regarded as central to improving long - term outcomes for patients with type 2 diabetes .
the insulin secretagogue sulfonylureas and biguanides represented the mainstay of oral glucose - lowering therapy from their development in the 1940s to the 1990s .
today , these agents are still used and are proving especially useful in early combination therapy regimens with agents that improve glycaemic control by different molecular mechanisms . in patients treated with a sulfonylurea
, there is a strong rationale to support the early combination with thiazolidinediones in type 2 diabetes .
in addition to improving and maintaining glycaemic control , the thiazolidinediones reduce -cell stress , improve insulin resistance and modify a variety of cardiovascular risk factors , including the abnormal lipid profile and increased low - grade inflammation activity associated with type 2 diabetes .
the combined benefits of thiazolidinediones and sulfonylureas may delay the progression of type 2 diabetes and the need for exogenous insulin therapy , and may also offer benefits in terms of reduced risk of cvd .
 type 2 diabetes is characterised by a gradual decline in glycaemic control and progression from oral glucose - lowering monotherapy to combination therapy and exogenous insulin therapy 
 . functional decline of the insulin - secreting -cells is largely responsible for the deterioration in glycaemic control . 
 preservation of -cell functionality , in addition to maintaining glycaemic control and reducing insulin resistance , is now regarded as a key target for long - term management strategies . early , aggressive intervention with combination therapy is emerging as a valid approach to optimise long - term outcomes and combining agents with differing modes of action and secondary effect profiles should prove valuable . 
 sulfonylureas and thiazolidinediones exert their glucose - lowering effect through differing mechanisms of action  the sulfonylureas by stimulating insulin secretion , whereas the thiazolidinediones are insulin sensitisers . 
 both agents offer excellent improvements in glycaemic control when given as monotherapy or in combination . 
 the thiazolidinediones protect -cell structural and functional integrity and functionality and complement the sulfonylureas by inducing and maintaining improvements in insulin resistance , the abnormal lipid profile associated with type 2 diabetes and other cardiovascular risk factors . 
 thus , there is a strong rationale to support the addition of thiazolidinediones to sulfonylureas as a treatment option for type 2 diabetes 
 . this combination may be particularly effective in the early stages of the disease when -cell function is at its highest , allowing maximal benefit to be obtained from the insulin secretion - promoting abilities of the sulfonylureas and the -cell - protective effects of the thiazolidinediones . 