Diabetology International
https://doi.org/10.1007/s13340-024-00724-7

ORIGINAL ARTICLE

Impact of treatment cessation on incidence and progressionof retinopathy in Japanese patients with type 2 diabetes mellitus:
a retrospective cohort study
Yukiko Shinzato1 · Yoshiro Nakayama1 · Shiki Okamoto1 · Jasmine F. Millman1 · Tsugumi Uema1 ·Ken‑ichiro Honma1 · Atsuko Tamaki1 · Moriyuki Uehara1 · Taiki Teruya1 · Takamitsu Yabiku1 · Yohei Ishiki1 ·Ken Yonaha1 · Ko‑ichiro Arakaki2 · Moritake Higa3 · Hideki Koizumi4 · Koshi Nakamura5 · Michio Shimabukuro6 ·Hiroaki Masuzaki1
Received: 31 October 2023 / Accepted: 2 April 2024
© The Japan Diabetes Society 2024

Abstract
Aims This cohort study investigated the association between treatment cessation and incidence/progression of diabetic
retinopathy (DR) in Japanese patients with type 2 diabetes mellitus (T2DM).
Materials and methods Data were extracted from electronic medical records at the University of the Ryukyu Hospital andthe Tomishiro Central Hospital of Okinawa, Japan. We enrolled 417 diabetic patients without DR (N = 281) and with nonproliferative DR (N = 136) at the baseline. Treatment cessation was defined as failing to attend outpatient clinics for at least
twelve months prior to the baseline. After a median follow-up of 7 years, we compared the incidence/progression rate of DR
including nonproliferative and proliferative DR between patients with and without treatment cessation and calculated theodds ratio (OR) in the treatment cessation group using a logistic regression model.
Results The overall prevalence of treatment cessation was 13% in patients with T2DM. Characteristics of treatment cessation included relative youth (57 ± 11 years vs. 63 ± 12 years, P < 0.01). Treatment cessation was tightly associated with theincidence of DR (OR 4.20 [95% confidence interval [CI] 1.46–12.04, P < 0.01) and also incidence/progression of DR (OR2.70 [1.28–5.69], P < 0.01), even after adjusting for age, sex, BMI, duration of T2DM, and HbA1c level.
Conclusions By considering major confounding factors, the present study demonstrates an independent association between
treatment cessation and incidence of DR in patients with T2DM, highlighting treatment cessation as an independent risk
for DR in T2DM.
Keywords Treatment cessation · Type 2 diabetes mellitus · Diabetic retinopathy · Incidence and progression · Retrospective
cohort study

Introduction
It has been well-documented that risk factors for the incidence of diabetic retinopathy (DR) include chronic hyperglycemia, disease duration, hypertension, dyslipidemia, anddiabetic nephropathy [1–3]. In a large-scale of observational
study consisting of approximately 20,000 patients with type2 diabetes mellitus (T2DM) without proliferative diabetic
retinopathy (PDR) in the UK, the baseline rate of patients
Yukiko Shinzato and Yoshiro Nakayama contributed equally to thiswork.
Extended author information available on the last page of the article

without DR (NDR) was 79% and nonproliferative retinopathy (NPDR) was 21% [4]. After 5 years, only a few patients
without retinopathy at the baseline developed NPDR (cumulative incidence 4%) and PDR (0.7%), and after 10 years,
the respective cumulative incidences were 16% for NPDR
and 1.5% for PDR. Among those with NPDR at the baseline, after 1 year, 6% developed PDR, and after 10 years, thecumulative incidence was 11% [4].
The 2022 American Diabetes Association and the European Association for the Study of Diabetes consensus
report on T2DM care highlights that reducing treatment
cessation is critical for therapeutic strategies [5]. As evidenced by meta-analyses [6–8], characteristics of patientswith treatment cessation [9–12], relationships between
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Y. Shinzato et al.

cessation and major clinical parameters [13–15], reasonsfor cessation [16–19], and also evaluation of interventions on patients with cessation [20–25] have been widely
recognized. To date, patients with treatment cessation
have been characterized by relative youth, smoking habit,
obesity, and poor glycemic control [13]. To our surprise,
however, there are limited reports investigating the association between treatment cessation and diabetic complications in diabetic patients. In a baseline observation ofa large cohort study investigating treatment cessation andall-cause mortality in 15,000 patients with T2DM receiving insulin in the UK, the prevalence of macroangiopathy
was comparable between treatment cessation and nontreatment cessation groups [26]. However, the prevalence ofDR or nephropathy was higher in patients with treatment
cessation as compared to nontreatment cessation [26].
Although a cohort study reported that treatment cessation
was associated with the subsequent occurrence of DR inpatients with T2DM [27], confounding factors including
HbA1c level and duration of T2DM were not taken into
account in this report. Based on these backgrounds, weinvestigated whether treatment cessation in patients with
T2DM would increase the risk of incidence and progression of DR, using preexisting medical records of hospitals
in Okinawa, Japan.

Materials and methods

Fig. 1   Research design. We enrolled 975 patients with type 2 diabetes mellitus (T2DM) from January to December in 2009 (Dataset1). After 157 patients of PDR were excluded, 818 patients either withNDR (N = 569) or NPDR (N = 249) were included (Dataset 2). The
full analysis set included 417 patients after the exclusion of patients
without follow-up (Dataset 3). NDR no diabetic retinopathy, NPDR
nonproliferative diabetic retinopathy; and PDR proliferative diabetic
retinopathy

Study design and subjects
The present study was approved by the institutional ethicalcommittee of the University of the Ryukyus for Medicaland Health Research Involving Human Subjects (No.765)
on February 27, 2015, and was conducted in accordancewith the Declaration of Helsinki. This study was a retrospective cohort study, and data were obtained from electronic
medical records at two hospitals in Okinawa, Japan. We
enrolled 975 patients with T2DM either at the Universityof the Ryukyu Hospital or the Department of Diabetes andLife-Style Related Disease Center, Tomishiro Central Hospital, from January to December in 2009. Based on the results
at the first fundus examination in 2009 and the first blood
sampling examination in 2009, in about 70% of cases, both
fundus examination and blood sampling were done on thesame day, but in about 30% of cases, there was a time point
difference ranging from 1 to 3 months. Among those 975
patients, 157 subjects with proliferative DR were excluded,
and also 401 subjects who had failed to attend ophthalmologist appointments or were only followed up for less than
4 years were excluded. Consequently, a total of 417 subjects
were eligible for analyses (Fig. 1).

Assessment of treatment cessation
Treatment cessation of patients was defined as failing toattend T2DM outpatient appointments for at least twelve
months prior to the baseline [28].

Assessment of incidence and progression of DR
The severity of DR was determined at the baseline andafter the follow-up, by qualified ophthalmologists at either
the University of the Ryukyu Hospital or the Tomishiro
Central Hospital. According to the modified international
clinical DR severity scales [29], we classified subjects
into the following three groups: no diabetic retinopathy(NDR), nonproliferative diabetic retinopathy (NPDR), andproliferative diabetic retinopathy (PDR). In the case where
the severity of the right or left eyes was different, the eye
condition was taken for more severe staging. Incidence
and progression of DR were assessed in diabetic subjects
with either NDR or NPDR at the baseline from a series ofImpact of treatment cessation on incidence and progression of retinopathy in Japanese patients…

examinations from 2009 to 2013 or later (i.e., from NDR
to NPDR or PDR or from NPDR to PDR). Incidence of DR
was assessed in diabetic subjects with NDR at the baseline
by worsening in stage (i.e., from NDR to NPDR or PDR),
and progression of DR in diabetic subjects with NPDR at
the baseline was defined as a worsening in stage (i.e., from
NPDR to PDR) [30, 31].

Assessment of other factors
Serum biochemical variables were measured by conventional automated analyzers. Dyslipidemia was identified by
the current use of anti-dyslipidemic drugs. Overt proteinuria
was defined as positive in case the result showed ± , 1 + ,
2 + , 3 + , and 4 + , as measured by semi-qualitative urinary
protein stick test after two consecutive months. Body massindex (BMI) was calculated as weight (kg)/height squared­(m2).

Statistical analyses
Initially, baseline clinical characteristics for the no treatment
cessation and treatment cessation groups were shown asmeans (with their standard deviations (SDs)) for continuous
variables with a normal distribution, medians (25%, 75%)
for continuous variables with a non-normal distribution, andthe number of subjects (n) (%) for categorical variables. The
characteristics were then compared between the groups oftreatment cessation status using unpaired t-tests for continuous variables with a normal distribution, Kruskal–Wallis test
for continuous variables with a non-normal distribution, andchi-square test for categorical variables.
Next, to compare the incidence of DR between T2DM
patients of NDR at the baseline with and without treatment
cessation, a logistic regression model was used to calculate the odds ratio (OR) (95% confidence interval [CI]) for
incidence of DR in the treatment cessation group with theno treatment cessation group serving as the reference after
adjusting for age (years as a continuous variable), sex (maleor female as a categorical variable), BMI (kg/m2 as a continuous variable), duration of T2DM (years as a continuous
variable), and HbA1c level (% as a continuous variable). In
addition, to compare the progression of DR between T2DM
patients of NPDR at the baseline with and without treatment
cessation, a logistic regression model was used to calculate
the OR (95% CI) for the progression of DR in the treatment cessation group after adjusting for possible confounding factors in the same fashion. Furthermore, to compare
the incidence/progression of DR between T2DM patientswith either NDR or NPDR at the baseline with and without
treatment cessation, a logistic regression model was used to
calculate the OR (95% CI) for incidence/progression of DR
in the treatment cessation group after adjusting for possible

confounding factors in the same fashion. Finally, we calculated all ORs (95% CIs) for all covariates in these multiple
logistic regression models.
Statistical analyses were performed using a standard software package (JMP version 12; SAS Institute Inc., Cary,NC) unless otherwise indicated. All probability values were
two-tailed, and the significance level was set at P < 0.05.

Results
Baseline clinical characteristics of study subjects
Clinical characteristics of the cohort at the baseline(N = 417) are shown in Table 1. The proportion of men was
56%, the mean age was 62 ± 12 years, and the mean BMI
was 25.4 ± 4.4 kg/m2. The average level of HbA1c at thebaseline was 7.7 ± 1.6%. The median duration of T2DM was
10 (5, 16) years. The prevalence of treatment cessation in all
patients was 13%. As compared to the no treatment cessationgroup, the treatment cessation group were relative youth inage (57 ± 11 years vs. 63 ± 12 years, P < 0.01). The treatment
cessation group also showed a higher HbA1c level than thegroup without treatment cessation, although the difference
was not statistically significant.

Rate of incidence of DR and its OR
The incidence rate of DR was 25% (N = 69, NPDR;
N = 65, PDR; N = 4) among T2DM patients with NDR at
the baseline (N = 281) over a follow-up with a median of
7 years (Fig. 2). As shown in Table 2, the incidence rateof DR among patients with treatment cessation was prominently higher at 58% as compared to incidence rate of DR
in patients without treatment cessation (20%). In logistic
regression analyses, the OR for incidence of DR in the treatment cessation group, with the no treatment cessation groupserving as the reference, was 5.71 (95% CI 2.59–12.57,
P < 0.01) after adjusting age and sex and was 4.20 (95%
CI 1.46–12.04, P < 0.01) after further adjusting BMI, duration of T2DM, and HbA1c level (Table 2 and Supplemental
Table 1). In addition, higher HbA1c was also significantly
associated with the incidence of DR (OR 1.50 [1.22–1.84]
per + 1%, P < 0.01) (Supplemental Table 1).

Rate of progression of DR and its OR
The progression rate of DR was 30% (N = 41) in T2DM
patients with NPDR at the baseline (N = 136) (Fig. 2). As
shown in Table 3, the progression rate of DR in patientswith treatment cessation was apparently higher at 40% ascompared to progression rate of DR in patients without treatment cessation (28%). The age and sex-adjusted OR for the

Y. Shinzato et al.
Table 1   Baseline clinicalcharacteristics of study subjects

Number (%)
Men (%)
Age (year)
BMI (kg/m2)
Duration of T2DM (years)
Anti-hypertensive drugs (%)
Dyslipidemia (%)
Overt proteinuria (%)
Diabetic retinopathy (%)
Diabetic nephropathy (%)
History of smoking (%)
Family history of diabetes (%)
HbA1c(%)
ALB (mg/dL)
Blood urea nitrogen (mg/dL)
Creatinine (mg/dL)
eGFR (mL/min/1.73 ­m2)
UA (mg/dL)
Triglyceride (mg/dL)
LDL-C (mg/dL)
HDL-C (mg/dL)
AST (IU/L)
ALT (IU/L)γGTP (IU/L)All

Treatment cessation

No treatment cessation

P

417
233/417 (56)62 ± 1225.4 ± 4.4
10 (5, 16)
272/417 (65)296/417 (71)
164/365 (45)136 /417 (33)
190/352 (54)160/417 (38)
123/417 (29)7.7 ± 1.6
4.0 ± 0.5
17.3 ± 10
1.0 ± 1.1
67 (40, 85)
5.5 ± 1.5
129 (84, 180)
106 ± 38
51 ± 1421 (16, 26)
21 (15, 31)
26 (17, 46)

53/417 (13)33/53 (62)57 ± 1125.5 ± 4.2
10 (5, 18)
30/53 (57)
40/53 (75)22/47 (47)
20/53 (38)26/42 (62)24/53 (45)14/53 (26)8.0 ± 1.5
4.0 ± 0.4
18.1 ± 17
1.0 ± 1.0
74 (28, 89)
5.4 ± 1.6
137 (80, 219)
112 ± 4948 ± 1117 (14, 25)
19 (13, 30)
32 (17, 53)

364/417(87)200/364 (55)63 ± 1225.4 ± 4.4
10 (5, 16)
242/364 (66)256/364 (70)142/318 (45)116/364 (32)
164/310 (53)136/364 (37)109/364 (30)7.6 ± 1.6
4.1 ± 0.5
17.2 ± 9.0
1.0 ± 1.1
67 (42, 84)
5.5 ± 1.5
126 (84, 177)
105 ± 3652 ± 1521 (17, 26)
21 (15, 31)
26 (17, 45)0.32< 0.01
0.83
0.82
0.16
0.44
0.78
0.39
0.27
0.27
0.60
0.20
0.54
0.57
0.90
0.91
0.53
0.32
0.41
0.06
0.11
0.30
0.91

Date are expressed as mean (SD), median [IQR], and n (%). Dyslipidemia means use of anti-dyslipidemia
drugs, Overt proteinuria means positive of urinary qualitative at two consecutive follow-up months
BMI body mass index, HbA1c glycated hemoglobin, ALB albumin, eGFR estimated glomerular filtration,
UA uric acid, LDL-C low- density lipoprotein cholesterol, HDL-C high-density lipoprotein cholesterol,
AST alanine aminotransferase, ALT aspartate aminotransferase, γGTP γ-glutamyltransferase.
P values were calculated by one-way ANOVA

progression of DR in the group with treatment cessation was
1.64 (95% CI 0.61–4.41, P = 0.32), and the multivariateadjusted OR was 1.72 (95% CI 0.56–5.34, P = 0.35) (Table 3
and Supplemental Table 2). There was no significant determinant associated with progression of DR (Supplemental
Table 2).

Rate of incidence and progression of DR and its OR
The incidence and progression rate of DR was 26%(N = 110) in T2DM patients with either NDR or NPDR at
the baseline (N = 417) (Fig. 2). As shown in Table 4, theincidence and progression rate of DR in patients with treatment cessation was prominently higher at 51% as compared
to progression rate of DR in patients without treatment cessation (23%). The age and sex-adjusted OR for incidence/progression of DR in the treatment cessation group was 3.48
(95% CI 1.91–6.35, P < 0.01), and the multivariate-adjusted
OR was 2.70 (95% CI 1.28–5.69, P < 0.01) (Table 4 andSupplemental Table 3). In addition, duration of T2DM (OR1.04 [1.00–1.07] per + 1 year, P = 0.03) and higher level of
HbA1c (OR 1.39 [1.19–1.62] per + 1%, P < 0.01) were alsosignificantly associated with the incidence and progressionof DR (Supplemental Table 3).

Discussion
The present cohort study demonstrated that treatment cessation was tightly associated with the incidence of DR in Japanese T2DM patients without DR, independently of majorclinical parameters including HbA1c level and duration of
T2DM. Treatment cessation was also independently associated with the incidence/progression of DR in T2DM patientswith either NDR or NPDR.
In a cross-sectional observation of 15,000 patients with
T2DM in the UK, Currie et al. reported that patients withtreatment cessation showed a higher prevalence of DR andnephropathy as compared to patients with non-cessation,
while the incidence of macroangiopathy was comparable

Impact of treatment cessation on incidence and progression of retinopathy in Japanese patients…
Fig. 2   Distribution of patientswith T2DM on the stage of DR
at baseline and during the follow-up. Numbers of incidence
are shown in the purple band,
those of progression are shownin light red band and those of
no changes are shown in light
blue band. NDR no diabetic
retinopathy, NPDR nonproliferative diabetic retinopathy,
and PDR proliferative diabetic
retinopathy

Table 2   Rate of incidence ofDR and its odds ratio

Subjects N = 281
Incidence cases N = 69
Incidence rate (%)
Age and sex-adjusted odds ratio
Multivariate-adjusted odds ratio

No treatment cessation

Treatment cessation

P

248
50
20% (50/248)
1 (reference)
1 (reference)33
19
58% (19/33)
5.71 (2.59–12.57)
4.20 (1.46–12.04)< 0.01< 0.01

A logistic regression model was used to calculate the odds ratio (95% confidence interval) with the notreatment cessation group serving as the reference after adjusting for age, sex, BMI, duration of T2DM,
and HbA1c level

Table 3   Rate of progression of
DR and its odds ratio

Subjects N = 136
Progression cases N = 41
Progression rate (%)
Age and sex-adjusted odds ratio
Multivariate-adjusted odds ratio

No treatment cessation

Treatment cessation

P

116
33
28% (33/116)
1 (reference)
1 (reference)20
840% (8/20)
1.64 (0.61–4.41)
1.72 (0.56–5.34)

0.32
0.35

A logistic regression model was used to calculate the odds ratio (95% confidence interval) with the notreatment cessation group serving as the reference after adjusting for age, sex,BMI, duration of T2DM, andHbA1c level

between two groups [26]. Archibald et al. reported from theUK that 37 patients (Type 1 diabetes mellitus and T2DM)
with treatment cessation showed both a higher level of
HbA1c and a higher prevalence of microvascular and macrovascular complications as compared to the other 37 patientswith non-cessation [32]. In 1985, Hammersley et al. reported

that treatment cessation was associated with the subsequent
occurrence of DR in 54 patients with T2DM, and there
were positive correlations between the occurrence of DR
and higher levels of HbA1c or diastolic blood pressure [27].
Importantly, however, the study showed the association ofinterest without allowing for clinical characteristics related

Y. Shinzato et al.
Table 4   Rate of incidence andprogression of DR and its odds
ratio

Subjects N = 417
Incidence and progression cases N = 110
Incidence annd progression rate (%)
Age and sex-adjusted odds ratio
Multivariate-adjusted odds ratio

No treatment cessation

Treatment cessation

P

364
83
23% (83/364)
1 (reference)
1 (reference)53
27
51% (27/53)
3.48 (1.91–6.35)
2.70 (1.28–5.69)< 0.01< 0.01

A logistic regression model was used to calculate the odds ratio (95% confidence interval) with the notreatment cessation group serving as the reference after adjusting for age, sex, BMI, duration of T2DM,
and HbA1c levelto treatment cessation [27]. Unlike these previous studies,to the best of our knowledge, the present study would be thefirst cohort study that demonstrates an association between
treatment cessation and the incidence (incidence/progression) of DR after adjusting for a variety of confounders using
multivariate analyses (Tables 2, 4). In consistent with a lineof previous reports [1–3], a higher level of HbA1c was alsosignificantly associated with the incidence of DR (Supplemental Table 1). Longer duration of T2DM and higher levelsof HbA1c were significantly associated with the incidence/progression of DR (Supplemental Table 3). Consequently,
the association between treatment cessation and the incidence (incidence/progression) of DR was independent ofthese clinical characteristics. It was notable that the association of interest was independent of increased HbA1c which
is somewhat linked with treatment cessation. However, ourstudy only provides evidence on the association of interest,
and precise molecular mechanisms whereby treatment cessation would induce DR still remain unsolved. In the present
study, with a sharp contrast to the case of incidence of DR,
treatment cessation was not significantly associated with
progression of DR. It has been reported that sustained hypertension coupled with a higher level of HbA1c is apparently
associated with the incidence of DR. In contrast, continuously high level of HbA1c per se has been shown to be associated with the progression of DR [4, 33]. This notion may
suggest that the incidence of DR is influenced by a variety offactors in a complexed fashion, whereas the progression of
DR would mainly depend on the quality of glycemic control.
In this sense, prospective clinical studies are warranted toclarify the differences in risk factors between incidence andprogression of DR.
As the present study was conducted using preexisting
medical records and treatment cessation was retrospectively checked, it has some limitations. For example, blood
examinations before and after treatment cessation could not
be precisely evaluated, and all examinations in the followup period were undertaken at different time schedules foreach patient. Thus, we could not examine whether treatment
cessation results in poor metabolic control. The incidenceof DR in each case may differ depending on the timing of

cessation in the course of treatment. There seem to be two
major scenarios on the possible association between treatment cessation and incidence of DR. First, in case treatment
was ceased early in the course of treatment, transient hyperglycemia would impact the aggravation of later complications, also known as the notion of “negative legacy effects”[34–37]. It has been suggested that mechanisms of the negative legacy effects are tightly linked with epigenetic modifications and exaggerated chronic oxidative stress [38–40].
Second, in case the treatment cessation occurred later in thecourse of treatment and also hyperglycemia improved rapidly after resuming treatment, DR is likely to worsen expeditiously, also known as the notion of “accelerated worseningof DR” [41–43]. The mechanisms of accelerated worseningof DR have been shown, at least partly, to link with the disruption of the autoregulation of capillary blood flow at theretina [44].
In accordance with the previous reports, the prevalence oftreatment cessation in the present study was 13% (Table 1).
The prevalence of treatment cessation ranges from 4 to 19%
in the UK [28, 32], 12–50% in the United States [45, 46],and 35–57% in Japan [47, 48]. Characteristics of the treatment cessation group in our data are relative youth as compared to the nontreatment cessation group (Table 1). Ourdata are in agreement with many previous reports in termsof relative youth [9–12], further confirming the validity of
the cohort in the present study.
We do acknowledge that there are a couple of critical limitations in the present study. First, because of theretrospective design, the present study failed to obtain aconsiderable amount of clinical data, and also the duration of treatment cessation or clinical parameters before
and after cessation or precise severity of DR could not beadequately considered. Various clinical factors such as thevalue of HbA1c during the course of follow-up may also
influence the development of DR. Also, we do recognize
the importance of a multivariate model including timedependent HbA1c level. However, just because the dataof the present study are anonymously obtained, we aresorry to have to say that we cannot detect new data at thistime. Second, our study did not investigate the detailed

Impact of treatment cessation on incidence and progression of retinopathy in Japanese patients…

therapeutic framework and the underlying reasons fortreatment cessation. Finally, we did not examine the relationship between treatment cessation and other diabetic
complications including neuropathy, nephropathy, andmacroangiopathy.
In summary, our data highlight that, independently ofglycemic control and duration of the disease, treatment cessation increases the incidence risk of DR in patients with
T2DM. Further studies are warranted to clarify the underlying mechanisms of the causal relationship between treatment
cessation and the incidence of DR, which should help toprevent the incidence of DR.
Supplementary Information The online version contains supplementary material available at https://d​ oi.o​ rg/1​ 0.1​ 007/s​ 13340-0​ 24-0​ 0724-7.
Acknowledgements This work was supported in part by Council for
Science, Technology and Innovation (CSTI), Cross-Ministerial Strategic Innovation Promotion Program (SIP), “Technologies for Creating
Next-Generation Agriculture, Forestry and Fisheries,” New Energy
and Industrial Technology Development Organization (NEDO), andConstruction of the Okinawa Science & Technology Innovation System. We are also grateful to T. Ikematsu, M. Hirata, and C. Noguchi
for excellent secretarial assistance.
Author contributions All authors contributed to the study’s conception and design. Material preparations were performed by Yoshiro
Nakayama, Moritake Higa, Hideki Koizumi, Michio Shimabukuro,and Hiroaki Masuzaki, data collections were performed by Yoshiro
Nakayama and Moritake Higa, and analyses were performed by Yukiko
Shinzato, Yoshiro Nakayama, Tsugumi Uema, Hideki Koizumi, Michio
Shimabukuro, Koshi Nakamura, and Hiroaki Masuzaki. The first draftof the manuscript was written by Yukiko Shinzato, Yoshiro Nakayama,Jasmine F Millman, Michio Shimabukuro, and Hiroaki Masuzaki, andall authors commented on previous versions of the manuscript. All
authors read and approved the final manuscript.
Data availability The data that support the findings of this study areavailable on request from the corresponding author.

Declarations
Conflict of interest None of the authors have any conflicts of interest
to disclose.
Ethical approval All procedures followed were in accordance with the
ethical standards of the responsible committee on human experimentation (The Ethics Committee of University of the Ryukyus for Medicaland Health Research Involving Human Subjects (No.765) on February
27, 2015) and with the Helsinki Declaration of 1964 and later versions.
Informed consent or substitute for it was obtained from all patients forbeing included in the study.

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Impact of treatment cessation on incidence and progression of retinopathy in Japanese patients…

Authors and Affiliations
Yukiko Shinzato1 · Yoshiro Nakayama1 · Shiki Okamoto1 · Jasmine F. Millman1 · Tsugumi Uema1 ·Ken‑ichiro Honma1 · Atsuko Tamaki1 · Moriyuki Uehara1 · Taiki Teruya1 · Takamitsu Yabiku1 · Yohei Ishiki1 ·Ken Yonaha1 · Ko‑ichiro Arakaki2 · Moritake Higa3 · Hideki Koizumi4 · Koshi Nakamura5 · Michio Shimabukuro6 ·Hiroaki Masuzaki1* Michio Shimabukuro
mshimabukuro-ur@umin.ac.jp* Hiroaki Masuzaki
hiroaki@med.u-ryukyu.ac.jp
1

Division of Endocrinology, Diabetes and Metabolism,
Hematology, Rheumatology (Second Department of Internal
Medicine), Graduate School of Medicine, Universityof the Ryukyus, 207 Uehara, Nishihara, Nakagami,
Okinawa 903‑0215, Japan2

Department of Ophthalmology, Tomishiro Central Hospital,
25 Ueda, Tomigusuku, Okinawa 901‑0243, Japan3

Department of Diabetes and Life‑Style Related Disease
Center, Tomishiro Central Hospital, 25 Ueda, Tomigusuku,
Okinawa 901‑0243, Japan

4

Department of Ophthalmology, Graduate Schoolof Medicine, University of the Ryukyus, 207 Uehara,
Nishihara, Okinawa 903‑0215, Japan

5

Department of Public Health and Hygiene, Graduate Schoolof Medicine, University of the Ryukyus, 207 Uehara,
Nishihara, Okinawa 903‑0215, Japan

6

Department of Diabetes, Endocrinology and Metabolism,
Fukushima Medical University School of Medicine, 1
Hikarigaoka, Fukushima, Fukushima 960‑1295, Japan