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Journal of Diabetes •• (2013) ••–••
O R I G I N A L A RT I C L E
Efficacy of structured education in patients with type 2 diabetes mellitus receiving insulin treatment* Xiao Hui GUO,1 Li Nong JI,2 Ju Ming LU,3 Jie LIU,4 Qing Qing LOU,5 Jing LIU,6 Li SHEN,1 Ming Xia ZHANG,2 Xiao Feng LV3 and Ming Jun GU7 1 Peking University First Hospital, 2Peking University People’s Hospital, 3Chinese People’s Liberation Army General Hospital of Beijing, Beijing, 4Shanxi Province People’s Hospital, Taiyuan, 5Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 6 Gansu Province People’s Hospital, Lanzhou, and 7Shanghai Pudong New Area Gongli Hospital, Shanghai, China
Correspondence Xiao Hui Guo, Peking University First Hospital, 8 Xishiku St, Xicheng District, Beijing 100034, China. Tel: +86 10 83575662 Fax: +86 10 66552883 Email: [email protected] *This study has been registered with ClinicalTrials.gov (Identifier: NCT01338376). Received 8 August 2013; accepted 11 October 2013. doi: 10.1111/1753-0407.12100
Abstract Background: The aim of the present study was to assess the efficacy of structured education in insulin-treated type 2 diabetes mellitus (T2DM) patients. Methods: In a 16-week open-label randomized controlled study, 1511 T2DM patients with inadequate responses to two or more oral antidiabetic drugs (OADs) for >3 months (HbA1c >7.5%) were randomized (1:1) to either an education group (structured diabetes education plus insulin therapy) or a control group (usual care plus insulin therapy). Both groups discontinued previous OADs (except biguanides and α-glucosidase inhibitors) and started twice daily injections of 30% soluble–70% isophane recombinant insulin. The primary endpoint was the change in HbA1c from baseline. Efficacy and safety data were analyzed for within- and between-group differences. Results: Of the initial 1511 patients, 1289 completed the study (643 in the control group; 646 in the education group). At the end of the study, significant reductions in HbA1c versus baseline were evident in both groups, but the reduction was greater in the education group (2.16% vs 2.08%; P < 0.05). A higher proportion of patients in the education group achieved target HbA1c levels 20 years of age was 9.7%, with 95% suffering from T2DM.6 In T2DM patients in whom oral antidiabetic drugs (OADs) are not achieving an adequate response, insulin therapy should be initiated as soon as possible.7 However, insulin users commonly have inadequate knowledge regarding the disease itself and their health condition.8 In recent years there has been a growing recognition that education is an important part of the integrated medical care of diabetes. Based on the important components of diabetes education, a randomized controlled prospective study, known as the Organization Program of DiabEtes INsulIN ManaGement (OPENING) study, was designed to evaluate the effectiveness of structured education in T2DM patients receiving insulin treatment. Methods The OPENING study was a 16-week open-label multicenter prospective randomized controlled investigation conducted at 48 centers throughout China from 14 January 2011 to 6 September 2012. Institutional review boards or independent ethics committees at each center approved the study protocol. Inclusion criteria for the study were: (i) a confirmed diagnosis of T2DM according to the American Diabetes Association (ADA) guidelines;9 (ii) men or women >18 years of age; (iii) HbA1c >7.5% despite previous therapy with two or more OADs for at least 3 months; (iv) an ability and willingness to accept structured education; and (v) provision of written informed consent. Exclusion criteria were: (i) type 1 or other types of diabetes; (ii) women who are pregnant, breast feeding, or unwilling to adopt effective contraceptive measures (sterilization, intrauterine device, oral contraceptive or condom); (iii) recurrent hypoglycemia; (iv) body mass index (BMI) >30 kg/m2; (v) hepatic dysfunction, as evidenced by (but not limited to) alanine aminotransferase (ALT) or alkaline phosphatase (ALP) levels greater than 2.5-fold the upper limits of normal; (vi) patients unwilling to communicate or those with language barriers that rendered them unable to fully understand or cooperate, 2
or affected their ability to use a glucometer; (vii) crucial organ failure or other severe diseases, including myocardial infarction, within the 12 months prior to enrollment, serious neurological or mental disorders, severe infections, or disseminated intravascular coagulation; (viii) malignancy; and (ix) a history of alcohol or drug abuse. Screening phase During a 2-week screening period before the start of the study, patients’ medical histories were recorded, a physical examination was performed, and fasting blood was drawn to determine serum creatinine, aspartate aminotransferase (AST), ALP, and HbA1c concentrations. Urinalysis and an electrocardiogram (ECG) were also performed during this time. Baseline measurements of fasting blood glucose (FBG) and self-monitoring of blood glucose (SMBG) values were obtained using a glucometer. Patients continued their previous OADs and treatments for any comorbidities during the screening phase and were familiarized with the use of an insulin pen and glucometer to perform SMBG at home. Assessments of a patient’s self-management and self-care were also performed using self-rating questionnaires, namely the Chinese version of the Diabetes Management SelfEfficacy Scale (C-DMSES), a 20-item questionnaire with a maximum score of 200),10 and the Summary of Diabetes Self-Care Activities (SDSCA) scale, a 12-item questionnaire with a maximum score of 84. Patients’ compliance with medications was assessed by the Morisky Medication Adherence Scale (MMAS), with a score of 0 denoting high compliance, a score of 1–2 indicating medium compliance, and a score of 3–4 indicating low compliance. Patients were required to complete all these examinations and questionnaires during the screening phase. Randomization and Visit 1 At the end of the screening phase, a blocked random assignment method with equal (1:1) allocation was used to assign patients who met the inclusion criteria to the control or education groups via a randomly generated numbers sequence. At Visit 1 (V1; Week 0), study medication and other study materials were dispensed. All patients were given a glucometer, testing strips, a diabetes knowledge manual, and a daily diary to record hypoglycemic events, adverse events (AEs), serious adverse events (SAEs), insulin dosage adjustments, and concomitant medications taken. Usual education was given with regard to diet, prevention, and treatment of hypoglycemia, as well as
© 2013 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd
X.H. GUO et al.
insulin injection techniques, which were to be followed throughout the study. Patients were taught to perform SMBG immediately prior to insulin injections before breakfast and dinner on two consecutive days in a week and to record the occurrence of hypoglycemic symptoms each day. Those assigned to the education group also had discussions to set a behavior goal for insulin injections and SMBG. All patients were required to discontinue prior OADs except for biguanides and α-glucosidase inhibitors, and then started injections of isophane recombinant–soluble human insulin pre-mix 30/70 (SciLin M30; Bayer Healthcare, Beijing, China) by the subcutaneous route, generally 30 min before breakfast and before dinner. Treatment phase During the treatment phase, all patients visited the research center on Weeks 0, 2, 4, 8, 12, and 16 (V1, V3, V5, V7, V8, and V9, respectively) in the morning before breakfast to have their FBG levels measured by clinic nurses. For the education group, three additional telephone follow-ups were scheduled at Weeks 1, 3, and 6 (V2, V4, and V6, respectively). At each study visit, body weight, vital signs, FBG, SMBG, hypoglycemic events, and AEs (if any) were recorded. In addition, HbA1c levels and C-DMSES, SDSCA, and MMAS scores were reassessed at V9 (Week 16). The education group received a structured educational program (known as the OPENING program), which was delivered by instructors (trained nurses) who had undergone a standardized training procedure. The structured education consisted of the following seven models: taking medication, insulin injection technique, SMBG, healthy diet, physical activity, prevention of hypoglycemia, and prevention of complications. Complication education was individualized to each patient according to his/her particular condition. The trained nurses could choose to educate patients as to how to prevent: (i) diabetic retinopathy and nephropathy; (ii) diabetic neuropathy and diabetic foot problems (as well as their daily care); and (iii) diabetic macrovascular complications. A short message was sent 2–3 days before every visit to remind patients about administering insulin injections at the right time, to perform regular SMBG, and when to visit the research center. Insulin injection assessment and complication education were also performed at each telephone follow-up. Patients were encouraged to ask questions of the clinicians during the study. To evaluate patients’ level of satisfaction with the structured educational program, the Minnesota Satisfaction Questionnaire (MSQ) was conducted in the education group at V3, V5, V7, V8, and V9. On the MSQ, a score of
Efficacy of structured education in T2DM
1 corresponds to “extremely dissatisfied”, whereas a score of 7 corresponds to “extremely satisfied”. The control group visited the study center on six occasions (no telephone follow-ups), at which education was provided by trained nurses according to each center’s own practices regarding aspects such as insulin injections, SMBG, hypoglycemia, and self-management. The insulin dose injected on the first day of treatment was set at 0.3–0.4 IU/kg and was subsequently adjusted according to individual patient’s pre-meal blood glucose values during the 16-week treatment period. Insulin dose adjustments were at the discretion of the investigator within 1 month after enrollment every week in the education group, and every 2 weeks in the control group. Dosage adjustments were recorded at every visit. Trial outcomes (education vs control) The primary efficacy assessment was the change in HbA1c from baseline to study end (V9). Secondary efficacy assessments at V9 were: (i) the proportion of patients achieving HbA1c levels of 0.05, ANCOVA). The trends in SMBG for the two groups at each of the study visits are shown in Fig. 1.
MMAS scores The proportion of patients with high medication compliance scores increased in both groups at the end of the study, whereas the proportion with low medication compliance scores decreased markedly (P < 0.0001 vs baseline). Compared with the control group, the education group had a larger proportion of high-compliance patients and a smaller proportion of medium- and lowcompliance patients (P = 0.0002; Table 2). Patients’ level of satisfaction with the structured educational program The education group maintained a high and increasing mean MSQ score (6.15–6.37; maximum score = 7) over time throughout the study. Adjustment of insulin dosages A higher percentage of patients in the education group had their insulin dosage adjusted compared with the control group (82.66% vs 76.52%, respectively; P = 0.0062). There were 3.15 ± 1.74 dosage adjustments for each patient in the education group, compared with 2.45 ± 1.28 in the control group. At the end of the study, the average total daily insulin dose was 30.39 IU (0.45 IU/ kg) in the education group and 29.13 IU (0.43 IU/kg) in the control group (P < 0.05).
Diabetes management rating scale scores Changes in C-DMSES and SDSCA scores At the end of the study, the total C-DMSES score increased to 167.15 ± 25.37 (P < 0.0001 vs baseline) in the
Changes in body weight and BMI Body weight increased significantly in both groups, but the education group had marginally less weight gain than
© 2013 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd
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Efficacy of structured education in T2DM
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Figure 2 Changes in body weight (BW) and body mass index (BMI) from baseline to study end in the control and education. Data show mean values for all patients in each group. *P < 0.05 compared with the control group.
the control group (1.00 ± 3.01 vs 1.34 ± 3.14 kg, respectively; P = 0.0534). Furthermore, BMI was increased significantly less in the education compared with control group (0.39 ± 1.12 vs 0.52 ± 1.17 kg/m2, respectively; P < 0.05; Fig. 2). Hypoglycemia The incidence of all hypoglycemic events in the education and control groups was 2.28 and 1.75 episodes per person-year, respectively (P > 0.05). The incidence of severe hypoglycemic events was 0.0096 and 0.0000 episodes per person-year in the education and control groups, respectively (P > 0.05). The education group reported a higher incidence of nocturnal hypoglycemic events than the control group (0.4092 vs 0.2088 episodes per person-year, respectively; P < 0.05). During the entire treatment phase, hypoglycemia was reported by 191 (29.57%) patients overall in the education group and 156 (24.26%) in the control group, with nocturnal hypoglycemia was reported by 52 (8.05%) and 30 (4.67%) patients, respectively (P < 0.05). Two patients (0.31%) in the education group experienced severe hypoglycemia, compared with none in the control group (P > 0.05). However, at each face-to-face interview (V3, V5, V7, V8, and V9), the education group reported fewer episodes of hypoglycemia than the control group. Safety analysis A total of 1457 patients who received at least one dose of the study insulin preparation and had at least one safety assessment was included in the safety set (control group n = 726; education group n = 731). Thirty-six patients (4.96%) in the control group and 31 (4.24%) in the education group reported AEs (P > 0.05). Six patients (0.83%) in the control group and two (0.27%) in the 6
education group withdrew from the study due to AEs (P > 0.05). The most frequent AEs noted were respiratory conditions (n = 6 [0.83%] in the control group; n = 8 [1.09%] in the education group). Seven patients (0.96%) in the control group and three (0.41%) in the education group reported SAEs (P > 0.05). All SAEs involved hospitalizations or prolongation of existing hospitalizations; there were no deaths in either group. The end-of-treatment laboratory results showed that blood chemistry and hematology parameters, as well as mean values for vital signs, were similar to those at baseline in both groups. Discussion The present randomized controlled study of the efficacy of structured diabetes education in the management of T2DM patients receiving insulin therapy has demonstrated a significant improvement in glycemic control and patients’ ability to self-care compared with usual care. Both treatment groups had high baseline HbA1c and blood glucose levels, as well as a high prevalence of diabetes complications and comorbidities. This indicates that, in China, the initiation of insulin treatment is relatively late and the overall glycemic control of such patients needs to be improved. Although the ADA guidelines12 recommend insulin use in newly diagnosed T2DM patients with markedly elevated blood glucose or HbA1c levels, or the addition of insulin to existing non-insulin regimens if the maximal tolerated doses do not achieve or maintain the HbA1c target over 3–6 months, patients with T2DM are usually reluctant to initiate insulin treatment when they respond inadequately to OADs. However, previous studies have shown a number of beneficial effects of early insulin treatment in patients with T2DM. For example, compared with rosiglitazone, insulin therapy has been found to be more cost-effective and to produce greater reductions in HbA1c when baseline HbA1c is >9.5%.13 In a comparison of an insulinbased regimen and triple OAD therapy in newly diagnosed T2DM patients, insulin therapy resulted in comparable weight gain, hypoglycemia incidence, medication compliance, quality of life, and treatment satisfaction to OAD therapy.14 Moreover, in a 6-year follow-up study, early insulin treatment preserved β-cell secretory function better than glibenclamide therapy.15 In the present study, both treatment groups received 30% soluble–70% isophane human insulin injections and exhibited significant reductions in HbA1c and blood glucose concentrations at the end of the study. In the control group, insulin usage may have served as a major intervention that may have contributed to the initial improvements in glycemic control in this group.
© 2013 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd
X.H. GUO et al.
Since the earliest days of diabetes management, healthcare providers have discovered that simply prescribing the correct dose of insulin, oral agents, or health diet plans is not enough to achieve adequate metabolic control or to prevent medical crises resulting from diabetes. Recently, a nationwide survey conducted in Chinese T2DM patients showed that patients who received diabetes education achieved better glycemic control than non-educated patients.16 Because formal diabetes education has proved effective in improving clinical and lifestyle outcomes,17,18 it can no longer be regarded as an optional add-on measure. Education needs to be seen as equally important in treatment as medication, and it therefore needs to be resourced, researched, evaluated and quality assured to a similar standard. Because good self-management behaviors predict better glycemic control, strategies to enhance and promote patients’ self-management ability and self-care behaviors are essential components of diabetes education programs.19 The OPENING program applied in the present study consisted of seven models of structured education, covering taking medication, insulin injection techniques, blood glucose monitoring, healthy diets, physical activity, hypoglycemia, and the prevention of complications. The education group in the present study had three telephone follow-ups that the control group did not, during which instructions regarding healthy diets, physical activity, prevention of complications, and insulin injection techniques were delivered by trained nurses. In addition, the education group received reminder messages, goal-setting discussions, and encouragement to communicate with their physicians. These components may have influenced the education group’s maintenance of healthy habits and engagement with medical providers, which, in turn, led to better glycemic control. Although there was no difference between the two groups in final (V9) FBG and SMBG values, the education group did achieve some better pre-breakfast blood glucose values at certain visits. Therefore, we presume that the improvement in HbA1c was derived from the daily glycemic profile, which cannot be actually represented by twopoint blood glucose values tested in a given day. This means that SMBG is a great method of self-managing diabetes. As noted in the education group, the OPENING program appeared to enhance the efficacy of insulin treatment in that it achieved a 0.16% greater reduction in HbA1c than seen in the control group. However, although the greater reduction in HbA1c in the education group was significant compared with the reduction seen in the control group, this has no clinical significance because the effect may have been due more to the marked effect of insulin in lowering blood glucose than to an effect of education.
Efficacy of structured education in T2DM
Other meaningful findings of our study were from between-group comparisons of body weight and BMI. The smaller, although not significant, weight gain and significantly smaller increase in BMI in the education group may have been a benefit of education. In this regard, several aspects of the OPENING program may have contributed to the positive clinical effects observed. This program has a multifaceted approach that focuses not only on glucose control, but also on the need to manage and prevent comorbid conditions. This may have contributed to achieving optimal self-management, selfcare, and medication compliance. We used several scales to evaluate the skill-building effect of the OPENING program. The behavior improvement in patients in the education group was verified by greater increments in the total scores on the C-DMSES and SDSCA, with the diet plan- and foot care-related items demonstrating significantly increased scores compared with the control group (P < 0.05). The level of medication compliance in the education group also markedly improved. Of interest, a “high-touch” effect was noted, in that subjects who were in more frequent contact with their healthcare providers showed larger HbA1c reductions. These results support the notion that educational interventions can contribute to improved clinical outcomes.20 The education group in the present study was receiving a slightly higher insulin dosage at the end of the study. This finding could have been attributed to more insulin dose adjustments because the OPENING program provided this group with more physician contact, which, in turn, led to better glycemic control. Although the incidence of all hypoglycemic events and severe hypoglycemic events in terms of episodes per person-years did not differ significantly between the two groups, the education group did experience more hypoglycemic events during the treatment period. This paradoxical result may have been due to the design of the study. Because the education group reported fewer episodes of hypoglycemia than the control group at each face-to-face interview (V3, V5, V7, V8, and V9), the three extra telephone follow-ups may have provided this group with more opportunities to report their experiences. Conversely, the longer betweenvisit times in the control group may have led to these patients not remembering to report all hypoglycemic events. In addition, because the OPENING program includes hypoglycemia education, including the detection and verification of hypoglycemic events, this may have made the education group more sensitive to hypoglycemic manifestations. Therefore, we cannot exclude the possibility that patients in the control group experienced some hypoglycemic events but neglected to report them, although we do not have data to verify this. In future, this problem may be avoided by a modified study design that
© 2013 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd
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incorporates features such as telephone follow-ups for the control group to unify hypoglycemia detection and monitoring techniques and collect event information. Conclusion This study makes an important contribution to the limited body of research that has formally evaluated the effectiveness of structured education on diabetes selfmanagement behavior as part of the standard care of disease. Although a longer-term study will be needed to determine whether educational interventions will result in sustained lifestyle changes and improved clinical outcomes that will ultimately reduce the complications and costs of diabetes, the present study showed that the seven modules of the OPENING program can deliver an integral component of diabetic self-management education that can enhance the quality of diabetes care. Consequently, economic, effective interventions that involve structured education may become a crucial part of our healthcare delivery system to achieve optimal outcomes. Acknowledgments This study was funded by the Bayer Healthcare Company and by grants from the Chinese Medical Association Foundation and the Chinese Diabetes Society. Disclosure None of the authors has any potential conflict of interest to declare. References 1. Pan XR, Yang WY, Li GW, Liu J. Prevalence of diabetes and its risk factors in China, 1994. Diabetes Care. 1997; 20: 1664–9. 2. National Diabetes Research Group. Diabetes mellitus survey of 300,000 in fourteen provinces and cities of China. Chin Med J. 1981; 20: 678–81. 3. Gu D, Reynolds K, Duan X et al. Prevalence of diabetes and impaired fasting glucose in the Chinese adult population: International Collaborative Study of Cardiovascular Disease in Asia (InterASIA). Diabetologia. 2003; 46: 1190–8. 4. Jia WP, Pang C, Chen L et al. Epidemiological characteristics of diabetes mellitus and impaired glucose regulation in a Chinese adult population: The Shanghai Diabetes Studies, a cross-sectional 3-year follow-up study in Shanghai urban communities. Diabetologia. 2007; 50: 286–92. 5. Li G, Hu Y, Pan X. Prevalence and incidence of NIDDM in Daqing City. Chin Med J (Engl). 1996; 109: 599–602.
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6. Yang W, Lu J, Weng J et al. Prevalence of diabetes among men and women in China. N Engl J Med. 2010; 362: 1090–101. 7. Chinese Diabetes Society. Chinese Guideline for Type 2 Diabetes. Peking University Medical Press, Beijing, 2010. 8. American Diabetes Association. Standards of medical care in diabetes. Diabetes Care. 2012; 35 (Suppl. 1): 11–63. 9. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2010; 33 (Suppl. 1): S62–9. 10. Wu SF, Courtney M, Edwards H, McDowell J, Shortridge-Baggett LM, Chang PJ. Development and validation of the Chinese version of the Diabetes Management Self-efficacy Scale. Int J Nurs Stud. 2008; 45: 534–42. 11. American Diabetes Association Workgroup on Hypoglycemia. Defining and reporting hypoglycemia in diabetes. Diabetes Care. 2005; 28: 1245–9. 12. American Diabetes Association. Standards of medical care in diabetes–2012. Diabetes Care. 2012; 35 (Suppl. 1): S11–63. 13. Rosenstock J, Sugimoto D, Strange P, Stewart JA, Soltes-Rak E, Dailey G. Triple therapy in type 2 diabetes: Insulin glargine or rosiglitazone added to combination therapy of sulfonylurea plus metformin in insulin-naive patients. Diabetes Care. 2006; 29: 554–9. 14. Lingvay I, Legendre JL, Kaloyanova PF, Zhang S, Adams-Huet B, Raskin P. Insulin-based versus triple oral therapy for newly diagnosed type 2 diabetes: Which is better? Diabetes Care. 2009; 32: 1789–95. 15. Alvarsson M, Berntorp K, Fernqvist-Forbes E et al. Effects of insulin versus sulphonylurea on beta-cell secretion in recently diagnosed type 2 diabetes patients: A 6-year follow-up study. Rev Diabet Stud. 2010; 7: 225–32. 16. Guo XH, Yuan L, Lou QQ et al. Chinese Diabetes Education Status Survey Study Group. A nationwide survey of diabetes education, self-management and glycemic control in patients with type 2 diabetes in China. Chin Med J (Engl). 2012; 125: 4175–80. 17. Norris SL, Lau J, Smith SJ, Schmid CH, Engelgau MM. Self-management education for adults with type 2 diabetes: A meta-analysis on the effect on glycemic control. Diabetes Care. 2002; 25: 1159–71. 18. Deakin T, McShane CE, Cade JE, Williams RD. Group based education in self-management strategies improves outcomes in type 2 diabetes mellitus. Cochrane Database Syst Rev. 2005; (2)CD003417. 19. Al-Khawaldeh OA, Al-Hassan MA, Froelicher ES. Selfefficacy, self-management, and glycemic control in adults with type 2 diabetes mellitus. J Diabetes Complications. 2012; 26: 10–6. 20. Philis-Tsimikas A, Fortmann A, Lleva-Ocana L, Walker C, Gallo LC. Peer-led diabetes education programs in high-risk Mexican Americans improve glycemic control compared with standard approaches: A Project Dulce promotora randomized trial. Diabetes Care. 2011; 34: 1926–31.
© 2013 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd
Journal of Diabetes •• (2013) ••–••
O R I G I N A L A RT I C L E
Efficacy of structured education in patients with type 2 diabetes mellitus receiving insulin treatment* Xiao Hui GUO,1 Li Nong JI,2 Ju Ming LU,3 Jie LIU,4 Qing Qing LOU,5 Jing LIU,6 Li SHEN,1 Ming Xia ZHANG,2 Xiao Feng LV3 and Ming Jun GU7 1 Peking University First Hospital, 2Peking University People’s Hospital, 3Chinese People’s Liberation Army General Hospital of Beijing, Beijing, 4Shanxi Province People’s Hospital, Taiyuan, 5Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 6 Gansu Province People’s Hospital, Lanzhou, and 7Shanghai Pudong New Area Gongli Hospital, Shanghai, China
Correspondence Xiao Hui Guo, Peking University First Hospital, 8 Xishiku St, Xicheng District, Beijing 100034, China. Tel: +86 10 83575662 Fax: +86 10 66552883 Email: [email protected] *This study has been registered with ClinicalTrials.gov (Identifier: NCT01338376). Received 8 August 2013; accepted 11 October 2013. doi: 10.1111/1753-0407.12100
Abstract Background: The aim of the present study was to assess the efficacy of structured education in insulin-treated type 2 diabetes mellitus (T2DM) patients. Methods: In a 16-week open-label randomized controlled study, 1511 T2DM patients with inadequate responses to two or more oral antidiabetic drugs (OADs) for >3 months (HbA1c >7.5%) were randomized (1:1) to either an education group (structured diabetes education plus insulin therapy) or a control group (usual care plus insulin therapy). Both groups discontinued previous OADs (except biguanides and α-glucosidase inhibitors) and started twice daily injections of 30% soluble–70% isophane recombinant insulin. The primary endpoint was the change in HbA1c from baseline. Efficacy and safety data were analyzed for within- and between-group differences. Results: Of the initial 1511 patients, 1289 completed the study (643 in the control group; 646 in the education group). At the end of the study, significant reductions in HbA1c versus baseline were evident in both groups, but the reduction was greater in the education group (2.16% vs 2.08%; P < 0.05). A higher proportion of patients in the education group achieved target HbA1c levels 20 years of age was 9.7%, with 95% suffering from T2DM.6 In T2DM patients in whom oral antidiabetic drugs (OADs) are not achieving an adequate response, insulin therapy should be initiated as soon as possible.7 However, insulin users commonly have inadequate knowledge regarding the disease itself and their health condition.8 In recent years there has been a growing recognition that education is an important part of the integrated medical care of diabetes. Based on the important components of diabetes education, a randomized controlled prospective study, known as the Organization Program of DiabEtes INsulIN ManaGement (OPENING) study, was designed to evaluate the effectiveness of structured education in T2DM patients receiving insulin treatment. Methods The OPENING study was a 16-week open-label multicenter prospective randomized controlled investigation conducted at 48 centers throughout China from 14 January 2011 to 6 September 2012. Institutional review boards or independent ethics committees at each center approved the study protocol. Inclusion criteria for the study were: (i) a confirmed diagnosis of T2DM according to the American Diabetes Association (ADA) guidelines;9 (ii) men or women >18 years of age; (iii) HbA1c >7.5% despite previous therapy with two or more OADs for at least 3 months; (iv) an ability and willingness to accept structured education; and (v) provision of written informed consent. Exclusion criteria were: (i) type 1 or other types of diabetes; (ii) women who are pregnant, breast feeding, or unwilling to adopt effective contraceptive measures (sterilization, intrauterine device, oral contraceptive or condom); (iii) recurrent hypoglycemia; (iv) body mass index (BMI) >30 kg/m2; (v) hepatic dysfunction, as evidenced by (but not limited to) alanine aminotransferase (ALT) or alkaline phosphatase (ALP) levels greater than 2.5-fold the upper limits of normal; (vi) patients unwilling to communicate or those with language barriers that rendered them unable to fully understand or cooperate, 2
or affected their ability to use a glucometer; (vii) crucial organ failure or other severe diseases, including myocardial infarction, within the 12 months prior to enrollment, serious neurological or mental disorders, severe infections, or disseminated intravascular coagulation; (viii) malignancy; and (ix) a history of alcohol or drug abuse. Screening phase During a 2-week screening period before the start of the study, patients’ medical histories were recorded, a physical examination was performed, and fasting blood was drawn to determine serum creatinine, aspartate aminotransferase (AST), ALP, and HbA1c concentrations. Urinalysis and an electrocardiogram (ECG) were also performed during this time. Baseline measurements of fasting blood glucose (FBG) and self-monitoring of blood glucose (SMBG) values were obtained using a glucometer. Patients continued their previous OADs and treatments for any comorbidities during the screening phase and were familiarized with the use of an insulin pen and glucometer to perform SMBG at home. Assessments of a patient’s self-management and self-care were also performed using self-rating questionnaires, namely the Chinese version of the Diabetes Management SelfEfficacy Scale (C-DMSES), a 20-item questionnaire with a maximum score of 200),10 and the Summary of Diabetes Self-Care Activities (SDSCA) scale, a 12-item questionnaire with a maximum score of 84. Patients’ compliance with medications was assessed by the Morisky Medication Adherence Scale (MMAS), with a score of 0 denoting high compliance, a score of 1–2 indicating medium compliance, and a score of 3–4 indicating low compliance. Patients were required to complete all these examinations and questionnaires during the screening phase. Randomization and Visit 1 At the end of the screening phase, a blocked random assignment method with equal (1:1) allocation was used to assign patients who met the inclusion criteria to the control or education groups via a randomly generated numbers sequence. At Visit 1 (V1; Week 0), study medication and other study materials were dispensed. All patients were given a glucometer, testing strips, a diabetes knowledge manual, and a daily diary to record hypoglycemic events, adverse events (AEs), serious adverse events (SAEs), insulin dosage adjustments, and concomitant medications taken. Usual education was given with regard to diet, prevention, and treatment of hypoglycemia, as well as
© 2013 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd
X.H. GUO et al.
insulin injection techniques, which were to be followed throughout the study. Patients were taught to perform SMBG immediately prior to insulin injections before breakfast and dinner on two consecutive days in a week and to record the occurrence of hypoglycemic symptoms each day. Those assigned to the education group also had discussions to set a behavior goal for insulin injections and SMBG. All patients were required to discontinue prior OADs except for biguanides and α-glucosidase inhibitors, and then started injections of isophane recombinant–soluble human insulin pre-mix 30/70 (SciLin M30; Bayer Healthcare, Beijing, China) by the subcutaneous route, generally 30 min before breakfast and before dinner. Treatment phase During the treatment phase, all patients visited the research center on Weeks 0, 2, 4, 8, 12, and 16 (V1, V3, V5, V7, V8, and V9, respectively) in the morning before breakfast to have their FBG levels measured by clinic nurses. For the education group, three additional telephone follow-ups were scheduled at Weeks 1, 3, and 6 (V2, V4, and V6, respectively). At each study visit, body weight, vital signs, FBG, SMBG, hypoglycemic events, and AEs (if any) were recorded. In addition, HbA1c levels and C-DMSES, SDSCA, and MMAS scores were reassessed at V9 (Week 16). The education group received a structured educational program (known as the OPENING program), which was delivered by instructors (trained nurses) who had undergone a standardized training procedure. The structured education consisted of the following seven models: taking medication, insulin injection technique, SMBG, healthy diet, physical activity, prevention of hypoglycemia, and prevention of complications. Complication education was individualized to each patient according to his/her particular condition. The trained nurses could choose to educate patients as to how to prevent: (i) diabetic retinopathy and nephropathy; (ii) diabetic neuropathy and diabetic foot problems (as well as their daily care); and (iii) diabetic macrovascular complications. A short message was sent 2–3 days before every visit to remind patients about administering insulin injections at the right time, to perform regular SMBG, and when to visit the research center. Insulin injection assessment and complication education were also performed at each telephone follow-up. Patients were encouraged to ask questions of the clinicians during the study. To evaluate patients’ level of satisfaction with the structured educational program, the Minnesota Satisfaction Questionnaire (MSQ) was conducted in the education group at V3, V5, V7, V8, and V9. On the MSQ, a score of
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1 corresponds to “extremely dissatisfied”, whereas a score of 7 corresponds to “extremely satisfied”. The control group visited the study center on six occasions (no telephone follow-ups), at which education was provided by trained nurses according to each center’s own practices regarding aspects such as insulin injections, SMBG, hypoglycemia, and self-management. The insulin dose injected on the first day of treatment was set at 0.3–0.4 IU/kg and was subsequently adjusted according to individual patient’s pre-meal blood glucose values during the 16-week treatment period. Insulin dose adjustments were at the discretion of the investigator within 1 month after enrollment every week in the education group, and every 2 weeks in the control group. Dosage adjustments were recorded at every visit. Trial outcomes (education vs control) The primary efficacy assessment was the change in HbA1c from baseline to study end (V9). Secondary efficacy assessments at V9 were: (i) the proportion of patients achieving HbA1c levels of 0.05, ANCOVA). The trends in SMBG for the two groups at each of the study visits are shown in Fig. 1.
MMAS scores The proportion of patients with high medication compliance scores increased in both groups at the end of the study, whereas the proportion with low medication compliance scores decreased markedly (P < 0.0001 vs baseline). Compared with the control group, the education group had a larger proportion of high-compliance patients and a smaller proportion of medium- and lowcompliance patients (P = 0.0002; Table 2). Patients’ level of satisfaction with the structured educational program The education group maintained a high and increasing mean MSQ score (6.15–6.37; maximum score = 7) over time throughout the study. Adjustment of insulin dosages A higher percentage of patients in the education group had their insulin dosage adjusted compared with the control group (82.66% vs 76.52%, respectively; P = 0.0062). There were 3.15 ± 1.74 dosage adjustments for each patient in the education group, compared with 2.45 ± 1.28 in the control group. At the end of the study, the average total daily insulin dose was 30.39 IU (0.45 IU/ kg) in the education group and 29.13 IU (0.43 IU/kg) in the control group (P < 0.05).
Diabetes management rating scale scores Changes in C-DMSES and SDSCA scores At the end of the study, the total C-DMSES score increased to 167.15 ± 25.37 (P < 0.0001 vs baseline) in the
Changes in body weight and BMI Body weight increased significantly in both groups, but the education group had marginally less weight gain than
© 2013 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd
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Figure 2 Changes in body weight (BW) and body mass index (BMI) from baseline to study end in the control and education. Data show mean values for all patients in each group. *P < 0.05 compared with the control group.
the control group (1.00 ± 3.01 vs 1.34 ± 3.14 kg, respectively; P = 0.0534). Furthermore, BMI was increased significantly less in the education compared with control group (0.39 ± 1.12 vs 0.52 ± 1.17 kg/m2, respectively; P < 0.05; Fig. 2). Hypoglycemia The incidence of all hypoglycemic events in the education and control groups was 2.28 and 1.75 episodes per person-year, respectively (P > 0.05). The incidence of severe hypoglycemic events was 0.0096 and 0.0000 episodes per person-year in the education and control groups, respectively (P > 0.05). The education group reported a higher incidence of nocturnal hypoglycemic events than the control group (0.4092 vs 0.2088 episodes per person-year, respectively; P < 0.05). During the entire treatment phase, hypoglycemia was reported by 191 (29.57%) patients overall in the education group and 156 (24.26%) in the control group, with nocturnal hypoglycemia was reported by 52 (8.05%) and 30 (4.67%) patients, respectively (P < 0.05). Two patients (0.31%) in the education group experienced severe hypoglycemia, compared with none in the control group (P > 0.05). However, at each face-to-face interview (V3, V5, V7, V8, and V9), the education group reported fewer episodes of hypoglycemia than the control group. Safety analysis A total of 1457 patients who received at least one dose of the study insulin preparation and had at least one safety assessment was included in the safety set (control group n = 726; education group n = 731). Thirty-six patients (4.96%) in the control group and 31 (4.24%) in the education group reported AEs (P > 0.05). Six patients (0.83%) in the control group and two (0.27%) in the 6
education group withdrew from the study due to AEs (P > 0.05). The most frequent AEs noted were respiratory conditions (n = 6 [0.83%] in the control group; n = 8 [1.09%] in the education group). Seven patients (0.96%) in the control group and three (0.41%) in the education group reported SAEs (P > 0.05). All SAEs involved hospitalizations or prolongation of existing hospitalizations; there were no deaths in either group. The end-of-treatment laboratory results showed that blood chemistry and hematology parameters, as well as mean values for vital signs, were similar to those at baseline in both groups. Discussion The present randomized controlled study of the efficacy of structured diabetes education in the management of T2DM patients receiving insulin therapy has demonstrated a significant improvement in glycemic control and patients’ ability to self-care compared with usual care. Both treatment groups had high baseline HbA1c and blood glucose levels, as well as a high prevalence of diabetes complications and comorbidities. This indicates that, in China, the initiation of insulin treatment is relatively late and the overall glycemic control of such patients needs to be improved. Although the ADA guidelines12 recommend insulin use in newly diagnosed T2DM patients with markedly elevated blood glucose or HbA1c levels, or the addition of insulin to existing non-insulin regimens if the maximal tolerated doses do not achieve or maintain the HbA1c target over 3–6 months, patients with T2DM are usually reluctant to initiate insulin treatment when they respond inadequately to OADs. However, previous studies have shown a number of beneficial effects of early insulin treatment in patients with T2DM. For example, compared with rosiglitazone, insulin therapy has been found to be more cost-effective and to produce greater reductions in HbA1c when baseline HbA1c is >9.5%.13 In a comparison of an insulinbased regimen and triple OAD therapy in newly diagnosed T2DM patients, insulin therapy resulted in comparable weight gain, hypoglycemia incidence, medication compliance, quality of life, and treatment satisfaction to OAD therapy.14 Moreover, in a 6-year follow-up study, early insulin treatment preserved β-cell secretory function better than glibenclamide therapy.15 In the present study, both treatment groups received 30% soluble–70% isophane human insulin injections and exhibited significant reductions in HbA1c and blood glucose concentrations at the end of the study. In the control group, insulin usage may have served as a major intervention that may have contributed to the initial improvements in glycemic control in this group.
© 2013 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd
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Since the earliest days of diabetes management, healthcare providers have discovered that simply prescribing the correct dose of insulin, oral agents, or health diet plans is not enough to achieve adequate metabolic control or to prevent medical crises resulting from diabetes. Recently, a nationwide survey conducted in Chinese T2DM patients showed that patients who received diabetes education achieved better glycemic control than non-educated patients.16 Because formal diabetes education has proved effective in improving clinical and lifestyle outcomes,17,18 it can no longer be regarded as an optional add-on measure. Education needs to be seen as equally important in treatment as medication, and it therefore needs to be resourced, researched, evaluated and quality assured to a similar standard. Because good self-management behaviors predict better glycemic control, strategies to enhance and promote patients’ self-management ability and self-care behaviors are essential components of diabetes education programs.19 The OPENING program applied in the present study consisted of seven models of structured education, covering taking medication, insulin injection techniques, blood glucose monitoring, healthy diets, physical activity, hypoglycemia, and the prevention of complications. The education group in the present study had three telephone follow-ups that the control group did not, during which instructions regarding healthy diets, physical activity, prevention of complications, and insulin injection techniques were delivered by trained nurses. In addition, the education group received reminder messages, goal-setting discussions, and encouragement to communicate with their physicians. These components may have influenced the education group’s maintenance of healthy habits and engagement with medical providers, which, in turn, led to better glycemic control. Although there was no difference between the two groups in final (V9) FBG and SMBG values, the education group did achieve some better pre-breakfast blood glucose values at certain visits. Therefore, we presume that the improvement in HbA1c was derived from the daily glycemic profile, which cannot be actually represented by twopoint blood glucose values tested in a given day. This means that SMBG is a great method of self-managing diabetes. As noted in the education group, the OPENING program appeared to enhance the efficacy of insulin treatment in that it achieved a 0.16% greater reduction in HbA1c than seen in the control group. However, although the greater reduction in HbA1c in the education group was significant compared with the reduction seen in the control group, this has no clinical significance because the effect may have been due more to the marked effect of insulin in lowering blood glucose than to an effect of education.
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Other meaningful findings of our study were from between-group comparisons of body weight and BMI. The smaller, although not significant, weight gain and significantly smaller increase in BMI in the education group may have been a benefit of education. In this regard, several aspects of the OPENING program may have contributed to the positive clinical effects observed. This program has a multifaceted approach that focuses not only on glucose control, but also on the need to manage and prevent comorbid conditions. This may have contributed to achieving optimal self-management, selfcare, and medication compliance. We used several scales to evaluate the skill-building effect of the OPENING program. The behavior improvement in patients in the education group was verified by greater increments in the total scores on the C-DMSES and SDSCA, with the diet plan- and foot care-related items demonstrating significantly increased scores compared with the control group (P < 0.05). The level of medication compliance in the education group also markedly improved. Of interest, a “high-touch” effect was noted, in that subjects who were in more frequent contact with their healthcare providers showed larger HbA1c reductions. These results support the notion that educational interventions can contribute to improved clinical outcomes.20 The education group in the present study was receiving a slightly higher insulin dosage at the end of the study. This finding could have been attributed to more insulin dose adjustments because the OPENING program provided this group with more physician contact, which, in turn, led to better glycemic control. Although the incidence of all hypoglycemic events and severe hypoglycemic events in terms of episodes per person-years did not differ significantly between the two groups, the education group did experience more hypoglycemic events during the treatment period. This paradoxical result may have been due to the design of the study. Because the education group reported fewer episodes of hypoglycemia than the control group at each face-to-face interview (V3, V5, V7, V8, and V9), the three extra telephone follow-ups may have provided this group with more opportunities to report their experiences. Conversely, the longer betweenvisit times in the control group may have led to these patients not remembering to report all hypoglycemic events. In addition, because the OPENING program includes hypoglycemia education, including the detection and verification of hypoglycemic events, this may have made the education group more sensitive to hypoglycemic manifestations. Therefore, we cannot exclude the possibility that patients in the control group experienced some hypoglycemic events but neglected to report them, although we do not have data to verify this. In future, this problem may be avoided by a modified study design that
© 2013 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd
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incorporates features such as telephone follow-ups for the control group to unify hypoglycemia detection and monitoring techniques and collect event information. Conclusion This study makes an important contribution to the limited body of research that has formally evaluated the effectiveness of structured education on diabetes selfmanagement behavior as part of the standard care of disease. Although a longer-term study will be needed to determine whether educational interventions will result in sustained lifestyle changes and improved clinical outcomes that will ultimately reduce the complications and costs of diabetes, the present study showed that the seven modules of the OPENING program can deliver an integral component of diabetic self-management education that can enhance the quality of diabetes care. Consequently, economic, effective interventions that involve structured education may become a crucial part of our healthcare delivery system to achieve optimal outcomes. Acknowledgments This study was funded by the Bayer Healthcare Company and by grants from the Chinese Medical Association Foundation and the Chinese Diabetes Society. Disclosure None of the authors has any potential conflict of interest to declare. References 1. Pan XR, Yang WY, Li GW, Liu J. Prevalence of diabetes and its risk factors in China, 1994. Diabetes Care. 1997; 20: 1664–9. 2. National Diabetes Research Group. Diabetes mellitus survey of 300,000 in fourteen provinces and cities of China. Chin Med J. 1981; 20: 678–81. 3. Gu D, Reynolds K, Duan X et al. Prevalence of diabetes and impaired fasting glucose in the Chinese adult population: International Collaborative Study of Cardiovascular Disease in Asia (InterASIA). Diabetologia. 2003; 46: 1190–8. 4. Jia WP, Pang C, Chen L et al. Epidemiological characteristics of diabetes mellitus and impaired glucose regulation in a Chinese adult population: The Shanghai Diabetes Studies, a cross-sectional 3-year follow-up study in Shanghai urban communities. Diabetologia. 2007; 50: 286–92. 5. Li G, Hu Y, Pan X. Prevalence and incidence of NIDDM in Daqing City. Chin Med J (Engl). 1996; 109: 599–602.
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6. Yang W, Lu J, Weng J et al. Prevalence of diabetes among men and women in China. N Engl J Med. 2010; 362: 1090–101. 7. Chinese Diabetes Society. Chinese Guideline for Type 2 Diabetes. Peking University Medical Press, Beijing, 2010. 8. American Diabetes Association. Standards of medical care in diabetes. Diabetes Care. 2012; 35 (Suppl. 1): 11–63. 9. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2010; 33 (Suppl. 1): S62–9. 10. Wu SF, Courtney M, Edwards H, McDowell J, Shortridge-Baggett LM, Chang PJ. Development and validation of the Chinese version of the Diabetes Management Self-efficacy Scale. Int J Nurs Stud. 2008; 45: 534–42. 11. American Diabetes Association Workgroup on Hypoglycemia. Defining and reporting hypoglycemia in diabetes. Diabetes Care. 2005; 28: 1245–9. 12. American Diabetes Association. Standards of medical care in diabetes–2012. Diabetes Care. 2012; 35 (Suppl. 1): S11–63. 13. Rosenstock J, Sugimoto D, Strange P, Stewart JA, Soltes-Rak E, Dailey G. Triple therapy in type 2 diabetes: Insulin glargine or rosiglitazone added to combination therapy of sulfonylurea plus metformin in insulin-naive patients. Diabetes Care. 2006; 29: 554–9. 14. Lingvay I, Legendre JL, Kaloyanova PF, Zhang S, Adams-Huet B, Raskin P. Insulin-based versus triple oral therapy for newly diagnosed type 2 diabetes: Which is better? Diabetes Care. 2009; 32: 1789–95. 15. Alvarsson M, Berntorp K, Fernqvist-Forbes E et al. Effects of insulin versus sulphonylurea on beta-cell secretion in recently diagnosed type 2 diabetes patients: A 6-year follow-up study. Rev Diabet Stud. 2010; 7: 225–32. 16. Guo XH, Yuan L, Lou QQ et al. Chinese Diabetes Education Status Survey Study Group. A nationwide survey of diabetes education, self-management and glycemic control in patients with type 2 diabetes in China. Chin Med J (Engl). 2012; 125: 4175–80. 17. Norris SL, Lau J, Smith SJ, Schmid CH, Engelgau MM. Self-management education for adults with type 2 diabetes: A meta-analysis on the effect on glycemic control. Diabetes Care. 2002; 25: 1159–71. 18. Deakin T, McShane CE, Cade JE, Williams RD. Group based education in self-management strategies improves outcomes in type 2 diabetes mellitus. Cochrane Database Syst Rev. 2005; (2)CD003417. 19. Al-Khawaldeh OA, Al-Hassan MA, Froelicher ES. Selfefficacy, self-management, and glycemic control in adults with type 2 diabetes mellitus. J Diabetes Complications. 2012; 26: 10–6. 20. Philis-Tsimikas A, Fortmann A, Lleva-Ocana L, Walker C, Gallo LC. Peer-led diabetes education programs in high-risk Mexican Americans improve glycemic control compared with standard approaches: A Project Dulce promotora randomized trial. Diabetes Care. 2011; 34: 1926–31.
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