subjects with type 2 diabetes were screened and enrolled if they were aged 1880 years , had a1c between 7 and 11% ( prestudy oad monotherapy for 3 months ) or 710% ( prestudy combination oad therapy for 3 months ) , and had bmi 45 kg / m . subjects who used insulin during the previous 3 months ( except short - term treatment ) were excluded . the protocol was approved by local institutional review boards , and subjects provided written informed consent before the initiation of any trial - related activities . the study was conducted in accordance with the declaration of helsinki and good clinical practice guidelines ( 12 ) . this 26-week , double - blind , randomized , placebo - control , parallel - group , multicenter ( 96 sites ) , two - country ( u.s . and canada ) trial randomized subjects ( 1:1:1 ) to receive 1.2 or 1.8 mg of once - daily liraglutide ( novo nordisk , bagsvrd , denmark ) or liraglutide placebo ( novo nordisk ) injected subcutaneously by subjects in combination with metformin and rosiglitazone in all three treatment groups . randomization was carried out using a telephone- or web - based randomization system . before randomization , eligible subjects underwent a 6- to 9-week metformin and rosiglitazone run - in and dose - titration period . subjects previously treated with pioglitazone underwent rosiglitazone titration ( by transferring to the corresponding rosiglitazone dose ) or went directly to the maximum dose if they were on the maximum pioglitazone dose . metformin was started at 500 mg at breakfast and increased weekly by increments of 500 mg to a final dose of 2,000 mg / day ( 1,000 mg at breakfast and at the evening meal ) . rosiglitazone was started at 4 mg in the morning and increased to 8 mg / day ( 4 mg in the morning and evening , the highest approved dose in the u.s . and canada ) . subjects who tolerated the final oad doses and had fasting plasma glucose ( fpg ) values 135230 mg / dl ( 7.512.8 mmol / l ) after 6 weeks ' treatment at the titrated doses were eligible for randomization . at randomization , subjects initiated liraglutide or placebo treatment with 100-l injections corresponding to a 0.6-mg dose and increased to 1.2 mg / day ( 200 l injections ) after 1 week and then to 1.8 mg / day ( 300 l injections ) after an additional week for those randomized to the highest dose . liraglutide ( active or placebo ) was injected subcutaneously once daily at any time of the day in the upper arm , abdomen , or thigh using a prefilled pen device . the titration period was followed by a 24-week maintenance period during which the doses of study drugs were to be maintained . the primary outcome measure was change in a1c from randomization to the end of the study . secondary end points included changes in body weight ; fpg ; seven - point plasma glucose profiles ; -cell function based on fasting insulin , fasting c - peptide , and fasting proinsulin - to - insulin ratio ; the homeostasis model assessment ( homa ) for -cell function ( homa - b ) and insulin resistance ( homa - ir ) ( 13 ) ; and lipids . laboratory analyses were performed by a central laboratory ( mds pharma services in canada and switzerland ) . subjects were provided with medisense precision xtra / medisense optium glucose meters ( abbott laboratories , abbott park , il ) calibrated to plasma glucose to determine self - measured plasma glucose ( smpg ) and were asked to record values in their diaries . the seven - point smpg profile measurements were performed before and 90 min after meals and at bedtime for 2 consecutive days at weeks 0 ( randomization ) , 12 , and 26 . serum insulin and c - peptide values were determined using a chemiluminescence immunoassay , and proinsulin was measured in serum using an enzyme - linked immunosorbent assay . safety variables included adverse events , vital signs , electrocardiogram , biochemical and hematology measures , and subject - reported hypoglycemic episodes ( plasma glucose < 56 mg / dl [ < 3.1mmol / l ] ) . a serious adverse event was defined as an adverse event that resulted in death , hospitalization , disability , or a birth defect ; was life threatening ; or required medical or surgical intervention to prevent one of the other outcomes . minor hypoglycemic episodes were defined as those that could be self - treated ; major episodes were defined as requiring third - party assistance or medical intervention . the analysis of efficacy end points was based on the intent - to - treat population , defined as subjects who were exposed to at least one dose of trial product and had one postbaseline measurement of the parameter . each end point was analyzed using an ancova model with treatment , country , and previous antidiabetes treatment as fixed effects and baseline as the covariate . sample size calculations were based on showing a1c and body weight differences of 0.5 and 3% , respectively . the combined power ( calculated as the product of the marginal powers for a1c and weight ) superiority of glycemic control with liraglutide versus comparators was concluded if the upper limit of the two - sided 95% ci for the treatment difference in change in a1c was < 0% ; equivalence was also tested . the proportion of subjects achieving a1c targets ( american diabetes association [ ada ] target : < 7% ; american association of clinical endocrinologists [ aace]/international diabetes federation [ idf ] target : 6.5% ) was compared between treatments using a logistic regression model with treatment and baseline a1c as covariates . hypoglycemic episodes were analyzed using a general linear model including treatment as a fixed effect . the analysis of efficacy end points was based on the intent - to - treat population , defined as subjects who were exposed to at least one dose of trial product and had one postbaseline measurement of the parameter . each end point was analyzed using an ancova model with treatment , country , and previous antidiabetes treatment as fixed effects and baseline as the covariate . sample size calculations were based on showing a1c and body weight differences of 0.5 and 3% , respectively . the combined power ( calculated as the product of the marginal powers for a1c and weight ) was > 95% . superiority of glycemic control with liraglutide versus comparators was concluded if the upper limit of the two - sided 95% ci for the treatment difference in change in a1c was < 0% ; equivalence was also tested . the proportion of subjects achieving a1c targets ( american diabetes association [ ada ] target : < 7% ; american association of clinical endocrinologists [ aace]/international diabetes federation [ idf ] target : 6.5% ) was compared between treatments using a logistic regression model with treatment and baseline a1c as covariates . hypoglycemic episodes were analyzed using a general linear model including treatment as a fixed effect . a total of 821 subjects were enrolled in the study ; 533 subjects were randomly assigned to liraglutide or placebo treatment after the metformin plus rosiglitazone run - in period ( 288 subjects were run - in failures due to fpg values out of range [ 135230 mg / dl ; 7.512.8 mmol / l ] or other reasons ) . baseline characteristics were balanced across treatment groups ( table 1 ) . the majority ( 83% ) of the randomized subjects characteristics of randomized population and subject disposition data are means  sd or n ( % ) unless otherwise indicated . a , asian ; b , black ; c , caucasian ; i , american indian ; o , other . at the end of the study , the mean a1c values for the overall population decreased by ( means  se ) 1.5  0.1% for both 1.2 and 1.8 mg / day liraglutide groups and 0.5  0.1% for the placebo group . liraglutide - treated subjects had superior glycemic control compared with those in the placebo group ( liraglutide 1.2 mg / day vs. placebo : 0.9% [ 95% ci 1.1 to 0.8 ] and liraglutide 1.8 mg / day vs. placebo : 1.1% [ 1.1 to 0.8 ] ) . within the first 12 weeks of the study , mean a1c values decreased from baseline for the liraglutide - treated groups and thereafter remained steady throughout the trial ( fig . b : percentage of subjects achieving ada and aace / idf a1c goals at the end of the study . data are intent to treat , last observation carried forward for all postbaseline values , with the exception of f , which is data from the safety analysis set . error bars shown in a , c , d , and e are 2  se . * * p = 0.0009 ; * * * p < 0.0001 . a logistic regression analysis demonstrated that a significantly greater percentage of subjects in both of the liraglutide groups achieved the ada and aace / idf a1c goals compared with placebo ( p < 0.0001 for all comparisons of liraglutide to placebo for both a1c goals ) ( fig . at the end of the study , 57.5 and 53.7% of subjects in the 1.2 and 1.8 mg liraglutide / day groups , respectively , had an a1c < 7% , compared with 28.1% in the placebo group , with 37.3 and 36.2% , respectively , reaching 6.5% compared with 14.4% with placebo . fpg values decreased within 2 weeks of randomization with liraglutide , remaining relatively stable thereafter , while with placebo , smaller decreases occurred ( fig . end - of - study fpg values were 139  49 mg / dl ( 7.7  2.7 mmol / l ) , 137  41 mg / dl ( 7.6  2.3 mmol / l ) , and 171  54 mg / dl ( 9.5  3.0 mmol / l ) in the 1.2 and 1.8 mg liraglutide / day and placebo groups , respectively . the decreases in fpg from baseline for the liraglutide groups ( 40 mg / dl [ 2.2 mmol / l ] and 44 mg / dl [ 2.4 mmol / l ] for 1.2 and 1.8 mg liraglutide / day groups , respectively ) were significantly greater than the decrease observed in the placebo group ( 8 mg / dl [ 0.4 mean 90-min ppg ( mean of three meals ) , from self - monitored seven - point plasma glucose measurements at the end of the study , decreased from baseline in all treatment groups by 47 mg / dl ( 2.6 mmol / l ) for 1.2 mg liraglutide / day , 49 mg / dl ( 2.7 mmol / l ) for 1.8 mg liraglutide / day , and 14 mg / dl ( 0.8 mmol / l ) for placebo ( p < 0.001 comparisons of all liraglutide groups to placebo ) . the postprandial increment ( postmeal value minus premeal ) was significantly reduced over breakfast with liraglutide treatment ( 16 , 14 , and 5 mg / dl [ 0.9 , 0.8 , 0.3 mmol / l ] , respectively ; p < 0.05 for both liraglutide treatment groups vs. placebo ) but not for lunch and dinner . weight loss was observed in the liraglutide - treated groups ( [ means  se ] 1.0  0.3 and 2.0  0.3 kg from baseline for 1.2 and 1.8 mg liraglutide / day groups , respectively ) and was significantly different ( p < 0.0001 ) from the weight gain in the placebo group ( 0.6  0.3 kg ) . the weight loss in the 1.8 mg liraglutide / day group was significantly greater than the 1.2 mg liraglutide / day group ( p = 0.011 ) . the 1.2 and 1.8 mg liraglutide / day groups had significant reductions in mean sbp compared with the placebo group ( table 2 ) ( fig . 1e ) ( placebo - corrected difference : 1.2 mg liraglutide / day : 5.6 mmhg , p < 0.0001 ; 1.8 mg liraglutide / day : 4.5mmhg , p = 0.0009 ) . there were no significant differences between treatment groups in diastolic blood pressure ( dbp ) . minor , but statistically significant , increases in pulse rate were observed in the liraglutide - treated groups versus placebo ( 2 and 3 bpm for 1.2 mg ( p = 0.0071 ) and 1.8 mg liraglutide ( p = 0.0001 ) , respectively ) with a decrease of 0.5 bpm for placebo . changes in lipids from baseline are presented in table 2 showing that free fatty acid values decreased with liraglutide treatment as compared with an increase with placebo , and ldl cholesterol and triglycerides decreased significantly more in the 1.2 mg liraglutide group than in the placebo group . other end points of interest / metabolic intermediates change from baseline to end of study data are means  se , unless otherwise noted . * the decreases in the proinsulin - to - insulin ratio from baseline ( baseline of 0.4 across all groups ) for the liraglutide groups were significant ( p < 0.05 ) compared with the placebo group , which increased from baseline ( table 2 ) . the increase in c - peptide was significantly greater in the liraglutide groups ( 131 and 144 pmol / l for 1.2 and 1.8 mg liraglutide , respectively ) compared with an increase of 51 pmol / l for placebo ( p < 0.05 for comparison of both liraglutide groups to placebo ) . both liraglutide treatment groups had significant improvements ( increase of 27 absolute percentage points ) in homa - b for both groups from baseline values of 34 to 37% , respectively , compared with an improvement in the placebo group of 6 absolute percentage points from a baseline of 40% ( p < 0.0001 for both groups vs. placebo ) . insulin resistance ( measured by homa - ir ) was reduced in all three treatment groups but was not significantly different between groups . no significant differences in the change - from - baseline of homa - ir and fasting insulin and glucagon values were observed between either of the liraglutide groups versus the placebo group ( table 2 ) . gastrointestinal disorders ( including nausea , vomiting , and diarrhea ) were the most frequently reported adverse events in the liraglutide groups and were reported by 45 , 56 , and 19% of the subjects in the 1.2 and 1.8 mg liraglutide and placebo groups , respectively . one episode or more of nausea was experienced by 29 and 40% in the 1.2 and 1.8 mg liraglutide groups , respectively , and vomiting was experienced by 7 and 17% , respectively . the majority of nausea was transient , as it occurred in the first 4 weeks of liraglutide treatment ( 216 events in weeks 14 vs. 65 events in weeks 426 ) ( fig . 1f ) . during the first 8 weeks of treatment , 7184% of subjects in the liraglutide groups and 98% of subjects in the placebo group reported 7 days of nausea . peripheral edema was reported by 5.1 , 1.7 , and 8.0% in the 1.2 mg liraglutide , 1.8 mg liraglutide , and placebo groups , respectively . the percentages of subjects withdrawn because of adverse events were greater in the liraglutide groups than in the placebo group ( table 1 ) . nausea , vomiting , and/or diarrhea were the gastrointestinal events that lead to the withdrawal of five subjects treated with 1.2 mg liraglutide and 19 subjects treated with 1.8 mg liraglutide ( table 1 ) . serious adverse events were infrequent ( 8 subjects [ 8 total events ] for 1.2 mg liraglutide , 7 subjects [ 10 events ] for 1.8 mg liraglutide , and 12 subjects [ 13 events ] for placebo ) . minor hypoglycemia occurred at low incidence ( 9.0 , 7.9 , and 5.1% of subjects ) resulting in a low rate of reported minor hypoglycemia ( 0.4 . 0.6 , and 0.2 events per year ) for the 1.2 mg liraglutide , 1.8 mg liraglutide , and placebo groups , respectively . the rate of minor hypoglycemia for the 1.8 mg liraglutide group was significantly higher than placebo ( p = 0.004 ) . no clinically relevant between - treatment differences were observed in physical examination findings , laboratory analyses ( hematology and biochemistry analyses ) , electrocardiogram , or ophthalmoscopy . geometric mean estimated repeated - measurement analysis showed calcitonin levels of 0.89 , 0.83 , and 0.75 ng / l for 1.2 mg liraglutide , 1.8 mg liraglutide , and placebo , respectively , at the end of the study ( all values within the normal range ) . there was a significant increase for the 1.2 mg liraglutide group versus placebo group ( p = 0.022 ) but no significant difference with the 1.8 mg liraglutide group . no difference in cardiovascular adverse events was reported between the liraglutide groups and placebo ( five events [ five subjects ] with liraglutide 1.2 , three events [ three subjects ] with liraglutide 1.8 , and four events [ four subjects ] with placebo ) . there were 4.1 and 6.7% of subjects treated with 1.2 and 1.8 mg liraglutide and positive for liraglutide antibodies at the end of the study ( versus none with placebo ) . at the end of the study , the mean a1c values for the overall population decreased by ( means  se ) 1.5  0.1% for both 1.2 and 1.8 mg / day liraglutide groups and 0.5  0.1% for the placebo group . liraglutide - treated subjects had superior glycemic control compared with those in the placebo group ( liraglutide 1.2 mg / day vs. placebo : 0.9% [ 95% ci 1.1 to 0.8 ] and liraglutide 1.8 mg / day vs. placebo : 1.1% [ 1.1 to 0.8 ] ) . within the first 12 weeks of the study , mean a1c values decreased from baseline for the liraglutide - treated groups and thereafter remained steady throughout the trial ( fig . b : percentage of subjects achieving ada and aace / idf a1c goals at the end of the study . data are intent to treat , last observation carried forward for all postbaseline values , with the exception of f , which is data from the safety analysis set . error bars shown in a , c , d , and e are 2  se . * * p = 0.0009 ; * * * p < 0.0001 . a logistic regression analysis demonstrated that a significantly greater percentage of subjects in both of the liraglutide groups achieved the ada and aace / idf a1c goals compared with placebo ( p < 0.0001 for all comparisons of liraglutide to placebo for both a1c goals ) ( fig . at the end of the study , 57.5 and 53.7% of subjects in the 1.2 and 1.8 mg liraglutide / day groups , respectively , had an a1c < 7% , compared with 28.1% in the placebo group , with 37.3 and 36.2% , respectively , reaching 6.5% compared with 14.4% with placebo . fpg values decreased within 2 weeks of randomization with liraglutide , remaining relatively stable thereafter , while with placebo , smaller decreases occurred ( fig . end - of - study fpg values were 139  49 mg / dl ( 7.7  2.7 mmol / l ) , and 171  54 mg / dl ( 9.5  3.0 mmol / l ) in the 1.2 and 1.8 mg liraglutide / day and placebo groups , respectively . the decreases in fpg from baseline for the liraglutide groups ( 40 mg / dl [ 2.2 mmol / l ] for 1.2 and 1.8 mg liraglutide / day groups , respectively ) were significantly greater than the decrease observed in the placebo group ( 8 mg / dl [ 0.4 mean 90-min ppg ( mean of three meals ) , from self - monitored seven - point plasma glucose measurements at the end of the study , decreased from baseline in all treatment groups by 47 mg / dl ( 2.6 mmol / l ) for 1.2 mg liraglutide / day , 49 mg / dl ( 2.7 mmol / l ) for 1.8 mg liraglutide / day , and 14 mg / dl ( 0.8 mmol / l ) for placebo ( p < 0.001 comparisons of all liraglutide groups to placebo ) . the postprandial increment ( postmeal value minus premeal ) was significantly reduced over breakfast with liraglutide treatment ( 16 , 14 , and 5 mg / dl [ 0.9 , 0.8 , 0.3 mmol / l ] , respectively ; p < 0.05 for both liraglutide treatment groups vs. placebo ) but not for lunch and dinner . weight loss was observed in the liraglutide - treated groups ( [ means  se ] 1.0  0.3 and 2.0  0.3 kg from baseline for 1.2 and 1.8 mg liraglutide / day groups , respectively ) and was significantly different ( p < 0.0001 ) from the weight gain in the placebo group ( 0.6  0.3 kg ) . the weight loss in the 1.8 mg liraglutide / day group was significantly greater than the 1.2 mg liraglutide / day group ( p = 0.011 ) . the 1.2 and 1.8 mg liraglutide / day groups had significant reductions in mean sbp compared with the placebo group ( table 2 ) ( fig . 1e ) ( placebo - corrected difference : 1.2 mg liraglutide / day : 5.6 mmhg , p < there were no significant differences between treatment groups in diastolic blood pressure ( dbp ) . minor , but statistically significant , increases in pulse rate were observed in the liraglutide - treated groups versus placebo ( 2 and 3 bpm for 1.2 mg ( p = 0.0071 ) and 1.8 mg liraglutide ( p = 0.0001 ) , respectively ) with a decrease of 0.5 bpm for placebo . changes in lipids from baseline are presented in table 2 showing that free fatty acid values decreased with liraglutide treatment as compared with an increase with placebo , and ldl cholesterol and triglycerides decreased significantly more in the 1.2 mg liraglutide group than in the placebo group . other end points of interest / metabolic intermediates change from baseline to end of study data are means  se , unless otherwise noted . * p < 0.05 vs. placebo . the decreases in the proinsulin - to - insulin ratio from baseline ( baseline of 0.4 across all groups ) for the liraglutide groups were significant ( p < 0.05 ) compared with the placebo group , which increased from baseline ( table 2 ) . the increase in c - peptide was significantly greater in the liraglutide groups ( 131 and 144 pmol / l for 1.2 and 1.8 mg liraglutide , respectively ) compared with an increase of 51 pmol / l for placebo ( p < 0.05 for comparison of both liraglutide groups to placebo ) . both liraglutide treatment groups had significant improvements ( increase of 27 absolute percentage points ) in homa - b for both groups from baseline values of 34 to 37% , respectively , compared with an improvement in the placebo group of 6 absolute percentage points from a baseline of 40% ( p < 0.0001 for both groups vs. placebo ) . insulin resistance ( measured by homa - ir ) was reduced in all three treatment groups but was not significantly different between groups . no significant differences in the change - from - baseline of homa - ir and fasting insulin and glucagon values were observed between either of the liraglutide groups versus the placebo group ( table 2 ) . gastrointestinal disorders ( including nausea , vomiting , and diarrhea ) were the most frequently reported adverse events in the liraglutide groups and were reported by 45 , 56 , and 19% of the subjects in the 1.2 and 1.8 mg liraglutide and placebo groups , respectively . one episode or more of nausea was experienced by 29 and 40% in the 1.2 and 1.8 mg liraglutide groups , respectively , and vomiting was experienced by 7 and 17% , respectively . the majority of nausea was transient , as it occurred in the first 4 weeks of liraglutide treatment ( 216 events in weeks 14 vs. 65 events in weeks 426 ) ( fig . , 7184% of subjects in the liraglutide groups and 98% of subjects in the placebo group reported 7 days of nausea . peripheral edema was reported by 5.1 , 1.7 , and 8.0% in the 1.2 mg liraglutide , 1.8 mg liraglutide , and placebo groups , respectively . the percentages of subjects withdrawn because of adverse events were greater in the liraglutide groups than in the placebo group ( table 1 ) . nausea , vomiting , and/or diarrhea were the gastrointestinal events that lead to the withdrawal of five subjects treated with 1.2 mg liraglutide and 19 subjects treated with 1.8 mg liraglutide ( table 1 ) . serious adverse events were infrequent ( 8 subjects [ 8 total events ] for 1.2 mg liraglutide , 7 subjects [ 10 events ] for 1.8 mg liraglutide , and 12 subjects [ 13 events ] for placebo ) . minor hypoglycemia occurred at low incidence ( 9.0 , 7.9 , and 5.1% of subjects ) resulting in a low rate of reported minor hypoglycemia ( 0.4 . 0.6 , and 0.2 events per year ) for the 1.2 mg liraglutide , 1.8 mg liraglutide , and placebo groups , respectively . the rate of minor hypoglycemia for the 1.8 mg liraglutide group was significantly higher than placebo ( p = 0.004 ) . no clinically relevant between - treatment differences were observed in physical examination findings , laboratory analyses ( hematology and biochemistry analyses ) , electrocardiogram , or ophthalmoscopy . geometric mean estimated repeated - measurement analysis showed calcitonin levels of 0.89 , 0.83 , and 0.75 ng / l for 1.2 mg liraglutide , 1.8 mg liraglutide , and placebo , respectively , at the end of the study ( all values within the normal range ) . there was a significant increase for the 1.2 mg liraglutide group versus placebo group ( p = 0.022 ) but no significant difference with the 1.8 mg liraglutide group . no difference in cardiovascular adverse events was reported between the liraglutide groups and placebo ( five events [ five subjects ] with liraglutide 1.2 , three events [ three subjects ] with liraglutide 1.8 , and four events [ four subjects ] with placebo ) . there were 4.1 and 6.7% of subjects treated with 1.2 and 1.8 mg liraglutide and positive for liraglutide antibodies at the end of the study ( versus none with placebo ) . liraglutide therapy in combination with metformin and tzd provided significant decreases in a1c , fpg , and ppg with weight loss ; decreases in sbp ; and a low rate of minor hypoglycemia . in addition , there were indications of improvement in -cell function with liraglutide treatment compared with placebo . while improvement in -cell function may have been a consequence of improved glucose control , it could well be a direct effect of liraglutide , which is known to stimulate glucose - dependent endogenous insulin secretion . gastrointestinal adverse events were reported more frequently with liraglutide treatment , with most of the events occurring early in treatment . the glucose - lowering effects of the two doses of liraglutide were similar , although there were significantly more gastrointestinal adverse events with the higher dose . however , it is likely that there is significant individual variation in the development of nausea and glycemic effectiveness . the underlying pathophysiology of type 2 diabetes is complex and involves three main factors : a relative decrease in -cell insulin secretory function ; increased glucose production by the liver , which is at least partially mediated by inappropriately increased glucagon levels ; and decreased glucose uptake by muscle . the triple therapy of metformin , tzd , and glp-1 receptor agonists has the potential of addressing all three underlying abnormalities and results in improved glycemic control , potential weight loss , and improvements in -cell function with minimal risk of hypoglycemia . the use of this triple therapy has demonstrated the largest decreases in a1c and sbp values in the lead program . it should be noted that 50% of the subjects initiated tzd treatment during the run - in period , and doses of metformin and tzd were maximized during this period , which may account for the improvements observed in the placebo arm of this study . exenatide , a commercially available glp-1 receptor agonist , is a synthetic version of exendin-4 . unlike liraglutide , which is dosed once daily independently of meals , exenatide is dosed twice daily within 60 min of breakfast and dinner ( 14 ) . the findings in this study support the findings of a previous study ( 15 ) in which 233 subjects inadequately controlled with a stable dose of tzd ( rosiglitazone 4 mg / day or pioglitazone 30 mg / day ) with or without metformin treatment ( 79% were treated with metformin ) were randomized to add exenatide treatment ( n = 121 ) or placebo ( n = 112 ) for 16 weeks of treatment . at the end of the study , a1c values decreased by 0.89% , compared with a slight increase of 0.09% in the placebo group ( p < 0.001 ) . body weight decreased by 1.75 kg ( vs. 0.24 kg in the placebo group ; p < 0.001 ) , and other measurements of glycemic control ( fpg , mean smpg , and mean postprandial smpg values ) all showed significant improvement with exenatide treatment . these studies support the effectiveness of this type of diabetes regimen , particularly as it is associated with modest weight loss and low risk of hypoglycemia . the very significant change in sbp observed in this study appears to be of larger magnitude than that observed in the other lead studies . tzd treatment is associated with a modest reduction in blood pressure but is also associated with fluid retention further study would be of obvious interest , particularly if there was potential for long - term cardiovascular benefit . the specific mechanism(s ) of sbp reduction and the slight increases in pulse with liraglutide remain to be further studied . based on data with native glp-1 , it could be speculated that the effect on sbp relates to reduced renal sodium reabsorption ( 16,17 ) . native glp-1 has been shown to improve endothelial function in patients with type 2 diabetes and coronary heart disease ( 18 ) and in vitro endothelial cell models ( 19 ) . potentially , the slight increases in pulse observed with liraglutide may be compensatory for the decreases in sbp . in summary , this study demonstrated that the triple combination of liraglutide , metformin , and tzd is an effective and safe treatment for patients with type 2 diabetes . this combination significantly improved glycemic control and other efficacy parameters , in addition to resulting in significant weight loss and improved blood pressure .
objectiveto determine the efficacy and safety of liraglutide ( a glucagon - like peptide-1 receptor agonist ) when added to metformin and rosiglitazone in type 2 diabetes.research design and methodsthis 26-week , double - blind , placebo - controlled , parallel - group trial randomized 533 subjects ( 1:1:1 ) to once - daily liraglutide ( 1.2 or 1.8 mg ) or liraglutide placebo in combination with metformin ( 1 g twice daily ) and rosiglitazone ( 4 mg twice daily ) . 
 subjects had type 2 diabetes , a1c 711% ( previous oral antidiabetes drug [ oad ] monotherapy 3 months ) or 710% ( previous oad combination therapy 3 months ) , and bmi 45 kg / m2.resultsmean a1c values decreased significantly more in the liraglutide groups versus placebo ( mean  se 1.5  0.1% for both 1.2 and 1.8 mg liraglutide and 0.5  0.1% for placebo ) . 
 fasting plasma glucose decreased by 40 , 44 , and 8 mg / dl for 1.2 and 1.8 mg and placebo , respectively , and 90-min postprandial glucose decreased by 47 , 49 , and 14 mg / dl , respectively ( p < 0.001 for all liraglutide groups vs. placebo ) . 
 dose - dependent weight loss occurred with 1.2 and 1.8 mg liraglutide ( 1.0  0.3 and 2.0  0.3 kg , respectively ) ( p < 0.0001 ) compared with weight gain with placebo ( 0.6  0.3 kg ) . 
 systolic blood pressure decreased by 6.7 , 5.6 , and 1.1 mmhg with 1.2 and 1.8 mg liraglutide and placebo , respectively . 
 significant increases in c - peptide and homeostasis model assessment of -cell function and significant decreases in the proinsulin - to - insulin ratio occurred with liraglutide versus placebo . 
 minor hypoglycemia occurred more frequently with liraglutide , but there was no major hypoglycemia . 
 gastrointestinal adverse events were more common with liraglutide , but most occurred early and were transient.conclusionsliraglutide combined with metformin and a thiazolidinedione is a well - tolerated combination therapy for type 2 diabetes , providing significant improvements in glycemic control .