eligible participants were insulin - nave adults ( 1880 years ) with type 2 diabetes treated for 3 months with 1,500 mg / day metformin and a1c values of 7.010.0% or with metformin and sulfonylurea ( less than or equal to half of the maximum approved dose ) and a1c values of 7.08.5% ( supplementary data online ) .
the trial was conducted in 202 office- or hospital - based sites in belgium , canada , france , germany , italy , the netherlands , spain , the u.k . , and the u.s . between 3 march 2009 and 19 april 2010 .
protocol , amendments , and informed consent documents were approved by independent local ethics committees and implemented according to good clinical practice ( 9 ) and the declaration of helsinki ( 10 ) .
this 38-week , open - label trial comprised a 12-week run - in followed by a 26-week , randomized , two - armed , parallel - group period for participants not achieving < 7% a1c . at run - in
start , sulfonylurea was discontinued ( in approximately one - third of participants ) , and liraglutide was initiated in 0.6-mg / day weekly increments to a final 1.8-mg / day dose ( fig .
* two participants who had been randomized to the metformin and liraglutide control group received the wrong trial treatment .
the other participant should not have been randomized as her a1c level at week 0 was < 7% . for the full analysis
, these participants appear in the randomized control group , and for the safety analysis , they appear in their respective  treatment  groups ( i.e. , insulin detemir and observational groups , respectively ) . participants with
a1c 7% at the end of run - in were randomized ( 1:1 ) to 26 weeks insulin detemir added to metformin + liraglutide 1.8 mg ( randomized detemir group ) or continued metformin + liraglutide 1.8 mg only ( randomized control group ) ( see supplementary data online for randomization details ) . a double - blind
, placebo - controlled approach was not used because titration with detemir placebo was not feasible . to determine the effects of continued treatment on initial responders , participants with a1c < 7% after run - in
insulin detemir ( 100 units / ml ) and liraglutide ( 6.0 mg / ml ) ( novo nordisk a / s , bagsvaerd , denmark ) were injected subcutaneously once daily with pen devices . insulin detemir was administered with evening meals or at bedtime ; liraglutide was administered at any ( consistent ) time of day .
insulin detemir treatment was started at 10 units and titrated by investigators on a weekly basis using a specific algorithm targeting 4.16.0 mmol / l self - measured fasting plasma glucose ( fpg ) values ( supplementary data online ) .
the primary end point was the change in a1c ( % ) from randomization ( week 0 ) to week 26 to determine whether adding insulin detemir to metformin + liraglutide was superior to continued metformin + liraglutide .
additional efficacy end points included the following : percentage of participants reaching a1c < 7 and 6.5% , fpg , postprandial plasma glucose from self - measured seven - point glucose profiles , weight , blood pressure , lipids , and percentage of participants reaching the composite end point of a1c < 7% with no weight gain or hypoglycemia ( during the 26-week period ) .
major episodes required third - party assistance , irrespective of plasma glucose levels . for the primary end point , superiority of the insulin detemir over the control group was concluded if the 95% ci upper limit for the treatment difference was < 0 .
assuming 20% run - in withdrawals and 40% randomization eligibility , 150 participants per group were needed to detect a 0.5% a1c between - group difference with 90% power . unless stated otherwise , efficacy end points were analyzed statistically using the full analysis set ( all randomized participants with greater than or equal to one efficacy value ) with missing values imputed by carrying forward the last observation . an ancova model with treatment , country , and previous oral antidiabetic therapy as fixed effects and randomization value as covariate was used to analyze change from randomization to week 26 .
percentages of participants reaching < 7 and 6.5% a1c were analyzed using logistic regression with the same fixed effects and covariate .
a similar logistic regression model was used for the composite end point ( proportion reaching < 7% a1c with no weight increase and no hypoglycemia during the 26-week period ) .
the safety analysis set comprised all participants exposed to at least one dose of trial drug .
run - in results were summarized by the randomized period treatment group ( i.e. , observational , randomized detemir , or randomized control ) , although all participants received the same run - in treatment .
eligible participants were insulin - nave adults ( 1880 years ) with type 2 diabetes treated for 3 months with 1,500 mg / day metformin and a1c values of 7.010.0% or with metformin and sulfonylurea ( less than or equal to half of the maximum approved dose ) and a1c values of 7.08.5% ( supplementary data online ) .
the trial was conducted in 202 office- or hospital - based sites in belgium , canada , france , germany , italy , the netherlands , spain , the u.k . , and the u.s . between 3 march 2009 and 19 april 2010 .
protocol , amendments , and informed consent documents were approved by independent local ethics committees and implemented according to good clinical practice ( 9 ) and the declaration of helsinki ( 10 ) .
this 38-week , open - label trial comprised a 12-week run - in followed by a 26-week , randomized , two - armed , parallel - group period for participants not achieving < 7% a1c . at run - in
start , sulfonylurea was discontinued ( in approximately one - third of participants ) , and liraglutide was initiated in 0.6-mg / day weekly increments to a final 1.8-mg / day dose ( fig .
* two participants who had been randomized to the metformin and liraglutide control group received the wrong trial treatment .
the other participant should not have been randomized as her a1c level at week 0 was < 7% . for the full analysis
, these participants appear in the randomized control group , and for the safety analysis , they appear in their respective  treatment 
groups ( i.e. , insulin detemir and observational groups , respectively ) . participants with a1c 7% at the end of run - in were randomized ( 1:1 ) to 26 weeks insulin detemir added to metformin + liraglutide 1.8 mg ( randomized detemir group ) or continued metformin + liraglutide 1.8 mg only ( randomized control group ) ( see supplementary data online for randomization details ) . a double - blind
, placebo - controlled approach was not used because titration with detemir placebo was not feasible . to determine the effects of continued treatment on initial responders , participants with a1c < 7% after run - in
insulin detemir ( 100 units / ml ) and liraglutide ( 6.0 mg / ml ) ( novo nordisk a / s , bagsvaerd , denmark ) were injected subcutaneously once daily with pen devices . insulin detemir was administered with evening meals or at bedtime ; liraglutide was administered at any ( consistent ) time of day .
insulin detemir treatment was started at 10 units and titrated by investigators on a weekly basis using a specific algorithm targeting 4.16.0 mmol
/ l self - measured fasting plasma glucose ( fpg ) values ( supplementary data online ) .
the primary end point was the change in a1c ( % ) from randomization ( week 0 ) to week 26 to determine whether adding insulin detemir to metformin + liraglutide was superior to continued metformin + liraglutide .
additional efficacy end points included the following : percentage of participants reaching a1c < 7 and 6.5% , fpg , postprandial plasma glucose from self - measured seven - point glucose profiles , weight , blood pressure , lipids , and percentage of participants reaching the composite end point of a1c < 7% with no weight gain or hypoglycemia ( during the 26-week period ) .
for the primary end point , superiority of the insulin detemir over the control group was concluded if the 95% ci upper limit for the treatment difference was < 0 . assuming 20% run - in withdrawals and 40% randomization eligibility , 150 participants per group were needed to detect a 0.5% a1c between - group difference with 90% power . unless stated otherwise , efficacy end points were analyzed statistically using the full analysis set ( all randomized participants with greater than or equal to one efficacy value ) with missing values imputed by carrying forward the last observation . an ancova model with treatment , country , and previous oral antidiabetic therapy as fixed effects and randomization value as covariate was used to analyze change from randomization to week 26 .
percentages of participants reaching < 7 and 6.5% a1c were analyzed using logistic regression with the same fixed effects and covariate .
a similar logistic regression model was used for the composite end point ( proportion reaching < 7% a1c with no weight increase and no hypoglycemia during the 26-week period ) . the safety analysis set comprised all participants exposed to at least one dose of trial drug .
run - in results were summarized by the randomized period treatment group ( i.e. , observational , randomized detemir , or randomized control ) , although all participants received the same run - in treatment .
during the run - in , 167 of 988 ( 17% ) participants withdrew ( fig .
1b ) ; 76 of 167 ( 46% ) of these withdrew due to gastrointestinal aes ( 7.7% of enrolled participants ) .
of 821 participants completing the run - in , 498 ( 61% ) reached < 7% a1c ; 323 ( 39% ) did not and were eligible for randomization . compared with participants that did not reach the target during run - in , those reaching the target had a shorter type 2 diabetes duration and lower a1c and fpg values and
more had been treated with metformin only before enrollment ( table 1 ) . at run - in completion ,
a1c was reduced by 1.3% in this observational group and by 0.6% in the randomized groups from a1c values at run - in start of 7.7 and 8.3% , respectively ( fig .
one major hypoglycemic event occurred ( blood glucose level , 5.2 mmol / l ) and minor hypoglycemia occurred at 0.0000.372 events per participant - year ( supplementary table 2 ) .
demographics and disease characteristics at run - in start ( week 12 ) and randomization ( week 0 ) glycemic efficacy , changes in body weight , and insulin detemir doses
. results from run - in to randomization ( vertical dotted line ) and from randomization to the end of the trial for change in a1c ( a ) , change in body weight ( b ) , and mean fpg ( c ) .
rt , randomized treatment group ; rc , randomized control group ; o , observational group .
d : self - monitored plasma glucose profiles before and after breakfast , lunch , and dinner and at bedtime for the treatment and control groups at weeks 0 and 26 .
 , randomized treatment group ;  , randomized control group ;  , observational group .
p values refer to differences between groups in the change from randomization ( week 0 ) to week 26 .
e : insulin detemir dose ( prescribed dose ,  , left ordinate ) and self - measured fpg (  , right ordinate ) during the 26-week randomized period for the insulin detemir treatment group .
nausea was the most frequently reported run - in ae ( table 2 ) but incidences fell to < 7% in all groups after 3 weeks ( supplementary table 3 and supplementary fig .
one case of acute pancreatitis was reported . in another participant , with elevated calcitonin level ( 23.5 ng / l ) before liraglutide administration
, a subsequent thyroidectomy revealed an incidental thyroid neoplasm ( 1-mm papillary microcarcinoma ) ( supplementary table 4 ) .
aes during run - in and randomized period with an incidence 5% by system organ class and preferred term and summary of saes participants not reaching glycemic target had a 7.6% mean a1c at completion of the run - in period .
they were then randomized to add insulin detemir to metformin + liraglutide ( n = 162 ) or to continue unchanged metformin + liraglutide ( randomized control subjects , n = 161 ) .
addition of insulin detemir further reduced a1c compared with continued metformin + liraglutide ( 0.51% [ n = 162 ] vs. + 0.02% [ n = 157 ] , respectively ; estimated treatment difference [ etd ] 0.52 [ 95% ci 0.68 to 0.36 ] ; p < 0.0001 ) , resulting in a1c values of 7.1 and 7.5% , respectively , at week 26 ( fig .
2a and supplementary tables 5 and 6 ) , and meeting the trial s primary end point .
mmol / l ) than control group ( 0.4 mmol / l ; etd 1.7 [ 2.2 to 1.3 ] ; p < 0.0001 ) ( fig .
2c ) . after a mean 3.5-kg weight loss during run - in , both groups experienced further modest weight reduction over the next 26 weeks : 0.16 kg with detemir and 0.95 kg without ( etd 0.79 [ 0.081.49 ] ; p = 0.03 ) ( fig .
compared with the control group , more than twice as many in the insulin detemir group achieved < 7% a1c ( 17 vs. 43% , respectively ; p < 0.0001 ) , and three times as many achieved 6.5% ( 6 vs. 18% , respectively ; p = 0.0016 ; logistic regression estimates ) ( supplementary fig .
the proportion reaching the composite end point ( < 7% a1c with no weight gain and no hypoglycemia ) after 26 weeks was significantly greater in the insulin detemir ( 21% ) than the control group ( 9% ; p = 0.0016 ; logistic regression estimates ) ( supplementary fig .
2 ) . excluding one outlier in the randomized control group with 25 minor hypoglycemic episodes , minor hypoglycemia rates were 0.286 and 0.029 events per participant - year for insulin detemir and control groups , respectively ( p = 0.004 ) ( supplementary table 2 ) .
self - measured plasma glucose levels decreased in both groups , with significantly greater reductions in postprandial values in the insulin detemir versus control group ( fig .
etds ranged from 0.60 mmol / l ( 95% ci 1.12 to 0.08 ; p = 0.02 ) to 1.12 mmol / l ( 95% ci 1.72 to 0.51 ; p = 0.0003 ) .
mean prescribed insulin detemir doses increased from 10 units / day to 39.5 units / day ( 0.41 units / kg ) , whereas mean self - measured fpg decreased from 7.9 to 6.2 mmol / l ( fig .
prescribed insulin detemir doses were consistent with algorithm recommendations , indicating good overall adherence to the titration algorithm .
there were no significant differences between groups in changes from randomization for serum lipids , except for free fatty acids ( insulin detemir group , 0.11 mmol / l ; control group , 0.03 mmol / l ; etd 0.08 [ 95% ci 0.13 to 0.03 ] ; p = 0.002 ) ( for more information regarding changes in lipid levels , see supplementary table 7 ) .
a total of 67% ( 109 of 163 ) and 59% ( 93 of 159 ) of participants had one or more aes , and 5.5% ( 9 participants ; 13 events ) and 3.8% ( 6 participants ; 8 events ) had serious aes ( saes ) , in the insulin detemir and control groups , respectively ( table 2 ) .
no pattern or clustering of saes was observed , with most being considered unlikely to be related to treatment ( supplementary table 8) .
although more aes of increased lipase were reported with insulin detemir , a minor increase in the median serum lipase levels ( below the upper limit of normal ) was observed across all groups , without apparent treatment differences ( supplementary table 9 ) .
one case of chronic pancreatitis occurred ( control group ) ( supplementary table 4 ) .
the 498 participants achieving the < 7% target with metformin + liraglutide at the end of run - in were followed for another 26 weeks .
this group experienced a mean 1.3% a1c reduction by the end of run - in , and 1.1% overall from start of run - in to week 26 ( from 7.7% at run - in start to 6.6% at study end ) .
the group also experienced overall reductions from start of run - in to week 26 in fpg of 2.1 mmol / l ( from 9.2
mmol / l at run - in start to 7.2 mmol / l ) and weight of 4.8 kg ( from 99.0 kg at run - in start to 94.6 kg ) ( fig .
2 ) , and improved seven - point blood glucose profiles ( completers ) ( fig .
aes for the 38-week period are summarized in supplementary table 10 . in the observational group , 81% ( 402 of 499 ) of participants had aes and 7.8% ( 39 of 499 ) experienced 49 saes , with 45 considered unlikely to be related to study drug and without obvious pattern ( supplementary table 8) .
no major hypoglycemic episodes occurred , whereas 9.0% ( 45 of 499 ) of participants experienced minor hypoglycemia ( 0.211 events per participant - year ) .
, systolic blood pressure was reduced from run - in start by 3.13 mmhg in the control group , 1.65 mmhg in the insulin detemir group , and 3.33 mmhg in the observational group ( supplementary table 11 ) .
heart rate was increased from run - in start to 26 weeks in all treatment groups : by 3.62 beats per minute ( bpm ) in the control group , 3.87 bpm in the insulin detemir group , and 3.64 bpm in the observational group ( supplementary table 12 ) .
during the run - in , 167 of 988 ( 17% ) participants withdrew ( fig .
1b ) ; 76 of 167 ( 46% ) of these withdrew due to gastrointestinal aes ( 7.7% of enrolled participants ) .
of 821 participants completing the run - in , 498 ( 61% ) reached < 7% a1c ; 323 ( 39% ) did not and were eligible for randomization . compared with participants that did not reach the target during run - in , those reaching the target had a shorter type 2 diabetes duration and lower a1c and fpg values and
more had been treated with metformin only before enrollment ( table 1 ) . at run - in completion ,
a1c was reduced by 1.3% in this observational group and by 0.6% in the randomized groups from a1c values at run - in start of 7.7 and 8.3% , respectively ( fig .
one major hypoglycemic event occurred ( blood glucose level , 5.2 mmol / l ) and minor hypoglycemia occurred at 0.0000.372 events per participant - year ( supplementary table 2 ) .
demographics and disease characteristics at run - in start ( week 12 ) and randomization ( week 0 ) glycemic efficacy , changes in body weight , and insulin detemir doses
. results from run - in to randomization ( vertical dotted line ) and from randomization to the end of the trial for change in a1c ( a ) , change in body weight ( b ) , and mean fpg ( c ) .
rt , randomized treatment group ; rc , randomized control group ; o , observational group .
d : self - monitored plasma glucose profiles before and after breakfast , lunch , and dinner and at bedtime for the treatment and control groups at weeks 0 and 26 .
 , randomized treatment group ;  , randomized control group ;  , observational group .
p values refer to differences between groups in the change from randomization ( week 0 ) to week 26 .
e : insulin detemir dose ( prescribed dose ,  , left ordinate ) and self - measured fpg (  , right ordinate ) during the 26-week randomized period for the insulin detemir treatment group .
nausea was the most frequently reported run - in ae ( table 2 ) but incidences fell to < 7% in all groups after 3 weeks ( supplementary table 3 and supplementary fig .
one case of acute pancreatitis was reported . in another participant , with elevated calcitonin level ( 23.5 ng / l ) before liraglutide administration
, a subsequent thyroidectomy revealed an incidental thyroid neoplasm ( 1-mm papillary microcarcinoma ) ( supplementary table 4 ) .
aes during run - in and randomized period with an incidence 5% by system organ class and preferred term and summary of saes
participants not reaching glycemic target had a 7.6% mean a1c at completion of the run - in period .
they were then randomized to add insulin detemir to metformin + liraglutide ( n = 162 ) or to continue unchanged metformin + liraglutide ( randomized control subjects , n = 161 ) .
addition of insulin detemir further reduced a1c compared with continued metformin + liraglutide ( 0.51% [ n = 162 ] vs. + 0.02% [ n = 157 ] , respectively ; estimated treatment difference [ etd ] 0.52 [ 95% ci 0.68 to 0.36 ] ; p < 0.0001 ) , resulting in a1c values of 7.1 and 7.5% , respectively , at week 26 ( fig .
2a and supplementary tables 5 and 6 ) , and meeting the trial s primary end point . accordingly ,
mmol / l ) than control group ( 0.4 mmol / l ; etd 1.7 [ 2.2 to 1.3 ] ; p < 0.0001 ) ( fig .
2c ) . after a mean 3.5-kg weight loss during run - in , both groups experienced further modest weight reduction over the next 26 weeks : 0.16 kg with detemir and 0.95 kg without ( etd 0.79 [ 0.081.49 ] ; p = 0.03 ) ( fig .
compared with the control group , more than twice as many in the insulin detemir group achieved < 7% a1c ( 17 vs. 43% , respectively ; p < 0.0001 ) , and three times as many achieved 6.5% ( 6 vs. 18% , respectively ; p = 0.0016 ; logistic regression estimates ) ( supplementary fig .
2 ) . similarly , the proportion reaching the composite end point ( < 7% a1c with no weight gain and no hypoglycemia ) after 26 weeks was significantly greater in the insulin detemir ( 21% ) than the control group ( 9% ; p = 0.0016 ; logistic regression estimates )
2 ) . excluding one outlier in the randomized control group with 25 minor hypoglycemic episodes , minor hypoglycemia rates were 0.286 and 0.029 events per participant - year for insulin detemir and control groups , respectively ( p = 0.004 ) ( supplementary table 2 ) .
self - measured plasma glucose levels decreased in both groups , with significantly greater reductions in postprandial values in the insulin detemir versus control group ( fig .
etds ranged from 0.60 mmol / l ( 95% ci 1.12 to 0.08 ; p = 0.02 ) to 1.12 mmol / l ( 95% ci 1.72 to 0.51 ; p = 0.0003 ) .
mean prescribed insulin detemir doses increased from 10 units / day to 39.5 units / day ( 0.41 units / kg ) , whereas mean self - measured fpg decreased from 7.9 to 6.2 mmol / l ( fig .
prescribed insulin detemir doses were consistent with algorithm recommendations , indicating good overall adherence to the titration algorithm .
there were no significant differences between groups in changes from randomization for serum lipids , except for free fatty acids ( insulin detemir group , 0.11 mmol / l ; control group , 0.03 mmol / l ; etd 0.08 [ 95% ci 0.13 to 0.03 ] ; p = 0.002 ) ( for more information regarding changes in lipid levels , see supplementary table 7 ) .
a total of 67% ( 109 of 163 ) and 59% ( 93 of 159 ) of participants had one or more aes , and 5.5% ( 9 participants ; 13 events ) and 3.8% ( 6 participants ; 8 events ) had serious aes ( saes ) , in the insulin detemir and control groups , respectively ( table 2 ) . no pattern or clustering of saes
was observed , with most being considered unlikely to be related to treatment ( supplementary table 8) . although more aes of increased lipase were reported with insulin detemir , a minor increase in the median serum lipase levels ( below the upper limit of normal )
was observed across all groups , without apparent treatment differences ( supplementary table 9 ) .
one case of chronic pancreatitis occurred ( control group ) ( supplementary table 4 ) .
the 498 participants achieving the < 7% target with metformin + liraglutide at the end of run - in were followed for another 26 weeks .
this group experienced a mean 1.3% a1c reduction by the end of run - in , and 1.1% overall from start of run - in to week 26 ( from 7.7% at run - in start to 6.6% at study end ) .
the group also experienced overall reductions from start of run - in to week 26 in fpg of 2.1 mmol / l ( from 9.2
mmol / l at run - in start to 7.2 mmol / l ) and weight of 4.8 kg ( from 99.0 kg at run - in start to 94.6 kg ) ( fig .
2 ) , and improved seven - point blood glucose profiles ( completers ) ( fig .
aes for the 38-week period are summarized in supplementary table 10 . in the observational group ,
81% ( 402 of 499 ) of participants had aes and 7.8% ( 39 of 499 ) experienced 49 saes , with 45 considered unlikely to be related to study drug and without obvious pattern ( supplementary table 8) .
no major hypoglycemic episodes occurred , whereas 9.0% ( 45 of 499 ) of participants experienced minor hypoglycemia ( 0.211 events per participant - year ) .
at 26 weeks , systolic blood pressure was reduced from run - in start by 3.13 mmhg in the control group , 1.65 mmhg in the insulin detemir group , and 3.33 mmhg in the observational group ( supplementary table 11 ) .
heart rate was increased from run - in start to 26 weeks in all treatment groups : by 3.62 beats per minute ( bpm ) in the control group , 3.87 bpm in the insulin detemir group , and 3.64 bpm in the observational group ( supplementary table 12 ) .
this large , prospective clinical study provides support for a new sequential treatment paradigm in type 2 diabetes , that is , adding a glp-1ra ( liraglutide ) to metformin followed ( if necessary ) by a basal insulin ( insulin detemir ) to achieve and maintain glycemic targets . with 12 weeks of liraglutide + metformin
for the 39% of completers not initially achieving target , adding insulin detemir provided clinically relevant further reductions of mean a1c from 7.6 to 7.1% .
a total of 43% of insulin detemir recipients then achieved the < 7% a1c target , compared with 17% continuing treatment with metformin + liraglutide . in the observational group ,
all of whom achieved a1c < 7% after the 12-week run - in , 74% remained at target after a further 26 weeks treatment .
translated into clinical practice , and extrapolating from all patients who completed run - in , sequential intensification enabled approximately three - quarters of patients to achieve an a1c < 7% . importantly ,
overall , the hypoglycemia risk was very low , and insulin detemir recipients maintained the significant weight reductions achieved during liraglutide run - in rather than gaining weight as typically occurs with insulin .
however , after metformin , commonly used oral agents such as sulfonylureas and thiazolidinediones carry side effects , particularly hypoglycemia and/or weight gain ; the exceptions are dipeptidyl peptidase-4 inhibitors and -glucosidase inhibitors , which are weight - neutral but appear to show less glucose - lowering activity than other agents ( 1,11 ) . because glp-1ras provide greater glycemic efficacy and weight loss ( 6 ) , they may be more beneficial than these oral agents after metformin , but less acceptable in some patients because of gastrointestinal side effects and the injection barrier .
insulin initiation also usually causes weight gain and an increased hypoglycemia risk ( 1,12 ) . in this study
, however , the insulin detemir group maintained the initial weight loss achieved by adding liraglutide to metformin .
subsequent intensification with insulin detemir allowed 43% of the group to reach the glycemic target .
it is conceivable that more aggressive insulin titration , giving higher insulin doses , would allow even more patients to reach a1c target , but perhaps at the expense of more hypoglycemia .
the incidence of confirmed minor hypoglycemia with insulin detemir in our study , 0.286 events per participant - year , was considerably lower than the 1.33.67 events per participant - year in previous trials with insulin detemir added to oral agents ( 13,14 ) .
although withdrawing sulfonylureas ( as in the run - in ) is associated with decreased hypoglycemia risks ( 3.2 vs. 1.6 events per participant - year , despite an increased insulin requirement ) ( 15 ) , initiating liraglutide before detemir may further reduce the hypoglycemia risk , perhaps by modulating endogenous glucose - dependent insulin secretion and glucagon secretion as well as body weight , thereby lowering exogenous insulin requirements .
it remains unknown whether an association exists between incretin - based therapies and pancreatitis ( 16 ) , but acute pancreatitis is known to be about three times more common in patients with type 2 diabetes than in the general population ( 17 ) . in the present trial , two cases of pancreatitis were reported ( one acute and one chronic ) and neither case of pancreatitis was preceded by elevated lipase levels .
reports of pancreatitis were similarly uncommon in other liraglutide studies , although imbalances in pancreatitis are noted for liraglutide and other incretin - based therapies ( 16,18 ) .
an initial small increase in median serum lipase below the upper limit of normal was observed across groups in the current study , and substantial fluctuations occurred over time . interpreting these changes is difficult in the absence of an active comparator or a placebo group ( i.e. , a group not receiving liraglutide ) .
elevated lipase ( or amylase ) levels by themselves are insufficient to make a diagnosis of pancreatitis without the presence of abdominal pain and ideally confirmation with imaging studies . most commonly , no gastrointestinal symptoms were associated with fluctuations in lipase observed during this trial .
we found no other published , prospective , controlled trials studying insulin added to a glp-1ra in type 2 diabetes .
a few previous studies have investigated the alternative intensification sequence , adding a glp-1ra ( specifically , twice - daily exenatide ) to insulin ( 19,2022 ) . in the only randomized , controlled trial to date , patients with more advanced disease at baseline ( compared with the current study ) already receiving 0.5 units / kg of insulin glargine were randomized to either add - on exenatide or continuation of basal insulin only ( 19 ) .
the insulin doses were optimized in both groups by further rigorous titration postrandomization . in this
setting , add - on exenatide with insulin optimization was associated with a 1.7% reduction in a1c levels ( from a baseline of 8.36.7% vs. 1.0% a1c reduction with basal insulin optimization only ) , modest weight loss , and no significant increase in risk of minor hypoglycemia . in other nonrandomized studies , a1c reductions ranged from 0.0 to 0.9% ( 2022 ) . in the current study , however , adding a glp-1ra before basal insulin was also effective , offering significantly improved glycemic control , substantial weight loss , and a very low hypoglycemia rate .
this intensification sequence may therefore be preferable provided that potential gastrointestinal aes can be accepted initially .
it may also be preferable to initiate with a longer - acting once - daily glp-1ra , such as liraglutide , rather than a twice - daily shorter - acting glp-1ra to facilitate better compliance .
more participants may have reached glycemic targets with a lower fpg target for insulin titration ( 23 ) . as some participants randomized to continued
liraglutide + metformin subsequently reached target without dose adjustments , it is also conceivable that fewer patients would have needed insulin with a longer run - in period .
first , the study used the higher ( 1.8 mg ) of the two liraglutide doses .
the higher dose may have favored efficacy outcomes and weight loss but adversely affected tolerability ( 11,24 ) .
potentially , fewer patients may have withdrawn early due to gastrointestinal aes if they had been permitted to return to the 1.2-mg dose or if upward titration was conducted more slowly .
second , one - third of participants were taking a sulfonylurea before the study ; this was discontinued at the start of run - in and may have negatively influenced improvements in glycemic control but favored weight loss .
however , neither factor should have affected the 26-week randomized - group comparisons . moreover ,
discontinuation of sulfonylureas increases the trial s translational validity because many physicians add an injectable therapy only after failure of more than one oral agent , and then tend to withdraw sulfonylureas .
we recognize that the randomized control group did not have a masked placebo or active comparator ; this was mainly due to logistic limitations with insulin comparators .
however , we also chose not to include an active comparator to retain the focus on the efficacy and safety of adding a basal insulin to a glp-1ra in combination with metformin .
it is possible that some participants were disappointed with their treatment allocation and withdrew , an effect that might not have occurred with an active comparator .
it would be informative , however , if future trials adhered to the comparative effectiveness concept ( 25 ) .
future studies might also be of a longer duration and consider the overall costs of diabetes care ( particularly the balance between the higher prices of new medications versus any potential for reduced costs associated with diabetes complications and less self - monitoring of blood glucose ) .
a 26-week extension to the current study has been undertaken , primarily to assess longer - term treatment safety . in conclusion , in type 2 diabetes with inadequate glycemic control on metformin  sulfonylurea , the addition of liraglutide was effective and safe , enabling the majority of participants to reach a1c levels < 7% , with sustained weight loss and low hypoglycemia risk . for those not reaching glycemic targets ,
intensification with insulin detemir provided clinically relevant additional glycemic control , sustaining previous weight loss and the very low hypoglycemia risk .
 objectivewe evaluated the addition of liraglutide to metformin in type 2 diabetes followed by intensification with basal insulin ( detemir ) if glycated hemoglobin ( a1c ) 7%.research design and methodsin 988 participants from north america and europe uncontrolled on metformin  sulfonylurea , sulfonylurea was discontinued and liraglutide 1.8 mg / day added for 12 weeks ( run - in ) . 
 subsequently , those with a1c 7% were randomized 1:1 to 26 weeks open - label addition of insulin detemir to metformin + liraglutide ( n = 162 ) or continuation without insulin detemir ( n = 161 ) . 
 patients achieving a1c < 7% continued unchanged treatment ( observational arm ) . 
 the primary end point was a1c change between randomized groups.resultsof 821 participants completing the run - in , 61% ( n = 498 ) achieved a1c < 7% ( mean change 1.3% from 7.7% at start ) , whereas 39% ( n = 323 ) did not ( 0.6% from 8.3% at start ) . during run - in , 167 of 988 ( 17% ) withdrew ; 46% of these due to gastrointestinal adverse events . at week 26 , a1c decreased further , by 0.5% ( from 7.6% at randomization ) with insulin detemir ( n = 162 ) versus 0.02% increase without insulin detemir ( n = 157 ) to 7.1 and 7.5% , respectively ( estimated treatment difference 0.52 [ 95% ci 0.68 to 0.36 ] ; p < 0.0001 ) . 
 forty - three percent of participants with insulin detemir versus 17% without reached a1c < 7% . 
 mean weight decreased by 3.5 kg during run - in , then by 0.16 kg with insulin detemir or 0.95 kg without insulin detemir . in the randomized phase , 
 no major hypoglycemia occurred and minor hypoglycemia rates were 0.286 and 0.029 events per participant - year with and without insulin detemir ( 9.2 vs. 1.3%).conclusionssupplementation of metformin with liraglutide and then insulin detemir was well tolerated in the majority of patients , with good glycemic control , sustained weight loss , and very low hypoglycemia rates . 
RESEARCH DESIGN AND METHODS
Participants
Trial design and interventions
Assessments and end points
Statistical analyses
RESULTS
Adding liraglutide to metformin: 12-week run-in
Adding insulin detemir to metformin and liraglutide in participants requiring additional glycemic control: the 26-week, randomized period
Efficacy and safety over 38 weeks: the observational group
Systolic blood pressure and heart rate: run-in to 26 weeks
CONCLUSIONS