intensive insulin therapy using basal - bolus insulin regimen is the standard therapy for patients with type 1 diabetes mellitus . by mimicking the endogenous insulin secretion profile in healthy subjects , it has been shown to improve glycemic control and reduce the risk of long - term complications compared with conventional insulin therapy [ 1 , 2 ] . unfortunately , many patients with type 1 diabetes can not achieve the target glycemic control , and insulin therapy leaves room for improvement . thus , the efficacy of basal insulin is especially important in this group of patients . importantly , in some type 1 diabetes patients with severe loss of endogenous insulin secretion capacity , once - daily injection of basal insulin does not always cover the basal effect of insulin over the 24-hour period [ 35 ] . in addition , the intraday and day - to - day variability in insulin agents could sometimes be an obstacle for optimized titration of insulin and a cause of increased frequency of hypoglycemia . given that increased frequency of injection and large fluctuations in blood glucose could be a burden in such patients , any improvement in the efficacy of basal insulin agents should be appreciated . insulin degludec is a new ultra - long - acting basal insulin that forms soluble multihexamers at the subcutaneous injection site from which insulin monomers are slowly and continuously absorbed into the circulation , leading to a peakless action profile over 42 hours . consistent with this pharmacological action , begin basal - bolus type 1 trial   showed that the rate of nocturnal - confirmed hypoglycemia was 25% lower with insulin degludec than with insulin glargine . in addition , it was reported that the day - to - day variability in plasma glucose in type 1 diabetes patients treated with insulin degludec was lower compared to insulin glargine . taking these unique actions of insulin degludec into consideration , switching from twice - daily injections of basal insulin to once - daily injection of insulin degludec could provide great benefit to patients with type 1 diabetes . in this study , to evaluate the efficacy of insulin degludec as a basal insulin for basal - bolus regimen for japanese patients with type 1 diabetes mellitus who are treated with twice - daily basal insulin injection therapy , we investigated glycemic control , daily , and day - to - day variability in plasma glucose using continuous glucose monitoring before and after switching to once - daily insulin degludec injection in 22 patients with type 1 diabetes . we recruited 24 eligible japanese patients ( 8 males and 16 females ) with type 1 diabetes who visited the outpatient clinic of juntendo university hospital between july 2013 and january 2014 . patients who satisfied the following conditions were included : ( 1 ) treated with basal - bolus insulin regimen with twice - daily injections by insulin glargine or detemir and ( 2 ) aged more than 20 and less than 80 years . also , patients were excluded if they ( 1 ) had serious liver disease ( ast and/or alt > 100 iu / l ) , ( 2 ) had serious kidney disease ( serum creatinine > 2.0  mg / dl ) , ( 3 ) had untreated severe diabetic retinopathy , ( 4 ) had adrenal or pituitary insufficiency , ( 5 ) had other conditions considered by the attending physician to be contraindicated to inclusion in the study , or ( 6 ) were pregnant or breastfeeding women . this trial was conducted in accordance with the declaration of helsinki , and the protocol was approved by the human ethics committee of juntendo university . all patients provided a written informed consent prior to trial initiation . in this prospective , single - center , single - arm , open - label , 12-week study , we compared the effects of switching from twice - daily basal insulin to once - daily insulin degludec on glycemic control , daily , and day - to - day variability in plasma glucose . figure 1 shows the patient enrolment process . at baseline before switching , the following laboratory tests were performed in each patient : fasting plasma glucose ( fpg ) , plasma c - peptide , hba1c , and glycosylated albumin . plasma c - peptide assay was performed using ultrasensitive c - peptide elisa kit ( mercodia , uppsala , sweden ) for precise determination of intrinsic basal insulin level . then , cgm and 7-point self - measured blood glucose ( smbg ) profiles ( before and 2 hours after meals and bedtime ) were obtained . after that , the patient was switched from twice - daily basal insulin to once - daily insulin degludec , which involved 10% reduction in insulin dosage without any change in the rapid acting insulin therapy . insulin degludec was administered once - daily at bedtime . at 4 weeks after switching , the same fasting laboratory tests , cgm and 7-point smbg , were repeated . after 4 weeks , the basal insulin dose was adjusted for each individual patient based on self - measured fbg levels taken before breakfast . the dose of insulin degludec was decreased by 1 unit if fbg was  80  mg / dl over three consecutive days just before the hospital visit . then , the increase of the dose of basal insulin or titration of rapid acting insulin was performed by the judgement of each physician in charge . at the end of the study ( 12 weeks ) , the same laboratory tests ( fpg , hba1c , and glycosylated albumin ) were repeated again . cgm data were obtained by using the ipro2 ( medtronic ; northridge , ca ) . patients were required to use cgm for six consecutive days . over each cgm occasion , at least 288/day cgm glucose values were to be recorded . as an index of day - to - day variability , the mean of daily difference ( modd ) was calculated from the absolute difference between paired cgm values during two successive days ( days 2 to 3 and days 4 to 5 ) , and the data were presented as the average of the two values . the patient was asked to record 7-point smbg profiles for one day during cgm for before and 2  hr after meals and at bedtime . the primary outcome of the study was change in hba1c before and 12 weeks after switching . the secondary outcomes based on cgm values were ( 1 ) changes in standard deviation ( sd ) and modd . safety variables included the frequencies of severe hypoglycemia , which was defined as low blood glucose level requiring assistance from another person to treat , nocturnal hypoglycemia , and adverse events . confirmed hypoglycemia was defined as a glucose value of less than 70  mg / dl by cgm and was reported in percentage (= times < 70  mg / dl / total time of measurement ) . hypoglycemic episodes occurring between 0:00 and 5:59 hours were classified as nighttime while daytime episodes occurred between 6:00 and 23:59 . data were expressed as mean  sd . the mann - whitney u test was used for analysis of cgm data before and 4 weeks after switching and , for analysis of fpg , hba1c and glycosylated albumin before and 12 weeks after switching were used . all statistical analyses were conducted using statview statistical software package , version 5.0 ( sas institute inc . , cary , nc ) . two patients withdrew from the study after the first treatment period ; one decided to withdraw during the conduct of the study and the other did not visit the outpatient clinic . the mean age and duration of type 1 diabetes mellitus were 54.8  14.5 and 14.6  9.0 years , respectively . fasting plasma c - peptide was below the detection limit of the ultrasensitive c - peptide elisa kit in 18 patients ( 81% ) , indicating severely low insulin secretion in most subjects . as shown in table 2 , hba1c levels at baseline and 4 and 8 weeks after switching to insulin degludec were 8.5  1.4% , 8.6  1.6% , and 8.7  1.6% , respectively . glycosylated albumin levels before and 4 and 8 weeks after switching were 24.9  5.0% , 25.3  5.2% , and 24.7  3.6% , respectively . furthermore , fasting blood glucose levels were 203.2  81.2  mg / dl , 165.5  82.1  mg / dl , and 206.5  122.4  mg / dl , respectively . based on these data , it is clear that switching to insulin degludec did not improve glycemic control throughout the study . the mean basal insulin and total daily doses at 12 weeks after switching to insulin degludec were significantly reduced compared to the baseline ( 15.2  7.6 versus 11.6  6.9  u , p < 0.01 , and 40.0  17.3 versus 37.9  16.7  u , p < 0.01 , resp . ) whereas the bolus insulin dose did not significantly change after switching . table 3 summarizes fluctuations in glucose level and the frequency of hypoglycemia recorded by cgm over 4 days before and after switching . the averages of blood glucose and standard deviation ( sd ) through the daytime ( 0:0023:59 ) were 184.1  45.8 versus 189.6  52.7  mg / dl and 68.4  14.5 versus 66.5  17.1  mg / dl , respectively . furthermore , the modd was 72.1  16.0 versus 74.0  23.0  mg / dl and the frequency of hypoglycemia below 70  mg / dl was 6.1  8.0 versus 6.5  9.7% , respectively . table 3 also shows fluctuations in glucose level and the frequency of hypoglycemic episodes recorded by cgm during the nighttime ( 0:005:59 ) . the averages of blood glucose before and after switching were 156.5  63.7 versus 174.6  58.5  mg / dl during the nighttime . the sd during nighttime did not change significantly ( before : 22.6  10.9 , after : 24.8  10.7  mg / dl ) . modd tended to increase during the nighttime both at baseline and after switching , however ; these changes were not significantly different . the frequency of hypoglycemic glucose ( below 70  mg / dl ) was 14.4  17.0 versus 11.1  15.0% during the nighttime , before and after switching . thus , the frequency of nocturnal hypoglycemia did not change significantly after switching , similar to other parameters , and no severe hypoglycemia was recorded during the study period . blood glucose level at 2 hours after lunch was significantly low before and after switching ( 207.6  87.7 versus 158.2  90.3  mg / dl , p < 0.01 ) . the present study investigated the efficacy and safety of switching from twice - daily basal insulin injections to once - daily insulin degludec injection in japanese patients with type 1 diabetes . however , some patients with extremely low insulin secretion capacity often need to use twice - daily basal insulin because the duration of action of insulin detemir is about 16 hours   and that of insulin glargine does not last up to 24 hours [ 4 , 12 ] . a few studies from japan have already investigated the outcome of switching from once - daily or twice - daily basal insulin to once - daily insulin degludec in patients with type 1 diabetes [ 1315 ] . specifically , these studies investigated the effects of switching to insulin degludec in type 1 diabetes patients who were being treated with a combination of once- or twice - daily injections of insulin glargine or detemir , though there are no studies that focused on type 1 diabetes patients treated only with twice - daily basal insulin . the basal insulin levels were very low in our patients and the level could not be detected in most patients even by using high - sensitivity c - peptide kits with detection limit of < 0.015  ng / ml . therefore , the selection of twice - daily basal insulin injections in our study seems reasonable to achieve better glycemic control . insulin degludec , an ultra - long - acting basal insulin , became available in japan in 2013 , ahead of other countries , and is known to have longer duration of action ( over 42 hours ) compared with insulin glargine and detemir . therefore , it is clinically worthy to investigate the efficacy and safety of switching from twice - daily insulin glargine or detemir to once - daily insulin degludec in type 1 diabetes patients with severely reduced insulin secretion . the results showed no significant changes in various parameters of glycemic control , such as fasting plasma glucose , hba1c , and glycosylated albumin , after switching to insulin degludec despite about 20% reduction in basal insulin dose at 12 weeks , indicating that insulin degludec has longer duration of action and a more potent glucose - lowering effect than insulin glargine or insulin detemir . the frequency of hypoglycemic episodes recorded by cgm did not increase at 4 weeks after switching to insulin degludec . in our study protocol , the bolus insulin dose was not changed before and after cgm recording because the effect of bolus insulin on glycemic control needed to be minimized . according to a previous report by the begin basal - bolus type 1 trial investigators , the mean doses of basal and premeal bolus insulin were significantly decreased by 14% and 10% in the insulin degludec group compared with the insulin glargine group at the end of the trial , leading to similar rate of overall hypoglycemia between insulin glargine and degludec groups . therefore , in daily clinical practice , adjustment of the premeal bolus insulin dose also needs be considered when switching to insulin degludec . the smbg data in our study showed that postlunch blood glucose level was significantly lower after switching to insulin degludec injected at bedtime , suggesting that the peak action of insulin degludec occurs 14 - 15 hours after injection . consistent with this finding , another study showed that the trough blood glucose was recorded at daytime when insulin degludec was injected at bedtime . in addition , one review showed that the peak of the glucose - lowering effect of insulin degludec appeared about 12 hours after injection . in addition to the longer duration of action of basal insulin , its effects on daily and day - to - day variability of plasma glucose should be noted . reported that the use of insulin degludec resulted in lower day - to - day variability in blood glucose compared to insulin glargine in type 1 diabetes patients . however , different from this study , our results showed that switching to insulin degludec did not reduce modd , an index of plasma glucose day - to - day variation , which was consistent with a previous study in japan [ 13 , 14 ] . heise et al .   examined the glucose fluctuation by the glucose clamp method after very long fasting , which was not different from our method by cgm . therefore , the inconsistency might be due to differences between experimental and real - world study . our study extended over a short period of time and included a limited sample size . in addition , the carry - over effect of hba1c could not be completely excluded because our study was not a randomized controlled trial . therefore , a crossover trial or randomized controlled trial of a larger sample size is needed in the future . in conclusion , our study demonstrated that glycemic control 12 weeks after switching to once - daily insulin degludec injection with 20% dose reduction was comparable to that in patients treated with twice - daily injection of basal insulin injections and that such switching did not change the frequency of nocturnal hypoglycemia recorded by cgm .
the aim of this study was to investigate the efficacy of insulin degludec used for basal - bolus insulin regimen after switching from twice - daily basal insulin in japanese patients with type 1 diabetes mellitus . 
 the subjects were 22 type 1 diabetes patients treated with basal - bolus insulin regimen with twice - daily basal insulin . 
 basal insulin was switched to once - daily injection of insulin degludec with 10% dose reduction . 
 hba1c and fasting plasma glucose ( fpg ) were measured before and 12 weeks after switching . 
 the frequency of hypoglycemic episodes , standard deviation ( sd ) of blood glucose , and mean of daily difference ( modd ) were evaluated by continuous glucose monitoring ( cgm ) before and 4 weeks after switching . hba1c and fpg before and 12 weeks after switching were comparable ( hba1c 8.5  1.4 versus 8.7  1.6% , p = 0.28 ; fpg 203.2  81.2 versus 206.5  122.4  mg / dl , p = 0.91 ) . 
 the frequency of hypoglycemia during nighttime was not significantly different at 4 weeks after switching ( 14.4  17.0 versus 11.1  15.0% , p = 0.45 ) . 
 in addition , sd and modd before and 4 weeks after switching were also comparable . in conclusion , 
 glycemic control under once - daily insulin degludec injection was almost comparable to that under twice - daily basal insulin injections in japanese type 1 diabetes patients . 
 this study was registered with i d : umin000010474 .