Abstract
Aims/introduction
Type 1 diabetes is rare in the general Japanese population, but becoming more common in adults with increased longevity owing to advancements in treatment. We aimed to examine the current state of glycemic control and diabetes management using real-world data on Japanese adults with type 1 diabetes in different age groups.
Materials and methods
This was a subanalysis of Japanese participants from a multinational, cross-sectional, observational study of adults with type 1 diabetes aged ≥ 26 years conducted in 2018 (Study of Adults’ Glycemia in T1DM). Glycemic control achievement rate and goal setting, incidence of hypoglycemia, and diabetes management of individuals aged 26‒44 years, 45‒64 years, and ≥ 65 years were summarized.
Results
The data on 528 participants were analyzed. The mean glycated hemoglobin (HbA1c) value was 7.8% (61.3 mmol/mol). Of the participants, 25.8% achieved an HbA1c level of < 7.0% (26–44 years, 33.7%; 45‒64 years, 18.9%; and ≥ 65 years, 24.3%). In total, 71.4% participants reported ≥ 1 symptomatic hypoglycemic episode within the last 3 months, and 5.5% participants reported ≥ 1 severe hypoglycemic episode within the last 6 months. A less stringent individualized goal was set for participants aged ≥ 65 years; they had the lowest incidence of ≥ 1 symptomatic hypoglycemic episode. Insulin pumps and continuous glucose monitoring were used in 23.5% and 33.9% participants, respectively.
Conclusion
Glycemic control was suboptimal; the low incidence of severe hypoglycemia suggests careful glycemic control, balancing benefits and risks, particularly in Japanese adults aged ≥ 65 years with type 1 diabetes.
Supplementary Information
The online version contains supplementary material available at 10.1007/s13340-021-00504-7.
Keywords: Type 1 diabetes mellitus, HbA1c, Japan, Adults, Glycemic control, Hypoglycemia
Introduction
Type 1 diabetes (T1D), caused by autoimmune β-cell destruction leading to absolute insulin deficiency [1], can cause serious clinical and psychosocial burdens, such as acute and chronic complications [2] and poorer health-related quality of life [3]. Although it can occur at any age, T1D frequently develops in children and young adults. When compared with Europe and the United States (US), T1D is considered rare in Japan [4], possibly reflecting the immunogenetic and/or environmental differences of the Japanese population from the Caucasoid populations. The incidence of T1D in Japanese children is lower than that of children in Europe and the US [2]. As in other regions of the world, Japanese studies on glycemic control and diabetes management in T1D were focused on children and young adults. Hence, more attention should be paid to managing adults or older age groups with T1D. This is because the incidence of T1D is increasing among adults and older adults [2], along with increased life expectancy owing to the advances in treatments [5–7].
The Diabetes Control and Complications Trial and the Epidemiology of Diabetes Interventions and Complications follow-up study demonstrated that intensive insulin therapy reduced glycated hemoglobin (HbA1c) values and the risk of microvascular complications [8, 9] and cardiovascular diseases when compared with conventional treatment [10], and these beneficial effects persisted long after the trial [11, 12]. Despite a good understanding of the importance of proper glycemic control, glycemic control among adults with T1D has been reported to be suboptimal [13–16]. In the US, a previous study using health record data in 2014–2016 reported that 19‒29% patients aged ≥ 26 years had an HbA1c level of < 7.0%, which increased in older age groups [16]. In Japan, a study focusing on older adults in 2007‒2009 revealed that among 394 people aged ≥ 40 years but < 75 years with T1D, 25.3% had an HbA1c level of < 7.0% [15].
Over the decades, diabetes care has improved with the development and advancement of technologies for diabetes management, including insulin devices (e.g., pumps), monitoring devices (e.g., continuous glucose monitoring [CGM]), and digital applications. The guidelines recommend the use of intensive insulin therapy, that is, multiple daily injection therapy or continuous subcutaneous insulin infusion (CSII or insulin pump therapy), along with self-monitoring of blood glucose to optimize glycemic control in people with T1D [17, 18]. The use of technology and devices was one of the factors that influenced glycemic control status, and the use of such devices might differ between age groups [14]. In addition, the guidelines recommend that glycemic targets for older people should be adjusted to minimize hypoglycemic events rather than setting strict glycemic targets [18, 19]. Optimal management strategies may differ among people depending on their age, comorbidities, and other factors. Thus, it is important to analyze the treatment status among Japanese adults with T1D according to age group to better understand the current trends and barriers in managing these people.
To obtain a current, real-world, global picture of glycemic control and treatment status, including the technology used in adults with T1D, the Study of Adults’ GlycEmia in T1DM (SAGE) was conducted in people with T1D aged ≥ 26 years in 17 countries worldwide in 2018 [20]. Given the differences in diabetes management patterns, people’s behaviors, healthcare systems, and availability of new technologies in countries or regions, further analysis at the country level would provide more insights into developing country-specific strategies to achieve better glycemic control in the target population. Therefore, we conducted a country-level subanalysis of the Japanese participants in SAGE to obtain a real-world picture of glycemic control status, diabetes management patterns, and clinical characteristics of adults with T1D in Japan according to different age groups.
Materials and methods
Study design and participants
The SAGE was a multinational, cross-sectional, observational study of adults with T1D, conducted in 17 non-US countries from January to December 2018 [20]. In each participating country, study sites examining at least 100 people with T1D per year on a regular basis were selected by the sponsors. In Japan, 21 centers participated in the study (Appendix in ESM), and the participating physicians (endocrinologist or diabetologists) examined an average of 71 patients with T1D per month.
At selected sites in each country, participants who met the following criteria and provided written informed consent were included: (1) aged ≥ 26 years, (2) with T1D for ≥ 1 year, (3) treated with insulin, and (4) with the available data on HbA1c within the past 30 days or whose HbA1c value was planned to be obtained within 7 days after the study visit. Participants (1) with nontype 1 diabetes; (2) who switched from insulin pump to multiple insulin injections, or vice versa, within 3 months; (3) who were treated with thiazolidinedione, sulfonylurea, or dipeptidylpeptidase-4 inhibitors at any time since diagnosis; or (4) who were treated with any investigational drug within 3 months were excluded. To ensure a well-balanced age distribution of participants, recruitment ratios of 40%, 40%, and 20% for age groups of 26‒44 years, 45‒64 years, and ≥ 65 years, respectively, were predefined at the country level.
The study involved a single study visit; participants responded to several questionnaires, and investigators collected the demographic and clinical data, including HbA1c values, from the participants’ files and interviews. No investigation or testing was performed for the purpose of the study. Results of the analysis of 528 Japanese participants in SAGE were presented in this study.
Outcomes and analyses
Participant characteristics, glycemic control status, hypoglycemia and hyperglycemia incidence, diabetes management patterns, and complications and comorbidities were descriptively summarized in this analysis. The participants’ characteristics included age, gender, body mass index (BMI) (≥ 25.0 kg/m2 was considered obese, according to the Japanese guidelines [18]), duration and family history of T1D, education level, employment status, health insurance, and lifestyle habits (e.g., physical activity, alcohol use, and tobacco use).
For the glycemic control status, the proportion of participants achieving the general glycemic goal (HbA1c level < 7.0%) was the primary outcome of interest. Additionally, we also analyzed the proportion of participants who achieved the individualized HbA1c target set by physicians based on their clinical opinion. As a history of treatment outcomes, episodes of symptomatic or severe hypoglycemia and severe hyperglycemia were reported.
To describe the diabetes management patterns, treatment regimens (e.g., insulin delivery device, insulin type and dose, dose adjustment, and oral glucose-lowering drugs), process of medical care (e.g., involvement of caregivers), and technology used (e.g., finger-stick blood glucose meter, CGM, and digital applications) were summarized.
For clinical outcomes, microvascular complications (i.e., diabetic neuropathy, diabetic retinopathy, and diabetes-related renal function impairment), macrovascular comorbidities (i.e., coronary heart disease, acute myocardial infarction, heart failure, stroke, transient ischemic attack, peripheral vascular disease, foot ulcer, and history of myocardial revascularization procedure, peripheral revascularization procedure, and lower limb amputation), and other comorbidities (i.e., hypertension, dyslipidemia, atrial fibrillation, fatty liver disease, malignant disease, depression, severe dementia, and hyperthyroidism) were reported.
All analyses were descriptive in nature, and the results were tabulated according to age group (i.e., 26‒44 years, 45‒64 years, and ≥ 65 years). Continuous values were expressed as mean ± standard deviation (SD), while categorical values were expressed as numbers and percentages. All analyses were performed using SAS statistical software, version 9.4.
Results
Participants’ characteristics
A total of 528 Japanese participants recruited from 21 centers were included in this subanalysis (Table 1). The mean age ± SD was 50.3 ± 13.7 years; 208 (39.4%) were aged 26–44 years, 217 (41.1%) were aged 45–64 years, and 103 (19.5%) were aged ≥ 65 years. The participants’ sociodemographic characteristics were generally similar across the age groups; females were predominant (> 60%), and approximately 75% participants were not obese (BMI < 25.0 kg/m2), with a mean BMI of about 23.0 kg/m2. The mean body weight ± SD was lowest in the ≥ 65-year-old group (56.0 ± 10.8 vs. 61.6 ± 13.1 in the 26–44-year-old group, and 61.0 ± 11.8 in the 45–64-year-old group). Overall, 65.1% participants had T1D for ≥ 10 years (mean duration ± SD: 14.3 ± 9.0 years in the 26–44-year-old group to 20.4 ± 12.2 years in the ≥ 65-year-old group), and most had no family history of T1D. In all age groups, 22.1‒25.5% participants were compliant with the recommended diet. Lifestyle habits varied across the age groups.
Table 1.
Participants’ characteristics by age group
| Parameter | Age groups | All (n = 528) |
||
|---|---|---|---|---|
| 26–44 years (n = 208) |
45–64 years (n = 217) |
≥ 65 years (n = 103) |
||
| Age (years), mean ± SD | 37.3 ± 5.2 | 52.6 ± 5.7 | 71.6 ± 5.9 | 50.3 ± 13.7 |
| Gender, n (%) | ||||
| Female | 142 (68.3) | 135 (62.2) | 63 (61.2) | 340 (64.4) |
| Male | 66 (31.7) | 82 (37.8) | 40 (38.8) | 188 (35.6) |
| Body mass index (kg/m2) | ||||
| Mean ± SD | 23.2 ± 4.2 | 23.1 ± 3.7 | 22.8 ± 3.8 | 23.1 ± 3.9 |
| Body mass index, n (%) | ||||
| < 25 kg/m2 | 156 (75.0) | 161 (74.5) | 81 (78.6) | 398 (75.5) |
| 25–30 kg/m2 | 42 (20.2) | 48 (22.2) | 17 (16.5) | 107 (20.3) |
| ≥ 30 kg/m2 | 10 (4.8) | 7 (3.2) | 5 (4.9) | 22 (4.2) |
| Missing | 0 | 1 | 0 | 1 |
| Duration of diabetes (years) | ||||
| Mean ± SD | 14.3 ± 9.0 | 15.9 ± 12.1 | 20.4 ± 12.2 | 16.2 ± 11.2 |
| Duration of diabetes, n (%) | ||||
| < 10 years | 78 (37.5) | 85 (39.2) | 21 (20.6) | 184 (34.9) |
| ≥ 10 years | 130 (62.5) | 132 (60.8) | 81 (79.4) | 343 (65.1) |
| Missing | 0 | 0 | 1 | 1 |
| Family history of T1Da, n (%) | ||||
| Yes | 21 (10.6) | 29 (13.9) | 6 (6.3) | 56 (11.2) |
| No | 177 (89.4) | 180 (86.1) | 89 (93.7) | 446 (88.8) |
| Unknown | 10 | 8 | 8 | 26 |
| Education level, n (%) | ||||
| Primary | 0 (0) | 0 (0) | 2 (1.9) | 2 (0.4) |
| Secondary | 106 (51.0) | 121 (55.8) | 73 (70.9) | 300 (56.8) |
| University/higher education | 97 (46.6) | 93 (42.9) | 25 (24.3) | 215 (40.7) |
| Does not want to answer | 3 (1.4) | 1 (0.5) | 3 (2.9) | 7 (1.3) |
| Unknown | 2 (1.0) | 2 (0.9) | 0 (0) | 4 (0.8) |
| Employment status, n (%) | ||||
| Employee | 160 (76.9) | 148 (68.2) | 9 (8.7) | 317 (60.0) |
| Independent | 12 (5.8) | 18 (8.3) | 13 (12.6) | 43 (8.1) |
| Unemployed | 17 (8.2) | 19 (8.8) | 5 (4.9) | 41 (7.8) |
| Retired | 4 (1.9) | 11 (5.1) | 52 (50.5) | 67 (12.7) |
| Incapacity | 1 (0.5) | 1 (0.5) | 1 (1.0) | 3 (0.6) |
| Other | 14 (6.7) | 19 (8.8) | 21 (20.4) | 54 (10.2) |
| Unknown | 0 (0) | 1 (0.5) | 2 (1.9) | 3 (0.6) |
| Health insurance, n (%) | ||||
| Yes | 207 (99.5) | 214 (98.6) | 103 (100) | 524 (99.2) |
| No | 1 (0.5) | 3 (1.4) | 0 (0) | 4 (0.8) |
| ≥ 30-min physical activity per week (days) | ||||
| Mean ± SD | 1.3 ± 1.9 | 1.8 ± 2.4 | 2.6 ± 2.6 | 1.8 ± 2.3 |
| ≥ 30-min physical activity per week, n (%) | ||||
| 0 days | 111 (53.4) | 108 (49.8) | 38 (36.9) | 257 (48.7) |
| 1–3 days | 70 (33.7) | 64 (29.5) | 29 (28.2) | 163 (30.9) |
| ≥ 4 days | 27 (13.0) | 45 (20.7) | 36 (35.0) | 108 (20.5) |
| Alcohol use, n (%) | ||||
| Never or on special occasions | 120 (57.7) | 127 (58.5) | 65 (63.1) | 312 (59.1) |
| Ex-consumer | 17 (8.2) | 15 (6.9) | 16 (15.5) | 48 (9.1) |
| Current consumer | 71 (34.1) | 75 (34.6) | 22 (21.4) | 168 (31.8) |
| Tobacco use, n (%) | ||||
| Never | 118 (56.7) | 120 (55.3) | 69 (67.0) | 307 (58.1) |
| Ex-smoker | 25 (12.0) | 41 (18.9) | 24 (23.3) | 90 (17.0) |
| Current smoker | 65 (31.3) | 56 (25.8) | 10 (9.7) | 131 (24.8) |
| Compliance with diet, n (%) | ||||
| Yes | 53 (25.5) | 48 (22.1) | 24 (23.3) | 125 (23.7) |
| No | 155 (74.5) | 169 (77.9) | 79 (76.7) | 403 (76.3) |
| Type of medical settingb, n (%) | ||||
| Clinic | 57 (27.4) | 53 (24.4) | 26 (25.2) | 136 (25.8) |
| Hospital | 152 (73.1) | 164 (75.6) | 77 (74.8) | 393 (74.4) |
SD standard deviation, T1D type 1 diabetes
Not all participants had complete data. The results presented are those of participants with the available data on each given parameter
aProportions were calculated for the number of participants, excluding those whose family history was reported “unknown”
bMultiple responses allowed
Glycemic control
The mean HbA1c value ± SD in the overall participants was 7.8 ± 1.2% (61.3 ± 13.4 mmol/mol), and the values did not greatly differ between the age groups (Fig. 1a). Overall, 25.8% participants achieved the general glycemic goal (HbA1c < 7.0%). Among the three age groups, the achievement rate ranged from 18.9% in the 45‒64-year-old group to 33.7% in the 26–44-year-old group.
Fig. 1.
Proportion of participants by a glycemic target achievement and b individualized HbA1c targets. When an individualized HbA1c target was not defined, a general glycemic goal of HbA1c < 7.0% was considered an individualized target. The individualized target was categorized as follows: < 6.5% (< 47.5 mmol/mol), 6.5–7.0%: ≥ 6.5 to < 7.0% (47.5 to < 53.0 mmol/mol), 7.0–7.5%: ≥ 7.0 to < 7.5% (53.0 to < 58.5 mmol/mol), 7.5–8.0%: ≥ 7.5 to < 8.0% (58.5 to < 63.9 mmol/mol), 8.0–9.0%: ≥ 8.0 to < 9.0% (63.9 to < 74.9 mmol/mol), and ≥ 9.0% (≥ 74.9 mmol/mol)
In all age groups, most participants had an individualized HbA1c target of 7.0–7.5%, although individualized targets were set at higher levels for participants aged ≥ 65 years, with > 20% participants in this age group having a target of ≥ 8.0% (Fig. 1b). The achievement rate of an individualized HbA1c target was 27.3% in the overall participants and 19.8–33.2% in the three age groups (Fig. 1a). The achievement rate was the lowest in the 45–64-year-old group. In younger age groups (i.e., 26–44- and 45–64-year-old), the achievement rate for a general glycemic goal was equivalent to that for an individualized target; however, in the ≥ 65-year-old group, the achievement rate of an individualized target was higher than of a general glycemic goal (31.1% vs. 24.3%).
Hypoglycemia and hyperglycemia
In total, 372 (71.4%) participants reported ≥ 1 episode of symptomatic hypoglycemia (blood glucose ≤ 70 mg/dL [≤ 3.9 mmol/L]) within the last 3 months; among the age groups, the proportion was lowest in the ≥ 65-year-old group (Table 2). A total of 29 (5.5%) participants reported ≥ 1 episode of severe hypoglycemia within the last 6 months, of whom 14 required hospital admission or emergency visit. The proportion of participants reporting ≥ 1 episode of severe hypoglycemia was the highest in the ≥ 65-year-old group (7.8%), although it did not exceed 10%. A total of 10 participants reported ≥ 1 episode of severe hyperglycemia leading to diabetic ketoacidosis, among whom 6 were aged 26–44 years.
Table 2.
Hypoglycemia and hyperglycemia
| Age groups | All (n = 528) |
|||||||
|---|---|---|---|---|---|---|---|---|
| 26–44 years (n = 208) |
45–64 years (n = 217) |
≥ 65 years (n = 103) |
||||||
| n | (%) | n | (%) | n | (%) | n | (%) | |
| Hypoglycemia | ||||||||
| ≥ 1 symptomatic hypoglycemia with BG ≤ 70 mg/dL (≤ 3.9 mmol/L) within the last 3 months | ||||||||
| Number of participants, n (%) | 147 | (71.7) | 158 | (73.5) | 67 | (66.3) | 372 | (71.4) |
| Number of events/participant (median, min–max) | 5, 0–90 | 5, 0–144 | 4, 0–180 | 5, 0–180 | ||||
| ≥ 1 symptomatic hypoglycemia with BG < 54 mg/dL (< 3.0 mmol/L) within the last 3 months | ||||||||
| Number of participants, n (%) | 114 | (55.6) | 106 | (49.3) | 49 | (48.5) | 269 | (51.6) |
| Number of events/participant (median, min–max) | 1, 0–70 | 0, 0–50 | 0, 0–80 | 1, 0–80 | ||||
| ≥ 1 severe hypoglycemiaa within the last 6 months | ||||||||
| Number of participants, n (%) | 10 | (4.8) | 11 | (5.1) | 8 | (7.8) | 29 | (5.5) |
| Number of events/participant (median, min–max) | 0, 0–12 | 0, 0–10 | 0, 0–6 | 0, 0–12 | ||||
| ≥ 1 hospitalization/emergency visit within the last 6 months linked to a severe hypoglycemiab | n = 10 | n = 11 | n = 8 | n = 29 | ||||
| Number of participants, n (%) | 5 | (50.0) | 3 | (27.3) | 6 | (75.0) | 14 | (48.3) |
| Hyperglycemia | ||||||||
| ≥ 1 severe hyperglycemia leading to DKA within 6 months | ||||||||
| Number of participants, n (%) | 6 | (2.9) | 2 | (0.9) | 2 | (2.0) | 10 | (1.9) |
| Number of events/participants (median, min–max) | 0, 0–5 | 0, 0–2 | 0, 0–1 | 0, 0–5 | ||||
BG blood glucose, DKA diabetic ketoacidosis
Not all participants had complete data. The results presented are those of participants with the available data on each given parameter
aSevere hypoglycemia is defined as an event requiring the assistance of another person to actively administer carbohydrate, glucagon, intravenous glucose, or other resuscitative actions
bProportions are calculated among participants with at least one episode of severe hypoglycemia
Diabetes management patterns
Treatment regimens
Most participants used injections or pens for insulin delivery (Fig. 2a). Overall, insulin pumps were not widely used (23.5%); when examining according to age group, pumps were used more commonly in younger age groups than in the oldest age group (22.1‒32.2% vs. 8.7%).
Fig. 2.
Proportion of participants who used a insulin device and b blood glucose meter. CGM continuous glucose mete. aPump alone and a combination of pump and injections/pens
The second-generation long-acting insulin analog was the most commonly used basal insulin for injections/pens users in all age groups (70.9‒84.2%), especially in the 45–64-year-old group (Table 3). The mean total insulin daily dose ± SD (U/day [U/kg/day]), regardless of insulin type, was 38.8 ± 19.8 (0.6 ± 0.3) in the overall participants and tended to be lower in the older age groups: 43.4 ± 21.2 (0.7 ± 0.3) in the 26–44-year-old group to 32.1 ± 15.8 (0.6 ± 0.2) in the ≥ 65-year-old group. Among the users of insulin injections or pens, the total basal daily dose accounted for 35–38% of the total daily dose in every age group (Fig. 3a). Among the users of insulin pumps, the total basal dose accounted for 58% of the total daily dose in the ≥ 65-year-old group, and 38% in the 26–44- and 45–64-year-old groups (Fig. 3b).
Table 3.
Insulin and other treatment regimens
| 26–44 years (n = 208) |
45–64 years (n = 217) |
≥ 65 years (n = 103) |
All (n = 528) |
|
|---|---|---|---|---|
| Insulin device, n (%) | ||||
| Pump alone | 67 (32.2) | 46 (21.2) | 7 (6.8) | 120 (22.7) |
| Injections/pens | 141 (67.8) | 169 (77.9) | 94 (91.3) | 404 (76.5) |
| Pump and injections/pens | 0 (0) | 2 (0.9) | 2 (1.9) | 4 (0.8) |
| Insulin type in injections/pens users (alone or in combination with pump), n (%) | n = 141 | n = 171 | n = 96 | n = 408 |
| Basal | 138 (97.9) | 167 (97.7) | 95 (99.0) | 400 (98.0) |
| Intermediate-acting NPH | 1 (0.7) | 2 (1.2) | 0 (0) | 3 (0.7) |
| Long-acting analogs | 137 (97.2) | 165 (96.5) | 95 (99.0) | 397 (97.3) |
| First generation | 37 (26.2) | 21 (12.3) | 20 (20.8) | 78 (19.1) |
| Second generation | 100 (70.9) | 144 (84.2) | 75 (78.1) | 319 (78.2) |
| Premix | 4 (2.8) | 3 (1.8) | 1 (1.0) | 8 (2.0) |
| Short-acting insulin | 139 (98.6) | 163 (95.3) | 95 (99.0) | 397 (97.3) |
| Short-acting analogs | 138 (97.9) | 161 (94.2) | 90 (93.8) | 389 (95.3) |
| Regular human insulin | 3 (2.1) | 4 (2.3) | 5 (5.2) | 12 (2.9) |
| Total insulin daily dose, mean ± SD | ||||
| U/day | 43.4 ± 21.2 | 37.5 ± 19.0 | 32.1 ± 15.8 | 38.8 ± 19.8 |
| U/kg/day | 0.7 ± 0.3 | 0.6 ± 0.3 | 0.6 ± 0.2 | 0.6 ± 0.3 |
| Recommended insulin dose adjustment approach, n (%) | ||||
| Physician driven | 100 (48.1) | 114 (52.5) | 64 (62.1) | 278 (52.7) |
| Participant driven | 108 (51.9) | 103 (47.5) | 39 (37.9) | 250 (47.3) |
| Frequency of titration of basal insulin, n (%) | n = 128 | n = 154 | n = 82 | n = 364 |
| More than weekly (1–6 days) | 14 (10.9) | 14 (9.1) | 8 (9.8) | 36 (9.9) |
| Weekly | 11 (8.6) | 15 (9.7) | 11 (13.4) | 37 (10.2) |
| Less than weekly but more than every 2 weeks | 0 (0) | 0 (0) | 2 (2.4) | 2 (0.5) |
| Less than every 2 weeks but more than monthly | 67 (52.3) | 82 (53.2) | 42 (51.2) | 191 (52.5) |
| Less than monthly | 36 (28.1) | 43 (27.9) | 19 (23.2) | 98 (26.9) |
| Missing | 10 | 13 | 13 | 36 |
| Frequency of titration of short-acting insulin, n (%) | n = 206 | n = 208 | n = 100 | n = 514 |
| More than weekly (1–6 days) | 85 (41.3) | 70 (33.7) | 26 (26.0) | 181 (35.2) |
| Weekly | 15 (7.3) | 21 (10.1) | 12 (12.0) | 48 (9.3) |
| Less than weekly but more than every 2 weeks | 1 (0.5) | 1 (0.5) | 2 (2.0) | 4 (0.8) |
| Less than every 2 weeks but more than monthly | 68 (33.0) | 81 (38.9) | 41 (41.0) | 190 (37.0) |
| Less than monthly | 37 (18.0) | 35 (16.8) | 19 (19.0) | 91 (17.7) |
| Missing | 0 | 1 | 2 | 3 |
| Number of bolus per day for pump users | n = 67 | n = 46 | n = 7 | n = 120 |
| Mean ± SD | 3.8 ± 1.4 | 3.5 ± 1.6 | 3.0 ± 1.5 | 3.6 ± 1.5 |
| Number of short-acting injections per day for injections/pens (basal + short acting) users | n = 136 | n = 161 | n = 93 | n = 390 |
| Mean ± SD | 3.0 ± 0.3 | 3.0 ± 0.4 | 3.0 ± 0.2 | 3.0 ± 0.3 |
| At least one glucose lowering drug, n (%) | ||||
| Yes | 15 (7.2) | 29 (13.4) | 13 (12.6) | 57 (10.8) |
| Alpha-glucosidases inhibitors | 7 (3.4) | 19 (8.8) | 9 (8.7) | 35 (6.6) |
| Metformina | 8 (3.8) | 14 (6.5) | 4 (3.9) | 26 (4.9) |
| Sodium-glucose linked transporter-2 inhibitorsb | 0 (0) | 3 (1.4) | 2 (1.9) | 5 (0.9) |
| GLP1a | 0 (0) | 2 (0.9) | 0 (0) | 2 (0.4) |
| No | 193 (92.8) | 188 (86.6) | 90 (87.4) | 471 (89.2) |
SD standard deviation
Not all participants had complete data. The results presented are those of participants with the available data on each given parameter
aNot officially approved for the treatment of type 1 diabetes in Japan as of January 2021
bThe first sodium-glucose linked transporter-2 inhibitor was approved for the treatment of type 1 diabetes in 2018 in Japan
Fig. 3.
Insulin dose for a injections/pens (basal + short-acting insulin) and b pumps. SD standard deviation
For insulin dose adjustment, physician-driven and participant-driven titrations were almost equally recommended in the 26–44- and 45–64-year-old groups, whereas physician-driven titration was more commonly recommended than the participant-driven titration in the ≥ 65-year-old group (62.1% vs. 37.9%) (Fig. 4). Irrespective of age group, the basal insulin dose was adjusted less than every 2 weeks but more than monthly in about 50% participants, while it was adjusted less than monthly in about 25% participants. The short-acting insulin dose was adjusted more than weekly or less than every 2 weeks but more than monthly by almost equal proportions of the overall population (35.2% and 37.0%, respectively) (Table 3).
Fig. 4.
Proportion of participants by method of insulin titration (physician or participant driven)
Overall, only 57 (10.8%) participants received oral glucose-lowering drugs, particularly alpha-glucosidase inhibitors (35 [6.6%]) and metformin (26 [4.9%]).
Process of medical care and technology use
In all age groups, over half of the participants reported that their partner or other adults living with them were involved in their medical care (Table 4). Diabetes support groups were involved in the care of 15.7% participants, with minimal differences between age groups. Overall, the latest technologies, including digital applications to aid in managing their diabetes, were not commonly used, regardless of age group. The CGM was used by about one-third of the overall participants and was less commonly used in the oldest age group (24.3% vs. 35.0–37.5%) (Fig. 2b). In contrast, most of the participants in all age groups used a finger-stick blood glucose meter, and this device was used most commonly in the ≥ 65-year-old group (95.1%).
Table 4.
Diabetes management: process of medical care and technology use
| 26–44 years (n = 208) |
45–64 years (n = 217) |
≥ 65 years (n = 103) |
All (n = 528) |
|||||
|---|---|---|---|---|---|---|---|---|
| n | (%) | n | (%) | n | (%) | n | (%) | |
| Process of medical care | ||||||||
| Glucagon availability at home | ||||||||
| Yes | 16 | (7.7) | 25 | (11.5) | 11 | (10.7) | 52 | (9.8) |
| No | 32 | (15.4) | 31 | (14.3) | 20 | (19.4) | 83 | (15.7) |
| Unknown | 160 | (76.9) | 161 | (74.2) | 72 | (69.9) | 393 | (74.4) |
| Person involved in participant’s medical carea | ||||||||
| Partner or other adults living with the participant | 126 | (60.6) | 118 | (54.4) | 64 | (62.1) | 308 | (58.3) |
| Home health aid | 0 | (0) | 1 | (0.5) | 0 | (0) | 1 | (0.2) |
| Diabetes support groups | 31 | (14.9) | 34 | (15.7) | 18 | (17.5) | 83 | (15.7) |
| Other medical care | 56 | (26.9) | 71 | (32.7) | 23 | (22.3) | 150 | (28.4) |
| Technology use | ||||||||
| Digital applications | ||||||||
| To monitor diet or count carbohydrate consumption | 8 | (3.8) | 6 | (2.8) | 0 | (0) | 14 | (2.7) |
| To monitor or improve exercise level | 8 | (3.8) | 6 | (2.8) | 1 | (1.0) | 15 | (2.8) |
| To remember to take diabetes medication | 2 | (1.0) | 3 | (1.4) | 0 | (0) | 5 | (0.9) |
| To adjust diabetes medication correctly | 1 | (0.5) | 4 | (1.8) | 1 | (1.0) | 6 | (1.1) |
| To manage weight | 7 | (3.4) | 6 | (2.8) | 2 | (1.9) | 15 | (2.8) |
aMultiple responses allowed
Complications and comorbidities
In total, 197 (36.7%) participants reported at least one microvascular complication (Table 5). Microvascular complications were more common in participants aged ≥ 65 years than in those aged 26–44 years (54.9% vs. 26.6%) and so were macrovascular comorbidities (17.6% vs. 1.4%). Microvascular complications were more common in participants with a longer diabetes duration than in those with a shorter duration (43.0% in those with ≥ 10 years vs. 25.1% in those with < 10 years). The other common comorbidities were dyslipidemia (31.2%) and hypertension (26.8%) and the proportion of participants with these comorbidities increased with age.
Table 5.
Complications and comorbidities
| 26–44 years (n = 208) |
45–64 years (n = 217) |
≥ 65 years (n = 103) |
All (n = 528) |
|||||
|---|---|---|---|---|---|---|---|---|
| n | (%) | n | (%) | n | (%) | n | (%) | |
| At least one microvascular complicationa | 55 | (26.6) | 82 | (37.8) | 56 | (54.9) | 193 | (36.7) |
| By the time since diabetes diagnosis | ||||||||
| ≥ 10 yearsb | 44 | (33.8) | 54 | (40.9) | 49 | (61.3) | 147 | (43.0) |
| < 10 yearsc | 11 | (14.3) | 28 | (32.9) | 7 | (33.3) | 46 | (25.1) |
| Diabetic neuropathy | 21 | (10.1) | 35 | (16.1) | 33 | (32.4) | 89 | (16.9) |
| Diabetic retinopathy | 27 | (13.0) | 35 | (16.1) | 41 | (40.2) | 103 | (19.6) |
| Leading to blindness | 0 | 0 | 0 | 0 | ||||
| Renal function impairment | 29 | (14.0) | 59 | (27.2) | 27 | (26.5) | 115 | (21.9) |
| Related to diabetes | 25 | (12.1) | 53 | (24.4) | 22 | (21.6) | 100 | (19.0) |
| End stage renal failured | 1 | (3.4) | 4 | (6.8) | 0 | (0) | 5 | (4.3) |
| At least one macrovascular comorbiditye | 3 | (1.4) | 17 | (7.8) | 18 | (17.6) | 38 | (7.2) |
| By the time since diabetes diagnosis | ||||||||
| ≥ 10 yearsb | 1 | (0.8) | 13 | (9.8) | 14 | (17.5) | 28 | (8.2) |
| < 10 yearsc | 2 | (2.6) | 4 | (4.7) | 3 | (14.3) | 9 | (4.9) |
| Coronary heart disease | 0 | (0) | 6 | (2.8) | 10 | (9.8) | 16 | (3.0) |
| Acute myocardial infarction | 0 | (0) | 2 | (0.9) | 3 | (2.9) | 5 | (1.0) |
| Heart failure | 1 | (0.5) | 2 | (0.9) | 3 | (2.9) | 6 | (1.1) |
| Stroke | 0 | (0) | 8 | (3.7) | 5 | (4.9) | 13 | (2.5) |
| Transient ischemic attack | 1 | (0.5) | 1 | (0.5) | 0 | (0) | 2 | (0.4) |
| Peripheral vascular disease | 0 | (0) | 3 | (1.4) | 2 | (2.0) | 5 | (1.0) |
| Foot ulcer | 1 | (0.5) | 0 | (0) | 1 | (1.0) | 2 | (0.4) |
| Myocardial revascularization procedure | 0 | (0) | 2 | (0.9) | 4 | (3.9) | 6 | (1.1) |
| Peripheral revascularization procedure | 0 | (0) | 1 | (0.5) | 0 | (0) | 1 | (0.2) |
| Lower limb amputation for arterial reason | 0 | (0) | 1 | (0.5) | 1 | (1.0) | 2 | (0.4) |
| Other comorbidities | ||||||||
| Hypertension | 21 | (10.1) | 65 | (30.0) | 55 | (53.9) | 141 | (26.8) |
| Dyslipidemia | 40 | (19.3) | 75 | (34.6) | 49 | (48.0) | 164 | (31.2) |
| Atrial fibrillation | 0 | (0) | 3 | (1.4) | 1 | (1.0) | 4 | (0.8) |
| Fatty liver disease (steatosis or steatohepatitis) | 8 | (3.9) | 8 | (3.7) | 9 | (8.8) | 25 | (4.8) |
| Ongoing malignant disease | 0 | (0) | 3 | (1.4) | 1 | (1.0) | 4 | (0.8) |
| Depression | 4 | (1.9) | 4 | (1.8) | 3 | (2.9) | 11 | (2.1) |
| Severe dementia | 0 | 0 | 0 | 0 | ||||
| Hyperthyroidism | 14 | (6.8) | 17 | (7.8) | 7 | (6.9) | 38 | (7.2) |
Not all participants had complete data. The results presented are those of participants with the available data on each given parameter
A number of participants whose complication and comorbidity data were missing: n = 1 in the 26–44-year-old group and n = 0 in the 45–64-year-old group, and n = 1 in the ≥ 65-year-old group, n = 2 in all age groups
aMicrovascular complication: diabetic neuropathy, diabetic retinopathy, or diabetes-related renal impairment
bA total number of participants who had type 1 diabetes ≥ 10 years since diagnosis: n = 130 in 26–44-year-old group, n = 132 in 45–64-year-old group, n = 81 in ≥ 65-year-old group, and n = 343 in all age groups
cA total number of participants who had type 1 diabetes < 10 years since diagnosis: n = 78 in 26–44-year-old group, n = 85 in 45–64-year-old group, n = 21 in ≥ 65-year-old group, and n = 184 in all age groups
dThe percentage was calculated for those who had at least one renal function impairment
eMacrovascular comorbidities: coronary heart disease, acute myocardial infarction, heart failure, stroke, transient ischemic attack, peripheral vascular disease, foot ulcer, and history of myocardial revascularization procedure, peripheral revascularization procedure, or lower limb amputation for arterial reason
Discussion
By including a large number of adult participants worldwide, the SAGE provided a clearer picture of adults living with T1D who were previously under-evaluated. This subanalysis of Japanese participants in the SAGE elucidated suboptimal glycemic control in Japanese adults with T1D across all age groups under the current real-world T1D management practice in Japan. Japanese management practices were characterized by the uncommon utilization of emerging technologies such as insulin pumps and CGMs.
Suboptimal glycemic control in adults living with T1D has been reported previously in other countries [13, 14, 16] as well as in Japan [15]. In the present subanalysis, > 70% of the overall population achieved neither the general HbA1c target of < 7.0% nor the individualized target. Similar nonachievement rates were also reported in the SAGE global cohort, where 75.7% and 79.1% did not achieve the general HbA1c target of < 7.0% and the individualized targets, respectively [20]. When considering the present results according to age group, the achievement rate was the lowest in the middle-aged group, suggesting that glycemic control is particularly difficult for this age group.
More than 70% of our Japanese subpopulation reported at least one episode of symptomatic hypoglycemia, although only 5.5% reported severe cases. In the SAGE global cohort, the proportion of participants reported ≥ 1 episode of symptomatic hypoglycemia was comparable (67.7%), while the proportion of participants with severe cases was far greater (11.9%) [20] than that of the Japanese subgroup. This trend may suggest that Japanese T1D management was more focused on the prevention of severe hypoglycemia. Such careful attitudes may be particularly evident in the oldest, ≥ 65-year-old group. A less rigid target was more commonly applied in the ≥ 65-year-old group when compared with that applied in the younger groups, probably because the guidelines recommend a goal setting prioritizing safety rather than adopting a more stringent glycemic control for older adults [18, 19]. Possibly due to less stringent goals and/or smaller body weight, the total daily insulin dose was the lowest in the ≥ 65-year-old group, resulting in the lowest incidence of symptomatic hypoglycemia in this age group. At the same time, the higher target level may have enabled the greater achievement of individualized targets than the generalized targets in the ≥ 65-year-old group, in contrast to the similar achievement rate of the general and individualized targets in the younger groups. Nevertheless, the low incidence of symptomatic hypoglycemia in this oldest group may be partially explained by hypoglycemia unawareness, to which older patients are susceptible to [18].
The mean total daily insulin dose corrected for body weight (0.6 U/kg/day) was numerically lower than that (0.71 U/kg/day) in the SAGE global cohort [20], possibly reflecting the ethnic difference in insulin requirement based on the body composition and variance in insulin resistance [21]. Furthermore, the basal/total insulin ratio of 35–38% in injections/pen users was slightly higher than the previously proposed ratio (30%) for the Japanese population [22–24]. Considering the high-carbohydrate composition of the Japanese diet, the bolus insulin dose may be slightly low in our population.
Derived from a large amount of data obtained from the daily clinical practice, the present results may closely reflect the current healthcare system in Japan. Under the Japanese universal health coverage, which guarantees freedom of access to any healthcare provider with relatively low cost, frequent consultation with physicians may contribute to more common physician-driven titration in this population. Physician-driven titration was particularly common in the oldest age group, possibly reflecting the heightened need to support this group of participants. The common physician-driven insulin titration may be associated with a lower frequency of insulin titration in the Japanese subgroup among the SAGE cohorts, when compared with those in the European regions (about 29% and > 67% titrated basal and short-acting insulin, respectively, more than weekly [20]; the respective proportion in Japanese participants: 9.9% and 35.2%). Furthermore, the proportion of participants who were hospitalized or visited the emergency department due to severe hypoglycemia was large, but the incidence of severe hypoglycemia was low in our Japanese subgroup among the SAGE cohorts. This trend may also project the easy access to health care ensured in Japan.
The present analysis demonstrated that new technologies and devices were not yet commonly utilized, although their use has gradually become incorporated into Japanese clinical practice. Considering that 15.0% Japanese adults aged ≥ 18 years with T1D used CSII in 2010–2012 [25], the use of insulin pump had gradually increased in Japan. Moreover, considering that SAGE was initiated just after the intermittently scanned CGM device (FreeStyle Libre; Abbott Diabetes Care, Witney, UK) was approved in September 2017 in Japan, the proportion of CGM users (33.9%) in the present population suggests that these devices may have been relatively rapidly introduced into Japanese management practices. However, the difference according to age group suggests that it was more difficult to introduce such new technologies in older participants, possibly because of various problems associated with aging. With accurate continuous monitoring, recording, and prediction of blood glucose levels, and automated dose control and delivery of insulin, these devices are expected to facilitate safe optimal glycemic control, thereby reducing burdens associated with day-to-day lifelong insulin treatment and self-care. Technologies continue to evolve, and the growing options of such technologies and devices are expected to change the diabetes treatment and management as well as glycemic control practices, thus warranting further research. Conducted before these technologies becomes widely available, this subanalysis would provide useful “baseline” data for future studies.
This study has some limitations. First, due to the nature of a cross-sectional study, causal relationships cannot be determined. Second, selection bias possibly exists; older participants may have included those with better glycemic control and thereby survived longer than the younger participants. The higher achievement rate of glycemic targets in the ≥ 65- than 45–64-year-old group may be partially due to this selection bias. Moreover, as individuals who were treated with sulfonylurea or dipeptidylpeptidase-4 inhibitors were excluded, the present study results may not fully reflect the trends of glycemic control and diabetes management in adults with slowly progressive insulin-dependent (type 1) diabetes mellitus. Third, the retrospective collection of data on hypoglycemia and hyperglycemia may be subject to information bias. At the same time, the maximum look-back period of 6 months may be short, considering the lifelong management of this disease. Because the data on C-peptide immunoreactivity were not available in the SAGE data, we were unable to assess the reliability of self-reported data on hypoglycemia. Despite these limitations because a large number of individuals with T1D across all age groups were included, this analysis provides a real-world picture of the trend and challenges of managing Japanese adults with T1D. Moreover, as a leading nation of super-aging society, this subanalysis of the data of many older adults may add valuable information to understand and improve diabetes management in this particular population.
Conclusion
Glycemic control was suboptimal in Japanese adults with T1D across all age groups, both in terms of the general target and individualized groups. Nevertheless, the lower incidence of severe hypoglycemia reported suggests careful glycemic control, balancing the benefits and risks, particularly for older adults aged ≥ 65 years. In the midst of rapid technological advancement, this subanalysis, well reflecting the “real-world” status of the management of Japanese adults with T1D, may be expected to serve as a useful baseline data for future studies.
Supplementary Information
Below is the link to the electronic supplementary material.
Acknowledgements
Editorial assistance was provided by Clinical Study Support, Inc., Nagoya, Japan, and funded by Sanofi K.K., Tokyo, Japan.
Funding
This work was supported by Sanofi K.K., Tokyo, Japan.
Declarations
Conflict of interest
NA received honoraria (lecture fees) from Novo Nordisk Pharma, Astellas Pharma and research funding from Ono Pharmaceutical, Bristol-Myers Squibb, Taisho Pharmaceutical, Astellas Pharma. AS received lecture fee from Astellas Pharma., Sanofi, Eli Lilly Japan, Novo Nordisk Pharma. RN received honoraria from Sanofi, Medtronic Japan, Nippon Boehringer Ingelheim, Takeda Pharmaceutical, KISSEI PHARMACEUTICAL, Novartis Pharma, Eli Lilly Japan, Novo Nordisk Pharma, MSD, and Astellas Pharma; and grants from Taisho Pharmaceutical, Ono Pharmaceutical, Takeda Pharmaceutical, and Nippon Boehringer Ingelheim. MM received honoraria from Sanofi, Takeda Pharmaceutical, Eli Lilly Japan, Mitsubishi Tanabe Pharma, Astellas Pharma, Novo Nordisk Pharma, and MSD; and research funding from Astellas Pharma, Nippon Boehringer Ingelheim, Daiichi Sankyo, Mitsubishi Tanabe Pharma, Novartis Pharma, Sanofi, Novo Nordisk Pharma, Takeda Pharmaceutical, MSD, and Ono Pharmaceutical. AO is an employee and holds stock of Sanofi. HI received Honoraria for lectures: Astellas Pharma, MSD, Terumo, Eli Lilly Japan, Novartis Pharma, Novo Nordisk Pharma; subsidies or donations: LifeScan Japan, Abbott Japan, Otsuka Pharmaceutical, Sanofi, Sanwa Kagaku Kenkyusho, Taisho Pharmaceutical, Sumitomo Dainippon Pharma, Takeda Pharmaceutical, Mitsubishi Tanabe Pharma, Eli Lilly Japan, Novo Nordisk Pharma.
Human rights statement
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and/or with the Helsinki Declaration of 1964 and later versions. This study was approved by the ethical committee of Nagasaki University Hospital (Date of approval: December 11, 2018, Approval no:18052134–2) and each participating site.
Informed consent
Informed consent or substitute for it was obtained from all patients for being included in the study.
Footnotes
Publisher's Note
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Change history
5/13/2021
First column of Table 4 was aligned incorrectly in PDF and corrected in this version.
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