Cost-effectiveness of intensive insulin therapy for type 2 diabetes: a 10-year follow-up of the Kumamoto study

Diabetes Research and Clinical Practice 48 (2000) 201 210 www.elsevier.com/locate/diabres Cost-effectiveness of intensive insulin therapy for type 2 diabetes: a 10-year follow-up of the Kumamoto study Nakayasu Wake a, Akinori Hisashige b, Takafumi Katayama b, Hideki Kishikawa a, *, Yasuo Ohkubo a, Masakazu Sakai a, Eiichi Araki a, Motoaki Shichiri a a Department of Metabolic Medicine, Kumamoto Uni ersity School of Medicine, 1-1-1 Honjo, Kumamoto 860 8556, Japan b Department of Pre enti e Medicine, School of Medicine, The Uni ersity of Tokushima, Tokushima, Japan Received 15 November 1999; received in revised form 5 January 2000; accepted 5 January 2000 Abstract To evaluate the cost and effectiveness of intensive insulin therapy for type 2 diabetes on the prevention of diabetes complications in Japan, we performed economic evaluation based on a randomized controlled trial. A total of 110 patients with type 2 diabetes were randomly assigned into two groups, a multiple insulin injection therapy (MIT) group or a conventional insulin injection therapy (CIT) group, and were followed-up for 10 years. Economic evaluation (cost consequences analysis) was applied to evaluate both health and economic outcomes. As outcome measures for effectiveness of intensive insulin therapy, the frequency of complications, such as retinopathy, nephropathy, neuropathy, macrovascular event, and diabetes-related death, was used. For estimating costs, a viewpoint of the payer (the National Health Insurance) was adopted. Direct medical costs associated with diabetes care during 10 years were calculated and evaluated. In a base case analysis, all costs were discounted to the present value at an annual rate of 3%. Sensitivity analyses were carried out to assess the robustness of the results to changes in the values of important variables. MIT reduced the relative risk in the progression of retinopathy by 67%, photocoagulation by 77%, progression of nephropathy by 66%, albuminuria by 100% and clinical neuropathy by 64%, relative to CIT. Moreover, MIT prolonged the period in which patients were free of complications, including 2.0 years for progression of retinopathy (P 0.0001), 0.3 years for photocoagulation (P 0.05), 1.5 years for progression of nephropathy (P 0.01) and 2.2 years for clinical neuropathy (P 0.0001). The total cost (discounted at 3%) per patient during the 10-year period for each group was $30 310 and 31 525, respectively. The reduction of total costs in MIT over CIT was mainly due to reduced costs for management of diabetic complications. Our results show that MIT is more beneficial than CIT in both cost and effectiveness. Therefore, MIT is recommended for the treatment of type 2 diabetic patients who require insulin therapy as early as possible from the perspective of both patients and health policy. 2000 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Type 2 diabetes; Microvascular complications; Intensive glycemic control; Multiple insulin injection treatment; Cost-effectiveness * Corresponding author. Tel.: +81-96-3735169; fax: +81-96-3668397. 0168-8227/00/$ - see front matter 2000 Elsevier Science Ireland Ltd. All rights reserved. PII: S0168-8227(00)00122-4

202 N. Wake et al. / Diabetes Research and Clinical Practice 48 (2000) 201 210 1. Introduction Diabetes mellitus is a major disease with high morbidity and mortality consuming high health care expenditure in most developed countries [1]. Clinical care of diabetic patients requires a relatively high use of health care resources compared with non-diabetic patients. In particular, the longterm complications associated with diabetes are expensive in terms of health care and quality of life. In the United States, where the prevalence rate of diabetes is approximately 7% in adults, it has been estimated that the combined direct and indirect costs of diabetes in 1997 were $98 billion [2]. In Japan, the number of patients with diabetes has markedly increased in recent decades. Approximately 6.9 million individuals or 6% of the Japanese population suffered from diabetes in 1997 [3]. Moreover, the health care expenditure for diabetes was $8 billion, which constituted 4% of total health care expenditure [4]. Although diabetes implies a relatively poor prognosis, there is a distinct prospect of significant improvement in prognosis with the implementation of effective preventive strategies [1]. Recently, a remarkable medical innovation has emerged in the prevention of diabetic complications, known as intensive insulin therapy, which is designed to achieve blood glucose level as close to the non-diabetic range as possible with three or more daily insulin injections [5 7]. Several small randomized controlled trials (RCTs) have compared intensive with conventional treatment in patients with type 1 diabetes [8 10]. These results and their systematic review showed a reduction in the development and progression of microvascular complications. A subsequent long-term and large RCT (the Diabetes Control and Complication Trial (DCCT)) has extended these findings [11]. Moreover, in type 2 diabetes, which constitutes about 80 90% of all cases of diabetes in developed countries, the Kumamoto Study demonstrated almost the same results as DCCT [12,13]. The United Kingdom Prospective Diabetes Study (UKPDS) also confirmed these findings [14]. However, it was suggested that intensive therapy consumed more resources and was substantially more expensive than conventional treatment [15]. Under considerable pressure on health care expenditure, additional resources for this therapy may need to be diverted from other health care practices or non-health care activities. Therefore, it is essential to analyze and consider the cost-effectiveness of intensive insulin therapy. In type 1 diabetes, economic evaluation of lifetime benefits and costs of intensive insulin therapy based on DCCT suggested that this therapy was within the range of cost-effectiveness [15]. In contrast, in type 2 diabetes, although a simulation model for economic evaluation of intensive therapy was developed and examined [16], the actual cost-effectiveness of intensive therapy based on RCT has not yet been reported. In the present study, we evaluate the cost-effectiveness of intensive insulin therapy for type 2 diabetes based on RCT, the Kumamoto Study, compared with conventional insulin therapy [12,13]. 2. Research design and methods 2.1. E aluation of clinical outcome For economic evaluation, cost consequences analysis based on RCT (the Kumamoto Study) was performed in this study [17,18]. The costs and consequences of intensive insulin therapy for type 2 diabetes, compared with conventional insulin therapy, were computed separately and listed. This analysis makes few assumptions in economic evaluation [17,18]. In evaluating consequences or health outcomes of each treatment modality, RCT was performed. During 1987 1988, a total of 110 patients with insulin-requiring type 2 diabetes were randomly assigned to a multiple insulin injection therapy (MIT) group or to a conventional insulin injection therapy (CIT) group [12,13]. Each group was further divided into two cohorts: the primary-prevention cohort (no retinopathy, and urinary albumin excretion 30 mg/24 h; n=55), and the secondary-intervention cohort (simple retinopathy, and urinary albumin excretion 300 mg/24 h; n=55). Follow-up examinations specific for diabetic complications were performed at the third month and every 6 months

N. Wake et al. / Diabetes Research and Clinical Practice 48 (2000) 201 210 203 after the commencement of the study. The endpoints were defined as progression of retinopathy, preproliferative or proliferative retinopathy, photocoagulation, progression of nephropathy, clinical neuropathy, macrovascular complications and diabetes-related death. Progression of retinopathy was defined as changes upward of at least two or more stages in modified Early Treatment Diabetic Retinopathy Study classification in the Kumamoto Study [19 21]. Patients with nephropathy were divided into three stages according to urinary albumin excretion (normoalbuminuria, 30 mg/day; microalbuminuria, 30 300 mg/day; or albuminuria, 300 mg/day), and the change from any one stage to a higher stage up was defined as progression of nephropathy [12,13,22,23]. Clinical neuropathy was defined as an abnormal neurologic examination that was consistent with the presence of either abnormal somatic-nerve testing (nerve conduction velocities and vibration thresholds) or abnormal autonomic-nerve testing (orthostatic hypotension and the coefficients of variation of R R interval on the electrocardiogram). Macrovascular complications were defined as the appearance of cerebrovascular, cardiovascular, or peripheral vascular disease. Diabetes-related death was defined as death due to myocardial infarction, stroke, peripheral vascular disease, renal disease, hyperglycemia, hypoglycemia or sudden death. The clinical goal of the CIT group was to avoid the development of symptoms related to hyperglycemia or hypoglycemia, and maintain fasting blood glucose concentration (FBG) below 140 mg/dl. The clinical goal of the MIT group was to maintain the FBG below 140 mg/dl, 2-h postprandial blood glucose concentration less than 200 Table 1 Characteristics of patients at baseline a MIT group CIT group Number (M/F) 55 (28/27) 55 (26/29) Age (years) 48.2 11 50.9 14 Duration of diabetes (years) 8.6 5.4 8.5 5.2 Body mass index (kg/m 2 ) 20.5 2.1 20.4 2.6 a Values presented as mean S.D. mg/dl, hemoglobin A1c below 7.0% and mean amplitude of glycemic excursions below 100 mg/ dl. There were no significant differences at entry between CIT and MIT groups, with regard to age, gender, duration of diabetes, and body mass index, as reported previously (Table 1). After 10 years, 97 patients remained in the study, nine patients died (three in the MIT group and six in the CIT group) and four patients moved to other cities (two in each of the MIT and CIT groups). The reduction in risk for the development and progression of diabetic microvascular and macrovascular complications, and diabetesrelated death in the combined cohort (primaryprevention and secondary-intervention groups) was calculated, and the number of years free from endpoints in the CIT and MIT groups were also calculated based on the 10-year results of the Kumamoto Study. 2.2. E aluation of costs From a viewpoint of the payer (the National Health Insurance), all medical services and costs for MIT and CIT were identified and estimated. This viewpoint considers all direct medical costs relative to diabetes such as those associated with inpatient care, outpatient care, medications, medical equipment, and laboratory tests [17,18]. Capital costs were not evaluated due to the lack of data related to such costs. Direct non-medical costs born by patients and their families, such as the costs of transportation, lodging and family care, were not included. Furthermore, indirect costs such as production losses associated with lost or impaired ability to work or to engage in leisure activities were not included. In this study, the costs of MIT and CIT were based on actual medical services used in Kumamoto Study, excluding research costs. All medical and insurance records of the patients during 1988 1998 were collected and analyzed. All costs of medical services were determined based on the uniform reimbursement fee schedule of the Japanese National Heath Insurance in 1998. Table 2 summarizes the main sources of information of unit costs. These unit costs were combined with the resource volumes to obtain a net cost per

204 N. Wake et al. / Diabetes Research and Clinical Practice 48 (2000) 201 210 Table 2 List of unit costs a Outpatient service $ Doctor s fee 8.4/visit Tests Blood Fee for interpretation of 9.2/month hematological examination Fee for interpretation of blood 10.0/month chemistry test Hemoglobin A1c 7.1/month Plasma glucose 1.5/test Serum creatinin 1.5/test Clinical chemistry test 16.7/test Lipid profile 2.3/test Urine Fee for interpretation of urinalysis 2.0/test Urinalysis 2.3/month Urine albumin 18.8/test Urine C-peptide 20.4/test Other tests Funduscopic analysis 9.3/test Fluorescein angiography 33.3/test Fee for interpretation of 9.2/month neurophysiological tests Electromyogram 20.8/test Procedure Venipuncture 1.0/procedure Electrocardiogram 12.5/recording Insulin R (rapid-acting) 5 ample 40.3 N (intermediate-acting) 5 ample 40.3 Administration cost of self-injection 76.7/month Insulin syringe 25.0/month Self-monitoring Once per day 41.7/month Twice per day Three times per day 58.3/month 66.7/month Inpatient service Nursing Nursing assistance ( 30 hospital days) Nursing assistance ( 30 hospital days) Room charge General room (1 14 days) General room (14 days 1 month) General room (1 2 months) 73.0/day 72.0/day 47.8/day 39.5/day 28.0/day Table 2 (Continued) Inpatient service $ Extra charge for specific functional Hp. 8.8/month Diet Cost of basic diet 17.7/test Additional cost for therapeutic diet 2.9/day Tests Basal test ( 21days) 12.1/test Basal test ( 21days) 10.0/test Fee of management and interpretation Fee for test 16.7/month Fee for interpretation of basal test 41.7/month Fee for management of drugs 40.0/month Fee for management of discharge 25.0/patient a This table shows the list of several unit costs in Japan. Inpatient service represents costs specific for inpatients or different from the cost for outpatients. Other costs for inpatients are the same as costs for outpatients. The basal test in inpatients represents the upper limit of the cost for blood chemistry. patient over the entire period in this trial. Costs were calculated in Japanese yen in 1998 and converted to US dollars using the exchange rate of $1=Y 120. In comparing costs between MIT and CIT, first, mean total costs per patient by category of cost were compared. All costs were classified into two categories: treatment and complication costs. Treatment costs included cost of outpatient clinic visits, cost of laboratory tests (blood, urine and other special tests), insulin-related cost (insulin, syringes and management cost for self-injection) and cost of self-monitoring of blood glucose level. On the other hand, complication costs include cost of hospitalization, cost of drugs (drugs for macrovascular and microvascular complications), and cost of specific treatment of ophthalmic complications such as cost of photocoagulation. Second, annual and cumulative costs over time were compared between MIT and CIT. Adjustments for differential timing of costs were made because of the existence of time preference [17,18]. Individuals and a society place a higher value on resources used today than at some point in the future. Therefore, costs were presented both undiscounted, and discounted at a rate of 3% as recommended by the US Panel on Cost-Effectiveness [18], or discounted at a rate of 5% as consistent with current practice [17].

N. Wake et al. / Diabetes Research and Clinical Practice 48 (2000) 201 210 205 Fig. 1. Risk reduction rates of microvascular and macrovascular complications, and diabetes-related death by intensive insulin therapy, over 10 years of the Kumamoto Study. The percentages of risk reduction by intensive glycemic control using multiple insulin injection therapy were calculated by subtracting the relative risk of multiple insulin injection therapy compared with conventional insulin injection therapy from one and multiplying by 100. Data represent the mean 95% CI. 2.3. Statistical analysis All analyses and comparisons were performed on the basis of intention to treat. The crude relative risk method and Kaplan Meier method were undertaken to calculate the risk reduction rates of endpoints and the average years free from endpoints, respectively. A t-test was used for the comparison of the annual costs and their unit costs, and the cumulative cost between CIT and MIT groups. In addition, sensitivity analyses were performed to assess the robustness of the results to changes in the values of variables incorporated into the analysis. The sensitivity to changes of complication costs with discounting varied between 0 and 5% were examined. P 0.05 was defined as statistically significant. Values were expressed as mean S.D. and mean differences in costs were expressed with 95% confidence intervals (CI). All analyses and comparisons were performed with the consent of participating subjects, and the study protocol was approved by the Human Ethics Review Committee of our institution. 3. Results 3.1. Clinical outcomes Fig. 1 shows the effect of treatment on the development and progression of diabetic microvascular and macrovascular complications, and diabetes-related death over 10 years. Compared with CIT, MIT reduced the relative risks of progression of retinopathy, preproliferative or proliferative retinopathy, photocoagulation, progression of nephropathy, albuminuria, clinical neuropathy, macrovascular complications and diabetes-related death by 67% (95% CI, 49 79%), 69% (34 86%), 77% (47 90%), 66% (42 80%), 100%, 64% (45 76%), 54% (2 78%) and 81% (28 95%), respectively. Since none of the patients suffered from end-stage renal disease, vision loss or lower extremity amputation during the period of the study, the reduction in these risks could not be evaluated. The years free from endpoints in the CIT and MIT groups, and their differences are shown in Table 3. Intensive insulin therapy prolonged the free period by 2.0 years for progression of retinopathy, 0.2 years for preproliferative or proliferative retinopathy, 0.3 years for photocoagulation, 1.5 years for progression of nephropathy, 2.2 years for clinical neuropathy, 0.3 years for macrovascular complications and 0.2 years for diabetes-related death, compared with CIT. The numbers of years free from preproliferative or proliferative retinopathy, macrovascular complications, and diabetes-related death were not statistically significant between MIT and CIT groups (P=0.06, 0.17 and 0.097, respectively). Discounted at 3 and 5% rates, intensive insulin therapy prolonged free period by 1.4 and 1.1 years for progression of retinopathy, 0.2 and 0.1 years for photocoagulation, 1.1 and 0.8 years for

206 N. Wake et al. / Diabetes Research and Clinical Practice 48 (2000) 201 210 progression of nephropathy, and 1.5 and 1.1 years for clinical neuropathy, respectively, compared with CIT. 3.2. Costs 3.2.1. Treatment and complication costs Table 4 shows the total costs per patient by category of cost over the duration of the study. Treatment costs, such as costs of clinic visits, laboratory tests, and self-monitoring were significantly higher for MIT (by $475, 631 and 3834, respectively) compared with those of CIT. Furthermore, the total treatment costs per patient for MIT was significantly higher (P 0.001) by $6080 (95% CI, $3891 8268) compared with the costs for CIT. In contrast, for costs of complications, CIT was associated with increased costs of hospitalization, drugs, and specific treatment of ophthalmic disorders by $3239, 3419 and 1315, respectively, compared with those under MIT. Total complication costs in the CIT group was $7974 higher than that in MIT (95% CI, $4694 11 253; P 0.001). The total cost per patient, representing the combined cost of treatment and complications costs, in MIT was lower than that in CIT ($34 792 versus $36 685). The difference in total cost between CIT and MIT was $1893 (95% CI, $6220 to 2433). Discounted at 3 and 5% rates, the total costs in MIT were still lower than those in CIT, albeit statistically insignificant. 3.2.2. Costs o er time Fig. 2 shows the annual trend of total costs and costs by category over time. In the first year, the annual total cost per patient was higher in MIT than in CIT ($3260 vs. $2655; P 0.001). However, these costs crossed each other in the fifth year. In the final year of observation, annual total costs ($5760) in CIT were higher ($4462) than in MIT. In CIT, while the treatment costs increased gradually from $2272 to 2555 over time with some fluctuation, complication costs increased more steeply from $383 to 3205. On the other hand, in MIT, treatment costs increased slightly from $2807 to 3148 over time, and complication costs increased progressively from $453 to 1314. Therefore, the difference in treatment costs between MIT and CIT remained at almost the same level throughout the study period, while that in complication costs widened during the same period. Consequently, as shown in Fig. 3, the cumulative total cost per patient in CIT exceeded that in MIT from the eighth year of the study. Even if the total cost per patient was discounted at the 5% rate, the cumulative total cost per patient in CIT exceeded that in MIT from the ninth year of the study. 3.3. Sensiti ity analysis The presented data suggest that total cost in the CIT and MIT groups was influenced by changes Table 3 Average years free from endpoint complications a MIT CIT P value Differences b Undiscounted 3% Discounted 5% Discounted Progression of retinopathy 8.76 6.78 0.0001 2.0 1.4 1.1 Preproliferative or proliferative retinopathy 9.56 9.38 0.06 0.2 0.1 0.06 Photocoagulation 9.69 9.39 0.03 0.3 0.2 0.1 Progression of nephropathy 9.27 7.76 0.001 1.5 1.1 0.8 Albuminuria 10.0 9.25 0.002 0.8 NA NA Clinical neuropathy 8.94 6.79 0.0001 2.2 1.5 1.1 Macrovascular complications 9.57 9.30 0.17 0.3 0.2 0.1 Diabetes-related death 9.85 9.68 0.097 0.2 0.1 0.08 a NA, not applicable. The P value indicates the difference of the years free from endpoint complication between MIT and CIT (calculated by log-rank test). b Differences were calculated by subtracting CIT from MIT (mean difference over median 10 years). The discount was not applicable in albuminuria, since there were no patients suffering from albuminuria in MIT during 10 years.

N. Wake et al. / Diabetes Research and Clinical Practice 48 (2000) 201 210 207 Table 4 Total costs per patient by category of cost Cost in MIT a Cost in CIT a Cost difference between MIT and CIT b ($/patient) ($/patient) ($/patient) Treatment costs Clinic visits 1733 392 1259 406 475 cc 324 to 625 Tests 5554 1254 4923 1208 631 c 165 to 1096 Insulin-related 15 617 3959 14 444 3988 1173 329 to 2675 Self-monitoring 4176 1074 342 466 3834 cc 3519 to 4148 Others 121 145 153 211 32* 101 to 36 Total 27 201 6135 21 121 5421 6080 cc 3891 to 8268 Complication costs Hospitalization 2642 2847 5881 4533 3239 *,cc 4673 to 1805 Drugs 4194 4297 7613 7472 3419 *,c 5730 to 1109 Specific treatment for ophthalmic 755 855 2070 2330 1315 *,cc 1983 to 647 complications Total 7591 5951 15 565 10 686 7974 *,cc 11 253 to 4694 Total costs of treatment and complications Undiscounted 34 792 9639 36 685 12 985 1893* 6220 to 2433 3% Discounted 30 310 8118 31 525 10 812 1215* 4832 to 2402 5% Discounted 27 822 7284 28 675 9624 853* 4081 to 2376 a Data presented as mean S.D. b Presented as 95% CI. * Negative cost differences indicate that cost in CIT exceeded that in MIT c P 0.05 of significant difference between MIT and CIT, respectively. cc P 0.001 of significant difference between MIT and CIT, respectively. in complication costs. Therefore, sensitivity analysis was performed by changing the risk reduction rate of each incidence of major complications (retinopathy, nephropathy and neuropathy) by MIT within the 95% CI. When the relative risk reduction for retinopathy, nephropathy, and neuropathy under MIT relative to CIT changed within the 95% CI, the total costs in MIT (undiscounted) varied in the range $33 235 38 274, 34 153 35 028 and 33 458 35 359, respectively, in contrast to the total cost in CIT ($36 685). Discounted at the 3% rate, these costs become in the range $28 843 33 168, 29 602 30 344 and 29 062 30 609, respectively, while total cost in CIT was $31 525 at a rate of 3% discount. Furthermore, discounted at the 5% rate, total costs became $26 409 30 340, 27 080 27 750 and 26 623 27 977, respectively, while total costs in CIT was $28 675 at 5% discount rate. 4. Discussion The results of this study confirmed and extended the major findings of 6- and 8-year follow-up of the Kumamoto Study that intensive insulin therapy could significantly reduce the risk of diabetic microvascular complications in Japanese patients with type 2 diabetes [12,13]. We also showed that intensive insulin therapy could prolong the period in which the patient is free from endpoint complications such as retinopathy, nephropathy and neuropathy. These findings were in principle consistent with the results of large scale RCTs, DCCT with type 1 diabetes [11] and UKPDS with type 2 diabetes [14]. In our study, cost-effectiveness analysis was performed to evaluate the economic effects of intensive insulin therapy for insulin-requiring type 2 diabetic patients. The results showed that intensive insulin therapy

208 N. Wake et al. / Diabetes Research and Clinical Practice 48 (2000) 201 210 was not as expensive as we had expected. The total cost (discounted at 3%) per patient throughout a period of 10 years under MIT and CIT was $30 310 and 31 525, respectively (Table 4). In MIT, increased treatment costs by 30% was offset by a reduction in complication costs of 50%. It is possible to assume that costs were equal among the two treatment modalities, since statistical significance in the reduction of total costs was not observed. If costs are identical, the largest outcome alternative should be selected, considering the decision matrix for incremental cost and effectiveness of the two programs. It could be called effectiveness-maximization analysis. Intensive insulin therapy is just this example. Therefore, from the viewpoint of the National Health Insurance, intensive insulin therapy is efficient (or value for money) health care technology. We also applied the sensitivity analysis to confirm the robustness of the results. In our study, the risk reduction rate of retinopathy was most potent factor in robustness of total cost for type 2 diabetic patients. For example, decreasing the relative risk reduction of MIT for retinopathy to the lower limit of the 95% CI increased the total costs of MIT from $30 310 to 33 168. In type 1 diabetes, the DCCT research group estimated the lifetime benefits and costs of intensive insulin therapy for approximately 120 000 persons in the US who met DCCT eligibility criteria, using a simulation model. They reported that intensive insulin therapy costs $28 661 per year of life gained and $19 987 per quality-adjusted life-year (QALY) gained [15]. Therefore, intensive insulin therapy for type 1 diabetic patients is in the category of technology that has strong evidence for adoption and appropriate utilization [24]. In this model, the DCCT group adopted annual treatment costs for intensive insulin therapy and conventional insulin therapy of $4014 and 1666 per year per patient, respectively [25]. Therefore, the annual treatment cost for intensive insulin therapy in DCCT was more expensive compared with ours, while that of conventional insulin therapy was less expensive than ours. The annual treatment costs in our study were $2807 3147 in MIT and $2272 2493 in CIT over 10 years. The differences in annual treatment Fig. 2. Comparison of annual trend of total, treatment and complication costs between patients under intensive insulin therapy and conventional insulin therapy in the Kumamoto Study., Annual total costs in the MIT group;, annual total costs in the CIT group;, annual treatment costs in the MIT group;, annual treatment costs in the CIT group;, annual complication costs in the MIT group;, annual complication costs in the CIT group; broken lines, costs of MIT; solid lines, costs of CIT. Discount was not performed for the values in this figure.

N. Wake et al. / Diabetes Research and Clinical Practice 48 (2000) 201 210 209 Fig. 3. Comparison of cumulative costs over a period of 10 years between MIT and CIT groups. (A) Undiscounted, (B) discount at 5%.,, cumulative medical costs of MIT and CIT groups, respectively. cost between DCCT and our study seemed to be mainly due to differences in costs of outpatient services and case management services. In DCCT, the annual cost of outpatient services and case management services was almost three times higher in MIT than in CIT group, while those costs were almost identical in our study [25]. Further analysis showed that differences in the frequency and costs of clinical visits and laboratory tests for glycemic control were also responsible for the difference in annual treatment costs between DCCT and our study. In type 2 diabetes, the economical effects of intensive insulin treatment have not been sufficiently evaluated. Recently, a simulation model based on the DCCT model has been developed and applied to evaluate the cost-effectiveness of intensive insulin therapy in type 2 diabetes [16]. In that simulation study, the treatment cost in MIT increased almost twofold, which was partially offset by a reduction in the complication costs. The incremental cost per QALY was $16 002, which was comparable with the costs reported in type 1 diabetes. In this model, $1099 per year per patient was used for the treatment of patients with standard insulin therapy and $3324 per year per patient for patients with multiple daily insulin injection therapy. In contrast, in our study, the difference of annual treatment costs in CIT and MIT ($2112 and 2720 per year per patient, respectively) was small but statistically significant (calculated from the total treatment costs of 10 years; shown in Table 4). Therefore, the difference in annual treatment costs between conventional insulin therapy and intensive insulin therapy in simulation model might induce incremental cost per QALY gained. The smaller difference between costs of MIT and CIT in Japan than that in the US could be mainly due to the difference in costs of outpatient service including doctor s fee and tests ($730 in US versus $110 in Japan) [25]. It could also be due to the lower costs for treatment of side effects of therapy, since there were no patients who experienced severe hypoglycemia or weight gain greater than 20% in the Kumamoto Study. Although the UKPDS research group reported the cost-effectiveness of tight blood pressure control compared with a less tight control, they could not demonstrate the cost-effectiveness of intensive insulin therapy in type 2 diabetes [26]. Economic analysis of glycemic control study in UKPDS would strengthen our result of the economic effects of intensive therapy using the actual costs in type 2 diabetic patients. In conclusion, these results indicate that intensive insulin therapy in patients with type 2 diabetes could prolong the period in which patients are free from diabetes-related endpoints and improve quality of life, thereby saving money through its beneficial effects on diabetic complications. Therefore, we recommend application of intensive therapy in insulin-requiring type 2 diabetic patients as early as possible.

210 N. Wake et al. / Diabetes Research and Clinical Practice 48 (2000) 201 210 References [1] WHO Study Group on Prevention of Diabetes Mellitus, Prevention of diabetes mellitus, WHO Technical report series, 844, WHO, Geneva, 1994. [2] American Diabetes Association, Economic consequences of diabetes mellitus in the U.S. in 1997, Diabetes Care 21 (1998) 296 309. [3] Ministry of Health and Welfare in Japan, Preliminary Report of Diabetes Mellitus Fact-Finding Survey, Japan Association for Diabetes Care and Education, Tokyo, Japan, 1998. [4] Report of Expenditure of Diabetes Mellitus, Ministry of Health and Welfare in Japan, Tokyo, Japan, 1996. [5] H. Kishikawa, Y. Hashimoto, Y. Hashiguchi, et al., Insulin treatment regimes for Type II (non-insulin dependent) diabetes mellitus as judged by residual B-cell function, Diabetic Nutr. Metab. 4 (1991) 305 312. [6] P.J. O Connor, S.J. Spann, S.H. Woolf, Care of adults with type 2 diabetes mellitus, a review of evidence, J. Fam. Pract. 47 (1998) S13 S22. [7] W.H. Herman, Glycaemic control in diabetes, Br. Med. J. 319 (1999) 104 106. [8] B. Feldt-Rasmussen, E.R. Mathiesen, T. Jensen, T. Lauritzen, T. Deckert, Effect of improved metabolic control on loss of kidney function in Type I (insulin-dependent) diabetic patients, an update of the Steno studies, Diabetologia 34 (1991) 164 170. [9] The Kroc Collaborative Study Group, Diabetic retinopathy after two years of intensified insulin treatment, J. Am. Med. Assoc. 260 (1988) 37 41. [10] O. Brinchmann-Hansen, K. Dahl-Jørgensen, L. Sandvik, K.F. Hanssen, Blood glucose concentrations and progression of diabetic retinopathy, the seven year results of the Oslo study, Br. Med. J. 304 (1992) 19 22. [11] The Diabetes Control and Complications Trial 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) 977 986. [12] Y. Ohkubo, H. Kishikawa, E. Araki, et al., Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with noninsulin-dependent diabetes mellitus a randomized prospective 6-year study, Diabetes Res. Clin. Pract. 28 (1995) 103 117. [13] M. Shichiri, H. Kishikawa, Y. Ohkubo, N. Wake, Longterm results of the Kumamoto Study on optimal diabetes control in Type 2 patients, Diabetes Care (2000) (in press). [14] UKPDS, Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33), Lancet 352 (1998) 837 853. [15] The Diabetes Control and Complication Trial Research Group, Lifetime benefits and costs of intensive therapy as practiced in the diabetes control and complication trial, J. Am. Med. Assoc. 276 (1996) 1409 1415. [16] R.C. Eastman, J.C. Javitt, W.H. Herman, et al., Model of complications of NIDDM, II. Analysis of the health benefits and cost-effectiveness of treating NIDDM with the goal of normoglycemia, Diabetes Care 20 (1997) 735 744. [17] M.F. Drummond, B.J. O Brien, G.L. Stoddart, G.W. Torrance, Methods for the Economic Evaluation of Health Care Programmes, 2nd ed., Oxford University Press, Oxford, 1997. [18] M.R. Gold, J.E. Siegel, L.B. Russell, M.C. Weinstein, Cost-effectiveness in Health and Medicine, Oxford University Press, New York, 1996. [19] Early Treatment Diabetic Retinopathy Study Research Group, Early Treatment Diabetic Retinopathy Study, Manual of Operations, Bethesda, MD, Public Health Service, 1980. [20] Early Treatment Diabetic Retinopathy Study Research Group, ETDRS report no. 10: grading diabetic retinopathy from stereoscopic color fundus photographs an extension of the modified Airlie House classification, Ophthalmology 98 (1991) 786 806. [21] Early Treatment Diabetic Retinopathy Study Research Group, ETDRS report no. 12: fundus photographic risk factors for progression of diabetic retinopathy, Ophthalmology 98 (1991) 823 833. [22] B. Feldt-Rasmussen, E.R. Mathiesen, T. Jensen, T. Lauritzen, T. Deckert, Effect of improved metabolic control on loss of kidney function in Type I (insulin-dependent) diabetic patients, an update of the Steno studies, Diabetologia 34 (1991) 164 170. [23] C.E. Mogensen, Management of diabetic renal involvement and disease, Lancet 1 (1988) 673 689. [24] A. Laupacis, D. Feeny, A.S. Detsky, P.X. Tugwell, How attractive dose a new technology have to be to warrant adoption and utilization?, Chin. Med. Assoc. J. 146 (1992) 473 481. [25] The Diabetes Control and Complications Trial Research Group, Resource utilization and costs of care in the diabetes control and complications trial, Diabetes Care 18 (1995) 1468 1478. [26] UK Prospective Diabetes Study Group, Cost effectiveness analysis of improved blood pressure control if hypertensive patients with type 2 diabetes, UKPDS 40, Br. Med. J. 317 (1998) 720 726..