Short-Term Diabetic Retinopathy Status in People with Type 1 Diabetes Commencing Automated Insulin Delivery

Abstract

Objective:

Rapid improvements in glucose control may lead to early worsening of diabetic retinopathy (EWDR). There is a need to demonstrate safety in people commencing automated insulin delivery (AID) due to the known efficacy in rapid glycemic improvement. We aimed to investigate short-term DR outcomes in people (aged ≥13 years) with type 1 diabetes after initiation of AID (use ≥6 months).

Research Design and Methods:

Retrospective four center observational study with participants drawn from hospital databases (Dunedin and Christchurch, New Zealand) and also from two research studies based out of Auckland, New Zealand, and Perth, Australia. Demographic and clinical characteristics and DR grading data before and after AID initiation were collected, and statistical analysis was performed.

Results:

DR grading data from 165 people using AID (three different AID systems) were available, and mean improvement in HbA1c for the total sample was 1.0 ± 1.3 percentage points. Improvements in grading were seen in 32/165 (19%), 99/165 (60%) were stable, and 34/165 (21%) worsened in their R- and/or M-grade. Age at AID initiation ≥18 years was the only significant risk factor for any worsening of DR (P = 0.028). Proliferative change and need for photocoagulation were uncommon but did occur in 3% (5/165); all noted to have prior DR, diabetes duration >10 years, and with at least another diabetes complication or prior DR treatment.

Conclusions:

In this study, stable or improved DR grades were evident in most who had recently commenced AID. Age at AID initiation <18 years appears protective.

Introduction

The worldwide prevalence of type 1 diabetes (T1D) is approximately 8.4 million individuals.¹ Despite the implementation of conventional treatment, it remains uncommon to attain glycemic targets known to diminish the risk of developing chronic diabetes complications and a subsequently reduced life expectancy.^2,3

Diabetic retinopathy (DR) is the most common microvascular complication of diabetes and a leading cause of blindness.⁴ The landmark Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications studies identified high HbA1c, long duration of T1D, albuminuria, and high diastolic blood pressure as the greatest risk factors for progression to proliferative DR.⁵ Other risk factors include frequency of severe hypoglycemia and diabetic ketoacidosis.⁶ While there have been reductions in the incidence and prevalence of DR in the last decades, the burden of this diabetes complication remains high.⁷

Large pivotal studies have shown that intensive therapy can reduce both the development and progression of DR compared with conventional therapy.^8

–11 Currently, the recommended intensive therapy option for people with T1D is automated insulin delivery (AID).¹² These systems combine an insulin pump, a continuous glucose monitor (CGM), and an algorithm that automatically adjusts and/or boluses insulin according to changing glucose levels. The first AID system received Food and Drug Administration’s (FDA) approval in September 2016,¹³ and innovation has progressed steadily from there with all AID systems demonstrating benefits for glycemia.^14

–18 In addition, research on individuals with very unhealthy glycemia suggests that dramatic and rapid improvements are possible for many.¹⁹

Given this potential for rapid improvements in glycemia with AID systems, concerns have been raised that this may lead to early worsening of diabetic retinopathy (EWDR)—often defined as DR progression during the first year after rapid improvement in glycemia.²⁰ EWDR has been previously described, most notably in the DCCT, after the initiation of intensive insulin therapy and resultant glucose improvement.^8

–11 It is still unclear which pathophysiological mechanisms may cause EWDR, but variations in the somatotropic axis and higher retinal concentrations of angiogenic factors have been suggested.²⁰

While the health benefits of intensively improving glycemia clearly outweigh the risks of EWDR in the long-term,²⁰ a greater understanding is required to monitor and manage these risks. Despite the growing use of AID, little data currently exist in this space. Therefore, this study aimed to investigate DR status, worsening, and potential risk factors in a cohort of people with T1D using AID for at least 6 months.

Methods

Study design

This was a four-site retrospective observational study involving 165 individuals with T1D (Fig. 1), drawn from clinical databases (Dunedin, Christchurch, New Zealand) and two research studies (Auckland, NZ; and Perth, Australia),²¹ all who had used AID for at least six months. The data collection was carried out from March to June 2024.

FIG. 1.

Participant flow diagram. *No data available in the database, no recent appointments, or moved to another district. ^†No available DR data at baseline (not eligible for screening, did not attend appointments, seen at a private clinic or moved to another district).^‡No available DR data after AID initiation (not eligible for rescreen, did not attend appointment, seen at a private clinic or moved to another district). AID, automated insulin delivery; DR, diabetic retinopathy.

Selection of participants

Inclusion criteria were known T1D, use of AID for ≥6 months, and age ≥13 years at the time of data collection. These criteria were pragmatically chosen to align with the 6–12 month time-window when EWDR is most likely to occur²⁰ and also spanning an age and time period when before and after retinal photography, assessments were likely to have been completed. Participants who did not have fundus photography with DR grading at baseline or following AID initiation were excluded.

Demographic and clinical variables

Basic demographic information was collected, including date of birth, date of diabetes diagnosis, type of AID system used, ethnicity, sex, home address to convert to NZDep2018 when available (a New Zealand measure of socioeconomic deprivation),²² smoking status (nonsmoker, smoker, or vape user), and body mass index (BMI). HbA1c values, at AID initiation and after 3 months, were collected as a marker of glycemia and to measure HbA1c change. If no HbA1c value was available at 3 months, the closest subsequent value was collected. DR grading data were collected from before AID initiation (closest data available prior to AID initiation) and after AID initiation (closest data available following AID initiation). As these were largely clinical data, collection time points varied, and timing is described in the results. Variation in timing in this largely clinical data was considered acceptable given the commonly used 1-year time frame for determining EWDR.²⁰ Data regarding other diabetes complications were also obtained, including nephropathy (elevated urinary albumin–creatinine ratio or formal diagnosis and/or treatment); dyslipidemia based on those already with a formal diagnosis/on therapy or pragmatically based on non-fasted laboratory American College of Cardiology/American Heart Association Practice Guidelines (defined as total cholesterol ≥5.0 mmol/L and/or LDL cholesterol ≥3.4 mmol/L)²³; neuropathy formal diagnosis; and hypertension formal diagnosis and/or treatment.

Assessment of DR

All grading in New Zealand was via the national clinical retinopathy screening service and was done using the New Zealand Ministry of Health guidelines, called “New Zealand National Diabetes Retinal Grading System.”²⁴ This grading system is modified from the “Airlie House Classification Scheme of the Early Treatment Diabetic Retinopathy Study”²⁵ and is similar to the “International Clinical Disease Severity Scale” (ICDSS),²⁶ but with a more discernible level of distinction among the grades, spanning from R0 to R5 and M0 to M5, compared with the four grades of DR in ICDSS. The grading classification for DR (R grade) consists of seven grades: no DR (R0), minimal (R1), mild (R2), moderate (R3), severe (R4), proliferative (R5), and “previously treated proliferative retinopathy” (RT). The grading classification system for diabetic macular disease (M) also consists of seven grades: no macular disease (M0), minimal (M1), mild (M2), mild (M3), moderate (M4), severe (M5), and “stable, treated macular disease” (MT). Perth assessments were done via ICDSS, and as all showed nil retinopathy, comparison between New Zealand and Perth data was straightforward.

Finally, DR is difficult to grade after laser treatment, and often there is a 2-year period from laser treatment before DR can be classified using the above classification system.²⁴ In this study, participants who had laser treatment before AID initiation were analyzed separately, and data on DR were collected to determine whether their condition remained stable or worsened after AID initiation.

Data analysis and statistical methods

Baseline demographic and clinical characteristics were described using means and standard deviation for continuous variables, respectively, numbers and percentages for categorical variables. The range for the continuous variables of age and baseline HbA1c was determined. Socioeconomic deprivation index deciles were divided into subgroups: low,^1
–3 medium,^4

–7 and high.^8
–10 Self-identified prioritized ethnicities were defined based on the NZ level 1 classification.²⁷

DR data were divided into subgroups (determined by the worst grade of the worst eye): nil (R0 and M0), minimal (R1 and/or M1), mild (R2 and/or M2/M3), moderate (R3 and/or M4), severe (R4 and/or M5), proliferative (R5), or previously treated DR (RT and/or MT). Proportions were determined for improvement, stability, or worsening. Improvement was defined as any decrease in either retinopathy or maculopathy grade (or both), stability as no change in either retinopathy or maculopathy grade, and worsening as any rise in either retinopathy or maculopathy grade (or both).

For further investigation, clinical characteristics were analyzed based on whether people experienced improvement, stability, or worsening in DR status. DR grading at baseline was also determined for each group, based on the previously mentioned subgroups (nil, minimal/mild, moderate/severe, proliferative, and previously treated). To highlight the individuals who worsened to proliferation and needed treatment, their characteristics were analyzed further, including their baseline characteristics, degree of HbA1c improvement (categorized as change post AID >1.5% or ≤1.5%), and DR outcomes. Lastly, DR outcomes were also determined based on diabetes duration (DD), in the following subgroups: DD <10 years and ≥10 years. Using the above grading, EWDR was defined as any deterioration in DR grading documented in the period after AID commencement. It should be noted that these are observational data and so retinopathy grading and HbA1c were not collected at uniform times. Therefore, median and range data from before and after AID commencement are provided for clarity in the results.

All statistical analyses were performed using IBM-SPSS software (26.0). χ² tests were performed for categorical variables. Relative risks were calculated by dividing the incidence of worsening DR outcomes among people with rapid HbA1c improvement as defined by the incidence of the remaining people. Relative risks were also calculated by dividing the incidence of worsening DR outcomes among people with DD <10 years by the incidence of those with ≥10 years. To adjust for multiple risk factors and further address the potential risk factors contributing to the outcomes of interests, binary logistic regression was performed and was adjusted to the age at AID initiation, BMI, insulin therapy, and duration from AID initiation to DR grading assessment. HbA1c at baseline is not included in the analysis due to collinearity with rapid HbA1c improvement.

Ethical considerations

Ethics approval was obtained from the Academic Committees and Services, University of Otago, number HD24/015. Locality approval was also obtained from Health NZ. Collecting ethnicity data and managing data in a culturally sensitive way is a core part of NZ research environment, and our community and consultation with Māori (indigenous people of NZ) was also completed.

Data and resource availability

The datasets generated during and/or analyzed in the current study are available from the corresponding author upon reasonable request.

Results

Baseline demographic and clinical characteristics

Data from 165 people with T1D using AID for at least 6 months were collected (Fig. 1). Table 1 shows their baseline demographic and clinical characteristics. Most (93%) used standard pump therapy before initiation of AID. Most (84%) had nil, minimal, or mild DR at baseline.

Table 1.

Baseline Demographic and Clinical Characteristics

Baseline characteristic	Participants (n = 165)
Age at AID initiation (years), mean ± SD [range]	28.4 ± 15.5 [9–70]
Female, n (%)	98 (59)
Prioritized ethnicity, n (%)
NZ European/European	113 (68)
Māori^a	15 (9)
Other ethnicity^b	4 (2)
Unknown	32 (19)
Socioeconomic deprivation index, n (%)
Low (1–3)	56 (34)
Medium (4–7)	59 (36)
High (8–10)	19 (12)
Unknown	31 (19)
BMI (kg/m2), mean ± SD	26.5 ± 5.3
Smoke/Vape,^c n (%)	10 (6)
Duration of diabetes (years), mean ± SD	15.7 ± 10.3
Age at diagnosis (years), mean ± SD	12.2 ± 11.4
Pump therapy before AID initiation	154 (93)
AID system^d
Medtronic 780G	82 (50)
Tandem t:slim Control-IQ	45 (27)
OpenAPS	38 (23)
HbA1c (%), mean ± SD [range]	8.4 ± 1.6 [5.5–17.6]
HbA1c (mmol/mol), mean ± SD [range]	68.8 ± 17.6 [37–169]
Other associated diabetes complications,^e n (%)
Nephropathy	17 (10)
Dyslipidemia	48 (29)
Hypertension	29 (18)
Neuropathy	4 (2)
Baseline DR grading^f
Nil (M0/R0)	76 (46)
Minimal (M1/R1)	19 (12)
Mild (M2/M3/R2)	43 (26)
Moderate (M4/R3)	5 (3)
Severe (M5/R4)	1 (1)
Proliferative (R5)	1 (1)
Previously treated^g (MT/RT)	20 (12)

The indigenous people of New Zealand.

Including one Pacific.

Two of 10 vapes.

AID system initiated at baseline.

Sixty-three percent had 0 complication; 18% had more than one complication.

Mean time from baseline examination to AID initiation was 7.9 ± 8.3 months.

Previously treated with panretinal photocoagulation (PRP) at baseline, their R and M grades were not collected.

AID, automated insulin delivery; BMI, body mass index; DR, diabetic retinopathy; SD, standard deviation.

DR outcomes related to glycemia

DR status following AID initiation, related to the magnitude of HbA1c improvement, is presented in Table 2. The mean time from AID initiation until follow-up grading was 8.7 ± 7.2 months. The mean time from AID initiation until measurement of HbA1c was 3.6 ± 2.6 months. Following AID initiation, the mean improvement in HbA1c for the total sample was 1.0 ± 1.3 percentage points (11 ± 14.4 mmol/mol).

Table 2.

Retinopathy Outcomes of People Categorized by Degree of HbA1c Improvement^a Following AID Initiation (≤1.5%; >1.5%)

	Non-worsening			Worsening				RR (95% CI)(NW:W)	P
	Total	Improvement	No change	Total	To minimal/Mild (R1/R2)	To moderate/Severe (R3/R4)	To proliferative (R5)	RR (95% CI)(NW:W)	P
R grade
Full sample (N = 145)	119 (82%)	25 (17%)	94 (65%)	26 (18%)	18 (12%)	4 (3%)	4 (3%)
HbA1c change ≤1.5% (N = 115)	94 (82%)	20 (17%)	74 (64%)	21 (18%)	17 (15%)	3 (3%)	1 (1%)	Reference	0.839^c
HbA1c change >1.5% (N = 30)	25 (83%)	5 (17%)	20 (67%)	5 (17%)	1 (3%)	1 (3%)	3 (10%)	1.02 (0.39, 2.17)	0.839^c
M grade
Full sample (N = 145)	129 (89%)	19 (13%)	110 (76%)	16 (11%)	12 (8%)	4 (3%)	0 (0%)
HbA1c change ≤1.5% (N = 115)	103 (90%)	15 (13%)	88 (77%)	12 (10%)	10 (9%)	2 (2%)	0 (0%)	Reference	0.743^c
HbA1c change >1.5% (N = 30)	26 (87%)	4 (13%)	22 (73%)	4 (13%)	2 (7%)	2 (7%)	0 (0%)	0.94 (0.70, 1.26)

Previously treated^b	Stable or improvement	Vision threatening worsening
Full sample (N = 20)	19 (95%)	1 (5%)
HbA1c change ≤1.5% (N = 15)	15 (100%)	0 (0%)
HbA1c change >1.5% (N = 5)	4 (80%)	1 (20%)

Mean time from AID initiation until measurement of HbA1c 3.6 ± 2.6 months.

PRP before AID initiation.

P value from Pearson chi-square.

CI, confidence interval; PRP, panretinal photocoagulation.

DR outcomes in participants with HbA1c improvement (≤1.5 percentage points)

Among the 130/165 participants who experienced more moderate glycemic improvements (≤1.5 percentage points [16.4 mmol/mol] improvement in HbA1c), the mean HbA1c improvement was 0.6 ± 0.7 percentage points (6.1 ± 7.2 mmol/mol). Of those who experienced improvements in R grade (n = 20), 19/20 improved one grade (12/19 from R1 to R0, 6/19 from R2 to R1, and 1/19 from R3 to R2) and 1/20 improved two grades (R2 to R0). Of those who worsened to R1/R2 (n = 17), 11/17 worsened one grade (6/11 from R0 to R1 and 5/11 from R1 to R2) and 6/17 worsened two grades (6/6 from R0 to R2). Of those who worsened to R3/R4 (n = 3), 1/3 worsened one grade (R2 to R3) and 2/3 worsened two grades (2/2 from R2 to R4). One participant worsened from R1 to R5, with further details summarized in Table 3 (case P1).

Table 3.

Characteristics of Participants Progressing to Proliferative Retinopathy Requiring Treatment

Characteristics	P1	P2	P3	P4	P5
Age, years	41	18	27	22	34
Sex	Female	Female	Male	Male	Female
Diabetes duration, years	35	16	27^a	10	24
Ethnicity	European	NZ European	NZ European	NZ European	NZ European
Socioeconomic deprivation index^b	Medium	Low	Medium	Medium	Low
BMI, kg/m²	30.6	23.2	23.8	24.1	24.6
Smoking	No	No	No	No	No
Baseline complications
Nephropathy	No	No	No	Yes	No
Dyslipidemia	Yes	Yes	Yes	No	No
Neuropathy	Yes	No	No	No	No
Hypertension	Yes	No	Yes	No	No
HbA1c at baseline, % (mmol/mol)	7.8 (62)	12.4 (112)	8.1 (65)	13.2 (121)	8.6 (70)
HbA1c improvement, percentage points (mmol/mol)	1.1 (12)	5.9 (64)	1.6 (18)	6.4 (70)	1.8 (20)
Baseline DR grading
R and M grades	R1M2	R2M3	R2M2	R4M2	Stable treated^c
Time to AID initiation, months	2	8	4	0	3
DR grading after AID
R and M grades	R5M2	R5M2	R5M2	R5M2	Worsened^d
Time from AID initiation, months	11	5	9	8	2

Diagnosed at 8 months of age.

NzDep index 1–3 (low), 4–6 (medium), and 8–10 (high).

Previously treated with panretinal photocoagulation for proliferative DR.

New neovascularization.

Of those who experienced improvements in M grade (n = 15), 6/15 improved one grade (4/6 from M1 to M0 and 2/6 from M2 to M1) and 9/15 improved two grades (6/9 from M2 to M0 and 3/9 from M4 to M2). Of those who worsened to M1/M2/M3 (n = 10), 3/10 worsened one grade (2/3 from M1 to M2 and 1/3 from M2 to M3) and 7/10 worsened two grades (6/7 from M0 to M2 and 1/7 from M1 to M3). Of those who worsened to M4 (n = 2), 1/2 worsened one grade (from M3 to M4) and 1/2 worsened three grades (M1 to M4). No treatment due to maculopathy was required among participants.

DR outcomes in participants with HbA1c improvement (>1.5 percentage points)

Among the 35/165 participants who experienced larger glycemic improvements (>1.5 percentage points [16.4 mmol/mol] improvement in HbA1c), the mean HbA1c improvement was 2.8 ± 1.7 percentage points (30.3 ± 18.2 mmol/mol). Of those who experienced improvements in R grade (n = 5), 4/5 improved one grade (4/4 from R1 to R0) and 1/5 improved two grades (R2 to R0). Of those who worsened in R grade (n = 5), 1/5 worsened one grade (R4 to R5), 2/5 worsened two grades (1/2 from R0 to R2 and 1/2 from R1 to R3), and 2/5 worsened three grades (2/2 from R2 to R5). Three participants progressed to proliferation (R5), with further details summarized in Table 3 (cases P2–P4).

Of those who improved in M grade (n = 4), 3/4 improved one grade (1/3 from R1 to R0 and 2/3 from R3 to R1) and 1/4 improved two grades (M2 to M0). Of those who worsened in M grade (n = 4), 2/4 worsened one grade (2/2 from M0 to M1), 1/4 worsened two grades (M2 to M4), and 1/4 worsened four grades (M0 to M4). No treatment due to maculopathy was required among participants.

DR outcomes among previously treated participants

Prior to AID initiation, 20/165 (12%) had received panretinal photocoagulation (PRP) but had no active disease at baseline, 19/20 continued to be stable after AID initiation, and 1/20 worsened with new vessels requiring further treatment.

Risk factors contributing to worsening DR outcomes

Logistic regression analysis to assess whether and how clinical characteristics contributed to worsening DR outcomes is presented in Table 4. Age at AID initiation ≥18 years was the only significant risk factor for any worsening of DR (P = 0.028). In addition, no participant with DD <10 years required treatment nor progressed beyond a minimal or mild stage. Additional clinical characteristics for those who improved, were stable, and worsened are separately presented in Supplementary Table S1. Supplementary Table S2 summarizes the DR change based on DD.

Table 4.

Logistic Regression Analysis to Assess Risk Factors Contributing to Worsening of Retinopathy Outcomes

Characteristics	Stable or improvement^a (N = 131)	Worsening^a (N = 34)	Odd ratios^b (95% CI)	P trend
Rapid HbA1c improvement (>1.5% points), n (%)
Yes	27 (20.6)	8 (23.5)	1.1 (0.4, 3.4)	0.841
No	104 (79.4)	26 (76.5)	1
Age at AID initiation, n (%)
≥18 years	75 (57.3)	30 (88.2)	4.7 (1.2, 16.4)	0.028
<18 years	56 (42.7)	4 (11.8)	1
Gender, n (%)
Male	43 (38.4)	17 (51.5)	1.7 (0.7, 4.0)	0.238
Female	69 (61.6)	16 (48.5)	1
Duration of diabetes mellitus, n (%)
>15 years	44 (33.6)	17 (50.0)	1.6 (0.5, 5.2)	0.500
10–15 years	39 (29.8)	9 (26.5)	1.2 (0.4, 3.8)	0.787
<10 years	48 (36.6)	8 (23.5)	1
Smoking/Vaping
Yes	7 (5.4)	3 (8.8)	2.0 (0.3, 11.8)	0.456
No	124 (94.7)	31 (91.2)	1
History of multiple (≥1) complications, n (%)
Yes	14 (41.2)	20 (58.8)	3.0 (1.1, 7.9)	0.094
No	89 (67.6)	42 (32.1)	1
Moderate/Severe DR at baseline,^c n (%)
Yes	6 (5.4)	1 (3.0)	0.4 (0.0, 3.4)	0.371
No	106 (94.6)	32 (97.0)	1

In R and/or M grade.

Logistic regression analysis was made after adjusting duration from AID initiation to DR grading.

Logistic regression analysis was performed in N = 145, excluding those with previous treatment (N = 20).

Worsening to proliferative DR requiring treatment

Of the 165 participants, only 5/165 (3%) had clinically important EWDR, 4/5 worsened from a non-proliferative stage to a proliferative stage (R5), and 1/5 had new proliferation after previously treated proliferative disease. Table 3 summarizes their data. All (n = 5) had DR present at baseline, all had other diabetes complications at baseline (or previous DR treatment), and all (n = 5) had a DD ≥10 years. Of the 5/165 participants who progressed to require DR treatment, 2/5 (40%) had baseline HbA1c of >100 mmol/mol (11.3%), compared with 3/5 (60%) with an HbA1c <100 mmol/mol (11.3%).

Discussion

These data report for the first time changes in DR grading following the initiation of AID. Overall, this observational study helps to demonstrate the genera safety of AID, as the vast majority of participants showed improvement, stability, or minimal worsening of DR (to no more than minimal/mild disease) in the months following AID initiation. However, EWDR that needed treatment was seen in <4%, a rate like that seen in a recent systematic review investigating different types of intensive therapy.²⁸ Age at AID initiation ≥18 years was the only statistically significant risk factor identified for EWDR on logistic regression. Risk factors collectively seen in all who worsened to require DR treatment were prior DR, DD >10 years, and coexistence of one or more confirmed diabetes complications/prior to DR treatment.

It is important to emphasize that the benefits of improving glycemia remain crucial and far outweigh the risk of short-term DR deterioration, because it is rare and can be successfully managed. These outweighing benefits have been clearly demonstrated in the past studies^5,29,30 and highlight that in the longer term, improved glycemia results in reduced risk of progression of diabetes complications, including DR (a 76% reduction in the risk for DR progression after 6.5 years of follow-up in the DCCT³¹). Thus, the risk of DR deterioration in the short term should not prevent AID use, but for those at higher risk, including longer DD and coinciding diabetes complications at baseline, a closer follow-up and monitoring may be needed, with the main goal of early detection of proliferative DR.

In this cohort, the benefits of AID and more physiological glucose management led to short-term improvement in DR grading (in M and/or R grade) in 19% and 60% of the participants were stable, data that support the safety of these systems. Improvements in DR were also seen in another study after 2 years of insulin pump use versus injection treatment.³² There is a further possibility that some individuals who were stable or improved at follow-up screening may have had initial EWDR that regressed within the follow-up period (8.7 ± 7.2 months). Nevertheless, these reassuring improvement data combined with the fact that no clinically important DR worsening occurred in those with a DD <10 years and without preexisting DR may suggest that additional long-term benefits can be gained by initiating AID therapy as soon as possible once a diagnosis of diabetes has been established,³³ as recommended by current International Society for Pediatric and Adolescent Diabetes (ISPAD) guidelines.¹² In the DCCT, early intensive control also led to a phenomenon termed “metabolic memory,”^31,34 which led to persisting long-term health benefits even in those who subsequently became less healthy.

There is currently no evidence that managing the magnitude of HbA1c change will lower the risk of DR deterioration in people with diabetes.²⁰ Interestingly, there was no higher risk of worsening in DR grade between those with or without rapid improvement in HbA1c in this dataset (RR 1.02 [0.39, 2.17]). Given those with very unhealthy diabetes may have the most to gain from AID,^35,36 this provides considerable reassurance of safety. This combined with the fact that age at AID initiation ≥18 years was the only statistically significant risk factor, and no clinically significant DR deterioration occurred in those with a DD <10 years and without preexisting DR, suggests that children and adolescents may generally experience low risk of EWDR following AID initiation. These reassuring DR data are also consistent with recent work following the initiation of CGM.³⁷ Interestingly, while baseline HbA1c has also been described as a dependable baseline risk factor for EWDR,^37,38 in our data, mean baseline HbA1c (8.1%–8.6%) was largely similar between all groups—those improved, were stable, or worsened. In addition, 3/5 needing treatment had a baseline HbA1c between 7.8% and 8.6%.

Overall, approximately one-fifth of the people in our cohort showed DR deterioration, although most who worsened only did so to minimal or mild disease. This aligns with previous research on intensive therapy.²⁸ In the DCCT study, a temporary worsening in DR was noted shortly after initiating intensive treatment in 13.1%, usually within the first 6–12 months.³⁸ This aligns with our follow-up period, which has a mean duration of 8 months. Of those with early DR deterioration, 51% had recovered within 18 months in the DCCT,³⁸ and 91% had recovered within 12 months in the Oslo Study.⁹ While these data are largely reassuring, we have seen a deterioration of DR to proliferative disease in a small proportion of the participants (3%) similar to previously published rates of clinically important EWDR.³⁸ It should be kept in mind that this sort of rate in retinopathy deterioration is within realms of that seen in natural history of retinopathy progression (with or without changes in therapy),³⁹ so caution with attributing causation is needed. DD, uncontrolled diabetes, and prior DR have been noted as risks for DR deterioration in past work.^20,28

Given these preliminary data, it appears reasonable at minimum to consider DR screening follow-up within 3–6 months of initiating AID for those ≥18 years of age who share a combined history of prior DR and DD of >10 years and have other known diabetes complications or prior DR treatment. In addition, laser treatment also needs to be considered at an earlier stage than usual due to the risk of EWDR.²⁰ As proposed previously, for people with severe non-proliferative DR, PRP treatment should be considered before starting intensive insulin therapy.²⁰ Much effort is currently placed into enhancing more durable treatment options to achieve lower burden and improve visual acuity for people with proliferative diabetic retinopathy (PDR) and diabetes-related macular edema (DME), and it is crucial to note that these are different manifestations of DR and must be evaluated separately.⁴⁰ Maintaining optimal control of glycemia, blood pressure, and lipid levels is crucial for DR treatment outcomes, as without proper control, any treatment approach is likely to be ineffective.⁴⁰ Glycemic control, which can be achieved through AID systems, is, in other words, also important for those who already have established DR and aim to achieve good treatment responses.

Strengths of this study include: real-world observational data in an area where little data have been published, and a study population of diverse age, and diabetes related clinical characteristics. The limitations of this study are the lack of a comparison group. While some of the included people were early adopters of AID having initially commenced AID in clinical trials, many were standard clinical users, and all were ongoing clinical users of AID. Further research involving a broader range of ethnic diversity and socioeconomic status is also required. Moreover, many people were on pump therapy prior to enrolment (93%), and many of those used CGM as well, which could influence the magnitude of HbA1c improvement at the initiation of AID. Finally, these data are real-world and not collected prospectively. Thus, HbA1c sampling and eye examinations were not done at identical time points. This is a strength in terms of reflecting clinical reality, but precise prospectively designed studies are required.

In conclusion, stable or improved DR grades were evident in most who had recently commenced AID. As with previous data on intensive therapy, in a minority, DR deterioration occurs, and while the vast majority only progressed to minimal or mild grades, proliferative changes requiring treatment did occur. Overall, these data support the premise that for people with diabetes, the benefits of AID on glycemia outweigh the short-term risks of DR deterioration. Vigilance for DR deterioration is recommended, particularly in those who share a combined history of prior diabetic retinopathy, a diabetes duration of >10 years, and have other known diabetes complications or prior retinopathy treatment.

Footnotes

Authors' Contributions

B.J.W. conceptualized the study. B.J.W. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. M.M.J., B.J.W., M.J.S., A.B., and M.B.A. collected the data for analysis. M.M.E., Y.Z., and B.J.W. designed and conducted the statistical analysis. M.M.J., B.J.W., and F.M.R. wrote the initial draft. All authors revised the manuscript. All the authors contributed to the refinement of the study protocol and approved the final article as submitted.

Author Disclosure Statement

No competing financial interests exist.

Funding Information

No funding was received for this article.

Supplementary Material

Supplementary Table S1

Supplementary Table S2

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Supplementary Material

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