Usefulness of three-dimensional computed tomography of the larynx for evaluation of unilateral vocal fold paralysis before and after treatment : technique and clinical applications Laryngoplasty is well-known technique for unilateral vocal fold paralysis -LRB- UVFP -RRB- . However , operation result are sometimes not as good as expected before surgery . Three-dimensional Computed tomography -LRB- 3DCT -RRB- is useful for visualizing complicated intralaryngeal structures . Moreover , 3DCT is suited for analyzing the movement of the vocal fold and arytenoid cartilage because the technique is based on actual data from live patients . We have been used 3DCT of the Larynx for evaluation of UVFP before and after treatment . We uncovered some new findings about UVFP and reasons of unsatisfactory outcomes after operation . Technique and clinical applications of 3DCT for UVFP are outlined in this paper . Introduction The movement of the arytenoid cartilage is complicated -LSB- 1 , 2 -RSB- . Three-dimensional computed tomography -LRB- 3DCT -RRB- is useful for visualizing the location of the arytenoid cartilage . However , complete understanding of the laryngeal anatomy is necessarily to reconstruct the cartilages in three dimensions . In our institution , an otolaryngologist who specializes in the larynx utilizes 3DCT reconstruction . The use of Windows ® XP-compatible image-processing software enables various analyses in unilateral vocal fold paralysis . This study reports the clinical application of 3DCT in the laryngeal region using the image-processing software Mimics -LRB- Materialise , Yokohama , Japan -RRB- . Production of 3DCT Computed tomography was performed in the horizontal plane using a CT scanner -LRB- Sensation Cardiac 64 ; Siemens , Munich , Germany -RRB- with a 1 mm slice width , a helical pitch of 1 , and an image production interval of 0.5 mm . Several other studies have used slice widths of around 1 mm -LSB- 3 -- 6 -RSB- . Scans were made when the glottis was closed -LRB- with phonation -RRB- and open . Each patient was scanned for about 2 s . The speed of the scan enables scanning of patients with unilateral vocal fold paralysis during a brief phonation and minimizes motion artifact . Before scanning , doctors -LRB- the authors -RRB- were consulting the patient about the timing between phonation and the scan . The data were transferred using the Dicom system . Mimics ver . 9.01 -LRB- Materialise -RRB- was used to create 3DCT images through its surface-rendering protocols . Using Windows ® XP -LRB- Microsoft ® , Redmond , WA , USA -RRB- , 3DCT images can be shown in axial , coronal , sagittal , and 3D display windows -LRB- Fig. 1 -RRB- . Fig. 1Actual view seen with the Mimics image-processing software . Using Windows ® XP -LRB- Microsoft ® -RRB- , 3DCT images can be created with axial , coronal , sagittal , and 3D display windows . The use of Windows XP-compatible image-processing software enables various analyses in unilateral vocal fold paralysis The threshold was set from 69 to 85 HU for the thyroid and cricoid cartilages and 52 to 69 HU for the arytenoid cartilage . Visualization of the vocal process is usually limited to its base because of its elastic cartilage . In addition , the laryngeal lumen was visualized . The threshold was set between − 600 and − 100 HU -LSB- 7 -RSB- . Stereoscopic location of the arytenoid cartilage in unilateral vocal fold paralysis First , we present a case of severe unilateral vocal fold paralysis with a mean flow rate -LRB- MFR -RRB- of 1,200 ml/s -LRB- Fig. 2 -RRB- . The patient was an 80-year-old man suffering from paralysis following aortic aneurysm surgery . Fig. 2The locations of the arytenoids in severe unilateral vocal fold paralysis . During inspiration , the healthy side -LRB- yellow -RRB- was located in the lateral part of the cricoarytenoid joint , while the paralyzed side -LRB- red -RRB- was located in the dorsocranial part of the cricoarytenoid joint . During phonation , the healthy side rocked and moved to the ventromediocaudal part of the cricoarytenoid joint , while the paralyzed side glided dorsocranially . This movement is a passive movement During inspiration , the arytenoid cartilage on the healthy side was located in the lateral part of the cricoarytenoid joint . Simultaneously , the vocal process was located outside and above the joint . In comparison , the arytenoid cartilage on the paralyzed side was located in the dorsocranial part of the cricoarytenoid joint , while the paralyzed vocal process was located inferiorly and the arytenoid cartilage dropped forward . This position on the paralyzed side was the result of posterior cricoarytenoid muscle paralysis . During phonation , the healthy side rocked and moved to the ventromediocaudal part of the cricoarytenoid joint to adduct the vocal cord , and the vocal process moved inward and downward . Conversely , the paralyzed side glided dorsocranially in comparison with its position during inspiration . Therefore , the arytenoid cartilage showed a rocking movement on the healthy side , and a gliding movement on the paralyzed side . This gliding movement on the paralyzed side was a passive movement . the paralyzed arytenoid underwent passive movement caused by contact with the mobile side during phonation . The vocal fold blown up may affect this passive movement . We call such arytenoids `` flaccid arytenoids . '' The position of the paralyzed arytenoid depends on the severity of paralysis . Surgical simulation This section describes type I thyroplasty . It is important to determine the level of the vocal folds in this procedure . Note that the arytenoid cartilage on the paralyzed side glides dorsocranially , as mentioned above . The paralyzed vocal fold becomes higher than the vocal fold on the healthy side during phonation . The type I thyroplasty window should be based on the vocal cord level on the healthy side during phonation . Therefore , the vocal fold level of the healthy side must be projected onto the thyroid cartilage of the paralyzed side . Figure 3 compares the upper surface of the vocal fold between our 3DCT simulation and the original type I procedure reported by Isshiki et al. -LSB- 8 -RSB- . The figure shows that the upper surface level of the vocal fold in the original procedure is consistent with the vocal fold level on the paralyzed side detected by 3DCT . This might have arisen because the upper surface level of the vocal cord in the original procedure was based on cadaveric studies of the larynx . However , the vocal process on the healthy side during phonation is lower than that on the paralyzed side . Therefore , the design should be made consistent with the healthy side . Individualized simulation for each case is needed because of the shape difference between left and right laminas of the thyroid cartilage -LRB- especially the laryngeal deviation -RRB- -LSB- 9 , 10 -RSB- . The program Mimics allows distances to be measured on a personal computer ; for example , the distances from the inferior notch or inferior nodule to the surface of the vocal fold may be measured . The 3DCT could contribute to a better oriented and designed thyroplasty window . Fig. 3A comparison of the upper surface of the vocal fold between the 3DCT simulation -LRB- red dotted line -RRB- and the original type I procedure reported by Isshiki -LRB- black dotted line -RRB- . The figure shows a 3D image processed to make the thyroid cartilage more radiolucent , allowing the healthy vocal fold to be visualized . The upper surface level of the vocal fold with the original procedure is consistent with the vocal fold level of the paralyzed side detected by 3DCT . However , the vocal process of the healthy side during phonation is located below than that of the paralyzed side Postoperative evaluation Case 1 A 69-year-old woman underwent arytenoid adduction for right recurrent nerve paralysis after thyroid carcinoma surgery . According to the postoperative 3DCT images -LRB- Fig. 4 -RRB- , the vocal process adducted to the appropriate position . However , a large glottal chink was observed during phonation . In this case , the cricothyroid joint was released , and a thread placed on the muscular process was fixed to the anterior part of the thyroid cartilage . Since the cricothyroid joint was released , the cricoid cartilage -LRB- arytenoid cartilage -RRB- and thyroid cartilage were close together , which shortened the anteroposterior diameter of the vocal fold . The vocal fold relaxed and lost its tension . Fig. 4Case 1 : A 69-year-old woman underwent arytenoid adduction for right recurrent nerve paralysis after thyroid carcinoma surgery . a In the postoperative 3DCT images , the vocal process appears to adduct to the appropriate position . b A large glottal chink is observed during phonation . c Since the cricothyroid joint is released , the cricoid -LRB- arytenoid cartilage -RRB- and thyroid cartilages are close together . d The anteroposterior diameter of the vocal fold -LRB- double-headed arrow -RRB- is shortened . The vocal fold relaxes and loses its tension Case 2 A 64-year-old man underwent type I thyroplasty for left recurrent nerve paralysis after esophageal cancer surgery -LRB- Fig. 5 -RRB- . This patient had relatively severe paralysis , but still underwent a type I thyroplasty only . The postoperative 3DCT image shows that the Gore-Tex ® is inserted at the proper level of the vocal fold . However , the posterior parts of the vocal fold were at different levels because the flaccid paralyzed arytenoid cartilage was blown toward the dorsocranial part of the cricoarytenoid joint , as mentioned above . The MFR was improved from 770 ml/s preoperatively to 290 ml/s postoperatively . If the posterior support of the vocal fold had been fixed , the vocal fold would have developed tension against the flow of expired air during phonation , further improving the voice . Fig. 5Case 2 : A 64-year-old man underwent type I thyroplasty for left recurrent nerve paralysis after esophageal cancer surgery . a The postoperative 3DCT image shows that the Gore-Tex ® was inserted at the proper level of the vocal fold . b A level difference is seen in the posterior part of the vocal fold because the flaccid paralyzed arytenoid cartilage was blown toward the dorsocranial part of the cricoarytenoid joint during phonation Case 3 A 70-year-old man was given a silicon injection 20 years earlier to treat left recurrent nerve paralysis after thoracic aortic aneurysm surgery -LRB- Fig. 6 -RRB- . The MFR was 650 ml/s , which improved insufficiently . The 3DCT showed that the silicon was injected widely from the anterior to posterior parts of the vocal fold . Silicon is also injected near the arytenoid cartilage . It was thought that the original surgeon had intended to adduct the arytenoid cartilage . However , the arytenoid cartilage glides dorsocranially , increasing the vertical difference in the level of the posterior part of the vocal fold . The vocal process was not adducted and the upper part of the arytenoid cartilage moved medially in an unnatural manner . As described earlier , during phonation , the arytenoid cartilage on the healthy side moves by rocking to the ventromediocaudal part of the cricoarytenoid joint , and the vocal process is moved inward . Arytenoid adduction -LSB- 10 , 11 -RSB- is a procedure that resolves the level difference between the two vocal fold by reproducing the rocking motion of the paralyzed arytenoid cartilage . In contrast , injection and type I surgery are techniques to medialize the vocal fold by increasing its volume . An injection near the arytenoid cartilage moves the arytenoids to a dorsocranial position , and they never adduct naturally . If arytenoid adduction is scheduled after these techniques , the injected materials could interfere with the second procedure . The effect of the injection on posterior vocal fold closure arises mainly from the increased volume in the posterior part of the vocal fold . Fig. 6Case 3 : A 70-year-old man underwent a silicon injection 20 years earlier to treat left recurrent nerve paralysis after thoracic aortic aneurysm surgery . a The 3DCT shows that the silicon is injected widely from the anterior to posterior parts of the vocal fold . b Silicon is also injected near the arytenoid cartilage . The arytenoid cartilage glides dorsocranially ; the vocal process is not adducted and the upper part of the arytenoid cartilage is unnaturally shifted medially . The vertical difference in the level of the posterior part of the vocal fold increased . c The effect of the injection on posterior vocal fold closure is thought to be due mainly to the volume increase in the posterior part of the vocal fold Case 4 A 77-year-old man received a fat injection for left recurrent nerve paralysis after esophageal cancer surgery . Three years after the fat injection , the maximum phonation time improved from 3 s before the injection to 7 s after the injection . The 3DCT image indicates that the vocal cord closure was sufficient -LRB- Fig. 7a -RRB- . In the lateral view , remaining fat is seen 3 years after the injection and it appears to be pushing the entire vocal fold -LRB- Fig. 7b -RRB- . However , the coronal section CT image revealed that the level difference of the two vocal folds had not improved . The vocal folds overlapped so that the incomplete closure was resolved -LRB- Fig. 7c -RRB- . Fat , unlike silicon , may not interfere with the vocal fold vibration of the healthy side , even if the vocal cords overlap , because fat is soft . Fig. 7Case 4 : A 77-year-old man underwent fat injection for left recurrent nerve paralysis after esophageal cancer surgery . a The 3DCT -LRB- CT endoscopic image -RRB- suggests that the vocal cord closure is sufficient . b The lateral view shows fat remaining 3 years after the injection , which seems to be pushing the entire vocal fold . c The coronal view revealed that the difference in the levels of the vocal fold had not improved Conclusions Laryngeal 3DCT is useful for determining the stereoscopic configuration of the arytenoid cartilage . In addition , 3DCT enables observation of the laryngeal framework from every angle , and is also useful for surgical simulation and feedback after surgery .

O O O O O O O O O O O B I I I O O O O O O O O O O O O O O B I I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I I O O O O O O O O B I I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O

unilateral vocal fold paralysis
thyroplasty


Donor site morbidity of the fasciocutaneous radial forearm flap : what does the patient really bother ? The objective of this study was the evaluation of donor site morbidity in head and neck cancer patients after reconstruction using a free vascularized radial forearm flap with emphasis on subjective complaints . Fifty patients who underwent at least 6 months before a reconstruction using a free vascularized radial forearm flap were asked to fill out two questionnaires regarding cosmetics and sensibility and forearm disabilities . Furthermore , a function test including movement extensions -LRB- flexion -- extension , ulnar -- radial deviation and pronation -- supination -RRB- , strength -LRB- pinch and grip -RRB- and temperature -LRB- digiti I and V -RRB- of the donor and non-donor site were measured and compared . Thirty-five percent of the patients reported no complaints regarding cosmetics and sensibility and 75 % mentioned no forearm disabilities . There was no difference in movement extensions , temperature and grip strength between donor and non-donor sites . The difference in pinch strength appeared to be significant -LRB- p < 0.001 -RRB- . The total score of the questionnaire on forearm disabilities correlated significantly with extension , pronation and grip strength of the donor arm . Donor site morbidity of the radial forearm flap measured by objective functional tests was limited but subjective self-ratings revealed complaints regarding cosmestics and sensibility and to a lesser extent regarding forearm disability . The present data may be used for solid patient counselling . Introduction The free radial forearm flap -LRB- FRFF -RRB- , introduced by Yang et al. in 1981 -LSB- 1 -RSB- , has established itself as a versatile , reliable and widely used method for reconstruction of defects in the head and neck region -LSB- 2 , 3 -RSB- . The pliability and thinness of FRFF allow its use in complex reconstructions . The vascular pedicle of the FRFF provides adequate vessel diameter and length for microvascular anastomosis . A split skin graft is most frequently used for the forearm donor site reconstruction . Donor site morbidity includes functional and aesthetical outcome . Hand and wrist function is the most important issue in the assessment of morbidity of the FRFF . In a previous study we found that donor site morbidity of the radial forearm flap measured by objective functional tests is negligible but in the patient 's perception this is substantial -LSB- 4 -RSB- . Some retrospective studies describe a reduced forearm and/or wrist mobility and a reduced strength -LSB- 5 -RSB- , stiffness of the wrist with movement disability , dysaesthesia , swelling of hand and/or wrist and pain -LSB- 6 -RSB- , reduced sensibility of the radial nerve area and a less aesthetic result -LSB- 7 , 8 -RSB- , while others describe rare or no movement disabilities after using the FRFF -LSB- 9 , 10 -RSB- . The subjective morbidity after harvest of the FRFF is one of the reasons that some reconstructive surgeons shift their attention to other fasciocutaneous flaps for reconstruction of defects in the head and neck -LSB- 11 , 12 -RSB- . The goal of the present study is to investigate these subjective complaints in more detail and in relation to the objective function tests in a larger group of patients . Methods Patients All patients who visited the outpatient clinic of the department of otolaryngology/head and neck surgery of the VU Medical Center during the period of March till July 2004 and had a reconstruction of the surgical defect by using a FRFF at least 6 months before were asked to participate in the study . Exclusion criteria were arthritis of the upper extremities or a recent trauma of the wrist and/or lower arm . During this period 69 patients , who underwent such a operation , visited the outpatient clinic . Fifty patients -LRB- 28 men and 22 women , aged between 26 and 77 years , mean 59.2 ± 11.1 years -RRB- met the inclusion criteria . Eight of these 50 patients had had a forearm or wrist injury before surgery -LRB- five patients had a wrist fracture , two had a Dupyutren 's contracture and one had surgery because of a ganglion on dorsal side of the wrist -RRB- , of which four patients at the donor side . None of these patients had pre-existing complaints and/or range of motion disability of the hand or wrist . In 45 patients the left arm was used for the harvest of the FRFF and in five patients the right arm . In three patients the donor side was the side of the dominant hand . Harvest of the flap was done simultaneously with the ablative procedure whenever possible . All patients underwent a preoperative and intra-operative Allen 's occlusion test to rule out inadequate blood supply from the ulnar artery . Fasciocutaneous flaps were raised under a tourniquet in a conventional subfascial or superfascial manner about 2 cm proximal to the wrist skin fold . The superficial radial nerve and branches of the lateral antecubital nerve were preserved . The cephalic vein was used as donor vein . The radial artery was not reconstructed in any patient . The donor defect was closed with a split skin graft -LRB- 0.6 mm -RRB- taken from the upper thigh at the same site . In order to aid healing the arm a pressure dressing of a paraffin gauze and foam was placed over the skin and the arm was immobilized for 7 days in a dorsal hand-to-upper-arm splint . Donor site morbidity questionnaires Subjectively the donor site morbidity was measured by means of a questionnaire regarding cosmetics and sensibility -LRB- Table 1 -RRB- and a questionnaire regarding forearm disabilities of the operated arm -LRB- Table 2 -RRB- . Response possibilities were yes , no , or not applicable . All themes relate to the last 24 h . A total score on each questionnaire was calculated by dividing all yes-scores by the number of questions answered yes or no . The total score ranged from 0 to 100 with 0 indicating no problems -LRB- no disability -RRB- and 100 indicating severe problems -LRB- severe forearm and/or wrist disabilities -RRB- . Table 1Questionnaire regarding sensibility and cosmetics of the donor arm -LRB- n = 50 -RRB- QuestionsNumber of positive answer -LRB- % -RRB- No complaints17 -LRB- 35 -RRB- Complaints 1 . Can you wear a wristwatch or bracelet ? 12 -LRB- 24 -RRB- 2 . Does the hand feel numb ? 11 -LRB- 22 -RRB- 3 . Does the scar itch ? 11 -LRB- 22 -RRB- 4 . Do you experience problems in the cold ? 4 -LRB- 8 -RRB- 5 . Does the appearance bother you ? 13 -LRB- 27 -RRB- In case of complaints , multiple answers were possibleTable 2Questionnaire regarding forearm disabilities in the last 24 h -LRB- n = 50 -RRB- Questions Number of positive answer -LRB- % -RRB- No forearm disabilities38 -LRB- 75 -RRB- Disabilities 1 . I wake up at night because of my forearm1 -LRB- 2.0 -RRB- 2 . I have complaints lying on my forearm 4 -LRB- 8.0 -RRB- 3 . I have complaints during daily life activities2 -LRB- 4.0 -RRB- 4 . I have complaints during movements of my wrist3 -LRB- 6.0 -RRB- 5 . I have complaints during leaning on my elbows or hands3 -LRB- 6.0 -RRB- 6 . I have complaints with writing -LRB- or typing -RRB- 1 -LRB- 2.0 -RRB- 7 . I have complaints holding my wheel of my car or bike2 -LRB- 4.0 -RRB- 8 . I have complaints during lifting an object5 -LRB- 10.0 -RRB- 9 . I have complaints opening or closing a door2 -LRB- 4.0 -RRB- 10 . I rub my wrist or forearm more than once a day9 -LRB- 18.0 -RRB- 11 . I am irritable for people in my environment due to my forearm1 -LRB- 2.0 -RRB- Donor site morbidity tests Three tests were used for objective measurement of donor site morbidity . All measurements were performed at the operated and non-operated side . The first test covers movement extensions of the wrist . The angles of the maximal flexion and extension of the wrist , the ulnar and radial abduction and the lower arm pronation and supination were measured by the Mediclino Inclinometer -LRB- Bodybow-Holland , Nieuwegein , The Netherlands -RRB- with an accuracy of 2 ° and a range of 0 -- 180 ° -LRB- Fig. 1 -RRB- . Fig. 1Inclinometer used for measuring of movements The second test measures the strength of the hand . The grip strength -LRB- strength measured in the hand -RRB- was measured in kg/m2 with a hydraulic dynamometer -LRB- Smith & Nephew Roylan , Germantown , WI , USA -RRB- with an accuracy of 2.0 kg and a range of 0 -- 90.0 kg -LRB- Fig. 2 -RRB- . The pinch-strength -LRB- strength of digiti I and V -RRB- was measured with a pinch gauge -LRB- B&L Engineering , Santa Fe Springs , CA , USA -RRB- with an accuracy of 0.5 kg and a range of 0 -- 12.5 kg -LRB- Fig. 3 -RRB- . Fig. 2Hydraulic dynamometer used for measuring grip strengthFig . 3Pinch gauge used for measuring pinch strength The third test measures the skin temperature of digiti I and V with a Tempcontrol MT 100 KC and probe -LRB- Tempcontrol Industrial Electronic Products , Voorburg , The Netherlands -RRB- on the skin surface with an accuracy of 0.1 °C and a range of − 200 to 1350 °C . Statistical analyses Descriptive statistics were generated for the range of outcome variables in the study . Student 's t-tests were used to determine the differences in objective tests between the donor and non-donor site . Spearman correlation-coefficients were calculated to assess correlations between subjective and objective forearm disability . For all tests , a two-sided p-value less than .05 was considered statistically significant . Results Regarding subjective evaluation of cosmetics and sensibility , 35 % of the patients had no complaints . The other patients scored positively -LRB- thus indicating complaints -RRB- on several of the questions -LRB- Table 1 -RRB- . Regarding forearm disabilities , 75 % of the patients had no complaints -LRB- Table 2 -RRB- . The other patients showed a variety of complaints , especially on rubbing and lifting an object . The mean total score on the forearm disability questionnaire was 4.6 -LRB- SD 12.6 -RRB- with a range from 0 to 82 . The results of the objective tests revealed that no differences were measured between the donor and non-donor arm regarding movement , grip and temperature . Pinch values appeared to be significantly different -LRB- Table 3 -RRB- . Table 3Movement extensions , strength and temperature of donor and non-donor wrist and hand Donor sideNon-donor sideMeanSDMeanSDExtension57 .311.759.811.0 Flexion71 .18.070.29.2 Ulnar abduction57 .78.258.98.0 Radial abduction15 .38.414.85.1 Pronation85 .410.885.311.0 Supination79 .612.280.412.9 Grip28 .710.429.99.7 Pinch7 .42.48.02.4 * Temperature digit I29 .33.329.43.6 Temperature digit V29 .03.929.14.1 * Significant difference -LRB- p-value < .01 -RRB- -RRB- The total score on the forearm disabilities questionnaire appeared to be significantly related to extension -LRB- r = 0.29 , p < 0.05 -RRB- , pronation -LRB- r = 0.30 , p < .05 -RRB- and grip strength -LRB- r = 0.30 , p < .05 -RRB- . Discussion The most important goal of reconstructive surgery in head and neck cancer patients is the optimal restoration of function . The FRFF is a very reliable flap which can restore function in the head and neck function very well -LSB- 13 , 14 , 15 -RSB- . However , the donor site morbidity after harvesting the flap is another important issue . While the main postoperative concern was the reconstruction site , during follow-up the donor site become more important to patients -LSB- 16 -RSB- . Hand and wrist functions are important in the assessment of morbidity of the FRFF . The only objectively observed difference in our study was pinch strength between operated and non-operated sides . It must be emphasized that in 94 % of the patients the FRFF was harvested from non-dominant side . Therefore , the pinch strength on the operated arm may be already less than on the non-operated side before surgery . All other functional tests revealed no statistically significant differences between operated and non-operated sides . Also Ho et al. -LSB- 17 -RSB- did not find any significant difference between the operated and the non-operated arm for strength , range of motion and dexterity . The questionnaires on the other hand revealed donor site complaints related to the FRFF . This difference between objective and subjective findings was also reported by others -LSB- 4 , 7 , 8 , 9 -RSB- . The questionnaire on forearm disabilities showed that the vast majority -LRB- 75 % -RRB- of the patients had no functional complaints at all . The most frequent positive answer was about rubbing the forearm , which may be more a sensibility than a functional problem . In a study of Toschka et al. -LSB- 18 -RSB- postoperative hand function received a subjective rating of 80 -- 100 % of the preoperative function by 89 % of their patients . Other studies report no subjective impairment of function in 63 -- 100 % of patients -LSB- 7 , 10 -RSB- . Ho et al -LSB- 17 -RSB- found using a questionnaire consisting of a list of activities of daily living -LRB- ADL -RRB- that required use of wrist and forearm , that postoperative function appears to be quite satisfactory . While the forearm disability questionnaire showed that functional problems are limited , the cosmetics and sensibility questionnaire revealed that only 39 % of the patients had no cosmetic or sensible complaints . The most frequent -LRB- 27 % -RRB- complaint was on the appearance of the donor site . Other studies found complaints of poor aesthetic results in up to 28 % of patients , particularly female patients -LSB- 7 , 9 , 10 , 16 -RSB- . Bardsley et al. -LSB- 10 -RSB- examined the cosmetic result by a subjective assessment on a scale of 0 -- 10 . The cosmetic result was acceptable in men -LRB- mean score 1.5 -RRB- but was less so in women -LRB- mean score 4 -RRB- . Ito et al. -LSB- 16 -RSB- scored the dissatisfaction about the FRFF donor site of 23 patients in five items : color -LRB- 4 % -RRB- , scar width -LRB- 0 % -RRB- , depression -LRB- 30 % -RRB- , wrist mobility -LRB- 0 % -RRB- and sensation -LRB- 4 % -RRB- . The majority of patients -LRB- 61 % -RRB- had no complaints at all . The mean number of items of which patients were dissatisfied was 0.39 . On the other hand in the study of Toschka et al. -LSB- 18 -RSB- 94 % of the patients rated the aesthetic outcome as fair or good . Lutz et al. -LSB- 8 -RSB- reported 98 % of patients rating the aesthetic outcome as satisfactory . Only extension , pronation and grip strength had a clear correlation with the score on the forearm disabilities questionnaire . For all other objective test no significant correlation with this score was found . Therefore , most objective test results may not be indicative for donor site complaints by the patient . This finding has been confirmed earlier by others -LSB- 4 , 7 , 8 , 9 -RSB- . To diminish donor site morbidity several harvesting and donor site closure technique modifications have been proposed . The technique of harvesting the flap may have some impact on donor site function . In the early days of this flap when radial bone was included for mandibular reconstruction , morbidity was substantial , even leading to wrist fractures -LSB- 7 -RSB- . Suprafascial dissection is claimed by some to lead to superior results from a standpoint of wound healing , but there are no comparative studies that confirm this -LSB- 8 , 18 -RSB- . Wolff et al. -LSB- 19 -RSB- reported on a small series of prefabricated fascial-split-thickness skin flap : after a split-thickness skin graft is transplanted to the forearm fascia the flap can be raised with complete preservation of the forearm skin and microsurgically transplanted like a conventional radial flap . The prelaminated fasciomucosal radial forearm flap as described by Nehrer-Tairych et al. -LSB- 20 -RSB- claims to provide better cosmetic and functional donor site effects , although the series of patients they describe is rather small . Avery et al. -LSB- 5 -RSB- reported good aesthetic results of repair of the FRFF donor site by full-thickness skin graft from the inner upper arm . Ho et al. -LSB- 17 -RSB- compared the functional and aesthetic outcomes of FRFF donor sites reconstructed with full-thickness skin graft , split skin graft alone and split skin graft overlying an acellular dermal matrix and found that all three methods of reconstruction have comparable low morbidity , postoperative satisfactory aesthetic and functional outcomes . Negative pressure wound dressing has been used for rapid healing and decreased donor site complications -LSB- 21 -RSB- . Bardsley et al. -LSB- 10 -RSB- used a ulnar artery-based transposition flap for primary closure to reduce wound healing and improve cosmetic results . Hsieh et al. -LSB- 22 -RSB- reported good results of primary closure of the FRFF donor site with a bilobed flap based on the fasciocutaneous perforator of the ulnar artery . Several types of tissue expansion have been reported to allow the use of local tissues for primary closure -LSB- 23 -RSB- . The preferred technique of closure is difficult to assess , because of limited comparative studies , limited number of patients and lack of significant differences . The presented data can be used for solid counselling patients who are scheduled for FRFF reconstruction . Elaborate pre-surgical counselling may reduce the impact of functional and cosmetic impairment at the FRFF donor site -LSB- 24 -RSB- . Moreover , these data may serve as benchmark for future studies that use other free fasciocutaneous flaps . Conclusion Donor site morbidity of the radial forearm flap measured by objective functional tests is negligible but in the patient 's perception this is substantial . Subjective measurements show especially problems in cosmesis and sensibility . The present data may be used for solid patient counselling .

B I I O O O O O O O O O O O O O O O O O O O O O O O B I I O B I I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O B I I O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O

free radial forearm flap
donor site morbidity
head and neck cancer
cosmetics


A

randomised

treat-to-target

trial

comparing

insulin

detemir

with

insulin

glargine

when

administered

as

add-on

to

glucose-lowering

drugs

in

insulin-naive

people

with

type

diabetes

Aims/hypothesis

This

multinational

randomised

open-label

parallel-group

non-inferiority

trial

compared

clinical

outcomes

following

supplementation

of

oral

glucose-lowering

drugs

with

basal

insulin

analogues

detemir

and

glargine

in

type

diabetic

patients

Introduction

People

with

type

diabetes

inadequately

controlled

by

oral

glucose-lowering

drugs

can

achieve

clinically

relevant

improvements

in

with

the

addition

of

insulin

therapy

-LSB-

-RSB-

However

patients

and

healthcare

providers

are

often

reluctant

to

initiate

insulin

due

to

concerns

over

injections

fear

of

hypoglycaemia

and

additional

weight

gain

and

also

because

insulin

treatment

is

perceived

as

complex

and

an

added

burden

to

diabetes

management

-LSB-

-RSB-

Moreover

once

insulin

is

initiated

recommended

targets

for

glycaemic

control

-LRB-

-RRB-

are

often

not

met

-LSB-

-RSB-

In

recent

years

the

basal

insulin

analogues

glargine

and

detemir

have

been

introduced

These

were

developed

to

improve

upon

the

limitations

of

NPH

insulin

-LRB-

NPH

-RRB-

and

other

conventional

basal

insulins

which

have

an

inadequate

duration

of

action

a

marked

peak

glucose-lowering

effect

and

variability

in

response

from

one

injection

to

another

-LSB-

-RSB-

These

analogues

might

help

to

overcome

some

of

the

barriers

to

insulin

initiation

and

optimisation

including

concerns

over

hypoglycaemia

and

weight

gain

Several

recent

studies

have

assessed

basal

insulin

as

an

add-on

therapy

to

oral

glucose-lowering

drugs

comparing

either

insulin

glargine

or

insulin

detemir

with

NPH

and

using

titration

algorithms

based

on

glucose

monitoring

-LSB-

-RSB-

These

studies

have

demonstrated

that

simple

regimens

involving

a

once

or

twice

daily

injection

of

a

basal

insulin

analogue

can

achieve

clinically

important

improvements

in

glycaemic

control

similar

to

those

achievable

with

NPH

but

with

less

risk

of

hypoglycaemia

Insulin

detemir

has

consistently

shown

less

body

weight

gain

than

NPH

when

used

in

this

way

as

well

as

when

used

in

basal

plus

mealtime

insulin

therapy

-LSB-

-RSB-

whereas

a

weight

advantage

has

been

reported

in

only

a

few

of

the

comparative

trials

of

glargine

vs

NPH

as

for

example

in

the

recent

LANMET

study

-LSB-

-RSB-

Insulin

glargine

is

licensed

only

for

once

daily

use

as

a

basal

insulin

for

people

with

diabetes

Insulin

detemir

in

contrast

is

available

for

once

or

twice

daily

use

Glucose

clamp

comparisons

between

these

insulins

have

given

contradictory

information

on

whether

their

duration

of

effect

is

comparable

-LSB-

-RSB-

The

only

direct

comparison

in

patients

with

type

diabetes

suggests

very

similar

pharmacodynamic

profiles

at

clinically

relevant

doses

-LSB-

-RSB-

but

methodological

issues

remain

controversial

The

objective

of

the

current

study

was

to

compare

treatment

with

insulin

detemir

and

insulin

glargine

in

line

with

their

licensed

indications

as

add-on

therapy

to

oral

glucose-lowering

agents

in

insulin-naive

patients

with

type

diabetes

Methods

Study

protocol

This

parallel-group

trial

was

conducted

in

and

at

sites

in

Europe

and

the

USA

and

included

insulin-naive

people

with

type

diabetes

who

were

randomised

-LRB-

-RRB-

and

treated

with

insulin

detemir

-LRB-

Levemir

Novo

Nordisk

Bagsværd

Denmark

-RRB-

or

insulin

glargine

-LRB-

Lantus

sanofi-aventis

Paris

France

-RRB-

as

add-on

therapy

to

oral

glucose-lowering

drugs

The

trial

was

conducted

in

accordance

with

the

Declaration

of

Helsinki

and

principles

for

Good

Clinical

Practice

and

was

approved

by

ethics

committees/review

boards

in

all

countries

All

participants

gave

written

informed

consent.Concealed

randomisation

was

carried

out

by

an

automatic

telephone

response

system

and

was

stratified

according

to

oral

glucose-lowering

drug

mono

or

combination-therapy

at

entry

An

open-label

design

was

required

to

allow

twice

daily

administration

of

insulin

detemir

if

needed

according

to

the

dosing

algorithm

targets

for

pre-dinner

plasma

glucose

-LRB-

PG

-RRB-

concentrations

-LRB-

Table

-RRB-

Glargine

was

only

administered

once

daily

at

bedtime

as

per

study

protocol

and

in

accordance

with

its

licence

-LSB-

-RSB-

To

reduce

potential

bias

results

were

only

disclosed

to

investigators

at

randomisation

and

at

trial

end

Table

used

for

insulin

dose

titrationAlgorithmAdjustment

of

insulin

dose

-LRB-

U

-RRB-

If

positive

response

to

previous

dose

adjustmentIf

no

response

to

previous

dose

adjustmentaEvening

insulin

dose

adjustment

Average

pre-breakfast

self-monitored

PG

mmol/l

mmol/l

mmol/l

mmol/l

mmol/l

If

one

self-monitored

PG

measurement

mmol/l

mmol/l

insulin

dose

adjustmentb

Average

pre-dinner

self-monitored

PG

mmol/l

mmol/l

mmol/l

mmol/l

mmol/l

If

one

self-monitored

PG

measurement

mmol/l

mmol/l

Non-responses

the

average

self-monitored

PG

level

is

increased

and/or

within

the

same

range

as

at

the

last

contactbSome

insulin

detemir-treated

participants

only

insulin

dose

titrated

up

insulin

dose

titrated

down

Participants

Insulin-naive

men

and

women

with

type

diabetes

and

the

following

characteristics

were

recruited

years

old

months

disease

duration

BMI

and

For

inclusion

they

had

to

be

receiving

one

or

two

oral

agents

-LRB-

metformin

insulin

secretagogues

α-glucosidase

inhibitors

-RRB-

months

on

at

least

one-half

the

maximum

recommended

dose

according

to

local

guidelines

Exclusion

criteria

included

treatment

with

thiazolidinediones

-LRB-

due

to

labelling

restrictions

in

Europe

-RRB-

use

of

more

than

two

oral

agents

within

months

hypoglycaemic

unawareness

or

other

medical

conditions

likely

to

interfere

with

trial

conduct

Withdrawal

criteria

included

pregnancy

after

the

first

weeks

of

treatment

and

initiation

of

medication

interfering

with

glucose

metabolism

Study

medications

Oral

glucose-lowering

therapy

diet

and

physical

activity

were

recommended

to

remain

stable

during

the

study

no

meal-time

insulin

was

allowed

Basal

insulin

was

initiated

once

daily

in

the

evening

at

a

dose

of

U

and

titrated

according

to

a

structured

treatment

algorithm

In

line

with

its

licence

people

allocated

to

insulin

detemir

were

allowed

to

receive

an

additional

morning

insulin

dose

if

pre-dinner

PG

was

mmol/l

but

only

if

pre-breakfast

PG

was

mmol/l

or

nocturnal

hypoglycaemia

-LRB-

major

episode

or

PG

mmol/l

-RRB-

precluded

achievement

of

the

fasting

plasma

glucose

-LRB-

FPG

-RRB-

target

Insulin

detemir

was

administered

with

a

pen-injector

-LRB-

FlexPen

Novo

Nordisk

-RRB-

h

before

to

h

after

dinner

and

if

needed

within

min

of

breakfast

Glargine

was

given

once

daily

at

bedtime

via

a

pen-injector

in

the

EU

-LRB-

OptiPen

Pro

sanofi-aventis

-RRB-

and

with

syringes

in

the

USA

The

evening

dose

of

insulin

detemir

was

administered

somewhat

earlier

than

that

of

insulin

glargine

to

allow

for

the

possibility

that

recipients

might

be

switched

to

a

twice

daily

schedule

in

which

case

a

more

even

distribution

of

the

dose

across

h

would

be

achieved

Titration

of

basal

insulin

Participants

attended

scheduled

visits

and

nine

telephone

contacts

over

year

Evening

insulin

doses

were

titrated

throughout

the

trial

to

a

FPG

target

mmol/l

in

the

absence

of

hypoglycaemia

An

identical

pre-dinner

glucose

target

was

applied

for

people

administering

a

morning

dose

of

insulin

detemir

-LRB-

Table

-RRB-

Participants

measured

capillary

PG

using

glucose

meters

-LRB-

Medisense

Xtra

Abbott

Wiesbaden

Germany

-RRB-

Dose

adjustments

were

to

be

based

on

the

average

of

three

self-measurements

before

breakfast

-LRB-

and

before

dinner

if

on

twice

daily

insulin

detemir

-RRB-

During

the

first

weeks

participants

had

weekly

investigator

contact

A

titration

committee

monitored

the

algorithm

for

insulin

dose

optimisation

and

reviewed

prescribed

insulin

doses

periodically

This

committee

was

not

informed

of

the

treatment

insulin

being

used

but

this

would

have

been

evident

for

participants

on

twice

daily

insulin

detemir

Outcome

measures

The

primary

endpoint

was

baseline-adjusted

at

end

of

treatment

Secondary

variables

included

clinic

FPG

within-participant

variation

in

PG

ten-point

self-measured

PG

profiles

proportion

of

participants

achieving

with

and

without

hypoglycaemia

change

in

body

weight

incidence

of

hypoglycaemia

adverse

events

and

standard

safety

parameters

Analyses

and

assessments

was

analysed

by

HPLC

-LRB-

Bio

Rad

Munich

Germany

-LSB-

EU

analyses

-RSB-

and

Bio

Rad

Hercules

CA

USA

-LSB-

US

analyses

-RSB-

DCCT-harmonised

-RRB-

with

a

reference

range

Clinic

FPG

was

measured

centrally

by

a

hexokinase

method

-LRB-

Gluco-quant

Roche

Mannheim

Germany

-RRB-

Body

weight

was

measured

using

calibrated

scales

Participants

recorded

ten-point

PG

profiles

during

the

last

week

of

treatment

Hypoglycaemia

was

classified

as

major

if

assistance

from

another

person

was

required

minor

if

confirmed

by

PG

mmol/l

or

symptoms

only

if

PG

mmol/l

or

no

measurement

was

made

Statistical

analyses

The

sample

size

was

based

on

non-inferiority

of

insulin

detemir

relative

to

insulin

glargine

for

after

weeks

To

achieve

a

power

of

with

an

expected

SD

for

change

in

of

and

allowing

a

dropout

rate

of

it

was

originally

planned

to

randomise

patients

However

this

was

extended

to

patients

to

allow

for

potential

regional

differences

between

the

EU

and

US

The

possibility

of

a

treatment

region

interaction

was

tested

but

eliminated

from

the

model

as

no

significant

interaction

was

found

Non-inferiority

was

accepted

if

the

upper

limit

of

the

two-sided

CI

for

the

difference

in

-LRB-

detemir

glargine

-RRB-

was

less

than

units

a

value

decided

in

discussion

with

the

Food

and

Drug

Administration

-LRB-

FDA

-RRB-

for

the

entire

insulin

detemir

phase

III

study

programme.Unless

otherwise

specified

all

analyses

were

based

on

the

intention-to-treat

-LRB-

ITT

-RRB-

population

this

being

all

randomised

patients

exposed

to

insulin

detemir

or

insulin

glargine

A

significance

level

of

was

used

for

all

analyses

Participants

were

regarded

as

being

on

once

or

twice-daily

insulin

detemir

according

to

the

regimen

used

at

trial

completion

Statistical

analyses

were

not

made

for

these

subsets

of

patients

as

this

was

non-randomised

and

protocol-determined

results

are

given

for

observational

comparison

only.Analyses

of

clinic

FPG

and

change

in

weight

after

weeks

were

by

ANOVA

with

treatment

region

and

oral

glucose-lowering

therapy

as

fixed

effects

and

baseline

-LRB-

randomisation

-RRB-

value

as

covariate

The

last

observation

carried

forward

-LRB-

LOCF

-RRB-

principle

was

specified

for

and

clinic

FPG

in

non-completers

treated

weeks

-LRB-

time

of

the

first

on-treatment

measurements

-RRB-

Change

in

weight

was

estimated

based

on

all

participants

completing

the

trial

Additional

weight

analyses

were

prepared

for

the

ITT

population

applying

the

same

LOCF

principle

or

using

imputed

data

by

treatment-specific

linear

regression

from

week

onwards

to

account

for

continuing

weight

change

and

limit

the

influence

of

differences

in

withdrawal

rates

and

times

between

treatments

Fisher

's

exact

test

was

used

to

compare

the

numbers

of

patients

on

insulin

detemir

and

insulin

glargine

with

an

without

symptomatic

hypoglycaemia

confirmed

by

PG

mmol/l

or

any

single

value

mmol/l

during

the

last

months

of

treatment.The

ten-point

self-monitored

PG

profiles

were

analysed

for

parallelism

using

repeated

measures

ANOVA

depending

on

treatment

region

oral

glucose-lowering

therapy

time

and

treatment

time

interaction

as

fixed

effects

Within-participant

variation

in

self-measured

fasting

and

pre-dinner

PG

was

determined

from

four

measurements

for

each

during

the

last

week

of

treatment

Hypoglycaemic

episodes

during

the

week

treatment

period

were

analysed

as

recurrent

events

in

a

Cox

regression

analysis

using

a

gamma

frailty

model

-LRB-

Splus

Insightful

Seattle

WA

USA

-RRB-

Nocturnal

episodes

-LRB-

to

hours

-RRB-

were

analysed

separately

Adverse

events

were

summarised

using

descriptive

statistics

All

other

analyses

were

performed

using

SAS

version

-LRB-

SAS

Institute

Cary

NC

USA

-RRB-

Results

Participants

Of

patients

screened

were

randomised

while

did

not

fulfil

the

selection

criteria

and

withdrew

consent

In

each

treatment

arm

patients

were

randomised

and

treated

of

whom

-LRB-

-RRB-

and

-LRB-

-RRB-

completed

the

trial

on

insulin

detemir

and

insulin

glargine

respectively

-LRB-

Fig.

-RRB-

The

higher

withdrawal

rate

observed

with

insulin

detemir

was

partly

due

to

adverse

events

ten

of

which

were

considered

possibly

or

probably

related

to

trial

drug

-LRB-

Electronic

supplementary

material

-LSB-

ESM

-RSB-

Table

-RRB-

These

included

two

cases

of

possible

cutaneous

allergy

five

of

injection

site

reactions

and

one

each

of

injection

site

inflammation

hypoglycaemia

and

weight

increase

Adverse

event

withdrawals

with

possible

or

probable

relation

to

glargine

included

one

case

each

of

pruritus

myalgia

hyperglycaemia

and

hypoglycaemia

Details

of

all

adverse

events

leading

to

withdrawal

are

provided

in

ESM

Table

Other

diabetes-related

reasons

for

withdrawal

with

insulin

detemir

included

-LRB-

n

-RRB-

and

multiple

hypoglycaemic

episodes

-LRB-

n

-RRB-

Other

reasons

for

withdrawal

included

the

closure

of

a

trial

site

and

various

circumstantial

events

unrelated

to

the

trial

medications

Fig.

disposition

during

the

trial

and

consequent

analysis

setsBaseline

characteristics

-LRB-

Table

-RRB-

were

comparable

between

the

two

treatment

groups

Participants

completing

the

trial

on

once

or

twice

daily

insulin

detemir

had

a

baseline

of

and

respectively

Table

characteristics

of

type

diabetic

participantsCharacteristicsDetemirGlargineRandomised/exposed/ITT

n

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Men/women

-LRB-

n

-RRB-

glucose-lowering

drugs

n

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Insulin

-LRB-

-RRB-

-LRB-

-RRB-

Combination

-LRB-

-RRB-

-LRB-

-RRB-

Metformin

Metformin

alpha

glucosidase

Secretagogue

alpha

glucosidase

Secretagogue

secretagogue

-LRB-

SU

glinide

-RRB-

-LRB-

years

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Weight

-LRB-

kg

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

BMI

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Duration

of

diabetes

-LRB-

years

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

C-peptide

-LRB-

nmol/l

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Values

are

n

-LRB-

-RRB-

or

mean

-LRB-

SD

-RRB-

aBefore

randomisationSU

sulfonylurea

Insulin

dosing

Of

participants

treated

with

insulin

detemir

-LRB-

-RRB-

completed

the

trial

on

one

daily

injection

while

-LRB-

-RRB-

administered

an

additional

morning

dose

The

majority

of

patients

administering

insulin

detemir

twice

daily

-LRB-

n

-RRB-

were

transferred

to

this

regimen

within

weeks

of

treatment

At

the

time

of

transfer

about

two-thirds

of

the

patients

adding

a

morning

injection

fulfilled

the

formal

dose

transfer

guidelines

the

other

one-third

were

changed

through

investigator

discretion

Participants

using

insulin

detemir

twice

daily

administered

about

of

their

daily

insulin

dose

before

breakfast

After

weeks

the

mean

daily

dose

of

insulin

detemir

-LRB-

n

-RRB-

was

U/kg

-LRB-

U/kg

on

once

daily

-LSB-

n

-RSB-

and

U/kg

on

twice

daily

-LSB-

n

-RSB-

-RRB-

and

the

mean

daily

dose

of

glargine

-LRB-

n

-RRB-

was

IU/kg

Glycaemic

control

decreased

by

with

both

insulins

and

was

comparable

after

weeks

at

-LRB-

n

-RRB-

and

-LRB-

n

-RRB-

for

detemir

and

glargine

respectively

-LRB-

Table

-RRB-

with

an

estimated

difference

of

-LRB-

-RRB-

thereby

meeting

the

criteria

for

non-inferiority

for

insulin

detemir

vs

glargine

was

similar

in

participants

completing

the

study

on

once

or

twice

daily

insulin

detemir

-LRB-

and

-RRB-

Clinic

FPG

was

mmol/l

at

baseline

in

both

arms

and

was

comparable

at

end

of

treatment

with

insulin

detemir

and

insulin

glargine

-LRB-

and

mmol/l

-RRB-

-LRB-

Table

-RRB-

The

profile

of

change

in

and

FPG

was

very

similar

-LRB-

Fig.

-RRB-

Mean

self-monitored

FPG

was

comparable

between

treatments

being

mmol/l

with

insulin

detemir

and

mmol/l

with

insulin

glargine

self-monitored

PG

pre-dinner

-LRB-

and

mmol/l

-RRB-

was

also

similar

Fig.

in

with

time

-LRB-

a

-RRB-

Black

circles

insulin

detemir

white

circles

insulin

glargine

b

Mean

ten-point

self-monitored

PG

profiles

during

the

last

week

of

treatment

Triangles

insulin

detemir

-LRB-

once

daily

-RRB-

squares

insulin

detemir

-LRB-

twice

daily

-RRB-

black

circles

insulin

detemir

-LRB-

all

patients

-RRB-

white

circles

insulin

glargineTable

control

in

type

diabetic

patients

treated

with

insulin

detemir

or

insulin

glargine

DetemirGlargineDifference

-LRB-

CI

-RRB-

-LRB-

detemir/glargine

-RRB-

p

valueCompleters

on

once

dailyCompleters

on

twice

-LRB-

SE

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Clinic

FPG

-LRB-

mmol/l

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

n

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

without

hypoglycaemia

n

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

variation

-LRB-

mmol/l

-RRB-

Pre-breakfast

-LRB-

mmol/l

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Pre-dinner

-LRB-

mmol/l

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

aMean

-LRB-

SE

-RRB-

n

number

of

patients

for

whom

data

are

availablebWithin-participant

SD

-LRB-

CV

-RRB-

Within-participant

variation

in

self-monitored

PG

pre-breakfast

and

pre-dinner

did

not

differ

significantly

between

insulin

detemir

and

insulin

glargine

-LRB-

Table

-RRB-

The

overall

shape

of

the

ten-point

self-monitored

PG

profiles

during

the

last

week

of

treatment

was

parallel

for

insulin

detemir

-LRB-

n

-RRB-

and

insulin

glargine

-LRB-

n

-RRB-

-LRB-

NS

-RRB-

and

appeared

identical

regardless

of

treatment

regimen

-LRB-

Fig.

-RRB-

Of

participants

in

both

arms

achieved

while

treated

with

insulin

detemir

and

treated

with

insulin

glargine

did

so

in

the

absence

of

hypoglycaemia

Fasting

and

pre-dinner

PG

targets

of

mmol/l

were

achieved

by

and

of

participants

treated

with

insulin

detemir

and

insulin

glargine

-LRB-

NS

-RRB-

respectively

the

pre-breakfast

target

alone

was

achieved

by

and

-LRB-

p

-RRB-

and

the

pre-dinner

target

by

and

respectively

-LRB-

p

-RRB-

Hypoglycaemia

The

risk

of

hypoglycaemia

of

any

type

was

comparable

between

treatments

-LRB-

Table

-RRB-

The

overall

rate

of

hypoglycaemia

was

low

at

vs

episodes

per

patient-year

with

insulin

detemir

versus

insulin

glargine

-LRB-

relative

risk

-LSB-

CI

-RSB-

-RRB-

while

the

rate

of

nocturnal

hypoglycaemia

was

only

episodes

per

patient-year

with

both

insulins

Adjustment

for

did

not

affect

the

outcome

of

the

analyses

Major

hypoglycaemic

episodes

were

rare

with

both

insulins

especially

at

night

and

could

not

be

statistically

analysed

Table

episodes

in

type

diabetic

patients

treated

with

insulin

detemir

or

insulin

glargineEvents

Insulin

detemir

-LRB-

n

-RRB-

Insulin

glargine

-LRB-

n

-RRB-

Relative

risk

-LRB-

detemir/glargine

-RRB-

-LRB-

CI

-RRB-

Participants

n

-LRB-

-RRB-

Episodes

-LRB-

n

-RRB-

Rate

-LRB-

per

patient-year

-RRB-

Participants

n

-LRB-

-RRB-

Episodes

-LRB-

n

-RRB-

Rate

-LRB-

per

patient-year

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Symptoms

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

No

statistical

analyses

were

performed

on

the

small

numbers

of

major

events

Body

weight

Weight

gain

in

participants

completing

weeks

of

treatment

was

lower

with

insulin

detemir

-LRB-

n

-RRB-

than

with

insulin

glargine

-LRB-

n

-RRB-

-LRB-

-LSB-

SE

-RSB-

vs

-LSB-

SE

-RSB-

kg

p

-RRB-

Change

in

weight

analysed

by

LOCF

-LRB-

detemir

n

glargine

n

-RRB-

confirmed

this

lower

weight

gain

-LRB-

vs

kg

p

-RRB-

as

did

analysis

with

imputation

for

non-completers

-LRB-

vs

kg

p

-RRB-

Patients

completing

the

study

on

once

daily

insulin

detemir

-LRB-

n

-RRB-

had

a

weight

gain

of

-LRB-

SE

-RRB-

kg

whereas

those

treated

twice

daily

-LRB-

n

-RRB-

gained

-LRB-

SE

-RRB-

kg

similar

to

glargine

-LRB-

Fig.

-RRB-

Fig.

weight

change

from

baseline

at

week

in

patients

completing

treatment

on

insulin

detemir

once

or

twice

daily

-LRB-

and

overall

-RRB-

and

insulin

glargine

p

p

Adverse

events

and

other

safety

measures

Serious

adverse

events

were

less

frequent

with

insulin

detemir

-LRB-

patients

with

events

-RRB-

than

with

glargine

-LRB-

patients

with

events

-RRB-

However

only

five

serious

events

with

insulin

detemir

-LRB-

two

hypoglycaemia

one

each

of

hypothyroidism

injection-site

reaction

and

a

motor

vehicle

accident

-RRB-

and

four

with

glargine

-LRB-

three

hypoglycaemia

one

hyperglycaemia

-RRB-

were

considered

by

local

investigators

to

be

probably

or

possibly

related

to

trial

products

A

participant

treated

with

insulin

detemir

was

found

dead

in

bed

-LRB-

no

autopsy

report

available

-RRB-

but

had

a

history

of

myocardial

infarction

A

patient

using

glargine

was

hospitalised

after

the

study

for

pulmonary

fibrosis

and

died

of

cryptogenic

fibrosing

alveolitis

Adverse

events

recorded

as

serious

tended

to

be

of

a

wide-ranging

disparate

nature

with

no

clear

pattern

of

between-treatment

differences

Full

details

of

all

serious

adverse

events

and

events

recorded

as

possibly

or

probably

related

to

the

study

insulins

are

given

as

in

the

ESM

Tables

and

-RRB-

The

only

differences

in

adverse

events

judged

as

possibly

or

probably

related

to

trial

drugs

between

treatments

were

injection-site

disorders

-LRB-

patients

-LSB-

-RSB-

on

insulin

detemir

compared

with

four

-LSB-

-RSB-

on

glargine

-RRB-

allergic

reactions

-LRB-

three

patients

on

detemir

vs

one

on

glargine

-RRB-

and

skin

disorders

including

pruritus

and

rash

-LRB-

six

patients

on

insulin

detemir

vs

one

on

glargine

-RRB-

There

were

no

differences

in

standard

safety

parameters

between

treatments

Discussion

The

results

of

this

first

head-to-head

comparison

of

insulin

detemir

and

insulin

glargine

as

add-on

for

treatment

with

oral

glucose-lowering

agents

in

people

with

type

diabetes

using

forced

insulin

titration

suggest

that

clinically

significant

and

similar

improvements

in

glycaemic

control

can

be

achieved

with

both

analogues

together

with

a

similarly

low

risk

of

hypoglycaemia

Insulin

doses

were

higher

with

insulin

detemir

overall

partly

as

a

result

of

the

doses

used

by

those

taking

it

twice

daily

The

withdrawal

rate

appeared

to

be

higher

with

insulin

detemir

-LRB-

vs

-RRB-

which

was

partly

accounted

for

by

adverse

events

-LRB-

vs

-RRB-

this

excess

being

primarily

due

to

injection

site

reactions

Insulin

detemir

was

associated

with

a

modest

relative

reduction

in

weight

gain

consistent

with

observations

in

previous

comparisons

of

this

analogue

with

NPH

in

type

diabetes

-LSB-

-RSB-

In

the

present

study

the

between-treatment

difference

in

weight

was

primarily

accounted

for

by

those

patients

completing

the

study

on

once-daily

insulin

detemir

It

is

however

possible

that

differences

in

eating

pattern

were

contributory

factors

in

both

the

insulin

detemir

dosing

schedule

and

the

different

levels

of

weight

gain

observed

between

the

two

insulin

detemir

dosing

schedules

The

mechanism

-LRB-

s

-RRB-

responsible

for

relatively

lower

weight

gain

observed

here

and

previously

with

insulin

detemir

remain

the

object

of

speculation

-LSB-

-RSB-

The

present

study

was

designed

to

compare

the

two

basal

insulin

analogues

as

they

had

been

used

in

previous

studies

and

according

to

label

Thus

insulin

glargine

was

given

once

daily

at

bedtime

regardless

of

glycaemic

profile

while

for

insulin

detemir

an

option

was

provided

for

adding

a

second

dose

primarily

based

on

pre-dinner

blood

glucose

level

following

a

structured

insulin

titration

protocol

The

decision

to

use

twice-daily

insulin

detemir

could

not

be

attributed

to

hypoglycaemia

as

patients

who

were

switched

to

a

twice-daily

regimen

had

on

average

hypoglycaemic

episodes

per

patient-year

prior

to

transfer

compared

with

episodes

per

patient-year

in

patients

completing

treatment

on

once-daily

insulin

detemir

The

frequency

of

nocturnal

hypoglycaemia

was

also

lower

in

relevant

patients

before

transfer

-LRB-

vs

episodes

per

patient-year

-RRB-

Interestingly

the

initiation

of

insulin

with

once-daily

insulin

detemir

has

recently

been

tested

by

Philis-Tsimikas

et

al.

in

type

diabetes

patients

on

oral

glucose-lowering

agents

resulting

in

reductions

of

-LRB-

morning

injection

-RRB-

and

-LRB-

evening

injection

-RRB-

from

baseline

values

of

and

respectively

-LSB-

-RSB-

These

improvements

in

glycaemic

control

approach

the

magnitude

of

reduction

shown

in

the

current

study

and

in

previous

studies

of

once-daily

insulin

glargine

-LSB-

-RSB-

although

the

insulin

detemir

doses

were

higher

at

trial-end

and

the

absolute

values

achieved

at

trial-end

were

relatively

high

The

design

of

the

current

study

does

not

allow

definitive

conclusions

for

comparison

of

once

and

twice

daily

dosing

with

insulin

detemir

although

these

post

hoc

observations

do

suggest

that

once

daily

administration

can

be

an

appropriate

starting

regimen

for

people

using

insulin

detemir

as

add-on

to

oral

glucose-lowering

drug

therapy

However

with

dose

optimisation

a

significant

proportion

of

patients

may

eventually

need

a

twice-daily

regimen

guided

by

structured

glucose

monitoring

Further

studies

are

required

to

better

define

the

differences

between

these

two

basal

insulin

analogues

on

the

basis

of

a

similar

insulin

administration

regimen

once

daily

only

for

both

insulins

Alternatively

if

the

option

of

adding

a

second

insulin

dose

is

available

for

both

insulins

then

a

properly

designed

study

protocol

should

allow

addition

of

this

second

insulin

injection

only

when

a

normal

or

much

lower

FPG

target

is

achieved

Indeed

the

use

of

lower

FPG

targets

-LRB-

e.g.

mmol/l

as

has

been

used

previously

-RRB-

should

also

enable

a

higher

proportion

of

patients

to

reach

guideline

targets

In

conclusion

the

use

of

insulin

detemir

or

insulin

glargine

as

add-on

to

oral

glucose-lowering

therapy

resulted

in

comparable

improvements

and

a

similarly

low

risk

of

hypoglycaemia

Further

comparisons

of

detemir

and

glargine

are

required

to

fully

understand

how

each

may

relatively

benefit

defined

groups

of

patients

starting

on

insulin

Electronic

supplementary

material

Below

is

the

link

to

the

electronic

supplementary

material

ESM

-LRB-

PDF

kb

-RRB-

ESM

Table

Treatment

emergent

adverse

events

probably

or

possibly

related

to

trial

product

by

system

organ

class

ITT

cohort

-LRB-

PDF

kb

-RRB-

ESM

Table

Adverse

events

leading

to

withdrawal

-LRB-

PDF

kb

-RRB-

ESM

Table

Treatment

emergent

serious

adverse

events

by

system

organ

class

ITT

cohort

-LRB-

PDF

kb

-RRB-

ESM

Table

Treatment

emergent

serious

adverse

events

preferred

term

occurring

in

more

than

one

subject

ITT

-LRB-

PDF

-RRB-

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O O O O O O O O O O O O O O O O O B I O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O B I O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O B I O O O O O O B O O O O O O O O O O O O O O O O O O O O O B I O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O B O O O O O O O O O O O O O O O O B O O O O O O O O O O B I O B I O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O B I O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O B I O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O B I O O B O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O B I O B I O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O B I O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O

body weight
fasting plasma glucose
hypoglycaemia
insulin detemir
insulin glargine
type 2 diabetes

glucose variability
glucose control
insulin supplementation
oral glucose-lowering agents