Diabetes Care

Volume 23 Supplement 2
Data, Results, and Consequences of Major Trials With Focus on Type 2 Diabetes
Proceedings from a Symposium


ORIGINAL ARTICLE


Long-Term Results of the Kumamoto Study on Optimal Diabetes Control in Type 2 Diabetic Patients


Motoaki Shichiri, MD, PHD
Hideki Kishikawa, MD, PHD
Yasuo Ohkubo, MD, PHD
Nakayasu Wake, MD


OBJECTIVE — To examine whether intensive glycemic control could decrease the frequency or severity of diabetic microvascular complications, an 8-year prospective study of Japanese patients with type 2 diabetes was performed.

RESEARCH DESIGN AND METHODS — A total of 110 patients with type 2 diabetes (55 with no retinopathy [the primary prevention cohort] and 55 with simple retinopathy [the secondary intervention cohort]) were randomly assigned to multiple insulin injection therapy (MIT) groups and administered three or more daily insulin injections or assigned to conventional insulin injection therapy (CIT) groups and administered one or two daily intermediate-acting insulin injections. Worsening of microvascular complications was regularly assessed during 8 years. Two or more steps up in the 19 stages of the modified Early Treatment of Diabetic Retinopathy Study classification in retinopathy and one or more stages up among three stages in nephropathy (normoalbuminuria, microalbuminuria, and albuminuria) were defined as worsening of complications.

RESULTS — In both primary prevention and secondary intervention cohorts, the cumulative percentages of worsening in retinopathy and nephropathy were significantly lower (P < 0.05) in the MIT group than in the CIT group. In neurological tests after 8 years, the MIT group showed significant improvement (P < 0.05) in the median nerve conduction velocities (motor and sensory nerves), whereas the CIT group showed significant deterioration (P < 0.05) in the nerve conduction velocities and vibration threshold. From this study, the glycemic threshold to prevent the onset and progression of diabetic microvascular complications was as follows: HbA1c <6.5%, fasting blood glucose concentration <110 mg/dl, and 2-h postprandial blood glucose concentration <180 mg/dl.

CONCLUSIONS — Intensive glycemic control can delay the onset and progression of the early stages of diabetic microvascular complications in Japanese patients with type 2 diabetes.

Diabetes Care 23 (Suppl. 2):B21–B29, 2000


Diabetic microvascular complications are now major problems for diabetic patients. The Diabetes Control and Complications Trial (DCCT) and European studies have demonstrated the efficacy of intensive insulin treatment in preventing the onset and/or progression of microvascular complications such as retinopathy, nephropathy, and neuropathy in patients with type 1 diabetes (15).

The Kumamoto Study was a randomized clinical trial designed to compare intensive insulin therapy using multiple insulin injections with conventional insulin injection therapy to evaluate the effects on the development and progression of microvascular complications in Japanese patients with type 2 diabetes. Two cohorts were designed to answer two different, but related, questions: will intensive insulin therapy prevent the onset of diabetic microvascular complications in type 2 diabetic patients with no retinopathy and a urinary albumin excretion level of <30 mg/24 h (primary prevention cohort), and will intensive insulin therapy reduce the progression of microvascular complications in type 2 diabetic patients with simple retinopathy and a urinary albumin excretion level of <300 mg/24 h (secondary intervention cohort)? In a previous 6-year study, we demonstrated in Japanese patients with type 2 diabetes that establishing good glycemic control could help reduce the development and progression of diabetic retinopathy, nephropathy, and neuropathy (6).

In this article, we present the results of the 8-year Kumamoto Study in Japanese patients with type 2 diabetes.

RESEARCH DESIGN AND METHODS

Patients
Patients with type 2 diabetes who had been treated with once- or twice-daily injections of intermediate-acting insulin in an outpatient clinic were selected on the basis of the following criteria: had no retinopathy or simple retinopathy determined by clinical funduscopic evaluation, had a urinary albumin excretion rate <300 mg/24 h and a serum creatinine level <1.5 mg/dl, had no diabetic somatic or had autonomic neuropathy severe enough to require treatment, was under 70 years of age, and was otherwise healthy. All patients were diagnosed as having type 2 diabetes if they had no history of ketoacidosis, had negative islet cell antibodies, and had a 24-h urinary C-peptide excretion rate of >20 µg. Informed consent was obtained from each patient.

Study design
There were 110 patients divided into two cohorts: the primary prevention cohort (no retinopathy and urinary albumin excretion rate <30 mg/24 h, n = 55) and the secondary intervention cohort (simple retinopathy and urinary albumin excretion rate <300 mg/24 h, n = 55). These patients were randomly assigned to either a conventional insulin injection therapy (CIT) group (n = 55) or a multiple insulin injection therapy (MIT) group (n = 55). The evaluation on the fundus photography was masked to the randomization status in both primary prevention and secondary intervention cohorts. The CIT group was administered once- or twice-daily injections of intermediate-acting insulin, whereas the MIT group was administered short-acting insulin at each meal and intermediate-acting insulin at bedtime. The clinical goal of the CIT group was to show no symptoms of hyperglycemia or hypoglycemia and to have glycemic control, which meant having a fasting blood glucose (FBG) level close to <140 mg/dl.

The goal of the MIT group was to maintain glycemic control, which meant having an FBG level close to <140 mg/dl, a 2-h postprandial blood glucose concentration <200 mg/dl, an HbA1c level <7.0%, and a mean amplitude of glycemic excursions (MAGE) <100 mg/dl (7). Daily blood glucose profiles were measured during 1 day of hospitalization, and frequent blood glucose measurements were also taken by the patients. Based on these results, insulin doses were corrected to improve MAGE. To correct fasting blood glucose levels, the doses of intermediate-acting insulin at bedtime were adjusted, whereas to correct postprandial blood glucose levels, the doses of short-acting insulin before each meal were adjusted. Adjustment doses of insulin were usually 2–4 U at each point. There was no significant difference at entry in either the primary prevention cohort or the secondary intervention cohort between CIT and MIT groups with regard to sex distribution, age, duration of diabetes, BMI, insulin doses, urinary C-peptide excretion, HbA1c, blood pressure, serum cholesterol, serum triglyceride, serum HDL cholesterol, degree of retinopathy, urinary albumin excretion, and nerve conduction velocity (Table 1). After 8 years, 99 patients remained in the study, 5 patients died (2 in the MIT group and 3 in the CIT group), 4 patients had moved to another city (2 in the MIT group and 2 in the CIT group), and 2 patients had changed from conventional insulin injection therapy to multiple insulin injection therapy. Follow-up examinations of glycemic control and diabetic microvascular complications were performed at the third month and every 6 months after the initiation of the study.

shichiriT1.jpg (52430 bytes)

Evaluation of glycemic control
Metabolic control was estimated by HbA1c, FBG, mean blood glucose (MBG), M value of Schlichtkrull, and MAGE calculated from diurnal blood glucose profiles (8). The mean values for HbA1c, FBG, MBG, M, and MAGE during the study were calculated to evaluate the glycemic control during a period from the third month to 8 years. Severe hypoglycemia was defined as an event with symptoms consistent with hypoglycemia in which the patient required the assistance of another person and which was associated with a blood glucose level <50 mg/dl and a prompt recovery after intravenous glucose loading. Mild hypoglycemia was defined as an event with symptoms consistent with hypoglycemia (sweating, palpitations, hunger, or blurred vision) in which the patient did not require the assistance of another person and which was associated with a blood glucose level <50 mg/dl by self-monitoring.

Evaluation of diabetic microvascular complications
Retinopathy
. All of the patients had direct ophthalmoscopy every 6 months, with their pupils dilated. Funduscopic findings were evaluated by at least two examiners (one by an ophthalmologist and one by an internist) and were followed by color fundus photography and fluorescein angiography. The degree of retinopathy for each patient was determined by the two eye examiners using the modified Early Treatment of Diabetic Retinopathy Study (ETDRS) classification with a scale of 19 stages (6,911). The development and progression of retinopathy were defined as a change of at least two steps up from stage 1 in the primary prevention cohort and as a change of two or more steps up from stages 2–5 in the secondary intervention cohort. Once changes were found, the funduscopic examinations were performed every month, and the worsening of retinopathy was confirmed when the changes were observed in two consecutive examinations.

Nephropathy. The patients with nephropathy were divided into three stages depending on their urinary albumin excretion: normoalbuminuria (<30 mg/24 h), microalbuminuria (30–300 mg/24 h), or albuminuria (>300 mg/24 h) (3,12). A change from any one stage to any higher stage was defined as progression.

Neuropathy. Peripheral nerve functions were evaluated by median nerve conduction velocity and by vibration threshold on the radial styloid process of the arm and the medial malleolus of the leg on both sides. The coefficient of variation (CV) of R-R intervals on an electrocardiogram and orthostatic hypotension were used to evaluate the autonomic nerve functions. The CV of R-R intervals was evaluated during both bed rest and deep breathing. In orthostatic hypotension, the decrease in systolic blood pressure caused by standing after 5 min of bed rest was measured. These neurological indexes at entry and after 8 years of the study in both CIT and MIT groups were compared in the combined cohort consisting of primary prevention and secondary intervention cohorts.

Comparison of the reduction in risk with intensive insulin therapy on the development and progression of microvascular complications between the Kumamoto Study and the DCCT
To compare the effects of intensive insulin therapy on the development and progression of diabetic microvascular complications between type 2 and type 1 diabetes, the reduction in risk for the development and progression of diabetic microvascular complications with intensive insulin therapy in the Kumamoto Study was compared with those in the DCCT.

Relationship between the worsening of microvascular complications and glycemic control indexes
The relationship between the worsening of retinopathy and nephropathy and glycemic control indexes, expressed as HbA1c, FBG, and 2-h postprandial blood glucose concentration, was evaluated in the combined cohort. The crude rate within the six grades evaluated according to their glycemic control indexes was calculated and expressed as 100 patient-years. The regression lines estimated as the function of the log of mean glycemic control indexes were calculated.

Evaluation of macrovascular complications
To evaluate the effect of intensive glycemic control on macrovascular complications in patients with type 2 diabetes in the Kumamoto Study, the events of cardiovascular, cerebrovascular, and peripheral vascular disease during 8 years in the MIT group were compared with those in the CIT group. Cardiovascular events (angina pectoris or myocardial infarction), cerebrovascular events (stroke), and peripheral vascular events (intermittent claudication, gangrene, or amputation) were confirmed by coronary angiography, electrocardiogram, brain computed tomography, or peripheral vascular angiography.

Assays
All of the assays were standardized before initiation of the follow-up. Blood glucose concentration was assayed using the glucose oxidase–peroxidase, 4-aminophenozone, phenol method (Autoanalyzer; Miles, Tarrytown, NY). HbA1c value was assayed using high-performance liquid chromatography (HLC 723 GHb type 2; Tosoh, Tokyo) (normal range 4.8–6.4%). HbA1c results obtained from 1987 to 1994 were corrected according to the recommendation of the Committee on an Interlaboratory Standardization of HbA1c Determination of the Japan Diabetes Society (13). Funduscopic findings were recorded using the CR-45 camera (Canon, Tokyo). Urinary albumin excretion rate in a 24-h specimen was measured by turbidimetric immunoassay (Automatic Analyzer 7150; Hitachi, Tokyo). The mean of the values measured on two or three independent days within 4 weeks were used (CV of the day-to-day variation: 30%). Nerve conduction velocity, vibration threshold, and CV of R-R intervals were measured by the Neuromatic 2000 (Dantec, Skovlunde, Denmark), the Vibratory Sensation Meter (TM-31A; Medic International, Tokyo), and the Electro Cardiograph Analysis System 12 (Nihon Kohden, Tokyo), respectively.

Statistical analysis
Wilcoxon's rank-sum test was used to compare the two treatment groups within the cohort with regard to ordinal and numerical variables, and the chireg.gif (915 bytes)2 test was used for comparison of categorical variables. The life-table method was used to estimate the cumulative incidence of events, with adjustment for periodically timed assessments. The difference between two cumulative incidence curves was tested by the Mantel (log-rank) test (14).

The relative risks of retinopathy and nephropathy were estimated as the crude relative risk in the primary prevention cohort, the secondary intervention cohort, and the combined cohort. The crude relative risk was calculated according to the following equation: 1 – P0/P1, where P0 and P1 represent the cumulative percentage of worsening in CIT and MIT groups, respectively.

In addition, the relative risks were also calculated using proportional-hazards analysis only in the combined cohort. Event rates of complications were presented as the number of events per 100 patient-years based on the ratio of observed number of events to the total number of patient-years of exposure. All results were expressed as mean ± SD. P < 0.05 was considered to be statistically significant. All analyses were undertaken by intention to treat.

RESULTS

Glycemic control
As shown in Fig. 1, near-normoglycemia was obtained in the MIT group during the third month after the initiation of intensive insulin therapy and was maintained over the 8 years of the study, whereas the glycemic control in the CIT group did not change significantly. The resultant mean values of FBG, HbA1c, MBG, M, and MAGE over the 8 years were significantly lower (P < 0.001) in the MIT group than in the CIT group (FBG 122 ± 30 vs. 162 ± 30 mg/dl, HbA1c 7.2 ± 1.0 vs. 9.4 ± 1.3%, MBG 155 ± 34 vs. 221 ± 40 mg/dl, M value 13 ± 9 vs. 44 ± 17, MAGE 90 ± 26 vs. 136 ± 35 mg/dl). On the other hand, there was a slight but not significant decrease in insulin doses from the baseline to 8 years in the MIT group (MIT group 0.40 ± 0.28 to 0.38 ± 0.39 U/kg/24 h, CIT group 0.41 ± 0.29 to 0.43 ± 0.33 U/kg/24 h).

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Figure 1—Glycemic control as assessed by FBG and HbA1c over an 8-year period in patients with type 2 diabetes receiving intensive (CircleOpen.gif (939 bytes)) and conventional (Circlesolid.gif (915 bytes)) insulin injection therapy. Mean values ± SD are shown. *P < 0.05 vs. conventional insulin injection therapy.

Retinopathy
Primary prevention cohort.
The cumulative percentage of patients who developed retinopathy after 8 years in the MIT group was significantly lower when compared with that in the CIT group (15.4 vs. 47.8%; 1.9 vs. 6.0 events/100 patient-years, P = 0.022, Fig. 2A). During the 8-year period, no patient developed preproliferative or proliferative retinopathy.

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Figure 2—Cumulative incidences of a change in retinopathy in patients with type 2 diabetes treated by intensive (dashm.gif (845 bytes)) and conventional (3blackbars.gif (860 bytes)) insulin injection therapy. A change in the severity of retinopathy was defined as at least two steps up from the baseline (ETDRS interim scale). The primary prevention (A) and secondary intervention (B) cohorts are shown. P values were tested using the Mantel (log-rank) test.

Secondary intervention cohort. The cumulative percentage of patients who progressed to retinopathy was 24.0% in the MIT group and 56.0% in the CIT group after 8 years (3.0 vs. 7.0 events/100 patient-years, P = 0.023, Fig. 2B). During the 8-year period, the progression to preproliferative and proliferative retinopathy was lower in the MIT group than in the CIT group (1.5 vs. 3.0 events/100 patient-years).

Nephropathy
Primary prevention cohort.
The cumulative percentage of patients who developed nephropathy after 8 years was significantly lower in the MIT group than in the CIT group (11.5 vs. 43.5%; 1.4 vs. 5.4 events/100 patient-years, P = 0.029, Fig. 3A). During the 8-year period, the progression to albuminuria was found only in the CIT group (1.1 and 0 events/100 patient-years for the CIT and MIT groups, respectively).

010636a.gif (20602 bytes)
Figure 3—Cumulative incidences of change in nephropathy in patients with type 2 diabetes treated by intensive (dashm.gif (845 bytes)) and conventional (3blackbars.gif (860 bytes)) insulin injection therapy. A change in the severity of nephropathy was defined as one or more stages up among three stages (normoalbuminuria, microalbuminuria, and albuminuria). The primary prevention (A) and secondary intervention (B) cohorts are shown. P values were tested using the Mantel (log-rank) test.

Secondary intervention cohort. The cumulative percentage of patients who progressed to nephropathy was significantly lower in the MIT group than in the CIT group (16.0 vs. 40.0%; 2.0 vs. 5.0 events/100 patient-years, P = 0.043), as shown in Fig. 3B. During the 8-year period, the progression to albuminuria was found in the CIT group (2.0 and 0 events/100 patient-years for the CIT and MIT groups, respectively).

Neuropathy
Peripheral nerve functions were evaluated in the combined cohort at entry and after 8 years. The median nerve conduction velocities (both motor and sensory nerves) significantly increased after 8 years in the MIT group as compared with the values at entry, while the median sensory nerve conduction velocities significantly decreased in the CIT group (Fig. 4A). There were significant differences in the motor and sensory nerve conduction velocities between the two groups after 8 years of study (P < 0.05). The vibration thresholds in the MIT group showed slight, but not significant, increases after 8 years, while those in the CIT group significantly increased after 8 years (P < 0.05). There were significant differences (P < 0.05) in vibration thresholds between the MIT and CIT groups after 8 years of study. The MIT group showed only slight improvements in the orthostatic hypotension and CV of R-R interval, whereas the CIT group showed slight deterioration in both tests (Fig. 4B).

010637a.gif (30607 bytes)

Figure 4—Peripheral nerve functions and autonomic nerve functions in the CIT and MIT groups at entry of the study and after 8 years in the Kumamoto Study. Peripheral nerve functions (A) and autonomic functions (B) are shown. In the CIT group, the values at entry (SquareOpen.gif (935 bytes)) and after 8 years (SquareSolid.gif (890 bytes)) are indicated. In the MIT group, the values at entry (squaredot.gif (981 bytes)) and after 8 years (SquareLined.gif (952 bytes)) are indicated. Mean values ± SD are shown. *P < 0.05 vs. CIT group; #P < 0.05 vs. at entry.

Development and progression of microvascular complications and reduction in risk with intensive insulin therapy
Table 2 demonstrates the reduction in risk for the development and progression of diabetic microvascular complications in the Kumamoto Study for type 2 diabetes. With intensive insulin therapy, the risks of retinopathy, calculated by crude relative risk, were reduced by 68 and 57% in the primary prevention and secondary intervention cohorts, respectively. The risk calculated by proportional-hazards analysis in the combined cohort was the same as that in the DCCT (63%). In addition, intensive insulin therapy also reduced the risk of microalbuminuria by 74% and albuminuria by 100% in the primary prevention cohort. It also reduced the risk of microalbuminuria by 60% and albuminuria by 100% in the secondary prevention cohort, respectively. The risk reduction in the combined cohort calculated by proportional-hazards risk analysis was greater in the Kumamoto Study with type 2 diabetes than in the DCCT with type 1 diabetes (74 vs. 39–54%, respectively).

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Relationship between the worsening in microvascular complications and glycemic control indexes
By analyzing the relationship between the rate of worsening of retinopathy and nephropathy and glycemic indexes, a continuously increasing risk of the worsening of retinopathy and nephropathy was observed with increasing HbA1c, FBG, and 2-h postprandial blood glucose concentration (Fig. 5). No worsening of retinopathy or nephropathy was observed in patients whose HbA1c, FBG, and 2-h postprandial blood glucose concentration were below 6.5%, 110 mg/dl, and 180 mg/dl, respectively.

010638a.gif (28552 bytes)
Figure 5—Relationship between the rate of worsening of retinopathy and nephropathy and glycemic control indexes expressed as HbA1c, FBG, and 2-h postprandial blood glucose concentration in the combined cohort.Squarecircle.gif (899 bytes), The crude rate within the six grades evaluated according to their glycemic control levels;  each square corresponds to more than 100 patient-years. dashm.gif (845 bytes), Regression lines estimated as a function of the log of the mean HbA1c, FBG, and 2-h postprandial glucose concentration.

Macrovascular complications
The total events of cardiovascular, cerebrovascular, and peripheral vascular diseases in the CIT group occurred twice as much as those in the MIT group (1.3 vs. 0.6 events/100 patient-years). In the MIT group, during the 8-year follow-up period, one patient died suddenly (probably because of myocardial infarction), two patients developed angina pectoris, and one other patient complained of intermittent claudication. On the other hand, in the CIT group, three patients died of cerebral vascular disease, two patients developed angina pectoris, and two patients complained of intermittent claudication.

Hypoglycemia, weight gain, blood pressure, and lipid profiles
Over the entire study period, episodes of mild hypoglycemic reactions in the MIT group occurred 1.6 times more than those in the CIT group (35 vs. 22 events/100 patient-years), but no patient experienced episodes of coma, seizure, or severe hypoglycemia that required the assistance of another person. Also, no patient in either the MIT or CIT group showed weight gain of >120% of the ideal body weight (MIT group 20.5 ± 2.1 to 21.5 ± 2.0 kg/m2, CIT group 20.3 ± 2.8 to 21.3 ± 2.6 kg/m2). There were no significant differences in blood pressure levels and lipid profiles or in therapeutic regimens for antihypertensive therapy (ACE inhibitors or beta.gif (968 bytes)-blockers) and lipid-lowering therapy (HMG-CoA reductase inhibitors or nicotinic acid) between the MIT and CIT groups at entry (Table 1) and after 8 years of follow-up (systolic blood pressure 129 ± 16 vs. 130 ± 17 mmHg, diastolic pressure 70 ± 12 vs. 72 ± 11 mmHg, total cholesterol 205 ± 27 vs. 207 ± 27 mg/dl, triglycerides 93 ± 35 vs. 102 ± 38 mg/dl, HDL cholesterol 51 ± 14 vs. 50 ± 14 mg/dl, antihypertensive therapy 14 vs. 19%, and lipid-lowering therapy 12 vs. 15%, for the MIT vs. CIT group, respectively).

CONCLUSIONS — In Japan, nonobese hypoinsulinemic insulin-requiring type 2 diabetic patients have been treated with once- or twice-daily injections of intermediate-acting insulin. However, this conventional insulin injection therapy seemed to be inappropriate for the prevention or intervention of diabetic complications, since conventional insulin injection therapy could not normalize postprandial hyperglycemia (15). Therefore, we evaluated the effect of the intensive insulin therapy on the prevention of the onset and progression of diabetic microvascular complications in Japanese patients with type 2 diabetes.

The results of 6 years of the Kumamoto Study and the superiority of multiple insulin injection therapy were explained to the patients, and the selection of insulin treatment regimens was left to them. Only two patients in the CIT group selected multiple insulin injection therapy, and other patients in both the CIT and MIT groups wanted to adhere to the same treatment regimens. Therefore, the follow-up study was continued by intention of the patients. As a result, it was demonstrated that intensive glycemic control with multiple insulin injection therapy effectively delayed the onset and progression of diabetic retinopathy, nephropathy, and neuropathy in Japanese type 2 diabetic patients.

In the recent report from the U.K. Prospective Diabetes Study (UKPDS) group, newly diagnosed patients with type 2 diabetes (BMI 27–28 kg/m2) randomly assigned to conventional treatment with diet or intensive treatment with sulfonylureas, metformin, or insulin were followed over 10 years. As a result, mean HbA1c was 7.0% in the intensive group as compared with 7.9% in the conventional group, and the risk of microvascular complications in the intensive group was significantly lower than that in the conventional group (16,17). The UKPDS group also reported that tight blood pressure control significantly decreases the risk of microvascular complications in hypertensive patients with type 2 diabetes (18). Together with the results from the Kumamoto Study, which evaluates insulin-requiring nonobese type 2 diabetic patients, it was determined that strict glycemic control, by whatever means, could be useful in preventing the onset and progression of diabetic microvascular complications in type 2 diabetic patients, whether they are obese or nonobese.

In the evaluation of retinal findings, the development and progression of retinopathy were defined as a change of 2 steps up or more in a modified ETDRS scale of 19 stages in the Kumamoto Study, 3 steps up or more in a ETDRS scale of 25 stages in the DCCT, and 2 steps up in a modified ETDRS scale of 21 stages in the UKPDS (2,6,911,16). Because the patients with preproliferative retinopathy at the initiation of the study were not included in the Kumamoto Study, this classification system of 19 stages allowed us to evaluate the retinal findings efficiently. The cumulative percentage of patients showing the worsening in retinal findings was significantly less in patients receiving intensive insulin treatment than in those receiving conventional insulin treatment. With intensive insulin therapy, the risks of retinopathy were reduced in the primary prevention, the secondary intervention, and the combined cohorts. The risk calculated by proportional-hazards analysis in the combined cohort was comparable to that in the DCCT. Intensive insulin therapy also reduced the risk of severe nonproliferative or proliferative retinopathy and that of treatment of photocoagulation. Analysis by Cox's proportional-hazards model in the Kumamoto Study revealed that the relative risk of developing retinopathy decreased by 47% for every 1% decrease in HbA1c. A similar result was obtained in the DCCT: a 10% lower HbA1c (e.g., 8 vs. 7.2%) was associated with a 43% lower risk of developing retinopathy in the intensive group and a 45% lower risk in the conventional group (19). At the 34th Annual Meeting of the European Association for the Study of Diabetes, held in 1998, the UKPDS group also reported that for every 1% decrease in HbA1c, the relative risk of developing microvascular complications decreased by 35%. Therefore, it was concluded that intensive glycemic control was effective in delaying the onset and/or progression of retinopathy, both in type 1 and type 2 diabetes.

Intensive glycemic control was also effective in patients with diabetic nephropathy. The development and progression of nephropathy was significantly lower in patients on intensive insulin therapy than in those receiving conventional treatment. In the primary prevention cohort, intensive insulin therapy reduced the risk of microalbuminuria by 74% and albuminuria by 100%. It also reduced the risk of microalbuminuria by 60% and albuminuria by 100% in the secondary intervention cohort. The risk reduction calculated by proportional-hazards risk analysis was greater in the Kumamoto Study with type 2 diabetes than that in the DCCT with type 1 diabetes (risk reduction in the combined cohort: 74 vs. 39–54%, respectively). Also, in the UKPDS, risk reduction of microalbuminuria was the highest among microvascular complications (34% for the difference of 0.9% in HbA1c) (16). This result was comparable to our result in which risk reduction of microalbuminuria was 74%, for the difference of 2.0% in HbA1c. The reason intensive glycemic control significantly reduced the risk of progression to microalbuminuria or albuminuria in the Kumamoto Study has not been explained thoroughly, but might possibly be the different susceptibility to nephropathy between the types of diabetes (type 2 and 1) and between the races (Caucasian and Asian). It has been known that Japanese patients with type 2 diabetes are susceptible to nephropathy (20,21). Further studies are necessary to solve this question.

After an 8-year period, there were significant differences between the CIT and MIT groups in the nerve conduction velocities and vibration threshold. The orthostatic hypotension and CV of the R-R interval in the MIT group tended to improve after 8 years, whereas these indexes in the CIT group tended to deteriorate. Therefore, we concluded that intensive glycemic control would have a beneficial effect on both somatic and autonomic nerve functions.

The effect of intensive glycemic control on macrovascular complications was also evaluated in type 2 patients in the Kumamoto Study. The total number of macrovascular events in the CIT group was twice that in the MIT group but was not statistically significant, probably because of the small number of patients studied in the Kumamoto Study. Jensen-Urstad et al. (22) reported that early atherosclerosis could be retarded by improved glycemic control. In the present study, intensive glycemic control might have a beneficial effect on the progression of macrovascular complications. This is another question that remains to be solved.

It has been reported that intensive insulin treatment can induce side effects, such as hypoglycemia or weight gain. The DCCT showed that the risk of severe hypoglycemia (defined as an episode with symptoms consistent with hypoglycemia, in which the patient required the assistance of another person and which was associated with a blood glucose level <50 mg/dl or prompt recovery after oral carbohydrate or glucagon or intravenous glucose) was three times higher with intensive insulin therapy than with conventional insulin therapy (2,23). In the UKPDS, 2.3% of insulin-treated patients experienced major hypoglycemic episodes (defined when third-party help or medical intervention was necessary). However, in the present study, no patient experienced a severe hypoglycemic attack, and any episodes of mild hypoglycemic reactions in the MIT group occurred only 1.6 times more than those in the CIT group (35 vs. 22/100 patient-years). This might be explained by the difference in insulin doses among the UKPDS and Kumamoto Study patients with type 2 diabetes, and the DCCT patients with type 1 diabetes (~0.4 [Kumamoto Study], 0.2 for nonobese and 0.5 for obese [UKPDS], and 0.7 U/kg of body wt/24 h [DCCT]. In intensive care groups, there was also a difference in clinic visits for patient care. Routine clinic visits were every 3 or 4 months in the UKPDS and every month in the DCCT, whereas in the Kumamoto Study, patients were assigned to visit every 2 weeks, and insulin doses were adjusted according to their degree of glycemic control during the 8-year follow-up study.

In the present study, the MIT group showed an improvement in glycemic control using the same insulin doses as the CIT group, regardless of having the same instructions for diet and exercise. This could be mainly explained by the usefulness of prandial supplementation with additional doses of short-acting insulin, although the possibility of the improvement of insulin sensitivity after long-term strict glycemic control should not be excluded. In a previous report, we demonstrated that optimal daily profiles of free plasma insulin were achieved during the periods with combined basal plus prandial insulin supplements and reported that instead of the basal insulin supplement with once- or twice-daily injections of intermediate-acting insulin, short-acting insulin supplements three times a day were essential to achieve the optimal glycemic control in Japanese type 2 diabetic patients (15). We also reported that in the MIT group, insulin sensitivity measured by the euglycemic clamp technique was improved significantly after 1–3 months, but not in the CIT group (24).

It is also notable that because most of the insulin-requiring type 2 diabetic patients in Japan are less obese and not hyperinsulinemic, glycemic control could be achieved with relatively smaller doses of insulin when compared with type 2 diabetic patients in Western countries.

There was a slight but not significant increase in BMI in both the MIT and CIT groups from baseline to 8 years. This increase was also smaller than that reported from the DCCT (2,25).

It is clinically important to indicate the glycemic threshold to prevent the development and progression of diabetic microvascular complications. As shown in Fig. 5, no worsening of retinopathy and nephropathy was observed in type 2 diabetic patients whose HbA1c, FBG, and 2-h postprandial blood glucose concentrations were below 6.5%, 110 mg/dl, and 180 mg/dl, respectively. Therefore, in the present study, the glycemic thresholds to prevent the onset and progression of diabetic microvascular complications are indicated as follows: an HbA1c level at least <6.5%, FBG <110 mg/dl, and 2-h postprandial blood glucose concentration <180 mg/dl. These glycemic thresholds suggested by the Kumamoto Study might possibly be oversimplified because of the analysis of the data with smaller numbers of patients studied. Epidemiological analyses of the DCCT and UKPDS data showed a continuous relationship between the risks of diabetic microvascular complications and glycemia, and there was no evidence of any glycemic thresholds for any of the microvascular complications above normal glucose levels (2,16,19). Therefore, the epidemiological analyses suggested that by whatever means, intensive therapy with the goal of achieving normal glycemia should be implemented as early as possible in as many type 1 and type 2 diabetic patients as safely possible.

In conclusion, intensive glycemic control can delay the onset and progression of the early stages of diabetic retinopathy, nephropathy, and neuropathy in type 2 diabetic patients as well as in type 1 diabetic patients. As the results show, intensive glycemic control could improve the quality of life and save medical resources.


Acknowledgments — The authors are grateful to Dr. H. Maruyama, Department of Cardiovascular Disease, Minamata General Medical Center, Kumamoto; Dr. S. Ueno, Department of Metabolic Medicine, Arao Citizen's Hospital, Kumamoto; and many other staff members in the Departments of Metabolic Medicine and Ophthalmology for their assistance throughout the follow-up study.


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From the Department of Metabolic Medicine, Kumamoto University School of Medicine, Kumamoto, Japan.

Address correspondence and reprint requests to Motoaki Shichiri, MD, PhD, Department of Metabolic Medicine, Kumamoto University School of Medicine, 1-1-1, Honjo, Kumamoto, 860-8556, Japan.

Received for publication 8 July 1999 and accepted in revised form 19 November 1999.

Abbreviations: CIT, conventional insulin injection therapy; CV, coefficient of variation; DCCT, Diabetes Control and Complications Trial; ETDRS, Early Treatment of Diabetic Retinopathy Study; FBG, fasting blood glucose; MAGE, mean amplitude of glycemic excursions; MBG, mean blood glucose; MIT, multiple insulin injection therapy; UKPDS, U.K. Prospective Diabetes Study.

A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.

This article is based on a presentation at a symposium. The symposium and the publication of this article were made possible by an unrestricted educational grant from Aventis Pharma.


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