physical exercise is beneficial for patients with type 1 diabetes ( t1d ) , although associated with an increased risk of hypoglycaemia 1 , 2 .
individuals with t1d lack the physiological adjustments of healthy individuals to maintain euglycaemia during physical activity 3 , 4 , and may avoid exercise 5 . published research and practical guidelines recommend individual adjustments to insulin dose and carbohydrate intake 6 , 7 , 8 ; however , variation in pharmacodynamic profiles and duration of action between different basal insulins may alter their contribution to hypoglycaemia risk .
the aim of the present study was to compare changes in blood glucose ( bg ) concentration and hypoglycaemia risk during and after exercise in patients with t1d treated with insulin degludec ( ideg ) or insulin glargine ( iglar ) .
this singlecentre , randomized , openlabel , twoperiod , multipledose , crossover trial complied with the declaration of helsinki 9 and good clinical practice guidelines 10 , and was approved by the local health authority and ethics committee .
healthy adults ( aged 1845  years , inclusive ) with t1d eligible for the study had a body mass index ( bmi ) 1827  kg / m , glycated haemoglobin ( hba1c ) level 9.5% ( 80  mmol / mol ) and peak rate of oxygen uptake ( vo2peak ) > 35 and < 60  ml o2/kg / min , and were performing regular physical cardiorespiratory activity ( 500 metabolic equivalent of task min per week 11 ) during the last 3  months before screening .
exclusion criteria included cancer , cardiac diseases , supine blood pressure outside the range 90140  mmhg for systolic blood pressure or 5090  mmhg for diastolic blood pressure , recurrent severe hypoglycaemia or hypoglycaemic unawareness , smoking and confirmed hyperglycaemia [ bg 17  mmol / l ( 306  mg / dl ) ] during the runin / steadystate periods .
patients were randomized to one of two treatment sequences : ideg ( tresiba , 100  units / ml in 3ml prefilled investigational pens , pds290 ; novo nordisk , bagsvrd , denmark ) followed by iglar ( lantus , 100  units / ml in 3ml solostar ; sanofi , paris , france ) or iglar followed by ideg .
insulin aspart ( iasp ) ( novorapid , 100  units / ml in 3ml flexpen ; novo nordisk , bagsvrd , denmark ) was used as bolus insulin .
treatment periods included a 14 to 28day titration runin on each basal insulin , to reach stable glycaemic control and a prebreakfast selfmeasured plasma glucose ( smpg ) value of 46  mmol / l ( 72108  mg / dl ) .
a 6day steadystate period followed , during which individual doses were kept constant , standard meals were served and usual physical activity maintained to obtain a reproducible bg profile from day to day , ensuring bg was controlled before exercise [ preexercise bg 5  mmol / l ( 90  mg / dl ) and 10  mmol / l ( 180  mg / dl ) ; maximum difference of 2  mmol / l ( 36  mg / dl ) between the two exercise bouts ] . on day  5 of the steadystate period ,
patients ' individual lunchtime iasp doses ( 12:00  hours ) and carbohydrate were reduced by 60% ( median 40  g carbohydrate , both treatments ) to achieve consistent preexercise bg levels , avoiding high bg levels > 10  mmol / l ( 180  mg / dl ) .
three hours after lunch ( 15:00  hours ) patients performed a 30min ergometer bicycle exercise bout at 65% vo2peak .
gas exchange and heart rate were measured and % vo2peak and carbohydrate oxidation rates during exercise were calculated 12 .
blood was drawn via venous cannula every 5  min during exercise and at various time points for 22.5  h for laboratory measurement of bg , counterregulatory hormones and hydroxybutyrate .
hypoglycaemic episodes [ plasma glucose < 3.1  mmol / l ( 56  mg / dl ) or episodes requiring assistance of another person ( nocturnal between 00:01 and 05:59  hours , inclusive ) ] were recorded for 24  h after start of exercise .
a clinically relevant treatment difference between preexercise bg concentration and minimum bg concentration during exercise of 0.65  mmol / l ( 11.7  mg / dl ) could be detected ( 80% power ) with a sample of 36 patients ( assuming standard deviation of 1.35 ) .
bg concentration endpoints were analysed in a linear mixed model ( bg concentration before exercise as covariate , treatment and period as fixed factors , and patient as a random effect ) . to account for unequal variances , the withinpatient variation depended on treatment .
rate of hypoglycaemia was analysed in a negative binomial regression model with a loglink function ( treatment and period as fixed factors and patient as a random effect ) .
of 72 patients screened , 41 were eligible and 40 randomized ( one withdrew ) .
thirtynine patients completed the trial , as one was excluded during the first runin ( bg
the 35 men and 5 women enrolled had a mean    standard deviation ( s.d . )
age of 33.9    7.7  years , bmi of 23.9    1.9  kg / m , vo2peak of 39.4    3.7  ml o2/kg / min , hba1c of 7.7    0.8% ( 61    9  mmol / mol ) and diabetes duration of 16.7    8.2  years .
the prerequisite that certain parameters were similar between the two treatments was fulfilled : basal and bolus insulin doses ( table s1 ) , glycaemic control during steadystate period ( figure s1 ) , bg concentration immediately before exercise ( figure 1a ) , mean relative intensity during the exercise [ vo2peak ideg : 64.6    4.1 ; iglar : 65.5    3.8% ; ( table s2 ) ] and pre and postexercise heart rate [ 64 and 158  bpm , respectively , with ideg and iglar ( figure s2 ) ] .
blood glucose concentration ( a ) during 30  min exercise and ( b ) for up to 22.5  h after start of exercise .
blood samples were taken frequently ( every 5  min during exercise and every 10  min for 2.5  h after exercise ) from time 0 to 3  h , while blood sampling time points in the remaining postexercise period are marked by symbols and vertical bars .
ideg , insulin degludec ; iglar , insulin glargine ; vertical bars are standard error of the mean . during exercise , endpoints were similar with ideg and iglar , including decrease in bg concentration ( figure 1a ) , estimated maximum bg decrease [ estimated treatment difference ( etd ) : 0.14 
mmol / l ; 95% confidence interval ( ci ) 0.15 , 0.42 ( 2.5  mg / dl ; 95% ci 2.7 , 7.57 ) ; p  =  0.34 ] , estimated mean bg concentration [ ideg : 7.28  mmol / l ( 131  mg / dl ) ; iglar : 7.43  mmol / l ( 134  mg / dl ) ; etd : 0.16  mmol / l ; 95% ci 0.36 , 0.05 (  2.9  mg / dl ; 95% ci 6.5 , 0.9 ) ; p  =  0.13 ] , respiratory equivalent ratio ( > 1 for both groups ) and carbohydrate oxidation [ ideg 2.9    0.6 and iglar 2.8    0.6  g / min ( table s2 ) ] . there were no hypoglycaemic episodes nor requirement for carbohydrate administration during exercise .
the bg concentration for 22.5  h after start of exercise is shown in figure 1b .
estimated mean bg concentration [ ideg : 7.12  mmol / l ( 128  mg / dl ) ; iglar : 7.61  mmol / l ( 137  mg / dl ) ; etd : 0.50  mmol / l ; 95% ci 1.14 , 0.15 (  9  mg / dl ; 95% ci 20.5 , 2.7 ) ; p  =  0.13 ] and estimated minimum bg concentration [ ideg : 6.05  mmol / l ( 109  mg / dl ) ; iglar : 6.39  mmol / l ( 115  mg / dl ) ; etd : 0.34 
mmol / l ; 95% ci 0.88 , 0.20 ( 6.1  mg / dl ; 95% ci 15.9 , 3.6 ) ; p  =  0.21 ] for the 2.5  h immediately after exercise were similar between groups . concentration of counterregulatory hormones and hydroxybutyrate showed similar exerciserelated changes for ideg and iglar ( figure s3 ) .
the number of hypoglycaemic episodes [ estimated rate ratio ( err ) 0.76 ( 95% ci 0.40 , 1.45 ) ; p  =  0.39 ] , nocturnal hypoglycaemic episodes [ err 1.00 ( 95% ci 0.40 , 2.47 ) ; p  =  1.00 ( table 1 ) ] and carbohydrate administrations ( ideg : 32 in 14 patients ; iglar : 33 in 12 patients ) for 24  h after start of exercise were similar with ideg and iglar .
bolus insulin dose for 24  h after start of exercise was similar ( ideg 0.29    0.13 and iglar 0.33    0.15  units / kg ) .
hypoglycaemic episodes [ plasma glucose 3.1  mmol / l ( 56  mg / dl ) or requiring assistance ] with insulin degludec ( ideg ) and insulin glargine ( iglar ) during the 24  h after start of exercise . 

ideg , n  =  39 ; iglar , n  =  40 .
one serious adverse event ( hypoglycaemic seizure ) occurred 5  days after the iglar period as a result of a medication error ( iglar / lispro mixup ) .
the results of the present study show that , despite different pharmacodynamic profiles and duration of action , bg concentrations during and after exercise were similar with ideg and iglar .
the number of hypoglycaemic episodes for 24  h after start of exercise was low and similar between ideg and iglar , concurring with a recent metaanalysis of selfreported exerciserelated hypoglycaemia with these insulins 13 . in the present study , moderateintensity cycling increased tissue fuel requirements above those required when at rest and represented a useful model for exploring the impact of basal insulin choice concomitant with the synergistic effect of muscular contraction on carbohydrate metabolism .
we observed a similarly high rate of carbohydrate oxidation ( ideg 2.9  g / min and iglar 2.8  g / min ) in exercising patients ( table s2 ) .
furthermore , submaximum cycling caused a significant counterregulatory hormone response ( figure s3 ) , which helped to minimize bg changes from rest during the exercise period .
the equivalent counterregulatory hormone response enabled the impact of different basal insulins to be explored .
we found no differences in bg responses despite markedly different pharmacodynamic profiles of ideg and iglar ( figure 1 ) .
the main strength of the present study was the controlled setting to achieve similar and reasonable preexercise bg concentrations that were kept within recommended limits 14 with both treatments .
morning dosing ensured the highest possible insulin concentration in the circulation at the time of exercise , particularly for iglar , with its halflife being half that of ideg 15 .
the tightly controlled setting limits the applicability of the study to a reallife situation where patients may not adjust carbohydrate intake before exercise .
this , in conjunction with a reduced bolus dose , can lead to high preexercise bg 1 .
in addition , the experimental design did not include any reduction in postexercise bolus dose as this would have complicated data interpretation , although this has been shown to preserve euglycaemia and prevent hypoglycaemia 8 .
finally , in the present study , we investigated only one form of exercise and further studies might usefully investigate others such as highintensity exercise or resistance training . in summary
, this study showed that the risk of hypoglycaemia in patients with t1d induced by moderate intensity exercise was low with ideg and similar compared with iglar .
none of the authors received any financial or monetary transfer of value for their participation in the writing of the manuscript . t. h. reports having received research funds from adocia , astra zeneca , bd , biocon , boehringer ingelheim , dance pharmaceuticals , grnenthal , eli lily and company , medtronic , novo nordisk , novartis , sanofi and senseonics and having received speaker honoraria and travel grants from eli lily and company , mylan and novo nordisk .
s. c. b. reports having received honoraria , teaching and research grants from the abbott , astra zeneca , boehringer ingelheim , bms , diartis , eli lily and company , glaxosmithkline , johnson & johnson , merck sharp & dohme , novartis , novo nordisk , pfizer , roche , sanofiaventis , scheringplough , servier and takeda .
r. b. reports having received honoraria , travel and educational grant support from , boehringeringelheim , eli lily and company , novo nordisk , sanofiaventis .
, r. r. , e. r. and h. l. h. are employees and shareholders in novo nordisk a / s .
t. h. is the guarantor of this work and , as such , had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis .
all authors were involved in the study design , contributed to the discussion of the results and reviewed and approved the manuscript .
the results of this study were presented in abstract form at the world diabetes congress , melbourne , australia , 26 december 2013 .
mean fivepoint selfmeasured plasma glucose profiles with insulin degludec and insulin glargine during the steadystate period ( the days leading up to the exercise bout ) .
mean concentration of glucagon ( a ) , cortisol ( b ) , epinephrine ( c ) , norepinephrine ( d ) , growth hormone ( e ) and hydroxybutyrate ( f ) before and after the 30min exercise bout .
daily basal doses of insulin degludec and insulin glargine and daily bolus insulin doses ( insulin aspart ) during the steadystate period .
exercise workload , respiratory exchange ratio and carbohydrate oxidation during 30min exercise with insulin degludec and insulin glargine .
 we compared changes in blood glucose ( bg ) and risk of hypoglycaemia during and after exercise in 40 patients with type 1 diabetes ( t1d ) treated with insulin degludec ( ideg ) or insulin glargine ( iglar ) in a randomized , openlabel , twoperiod , crossover trial . 
 after individual titration and a steadystate period , patients performed 30  min of moderateintensity cycle ergometer exercise ( 65% peak rate of oxygen uptake ) . 
 bg , counterregulatory hormones and hypoglycaemic episodes were measured frequently during and for 24  h after exercise . 
 bg changes during exercise were similar with ideg and iglar [ estimated treatment difference ( etd ) for maximum bg decrease : 0.14  mmol / l ; 95% confidence interval ( ci ) 0.15 , 0.42 ; p  =  0.34 ] , as was mean bg ( etd 0.16  
 mmol / l ; 95% ci 0.36 , 0.05 ; p  =  0.13 ) . 
 no hypoglycaemic episodes occurred during exercise . 
 postexercise mean bg , counterregulatory hormone response and number of hypoglycaemic episodes in 24  h after starting exercise were similar with ideg ( 18 events in 13 patients ) and iglar ( 23 events in 15 patients ) . 
 this clinical trial showed that , in patients with t1d treated with a basalbolus regimen , the risk of hypoglycaemia induced by moderateintensity exercise was low with ideg and similar to that with iglar . 
Introduction
Methods
Results
Discussion
Conflict of Interest
Supporting information