Improvement of glycemic control and quality-of-life by insulin lispro therapy: Assessing benefits by ITR-QOL questionnaires

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1 diabetes research and clinical practice 81 (2008) available at journal homepage: Improvement of glycemic control and quality-of-life by insulin lispro therapy: Assessing benefits by ITR-QOL questionnaires Hitoshi Ishii a, *, James H. Anderson Jr. b, Ayuko Yamamura c, Masakazu Takeuchi c, Ichiro Ikeda d a Department of Endocrinology, Tenri Hospital, 200, Mishimacho, Tenri, Nara , Japan b Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, United States c Lilly Research Laboratories Japan, Eli Lilly Japan K.K., Kobe, Japan d Global Patient Safety Japan, Eli Lilly Japan K.K., Kobe, Japan article info Article history: Received 17 July 2007 Accepted 26 March 2008 Published on line 20 May 2008 Keywords: QOL ITR-QOL Insulin lispro Diabetes mellitus abstract Objective: To investigate the impact of insulin lispro on patients quality of life (QOL) in diabetic patients who need insulin treatment. Methods: In this open-label, 12-week study 770 diabetic patients whose medications were switched to insulin lispro from human insulin were evaluated. Main outcome measures were compliance with insulin injection timing, HbA 1c, postprandial blood glucose, frequency and time of onset of hypoglycemia, and QOL measurements. Results: After switching to insulin lispro, approximately 95% of patients Always or Usually complied with the timing of insulin injections as instructed by their physician. HbA 1c was improved from 8.2 to 7.8% without increasing the number of hypoglycemic episodes. In terms of QOL, statistically significant improvements were observed in the insulin-therapy-related QOL measure questionnaire (ITR-QOL) total score. Statistically significant correlations were found between compliance with insulin injection timing and glycemic control, as well as glycemic control and QOL. Conclusion: The improvement in patient convenience obtained by switching to insulin lispro provided better compliance with insulin injection timing, and this in turn led to better glycemic control and improved QOL. Especially, a better QOL was seen to be clearly related with better glycemic control. # 2008 Elsevier Ireland Ltd. All rights reserved. 1. Introduction One key objective in the treatment of diabetes mellitus is to prevent both macrovascular and microvascular complications by maintaining the best possible glycemic control. Past interventional studies like the Diabetes Control and Complications Trial (DCCT) [1], the United Kingdom Prospective Diabetes Study (UKPDS) [2], and the Kumamoto Study [3,4] consistently demonstrated the importance of intensive therapy in preventing the onset or progression of diabetic complications in both of type 1 and 2 diabetic patients. The most recent national survey of diabetes mellitus in Japan [5] showed that the number of Japanese patients with diabetes mellitus continues to increase. According to this * Corresponding author. Tel.: ; fax: addresses: hit@tenriyorozu-hp.or.jp, ish@mbd.ocn.ne.jp (H. Ishii) /$ see front matter # 2008 Elsevier Ireland Ltd. All rights reserved. doi: /j.diabres

2 170 diabetes research and clinical practice 81 (2008) survey, in 2002 an estimated 7.4 million Japanese were strongly suspected of having diabetes mellitus compared with 6.9 million in Clearly this indicates that the need of therapeutic intervention will be more important than ever in order to prevent even greater increases in the number of patients with diabetic complications. In the present state of affairs, however, patient compliance with various interventions such as diet, exercise and/or drug therapies such as oral antihyperglycemic drugs or insulin is often not as high as it could be because these interventions, especially treatment with insulin, pose problems in daily activities and social life, and can also become a psychological burden [6 8]. Insulin lispro (Humalog 1, Eli Lilly and Company, Indianapolis, USA) was the first rapid-acting insulin analogue launched in Japan in Since this drug can be administered just before meals, it was expected to reduce the types of problems most users of regular human insulin face daily. In this post-marketing surveillance study, we investigated the impact of switching to insulin lispro from regular human insulin on patient quality of life (QOL) with diabetes treatment. And also, we investigated the correlations between QOL and other measurements related to insulin therapy. 2. Materials and methods 2.1. Study sites and patients In this study, a random sampling method was not used for the selection of medical institutions, but the institutions were selected throughout Japan with intent to avoid geographical localization. The subjects were Japanese patients with diabetes who had been treated with insulin but not used insulin lispro within 6 months, and who had been receiving medical treatment for their diabetes at the study institutions for more than 3 months at study entry. There were no restrictions regarding concomitant agents Study protocol This QOL assessment was conducted as part of a postmarketing, open-label, non-interventional observation study of insulin lispro injection (Humalog 1, Cartridge, Kit, Vial for injection; Eli Lilly Japan K.K., Kobe, Japan) in Japan. The study duration time for each patient was 12 weeks. In this study, HbA 1c and self-monitoring postprandial blood glucose (2-h after breakfast; PPG 2 h) were evaluated at baseline and endpoint. Also, spontaneously reported adverse events, laboratory abnormalities observed during the study period, and concomitant medication were recorded in the case report form. Assessments of frequency and compliance with insulin injection timing as instructed by doctor, frequency and on-set timing of hypoglycemia, and QOL scores were recorded on questionnaires provided to the patients who sent them directly to the central data center. Patients reported compliance with insulin injection timing as instructed by doctor before breakfast, lunch, and dinner using the following 5 grade scale: Always, Usually, Sometimes, Hardly, or Never. For assessing the frequency of hypoglycemic episodes, subjective hypoglycemic symptoms or documented hypoglycemia (less than or equal to 50 mg/dl) in the past 1 month were counted, and the onset timing of hypoglycemia was also assessed at baseline and endpoint. For assessing QOL, a Japanese version of the insulin therapy related quality-of-life measure (ITR-QOL) [9 11] was used in this study, and these were assessed at baseline and endpoint. The ITR-QOL was developed by Ishii et al. in This questionnaire consists of 23 questions concerning common complaints from patients under treatment with insulin injection. Detail of each question is shown in Table 7 along with the study results. The total score of the questionnaire ranges from 23 to 115 with higher scores showing a better QOL. The questionnaire is divided into two parts: a Status domain and a Perception domain. The questions dealing with status (Items 1 12) assess the frequency of various patient burdens due to the consequences of their diabetes and/or insulin injections. Status domain consists of three subdomains: social activities (Items 3, 4, 5, 10, and 11), physical function (Items 6, 7, 9, and 12) and daily activities (Items 1, 2, and 8). The second set of questions, Perception domain which comprise the subdomain of therapy-related feelings (Items 13 23) focuses on the feelings of patients and how they perceive the severity of various burdens related to insulin therapy. Ishii et al. [9] confirmed that this questionnaire consists of four subdomains: a daily activity score, a social activity score, a physical function score, and a therapy-related feelings score using factor analysis and that the questionnaire had the internal consistency and high reproducibility using the following statistics, Cronbach s a coefficient and weighted k coefficient, respectively Statistical analysis The analysis set for this assessment was defined as the enrolled eligible patients whose ITR-QOL questionnaires were collected, and whose baseline and 12-week measurement points were both within allowable limits. No imputation for missing data was performed. Changes from baseline to 12 weeks for mean daily insulin dose, mean number of injection per day, HbA 1c, PPG 2 h, frequency of hypoglycemia, and ITR-QOL measurements were analyzed using the Wilcoxon signed rank test (onesample Wilcoxon test) or the McNemar test. Correlations between compliance with insulin injection timing as instructed by doctor, blood glucose measurements (HbA 1c ), and ITR-QOL total score were also tested using the Jonckheere test [12]. A significance level of 0.05 (two-sided) was used for all tests. SAS Release 8.02 software was used for the statistical analyses. 3. Results 3.1. Baseline characteristics Overall, eligible QOL assessment reports were obtained from 770 patients. These patients were enrolled in this study from September 2001 to December Patient background characteristics are listed in Table 1. Approximately one third (35.1%) of patients were diagnosed as having type 1 diabetes, and 61.8% of patients were diagnosed as having type 2 diabetes. The mean (standard deviation) age were years in type 1 patients and

3 diabetes research and clinical practice 81 (2008) Table 1 Characteristics of study participants Baseline characteristics Total (n = 770) Type 1 (n = 270) Type 2 (n = 476) Type of disease Type 1 N (%) 270 (35.1%) Type 2 N (%) 476 (61.8%) Others N (%) 24 (3.1%) Age (years) Mean S.D Sex Male N (%) 339 (44.0%) 92 (34.1%) 230 (48.3%) Female N (%) 431 (56.0%) 178 (65.9%) 246 (51.7%) Duration of illness (years) Mean S.D Duration of insulin treatment (years) Mean S.D Frequency of insulin injection per day 1 2 N (%) 244 (31.7%) 50 (18.5%) 190 (39.9%) 3 N (%) 524 (68.1%) 219 (81.1%) 285 (59.9%) Unknown N (%) 2 (0.2%) 1 (0.4%) 1 (0.2%) Complications Diabetic retinopathy N (%) 287 (37.3%) 70 (25.9%) 211 (44.3%) Diabetic nephropathy N (%) 184 (23.9%) 42 (15.6%) 136 (28.6%) Diabetic neuropathy N (%) 258 (33.5%) 58 (21.5%) 193 (40.6%) Height (cm) Mean S.D Weight (kg) Mean S.D BMI Mean S.D years in type 2 patients. For the male female ratio, percentage of female was slightly higher in type 1 patients and almost equal in type 2 patients. The mean duration of illness was longer in type 2 patients, but the mean duration of insulin treatment was longer in type 1 patients, which was approximately double of the duration for type 2 patients. In terms of the frequency of insulin injection per day, 81.1% of type 1 patients and 59.9% of type 2 patients had insulin intensive therapy (more than or equal to three times per day) Dose and frequency of insulin injection Changes from baseline in the mean daily insulin dose and number of injection per day are summarized in Table 2. Statistically significant increase of total insulin dose was observed in both disease types. The quantity of the increase of insulin dose was similar between the disease types, but the content was slightly different. In type 1 patients, the dose of rapid-acting insulin was increased and the dose of basal insulin was stable. In type 2 patients, the dose of rapid-acting insulin was increased twice higher than that in type 1 and the dose of basal insulin was decreased. The mean number of injection per day was also increased in both of type 1 and type 2 patients. As a result, the percentage of patients who took insulin injection three or more times a day was increased from 68.1% (81.1% for type 1 and 59.9% for type 2) at baseline to 96.9% (97.8% for type 1 and 96.2% for type 2) at end point Glycemic control Changes from baseline in mean HbA 1c and PPG 2 h after breakfast are summarized in Table 2. HbA 1c was measured in 92% of patients, but PPG 2 h was measured in only 55% of patients. Statistically significant improvements were observed in both efficacy measurements (one-sample Wilcoxon test, p < 0.001) in both of type 1 and type 2 patients. In terms of HbA 1c, more improvement was observed in type 2 patients against a background where baseline value was lower than that in type 1 patients Compliance with insulin injection timing In this study, compliance with insulin injection frequency was consistently good. More than 95% of patients Always or Usually took their insulin injections at both baseline and endpoint (data not shown). From our baseline data, however, patients were less likely to follow their doctors instructions on the proper timing for their injections: only 81.5% of patients Always or Usually complied with the prescribed timing before breakfast, 75.2% of patients before lunch, and 81.3% of patients before dinner. After switching from the previous regular human insulin to insulin lispro, approximately 95% of patients Always or Usually complied with the timing of insulin injections as instructed by their physician, and statistically significant improvement was observed at any time points in both of type 1 and type 2 patients (one-sample Wilcoxon test, p < 0.001) (Table 3) Frequency of hypoglycemia Overall frequency of hypoglycemia during the past 1 month and time periods during which hypoglycemia occurred was assessed in this study (Table 4). The percentage of patients who experienced hypoglycemia at any time period was significantly decreased from 59.7% at baseline to 54.8% at endpoint (McNemar test, p = 0.004) and from 46.6% at baseline to 40.8% at endpoint (McNemar test, p = 0.011) in type 2 patients.

4 172 diabetes research and clinical practice 81 (2008) Table 2 Changes from baseline in daily insulin dose, number of injection per day, and glycemic control measurements Baseline 12 weeks Change from baseline One-sample Wilcoxon test, p Daily insulin dose (IU/day) Total Total N Mean S.D <0.001 Type 1 N Mean S.D <0.001 Type 2 N Mean S.D <0.001 Rapid-acting Total N Mean S.D <0.001 Type 1 N Mean S.D <0.001 Type 2 N Mean S.D <0.001 Basal Total N Mean S.D <0.001 Type 1 N Mean S.D Type 2 N Mean S.D <0.001 Number of injection per day (times/day) Total N Mean S.D <0.001 Type 1 N Mean S.D <0.001 Type 2 N Mean S.D <0.001 Glycemic control measurements HbA1c (%) Total N Mean S.D <0.001 Type 1 N Mean S.D <0.001 Type 2 N Mean S.D <0.001 PPG 2 h (mg/dl) Total N Mean S.D <0.001 Type 1 N Mean S.D <0.001 Type 2 N Mean S.D <0.001 The percentage of patients who experienced hypoglycemia at any time period was decreased from 82.2% at baseline to 78.9% at endpoint in type 1 patients, but the decrease was not statistically significant (McNemar test, p = 0.180). Patients had also been asked which time periods they felt it to be undesirable to experience hypoglycemia (Table 5). From the view of the time period of hypoglycemia occurring, although the frequency of hypoglycemia was significantly increased at between breakfast and 2-h after breakfast, the frequency of hypoglycemia was significantly decreased at between going to bed and next morning wake-up (which patients reported as the most undesirable time to have hypoglycemia) and between 2-h after lunch and before dinner (reported as the second most undesirable time). These results reflected the faster on-set profile of lispro insulin compared with regular human insulin ITR-QOL score In terms of ITR-QOL score, statistically significant increases were observed in the total score, perception domain score, and status domain score in total, in type 1, and in type 2 patients

5 Table 3 Baseline and change in steps from baseline in compliance with insulin injection timing as instructed by doctor Total Type 1 Type 2 breakfast lunch dinner breakfast lunch dinner breakfast Frequency at baseline N Always 492 (67.3%) 384 (59.5%) 481 (66.3%) 146 (56.4%) 125 (50.8%) 147 (56.5%) 334 (74.6%) 250 (66.1%) 319 (72.2%) Usually 104 (14.2%) 101 (15.7%) 109 (15.0%) 39 (15.1%) 39 (15.9%) 41 (15.8%) 57 (12.7%) 57 (15.1%) 64 (14.5%) Sometimes 44 (6.0%) 52 (8.1%) 45 (6.2%) 21 (8.1%) 21 (8.5%) 23 (8.8%) 22 (4.9%) 29 (7.7%) 22 (5.0%) Hardly 65 (8.9%) 59 (9.1%) 62 (8.5%) 38 (14.7%) 36 (14.6%) 34 (13.1%) 25 (5.6%) 19 (15.0%) 24 (5.4%) Never 12 (1.6%) 22 (3.4%) 14 (1.9%) 9 (3.5%) 15 (6.1%) 10 (3.8%) 3 (0.7%) 7 (1.9%) 4 (0.9%) Unknown 14 (1.9%) 27 (4.2%) 15 (2.1%) 6 (2.3%) 10 (4.1%) 5 (1.9%) 7 (1.6%) 16 (4.2%) 9 (2.0%) Frequency at endpoint N Always 632 (84.7%) 541 (73.9%) 609 (81.7%) 220 (84.3%) 189 (73.0%) 217 (83.1%) 392 (85.0%) 335 (74.4%) 372 (80.9%) Usually 82 (11.0%) 143 (19.5%) 103 (13.8%) 29 (11.1%) 48 (18.5%) 33 (12.6%) 51 (11.1%) 91 (20.2%) 67 (14.6%) Sometimes 12 (1.6%) 18 (2.5%) 14 (1.9%) 5 (1.9%) 9 (3.5%) 4 (1.5%) 7 (1.5%) 9 (2.0%) 10 (2.2%) Hardly 12 (1.6%) 18 (2.5%) 11 (1.5%) 4 (1.5%) 10 (3.9%) 5 (1.9%) 6 (1.3%) 6 (1.3%) 5 (1.1%) Never 3 (0.4%) 4 (0.5%) 3 (0.4%) 1 (0.4%) 0 (0.0%) 0 (0.0%) 2 (0.4%) 4 (0.9%) 3 (0.7%) Unknown 5 (0.7%) 8 (1.1%) 5 (0.7%) 2 (0.8%) 3 (1.2%) 2 (0.8%) 3 (0.7%) 5 (1.1%) 3 (0.7%) Change of steps from baseline (number of steps) N or (8.0%) 54 (9.0%) 48 (6.9%) 36 (14.6%) 32 (13.9%) 31 (12.5%) 19 (4.4%) 21 (5.9%) 15 (3.6%) +2 or (18.8%) 122 (20.2%) 143 (20.6%) 54 (21.9%) 53 (22.9%) 63 (25.4%) 71 (16.4%) 62 (17.6%) 75 (17.8%) (65.8%) 356 (59.0%) 443 (63.9%) 144 (58.3%) 128 (55.4%) 141 (56.9%) 305 (70.6%) 220 (62.3%) 288 (68.2%) 1 or 2 46 (6.6%) 64 (10.6%) 53 (7.6%) 12 (4.9%) 17 (7.4%) 12 (4.8%) 32 (7.4%) 44 (12.5%) 39 (9.2%) 3 or 4 6 (0.9%) 7 (1.2%) 6 (0.9%) 1 (0.4%) 1 (0.4%) 1 (0.4%) 5 (1.2%) 6 (1.7%) 5 (1.2%) One-sample Wilcoxon test, p <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 lunch dinner diabetes research and clinical practice 81 (2008)

6 174 diabetes research and clinical practice 81 (2008) Table 4 Time periods during which hypoglycemia occurred during past 1 month Time period Total Type 1 Type 2 McNemar test p-value 12 weeks (N =476) Baseline (N = 476) McNemar test p-value 12 weeks (N = 270) Baseline (N = 270) McNemar test p-value 12 weeks (N = 770) Baseline (N = 770) Overall 460 (59.7%) 422 (54.8%) (82.2%) 213 (78.9%) (46.6%) 194 (40.8%) Between wake-up and 51 (11.2%) 41 (9.7%) (15.0%) 27 (12.7%) (7.7%) 13 (6.7%) before breakfast Between breakfast 26 (5.7%) 60 (14.3%) < (7.3%) 30 (14.2%) (4.5%) 26 (13.4%) and 2-h after breakfast Between 2-h after 209 (45.7%) 202 (48.0%) (44.1%) 108 (50.9%) (46.6%) 87 (44.8%) breakfast and before lunch Between lunch and 29 (6.3%) 42 (10.0%) (6.4%) 24 (11.3%) (6.3%) 18 (9.3%) h after lunch Between 2-h after 221 (48.4%) 172 (40.9%) (52.7%) 91 (42.9%) (44.3%) 78 (40.2%) lunch and before dinner Between dinner and 91 (19.9%) 81 (19.2%) (24.5%) 49 (23.1%) (15.8%) 32 (16.5%) before going to bed Between going to bed and 173 (37.9%) 118 (28.0%) < (50.5%) 78 (36.8%) (24.4%) 36 (18.6%) next morning wake-up (One-sample Wilcoxon test, p < 0.001) (Table 6). Furthermore, statistically significant increases were observed in the scores of each of the three subclasses in the status domain: daily activity score (Items 1, 2, and 8), social activity score (Items 3, 4, 5, 10, and 11), and physical function score (Items 6, 7, 9, and 12). Individual changes for each score are shown in Fig. 1 per disease type. Overall, the ITR-QOL scores are lower in type 1 patients, which mean type 1 patients have a heavier mental burden with insulin treatment. Table 7 shows the p-values of one-sample Wilcoxon test for mean change from baseline in each ITR-QOL score item for all, in type 1, and in type 2 patients. Statistically significant improvements were observed in 19 of 23 items in the ITR-QOL scores. The items in which statistically significant improvement was observed in type 1 patients and was not observed in type 2 patients were 5. Leisure activities (e.g. hobbies) are restricted because of insulin injection, 14. My field of activity is restricted because of insulin injection, and 22. Pain associated with insulin injection is discomforting. On the other hand, the items in which statistically significant improvement was not observed in type 1 patients and was observed in type 2 patients were 6. Need to abstain from physical activity because of concern about low blood glucose, 12. I don t feel well, and 18. I am worried that blood glucose may become too low after injecting insulin. 4. Discussion The results from this study demonstrate that when patients switched to insulin lispro from regular human insulin, compliance with insulin injection timing as instructed by the doctor, glycemic control, and QOL assessed by the ITR-QOL were improved in both of type 1 and type 2 patients. Because mean daily insulin dose and number of injection per day were increased in both of type 1 and type 2 patients, improvement of glycemic control might be related to increasing intensity of insulin therapy. However, reducing stress related to insulin injection timing seems to be one of the primary factors in achieving better compliance with insulin injection timing. Evidence from this study confirms that switching to insulin lispro helped to ameliorate this type of stress. To assess the impact of improvement of compliance with insulin injection timing as instructed by doctor and HbA 1c to the ITR-QOL total score, we conducted correlation analysis among the three key measurements additionally. The analysis results are illustrated in Fig. 2. Statistically significant interactive correlations were found between compliance with insulin injection timing and glycemic control, as well as glycemic control and QOL. However, even though better QOL implied higher compliance with insulin injection timing, the reverse, higher compliance with insulin injection timing implied better QOL, did not indicate to be statistically significant. In our previous study [13,14], which was a parallel comparison between insulin lispro and regular human insulin, we showed a statistically significant improvement of the patients QOL and satisfaction using ITR-QOL and DTSQ to assess changes in the insulin lispro group. In the previous study, however, no change in HbA 1c values was observed

7 diabetes research and clinical practice 81 (2008) Table 5 Undesirable time of hypoglycemia for patients Total (N = 457) Type 1 (N = 220) Type 2 (N = 221) Between wake-up and before breakfast 39 (8.5%) 25 (11.4%) 12 (5.4%) Between breakfast and 2-h after breakfast 40 (8.8%) 24 (10.9%) 16 (7.2%) Between 2-h after breakfast and before lunch 135 (29.5%) 67 (30.5%) 62 (28.1%) Between lunch and 2-h after lunch 49 (10.7%) 29 (13.2%) 17 (7.7%) Between 2-h after lunch and before dinner 145 (31.7%) 69 (31.4%) 71 (32.1%) Between dinner and before going to bed 32 (7.0%) 23 (10.5%) 8 (3.6%) Between going to bed and next morning wake-up 282 (61.7%) 157 (71.4%) 118 (53.4%) Table 6 Changes from baseline in ITR-QOL score Baseline 12 weeks Change from baseline One-sample Wilcoxon test, p Total score (Items 1 23) Total N Mean S.D <0.001 Type 1 N Mean S.D <0.001 Type 2 N Mean S.D <0.001 Perception domain score (Items 13 23) Total N Mean S.D <0.001 Type 1 N Mean S.D <0.001 Type 2 N Mean S.D <0.001 Status domain score (Items 1 12) Total N Mean S.D <0.001 Type 1 N Mean S.D <0.001 Type 2 N Mean S.D <0.001 Daily activity score (Items 1, 2, 8) Total N Mean S.D <0.001 Type 1 N Mean S.D <0.001 Type 2 N Mean S.D <0.001 Social activity score (Items 3, 4, 5, 10, 11) Total N Mean S.D <0.001 Type 1 N Mean S.D <0.001 Type 2 N Mean S.D Physical function score (Items 6, 7, 9, 12) Total N Mean S.D <0.001 Type 1 N Mean S.D Type 2 N Mean S.D <0.001

8 176 diabetes research and clinical practice 81 (2008) Table 7 p-values of one-sample Wilcoxon test for mean change from baseline in each ITR-QOL score items No. Question Total (N = 770) Type 1 (N = 270) Type 2 (N = 476) 1 Work and/or house work is disrupted because of insulin injection Meals cannot be taken at the planned time after injecting insulin Length of time when going out is restricted because of insulin injection Social activities (with friends, with neighbors, with relatives, at work, etc.) are restricted because of insulin injection 5 Leisure activities (e.g. hobbies) are restricted because of insulin injection Need to abstain from physical activity because of concern about low blood glucose 7 Work and/or house work is disrupted because of low blood glucose Difficult to find a location to inject insulin at the appointed hour I am aware of the symptoms of low blood glucose I cannot adjust to unexpected invitations or work because of insulin injection 11 I need to explain to other people that I need to inject insulin I don t feel well Too much of my time is restricted because of treatment for diabetes My field of activity is restricted because of insulin injection I am always worried about and feel burdened by the time for insulin injection 16 Time to start meal is restricted because of insulin injection I feel burdened by having to wake up early in order to inject insulin I am worried that blood glucose may become too low after injecting insulin 19 Group activities or relationships with other people are restricted because of insulin injection 20 Time between insulin injection and meal is wasted It is difficult to inject insulin when I eat out Pain associated with insulin injection is discomforting I am satisfied with current insulin therapy Status domain: 1 12 (1: Yes, always; 2: Yes, often; 3: Yes, sometimes; 4: Yes, rarely; 5: No), Perception domain: (1: Completely agree; 2: Between 1 and 3; 3: Neither agree nor disagree; 4: Between 3 and 5; 5: Completely disagree): 23 (1: Completely disagree; 2: Between 1 and 3; 3: Neither agree nor disagree; 4: Between 3 and 5; 5: Completely agree). during the 24-week study period (insulin lispro group: % at baseline to % at endpoint; regular human insulin group: % at baseline to % at endpoint) because relatively well-controlled patients participated into the study. The patients enrolled in the previous study were type 1 and type 2 diabetic patients who had been treated with regular human insulin three times a day for at least 12 weeks. On the other hand, since the current study included patients who did not have sufficient diabetes treatment at study entry, the percentage of patients who took insulin injection three or more times a day was increased from 68.1% at baseline to 96.9% at endpoint. The increase in the number of injections would be a new burden in approximately 30% of patients who participated in the current study, and it might interfere the correlation between improvement of compliance with insulin injection timing as instructed by doctor and ITR-QOL scores. The ITR-QOL scores indicated that statistically significant improvements were observed in 19 of 23 items (see Table 7). Overall, more significant improvements were observed in the items related the time or timing of insulin injection. The items, in which statistically significant improvement was observed in each of type 1 or type 2 patients, indicated the difference of the mental burdens between the disease types. For type 1 patients, 2 of identified 3 items were relatedtoleisureandfieldactivities.fortype2patients,2of identified 3 items were related to hypoglycemia. This difference may be related to generation of the population ( years for type 1 patients and years for type2patients). In terms of frequency of hypoglycemia, the frequency was reduced with statistically significance, but the amount of reduction was small. Also, although the frequency of hypoglycemia was significantly decreased at between 2-h after lunch and before dinner and between going to bed and next morning wake-up, the frequency of hypoglycemia was significantly increased at between breakfast and 2-h after breakfast. In spite of the situation, however, significantly improvement was observed in the items related to hypoglycemia in ITR-QOL scores. These results suggested that diabetic patients have worries about uncontrollable hypoglycemia such as nocturnal hypoglycemia, and insulin lispro could reduce the burden. This study has some limitations. First, there was a possibility that patients became more positive toward diabetic therapy by participating this study because insulin lispro was the first rapid-acting insulin analogue at the start this study in Japan. Since this drug can be administered just before meals, it was expected to reduce the types of problems most users of regular human insulin face daily. Second, this study included various types of patients with a wide range of conditions related to glycemic control, insulin dose, and frequency of

9 diabetes research and clinical practice 81 (2008) Fig. 1 Differences between baseline and 12-week in ITR-QOL score items. Acknowledgements The all authors wish to acknowledge all of the investigators, study staff, and patients participating in the post-marketing surveillance study for insulin lispro. Fig. 2 Correlation between key measurements. references insulin injection. Since intensive insulin therapy might also lead to good glycemic control and improvement of patient QOL, we could not completely explain how a rapid-acting insulin analogue alone could improve the above measurements. However, the results of this study reflect actual medical conditions, so we believe our results will provide useful information to better understand patient worries and wishes when using rapid-acting insulin. Conflict of interest statement We have a competing interest to declare. This study was supported by Eli Lilly Japan K.K. H. Ishii has served as consultant and on advisory boards for Eli Lilly Japan K.K. Another member belong to the sponsor. [1] Diabetes Control and Complications Trial (DCCT) Research Group, The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus, N. Engl. J. Med. 329 (1993) [2] UK Prospective Diabetes Study (UKPDS) Group, Intensive blood glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications with type 2 diabetes (UKPDS 33), Lancet 352 (1998) [3] Y. Ohkubo, H. Kishikawa, E. Araki, T. Miyata, S. Isami, S. Motoyoshi, et al., Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study, Diabetes Res. Clin. Pract. 28 (1995) [4] M. Shichiri, H. Kishikawa, Y. Ohkubo, N. Wake, Long-term results of the Kumamoto Study on optimal diabetes control in type 2 diabetic patients, Diabet. Care 23 (Suppl. 2) (2000) B21 29.

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